Indazole Compounds and Pharmaceutical Compositions for Inhibiting Protein Kinase, and Method for The

专利摘要:
The present invention relates to indazole compounds that alter and / or inhibit the activity of protein kinases. The compounds according to the invention and the pharmaceutical compositions of these compounds have the ability to modulate tyrosine kinase signaling to alter and / or inhibit unwanted cell proliferation. The present invention also provides a method of treating or preventing diabetic retinopathy, neovacular glaucoma, rheumatoid arthritis, and psoriasis by administering an effective therapeutic or prophylactic method using the pharmaceutical composition containing the compound, , As well as various other diseases associated with undesired angiogenesis and / or cell proliferation, such as cancer.
公开号:KR20020027379A
申请号:KR1020017016850
申请日:2000-06-30
公开日:2002-04-13
发明作者:로버트스티븐 카니아；스티븐리 벤더；알렌제이 보르카드트；존에프 브라간자；스테판제임스 크립스；예 휴；미첼데이비드 존슨；테오도르오토제이알 존슨；헵더 류；신시아로이스 팔머；세그프라이드헤인즈 레이치；안나마리아 템프치크-러셀；민 텡；크리스틴 토마스；미첼데이비드 바니；미첼브레난 웰레이스
申请人:개리 이. 프라이드만；아구론 파마슈티컬스, 인크.；
IPC主号:

专利说明:

TECHNICAL FIELD The present invention relates to an indazole compound and a pharmaceutical composition for inhibiting protein kinase and a method for preparing the same,
[5] Protein kinase refers to a set of enzymes that catalyze the phosphorylation of a hydroxy group in a specific tyrosine, serine, or threonine residue in a protein. Generally, because such phosphorylation changes protein function significantly, protein kinases play a pivotal role in the regulation of a wide variety of cellular functions, including metabolism, cell proliferation, cell differentiation and cell survival . Among the numerous cellular activities known to require the activity of protein kinases, some actions have become interesting targets for therapeutic intervention for certain disease states. As such examples, there are two types of angiogenesis and cell-cycle regulation, in which protein kinase plays a pivotal role; The actions of these kinases are essential for the growth of solid tumors and for various diseases.
[6] Angiogenesis is the mechanism by which new capillaries are formed from existing blood vessels. The vascular system has the ability to form a new capillary network in order to maintain the proper functioning of tissues and organs, where angiogenesis is required. However, angiogenesis in adults is clearly limited and only occurs in the neovascularization of the endometrium in the wound healing and menstrual periods (Merenmies et al., Cell Growth & Differentiation , 8, 3-10 ) Reference). Conversely, unwanted angiogenesis is characterized by the occurrence of certain diseases such as retinophathias, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (solid tumors) (Folkman, Nature Med., 1, 27-31 (1995)). Protein kinases that have been shown to be involved in angiogenesis involve three components of the following growth factor receptor tyrosine kinase family: VEGF-R2 (KDR (kinase insert domain receptor) and vascular endothelial growth factor receptor 2, also known as FLK-1 : Vascular Endothelial Growth Factor); FGF-R (Fibroblast Growth Factor); And TEK (also known as Tie-2).
[7] VEGF-R2, which is expressed only in endothelial cells, binds to the potent angiogenic growth factor VEGF and mediates secondary signaling through activation of intracellular kinase activity. Thus, the mutation of VEGF-R2 is directly related to the kinase activity of VEGF-R2 (see Millauer et al., Cancer Research , 56, 1615-1620 (1996) Inhibition is expected to induce a reduction in angiogenesis in the presence of exogenous VEGF (Strawn et al., Cancer Research , 56, 3540-3545 (1996)). In addition, VEGF-R2 appears to have no function in adults other than mediating angiogenic activity of VEGF. Therefore, inhibitors that selectively inhibit the kinase activity of VEGF-R2 are expected to show little toxicity.
[8] Similarly, FGF-R binds angiogenic growth factors aFGF and bFGF and mediates secondary intracellular signaling. Recently, it has been suggested that growth factors such as bFGF play a very important role in inducing angiogenesis in solid cells reaching a certain size (Yoshiji et al., Cancer Research , 57, 3924-3928 (1997)) . However, unlike VEGF-R2, FGF-R may or may not play an important role in many common physiological processes in adults, since it is expressed throughout the body in many different cell types. Nevertheless, it has been reported in mice that systemic administration of small molecule inhibitors of the kinase activity of FGF-R inhibits bFGF-induced angiogenesis without pronounced toxicity (Mohammadi et al., EMBO Journal , 17, 5896- 5904 (1998)).
[9] TEK (also known as Tie-2) is another receptor tyrosine kinase that is expressed only in endothelial cells and plays an important role in angiogenesis. The kinase domain of TEK is autophosphorylated by the binding of angiopoietin-1, signaling to mediate the interaction of peri-enthothelial supporting cells with endothelial cells By action, maturation of newly formed blood vessels is promoted. In contrast, angiopoietin-2 is known to antagonize the action of angiogenic factor-1 on TEK and to disturb the tubular formation (Maisonpierre et al., Science , 277, 55- 60 (1997)).
[10] As a result of the growth of the above-mentioned studies, the use of compounds which inhibit the kinase activity of VEGF-R2, FGF-R and / or TEK as a method for treating angiogenesis has been proposed. For example, WIPO International Publication No. WO 97/34876 discloses certain cinnoline derivatives as inhibitors of VEGF-R2, which are useful in the treatment of cancer, diabetes, psoriasis, rheumatoid arthritis, Ophthalmic diseases with Kaposi's sarcoma, haemangioma, acute and chronic nephrophathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation and retinal vascular proliferation And / or < / RTI > increased vascular permeability.
[11] Phosphorylase kinase is activated with glycogen phosphorylase, thus increasing consumption of glycogen and releasing glucose in the liver. Glucose supply in the liver is not controlled in type 2 diabetes and is the first cause of hyperglycemia resulting in many secondary complications of these diseases. Thus, the decrease in glucose released from the liver will be lowered to the plasma glucose level. Inhibitors of phosphorylase kinase activity increase phosphorylase activity and glycogenolysis, while reducing hyperglycemia in patients.
[12] Another physiological response of VEGF is the hyperpermeability of blood vessels that play a role in the early stages of angiogenesis. Hypoxia in ischemic tissues, such as those caused by seizure patients, causes VEGF expression, which increases vascular permeability and eventually causes edema of the surrounding tissue. Administration of monoclonal antibodies against VEGF in a rat model of seizures as shown in Bruggen et al., J. Clinical Invest., 104, 1613-20 (1999) reduced the volume of infarct. Therefore, inhibitors of VEGFR are expected to be available for treatment of seizures.
[13] In addition to protein kinases playing an important role in angiogenesis, protein kinases also play a crucial role in cell cycle regulation. Uncontrolled cell proliferation is the cancer's insignia. In response to various stimuli, the control of the cell division cycle is eliminated, and cell proliferation appears, and the cells multiply and divide by this action. In general, tumor cells are damaged by genes that directly or indirectly modulate progression through the cell division cycle.
[14] Cyclin-dependent kinases (CDKs) are serine-threonine protein kinases that play a crucial role in regulating metastasis between different phases of the cell line phase (see, for example, Science, 274, 1643-1677 (1996 )). ≪ / RTI > CDK complexes are produced by catalytic kinase subunits (e. G., Cdc2 (CDK1), CDK2, CDK4) with regulatory cyclin subunits (e. G., Cyclins A, B1, B2, D1, D2, D3 and E) , CDK5 and CDK6) are combined. As implied in the name, CDKs appear to depend absolutely on cyclin subunits in order to phosphorylate their target substrates, and several other kinase / cyclin conjugates are involved in the progression of the special phases of the cell line phase Function.
[15] CDK4 complexed with D-cyclins plays a crucial role in initiating the transfer from dormancy or stasis to the cell division cycle, through which cells undergo cell division. In this process, various growth regulatory mechanisms (including both negative and positive mechanisms) are performed. Deviations from these regulatory systems, particularly those affecting the function of CDK4, have led to the development of malignancies of general cells, particularly familial malignancies, esophageal carcinomas and pancreatic cancer, (See, for example, Kamb, Trends in Genetics, 11, 136-140 (1995); Kamb et al., Science, 264, 436-440 (1994)).
[16] Numerous publications refer to various chemical compounds that can be used in place of the targets of various treatments. For example, WIPO International Publication Nos. WO 99/23077 and WO 99/23076 disclose compounds having phosphodiesterase type IV inhibitor activity produced by indazole to obtain a catechol bioisostere Indazole-containing compounds. U. S. Patent No. 5,760, 028 discloses 3- [1- [3- (imidazolin-2-ylamino) propyl], which is used against competitors of a _{v v 4} integrin in association with tacky protein receptors on the cell surface 5-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid. The term " heterocycles " WIPO International Publication No. WO 98/09961 discloses the use of certain indazole derivatives and their use as phosphodiesterase (PDE) type IV or mammalian tumor necrosis factor (TNF) inhibitors. . Virtual libraries of recently-disclosed compounds include those referred to as anti-proliferative agents that inhibit CDKs. For example, U.S. Pat. No. 5,621,082 discloses nucleic acids encoding inhibitors of CDK6 by Xiong et al. European Patent Publication No. 0 666 270 A2 discloses peptides that act as inhibitors of CDK1 and CDK2, ≪ / RTI > WIPO International Publication No. WO 97/16447 discloses the use of chromones as inhibitors of the specific cyclin-dependent kinases of CDK / cyclin complexes, such as CDK4 / cyclin D1, which inhibit excessive or abnormal cell proliferation and are used for cancer therapy. ) ≪ / RTI > WIPO International Publication No. WO 99/21845 refers to 4-aminothiazole derivatives used as CDK inhibitors.
[17] However, there is a need for research into small molecule compounds that can be easily synthesized and effectively inhibit one or more CDK or CDK / cyclin complexes. Since CDK4 is expressed in most cells as a common activator of cell division and complexes of CDK4 and D-type cyclins dominate the early G1 phase, CDK4 and its D Lt; RTI ID = 0.0 > cyclin < / RTI > In addition, the pivotal role of the cyclin E / CDK2 and cyclin B / CDK1 kinases in the G1 / S and G2 / M transitions, respectively, is due to the additional targets for therapeutic intervention to inhibit uncontrolled cell cycle progression in cancer .
[18] As another protein kinase, CHK1 acts as a checkpoint in the progression of the cell cycle. Checkpoints are regulatory systems that regulate cell cycle progression by engaging in the formation, activation, and subsequent inactivation of cyclin-dependent kinases. Checkpoints inhibit the progression of the cell cycle at a suboptimal time, maintain the metabolic equilibrium of the cell when the cell is in a quiescent state, and occasionally cause apoptosis (planned apoptosis) if the checkpoint requirement is not met. Nurse, Cell, 91, 865-867 (1997); Hartwell et al., Science, 266, 1821-1828 (1994) ; Hartwell et al., Science, 246, 629-634 (1989)).
[19] A series of checkpoints monitor the integrity of the genome and, if a DNA damage is detected, these "DNA Damage Checkpoints" block the progression of the cell cycle in the G1 and G2 phases and slow the progression through the S phase (1994). This action is completely complementary to the DNA repair phase prior to cloning of the genome (O'Conor, Cancer Surveys, 29, 151-182 (1997), Hartwell et al., Science, 266, 1821-1828 The p53 tumor-suppressor gene, the most common mutation gene in human cancer, plays an important role in cell cycle arrest in the G1 phase. (Hartwell et al., Science, 266, 1821-1828 (1994)). In addition, p53 tumor suppressors have been shown to induce apoptosis (planned cell death) after DNA damage and / DNA damage in the G2 phase of the cell line Oncogene, 17, 673-684 (1998); Thompson, Oncogene, 15, 3025 (1998); Winters et al. -3035 (1997)).
[20] As pivotal features of p53 tumor suppressors in human cancers have become known, therapeutic interventions using the weaknesses of p53-defective cancer have been actively underway. One new weakness is the action of G2 checkpoints in p53-defective cancer cells. Cancer cells are particularly vulnerable to the elimination of G2 checkpoints as the last remaining obstacle to protecting them from the cancer cell-depleting action of DNA-damaging agents, since they lack G1 checkpoint regulation. The G2 checkpoint is a controlled system that is preserved from yeast to humans. In this conserved regulatory system, CHK1 is important as a kinase that inhibits the activation of cyclin B / Cdc2 kinase, which transmits signals from DNA-damaging monitoring complexes and promotes mitotic entry (Peng et al., Science , 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997)). Inactivation of CHK1 is known to escape from retention in the G2 phase induced by DNA damage by anticancer drugs or endogenous DNA damage and to cause preferential removal of the resulting checkpoint defective cells (Nurse, Cell, 91 (1993); and Al-Khodairy et al., Molec. Biol. Cell (1997); Walworth et al., Nature, 363, 368-371 , 5, 147-160 (1994)).
[21] Selective manipulation of checkpoints in cancer cells provides "genomic instability", a common feature of human cancer that can be used extensively in cancer chemotherapy and radiotherapy and can also be used as a selective basis for cancer cell destruction can do. Numerous factors are located in CHK1 as a central target for DNA-damage checkpoint control. (Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897 (1998)), a recently discovered kinase that cooperates with CHK1 in controlling the progression of CHK1 and S phase 1998), provides a valuable new therapeutic direction for cancer treatment.
[22] Integrin receptors that bind to ECM are involved in cell motility, cell proliferation and survival and initiate intracellular signaling mediated by FAK (focal adhesion kinase). In human cancers, overexpression of FAK is implicated in tumorigenesis and metastatic potential due to its important role in its integrin-mediated signal transduction pathway.
[23] The tyrosine kinases may be in the form of a receptor (extracellular, with transmembrane and intracellular domains), or in a non-aqueous form (entirely within the cell). It is believed that at least one of the non-receptor protein kinases, i. E. LCK, mediates signaling from the interaction of the cell surface protein (Cd4) and the cross-linked anti-Cd4 antibody in T-cells. A more detailed discussion of nonreceptor tyrosine kinases is found in Bolen, Oncogene, 8, 2025-2031 (1993), incorporated herein by reference.
[24] In addition to the protein kinases mentioned above, it is believed that many other protein kinases can be therapeutic targets and a number of published data disclose inhibitors for kinase activity, as will be discussed in the following data: McMahon et al., Oncologist , 5, 3-10 (2001); Holash et al., Oncogene , 18, 5356-62 (1999); Thomas et al., J. Biol. Chem., 274, 36684-92 (1999); Klohs et al., Curr. Op. Chem. Biol., 10, 544-49 (1999); McMahon et al., Current Opinion in Drug Discovery & Development, 1, 131-146 (1998); Strawn et al., Exp. Opin. Invest. Drugs , 7, 553-573 (1998). WIPO WO 00/18761 opened some substituted 3-cyanoquinolines as protein kinase inhibitors.
[25] As is commonly recognized in the art, there is a need for kinase inhibitors that possess both high affinity for target kinases and high selectivity distinct from other protein kinases.
[1] Cross-reference to related application
[2] This application claims priority from U.S. Provisional Application No. 60 / 142,130, filed July 2, 1999.
[3] Field of the Invention
[4] The present invention relates to indazole compounds which modify and / or inhibit the activity of certain protein kinases, and to pharmaceutical compositions containing such compounds. The present invention also relates to the therapeutic or prophylactic use of such compounds and compositions and is directed to the treatment of various disease states associated with cancer and undesired angiogenesis and / or cell proliferation by administration of an effective amount of such compounds. ≪ / RTI >
[26] The present invention aims to find potential inhibitors of protein kinases. It is a further object of the present invention to find effective kinase inhibitors which are potent and have affinity for one or more unique kinases.
[27] Other objects of the invention which will be set forth in the foregoing and subsequent description of the invention are the indazole compounds corresponding to formula I which are capable of altering and / or inhibiting the activity of protein kinases, Prodrugs, their pharmaceutically active metabolites, and their pharmaceutically acceptable salts (hereinafter such compounds, prodrugs, metabolites and salts are collectively referred to as "agonists"). The present invention also relates to pharmaceutical compositions containing such agents and is useful for the treatment of cancer and undesirable angiogenesis such as diabetic retinopathy, neovacular glaucoma, rheumatoid arthritis and psoriasis, ≪ RTI ID = 0.0 > and / or < / RTI > various other diseases associated with cell proliferation, and the like. The present invention also relates to a method for altering or inhibiting kinase activity associated with VEGF-R, FGF-R, CDK complexes, CHK1, LCK, TEK, FAK and / or phosphofetilase kinase.
[28] One general feature of the present invention relates to protein kinase inhibitors represented by formula I:
[29]
[30] Wherein R ¹ is a substituted or unsubstituted aryl, heteroaryl or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from the group consisting of substituted or unsubstituted alkyl, , Heterocycloalkyl, aryl, or heteroaryl; And
[31] R ² is a substituted or unsubstituted aryl, heteroaryl or XY wherein Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , alkylidene, C ₁ -C ₈ alkyl), X is a substituted or unsubstituted Ar wherein Ar is aryl, heteroaryl, NH- (alkyl), NH- (cycloalkyl), NH- (heterocycloalkyl) NH (aryl), NH (heteroaryl), NH- (alkoxy) or NH- (dialkylamide);
[32] The present invention also relates to pharmaceutically acceptable prodrugs, pharmacologically active metabolites and pharmaceutically acceptable salts of the compounds of formula (I), and to a convenient method of preparing the compounds of formula (I).
[33] One general feature of the present invention relates to protein kinase inhibitors represented by the formula (Ia)
[34]
[35] Wherein R ¹ is a substituted or unsubstituted aryl, heteroaryl or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from the group consisting of substituted or unsubstituted alkyl, , Heterocycloalkyl, aryl, or heteroaryl; And
[36] R ² is a substituted or unsubstituted aryl or Y-Ar, where Y is _{O, S, C = CH 2} , C = O, S = O, SO 2, CH 2, CHCH 2, NH or N- (C ₁ -C ₈ alkyl), Ar is aryl which is optionally substituted.
[37] The present invention also relates to the pharmaceutically acceptable prodrugs, the pharmaceutically active metabolites and the pharmaceutically acceptable salts of the compounds of formula (Ia), and to a convenient method of preparing the compounds of formula (Ia).
[38] In a preferred general embodiment the present invention relates to a compound represented by the formula (II)
[39]
[40] Wherein R ¹ is a substituted or unsubstituted aryl, heteroaryl or a group of the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is optionally substituted alkyl, cycloalkyl, heterocyclo Alkyl, aryl, or heteroaryl;
[41] R ⁴ and R ⁷ are each independently selected from the group consisting of hydrogen, OH, halo, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkenyl, aryloxy, thioaryl ), CH ₂ -OH, CH ₂ -O- (C ₁ -C ₈ alkyl), CH ₂ -O-aryl, CH ₂ -S- (C ₁ -C ₈ alkyl) or CH ₂ -S-aryl;
[42] R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, OH, halo, Z-alkyl, Z-aryl or Z-CH ₂ CH═CH ₂ wherein Z is O, S, NH, or CH ₂ , Alkyl and aryl moieties of alkyl and Z-aryl are each optionally substituted;
[43] And pharmaceutically acceptable prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts of said compounds.
[44] Preferably, in the compound represented by the above formula II, R ¹ is a substituted or unsubstituted bicyclic heteroaryl, or CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted Unsubstituted aryl or heteroaryl; R ⁴ and R ⁷ are each independently hydrogen or C ₁ -C ₈ alkyl; And R ⁵ and R ⁶ are each independently halo, Z-alkyl, or Z-CH ₂ CH = CH ₂ , wherein Z is O or S.
[45] In another preferred general embodiment, the present invention provides a compound represented by the following general formula III:
[46]
[47] Wherein R ¹ is a substituted or unsubstituted aryl or heteroaryl, or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from substituted or unsubstituted alkyl, cycloalkyl , Heteroalkyl, aryl, or heteroaryl;
[48] Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N- (C ₁ -C ₈ alkyl);
[49] R ⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxyl;
[50] R ¹⁰ is independently selected from hydrogen, halogen, and lower alkyl;
[51] And pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites and pharmaceutically acceptable salts thereof.
[52] More preferably, in the compound represented by the general formula III, R ¹ is a substituted or unsubstituted bicyclic heteroaryl, or CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or Heteroaryl; Y is O, S, C = CH ₂ , C = O, NH or N- (C ₁ -C ₈ alkyl); Wherein R ⁸ is substituted or unsubstituted aryl, heteroaryl, alkyl and alkenyl, and R ¹⁰ is hydrogen or halogen.
[53] In another preferred general embodiment, the invention relates to a compound represented by the general formula IIIa:
[54]
[55] Wherein R ¹ is a substituted or unsubstituted aryl or heteroaryl, or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from substituted or unsubstituted alkyl, cycloalkyl , Heterocycloalkyl, aryl, or heteroaryl;
[56] Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N- (C ₁ -C ₈ alkyl);
[57] R ³ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxyl;
[58] And pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites and pharmaceutically acceptable salts thereof.
[59] More preferably, in the compound represented by the general formula IIIa, R ¹ is a substituted or unsubstituted bicyclic heteroaryl, or CH = CH-R ³ wherein R ³ is a substituted or unsubstituted aryl or Heteroaryl; Y is O, S, C = CH ₂ , C = O, NH or N- (C ₁ -C ₈ alkyl); And R < ⁸ > is optionally substituted aryl or heteroaryl.
[60] In another preferred general embodiment, the present invention relates to a compound represented by the following general formula IV:
[61]
[62] Wherein R ¹ is a substituted or unsubstituted aryl or heteroaryl, or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is optionally substituted alkyl, cycloalkyl, Heterocycloalkyl, aryl or heteroaryl;
[63] Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N- (C ₁ -C ₈ alkyl);
[64] R ⁹ is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NH- (C ₁ -C ₈ alkyl), NH- - (heteroaryl), N = CH- (alkyl), NH (C = O) R ¹¹ , or NH ₂ where R ¹¹ is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, Or heteroaryl; And
[65] R < ¹⁰ > is independently selected from hydrogen, halogen, hydroxy, lower alkyl;
[66] And their pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.
[67] More preferably, in the compound represented by formula (IV), R ¹ is a group represented by the formula CH = CH-R ³ , wherein R ³ is substituted or unsubstituted aryl or heteroaryl; Y is S or NH, and R < ⁹ > is optionally substituted alkyl, alkoxyl or NH- (heteroaryl).
[68] The most preferred compounds in the present invention were selected from the following:
[69]
[70]
[71]
[72] The present invention also relates to the use of a compound of formula I, II, III or IV or a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof for the preparation of VEGF-R, FGF-R, TEK , CDK complexes, CHK1, TEK, LCK and / or FAK. The present invention also provides a compound having selective kinase activity, that is, a compound having significant activity only for one specific kinase, with less or minimal activity for other kinases. According to a preferred embodiment of the present invention, the compounds of the present invention are compounds of Formula I that have a substantially higher effect on the VEGF receptor than on the FGF-R 1 receptor tyrosine kinase. The present invention also relates to a method of modifying the VEGF receptor tyrosine kinase activity without significantly altering the FGF receptor tyrosine kinase activity.
[73] The compounds according to the invention are advantageously used in combination with other known therapeutic agents. For example, the compounds of formula I, II, III, IV having anti-angiogenic activity are selected from the group consisting of taxol, taxotere, vinblastine, cis-platin, May be administered in conjunction with cytotoxic chemotherapeutic agents including doxorubicin, adriamycin, and products that enhance similar anti-tumor efficacy. Additional or synergistic therapeutic efficacy may also be achieved by administering to a mammal an effective amount of a compound selected from the group consisting of combretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib, EMD121974 II, III, IV having anti-angiogenic activity with other anti-angiogenic agents including anti-angiogenic agents, anti-VEGF monoclonal antibodies, IM862, anti-VEGF monoclonal antibodies, and anti-KDR monoclonal antibodies Anti-angiogenic activity.
[74] The present invention also provides an effective amount of an agent selected from the compounds of Formula I and pharmaceutically acceptable salts, pharmaceutical active metabolites and pharmaceutically acceptable prodrugs thereof; And a pharmaceutical acceptable carrier or a vehicle for such an agent. The present invention also provides a method for treating such diseases, comprising administering an effective amount of the above agents to a patient in need of treatment of cancer and various other disease states associated with undesired angiogenesis and / or cell proliferation.
[75] DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[76] The compounds according to the invention of the above general formulas I, II, III and IV are useful for mediating protein kinase activity. More particularly, the compounds of the present invention are useful as agents for modifying and / or inhibiting the activity of anti-angiogenic agents and protein kinases, and are useful for the treatment of various other diseases associated with cancer or protein kinase mediated cell proliferation ≪ / RTI >
[77] As used herein, the term " alkyl " means a straight chain alkyl group having from 1 to 12 carbon atoms or an alkyl group comprising side chains. Examples of the alkyl group include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Hexyl, and the like. The term " lower alkyl " refers to alkyl (Ci- ₈ -alkyl) having from 1 to 8 carbon atoms. Suitably substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. do.
[78] The term " alkylidene " means a divalent radical having from 1 to 12 carbon atoms. The alkylidene group includes CH ₂ , CHCH ₃ , (CH ₃ ) ₂ , and the like.
[79] The term " alkenyl " means a straight chain alkenyl group having from 1 to 12 carbon atoms and an alkenyl group having a side chain. Examples of such alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex- .
[80] The term " alkynyl " means a straight chain alkyl group having from 1 to 12 carbon atoms or an alkyl group comprising side chains.
[81] The term " cycloalkyl " refers to partially saturated or unsaturated carbocycles having from 3 to 12 carbon atoms, including double rings and tri-cyclic cycloalkyl structures. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[82] The term " heterocycloalkyl " refers to a partially saturated or unsaturated monocyclic radical containing a carbon atom, preferably 4 or 5 ring carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur atoms, It is intended to mean radical.
[83] The term " Aryl " and " heteroaryl " refer to monocyclic and polycyclic unsaturated or aromatic ring structures wherein " aryl " refers to carbon ring compounds and " heteroaryl " refers to heterocyclic compounds do. Examples of aromatic ring structures include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1-H- Indolyl, quinolinyl, benzofuranyl, bezothiophenyl (thianaphthenyl), and the like. Such moieties may be optionally substituted by a fused or bridged structure (e.g., OCH ₂ -O).
[84] The term " alkoxy " is intended to mean an-O-alkyl radical. Examples thereof include methoxy, ethoxy, propoxy, and the like.
[85] The term " aryloxy " refers to-O-aryl, wherein aryl is as defined above.
[86] The term " cycloalkoxyl " refers to-O-cycloalkyl, wherein cycloalkyl is as defined above.
[87] The term " halogen " refers to chlorine (Cl), fluorine (F), bromine (Br) or iodine (I). The term " halo " refers to chlorination, fluorination, bromination, iodination.
[88] In general, the various partial structures or functional groups within the formula may be optionally substituted by one or more substituents. Examples of such substituents include halogen (F, Cl, Br or I), lower alkyl, -OH, -NO ₂ , -CN, -CO ₂ H, -O- lower alkyl, -aryl, _{, -CO 2 CH 3, -CONH 2} , -OCH 2 CONH 2, -NH 2, -SO 2 NH 2, haloalkyl _{(e.g., -CF 3, -CF 2 CF 3} ), -O- haloalkyl (E.g., -OCF ₃ , -OCHF ₂ ), and the like.
[89] The terms " comprising " and " including " are used in an open, non-limiting sense.
[90] The compounds of formula (I) exhibit mutual variability as a formula, in which the specificity, which appears only in one of possible possible mutational forms (tautomerism), is indicated. The formulas in the present invention mean that they are expressed in the form of the mutual mutation of the described compound and do not limit the form of the mutual mutation expressed by the represented formulas only.
[91] Some of the compounds according to the present invention may be prepared by reacting a single stereoisomer (i.e., essentially free of other stereoisomers), racemates, and / or enantiomers and / or partially-stereoisomers (e. diastereomers). Such single stereoisomers, racemic mixtures and mixtures thereof are intentionally included within the scope of the present invention. It is preferred that the compounds according to the invention, which are selectively active, are optionally used in pure form.
[92] As is commonly understood in the art, an optionally pure compound having one chiral center (i. E. One asymmetric carbon atom) is one composed of one of the two possible enantiomers (i. E. Isomerically pure), and the selectively pure compounds having one or more chiral centers are both pure-stereoisomeric and enantiomerically pure. The compounds according to the present invention are preferably at least 90% pure, optionally in pure form, i.e. at least 90% of the single isomer (80% enantiomerically excess (referred to as "ee" More preferably at least 95% (90% ee or de), even more preferably 97.5% (95% ee or de), most preferably 99% (98% ee or de) % ee or de).
[93] In addition, the above formulas intentionally include solvated and unsolvated forms of the same structure. For example, the above Formula I includes both hydrated and non-hydrated forms of the compound shown therein. Other examples of solvent compounds include structures combined with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.
[94] The present invention includes the compounds of formula I, II, III and IV as well as pharmaceutically acceptable prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts of such compounds.
[95] As used herein, " pharmaceutically acceptable prodrugs " refers to compounds that can be converted to a particular compound or a pharmaceutically acceptable salt of such a compound under any physiological conditions or by solvolysis.
[96] &Quot; Pharmaceutically active metabolites " means pharmaceutical active products in which certain compounds or salts thereof are metabolically produced in the body. Metabolites of the compounds may be identified using conventional techniques known in the art, and their activity may be measured by performing the tests mentioned herein.
[97] Prodrugs and activated metabolites of the compounds could be identified using conventional techniques known in the art. See, for example, Bertolini, G. et al., J. Med. Chem., 40, 2011-20116 (1997); Shan, D. et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe K., Drug Dev. Res., 34, 220-230 (1995); Bodor, N., Advances in Drug Res., 13, 224-331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); And Larsen, IK, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., Eds., Harwood Academic Publishers, 1991).
[98] &Quot; Pharmaceutically acceptable salt " is intended to mean salts that have no biological or other adverse side effects while maintaining the biological effectiveness of the free acids and bases of the particular compound. The compounds according to the invention can possess sufficient acidic, basic or both functional groups to react with numerous inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts can do. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, hydrogen sulfates, hydrogen sulfites, phosphates, monohydrogenphosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorine, bromine, iodine, Propionates, decanoates, carylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, and the like. Oxalates, malonates, succinates, sebacates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, Benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, But are not limited to, nitrate, nitropropionate, phenylbutyrate, citrates, lactate, gamma -hydroxybutyrate, glycollates, tartrates, methane-sulphonate, propane sulphonate, naphthalene- Naphthalene-2-sulfonate and mandelates, and salts prepared by reacting the compounds according to the invention with organic acids or inorganic bases.
[99] If the compound of the present invention is a base, the preferred pharmaceutically acceptable salts can be obtained by any suitable method used in the art, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acid, phosphoric acid and the like; Or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycol Such as pyranosidyl acid, citric acid or tartaric acid, such as glycolic acid, salicylic acid, glucuronic acid or galacturonic acid, Amino acids such as alpha-hydrozy acid, aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, organic acids such as sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid; Or by treating the free base with such an acid.
[100] If the compound of the present invention is an acid, the preferred pharmaceutically acceptable salts can be obtained by any suitable method, including, but not limited to, using an amine (primary, secondary or tertiary), alkali metal hydroxide, alkaline earth metal hydroxide Or by treatment of the free acid with an organic base. Examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and the like; And inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
[101] It will be appreciated by those skilled in the art that if the agonist is a solid, the compounds and salts of the present invention may exist in various forms of crystal structure or in various forms, all of which are intentionally included within the scope of the present invention and specific generic formulas hereinabove . ≪ / RTI >
[102] A therapeutically effective amount of the compounds of the present invention may be used to treat diseases mediated by modulation or modulation of protein kinases. Means an amount of an agent which, when administered to a mammal in need of such treatment, is capable of effectively treating a disease mediated by the activity of one or more protein kinases such as tyrosine kinase do. For example, a therapeutically effective amount of a compound of Formula I, a salt, an activating metabolite, or a prodrug thereof may be determined by the activity of one or more protein kinases to reduce or alleviate the disease state mediated by the activity of the protein kinase Quot; means an amount capable of sufficiently deforming, controlling, or inhibiting.
[103] The amount of the agent corresponding to the therapeutically effective amount may vary depending on factors such as the particular compound, the condition and severity of the disease, and the characteristics (e.g., weight) of the mammal in need of such treatment , Even so, such amounts can be routinely determined by one of ordinary skill in the art. By " treating ", on the other hand, is intentionally meant to alleviate a disease state in a mammal such as a human, at least partially affected by the activity of one or more protein kinases such as tyrosine kinase; Preventing mammalian animals from developing such disease states when they have been found to be susceptible to the disease condition but have not yet been diagnosed as having such a disease; Modifying and / or inhibiting the disease state; And / or alleviating the disease state.
[104] Agents according to the present invention can be prepared using techniques commonly used in the art using readily available starting materials and using the reaction pathways and synthetic schemes described below.
[105] In one general synthetic method, the compounds of formula I can be prepared according to the following reaction scheme:
[106]
[107] The 6-nitroindazole (Compound V) treats a solution in which a base such as iodine and NaOH is dissolved in a water-soluble / oil-soluble mixture, preferably dioxane. The mixture was filtered through an acidification reaction. The resulting 3-iodo-6-nitroindazole is dissolved in dichloromethane-50% aqueous KOH at 0 ° C and protected group ("Pg") reagent (where X is halo), preferably trimethyl Silylethoxymethyl chloride (SEM-Cl) and tetrabutylammonium bromide (TBABr), a phase transfer catalyst, were added. After 1 to 4 hours, the two phases were diluted. Organics were separated, dried over sodium sulfate, and concentrated by filtration. The crude product was purified by silica gel chromatography to give the compound of formula VI. The compound of formula VI is treated with a suitable organic solvent, R ¹ -organic acid reagent, preferably R ¹ -bronic acid present in a water-soluble base such as sodium carbonate, and a suitable catalyst, preferably Pd (PPh ₃ ) ₄ And the resultant was subjected to silica gel chromatography to obtain the compound of the formula VII. The aldehyde functional group produced by Wittig or condensation deformation (illustrated in Example 42 (ae)) after the R ¹ -substituent is oxidatively cleaved (ozone decomposition) is added to give the compound of formula VII or all It can be converted into an intermediate. The compound of formula (VII) is treated with a reducing agent, preferably SnCl ₂ , followed by condensation, water-soluble finishing and purification to give a compound of formula (VIII). Preferably a Cs ₂ CO ₃ , present in aryl or heteroaryl chloride, bromide, iodine or base to a compound of formula (VIII) in the series of derivatives where Y = NH or N- Pd-BINAP (Y is a N-lower alkyl, followed by an alkylation step) to produce a compound of formula X. To prepare another Y bond, sodium nitrile is added to the compound of formula (VIII), cooled in standard oxidation state and warmed by addition of iodine potassium. Compounds of general formula IX are prepared with general work up and purification.
[108] The compound of formula IX is converted to lithium halide by treatment with an organometallic reagent such as butyllithium. This intermediate was reactivated in the R ² electrophile such as carbonyl or triflate by possible addition of a metal or catalyst, preferably zinc chloride and Pd (PPh ₃ ) ₄ , to prepare the compound of formula IX . Further, by treating the compound of formula Ⅸ in carbon monoxide atmosphere in the presence of a catalyst such as Pd (PPh _{3) 4} with an organometallic reagent such as an organic boronic acid to give the compound of formula X. In a compound of formula Ⅸ derivatives (wherein Y is NH or S) using Cs ₂ CO ₃ or K ₃ PO ₄ and a base such as Pd-BINAP or Pd- (bis-cyclohexyl) bis-phenyl phosphine, such as a pin The appropriate amine or thiol is treated in the presence of a catalyst to give a compound of formula X. After replacement of the functional groups by conventional oxidation, reduction, alkylation, acylation, condensation and using the separating material as a derivative, the final compound of this series, the compound of formula I, was obtained.
[109] The compounds of formula I of the present invention may also be prepared by the general procedure shown in the following scheme:
[110]
[111] A solution of 6-iodoindazole (XI) in which a base such as iodine and NaOH was dissolved in a water-soluble / solvent-soluble solvent, preferably dioxane, was treated. The mixture was acidified, filtered and separated to obtain the product XII. To prepare 3,6-di-iodoindazole dissolved in dichloromethane-50% water-soluble KOH at 0 < 0 > C, a protecting group reagent such as SEM-Cl and a phase change catalyst such as TBABr were added. The two phases were diluted and the organic material was separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give the compound of formula XIII. Suitable R ² -ZnCl or boron R ² - organometallic reagent and Pd (PPh ₃₎ after a suitable organic solvent is dissolved in a suitable catalyst such as _4-extracted finishing processes the compound of Formula XⅢ silica gel-boron reagent, such as R ² Purification by chromatography gave the compound of formula XIV. It was dissolved in a suitable organic solvent dissolving the (boron reagent or R ¹ -ZnCl R ¹⁾ - The compound of formula XⅣ aqueous base, sodium carbonate, Pd (PPh _{3) 4} and the appropriate R ¹ in the presence of a suitable catalyst such as an organometallic reagent After finishing extraction, the product was purified by silica gel chromatography to obtain the formula (XV). After replacement of the functional groups by conventional oxidation, reduction, alkylation, acylation, condensation and using the separating material as a derivative, the final compound of this series, the compound of formula I, was obtained.
[112] Alternatively, a compound of formula (I) wherein R is a substituted or unsubstituted Y-Ar, wherein Y is O or S, can be prepared by the following general reaction scheme:
[113]
[114] The acetone solution in which 3-chloro-cyclohex-2-enone (XV), HR ² , and anhydrous potassium carbonate were mixed was refluxed for 15-24 hours, cooled and filtered. The mixture was concentrated and filtered through silica gel chromatography to give 3-R ² -cyclohex-2-enone (XVI).
[115] The ketone of formula XVI is reactivated with a suitable base (MB) such as lithium bis (trimethylsilyl) amide, reacted with R ¹ -CO-X where X is halogen and then worked up with a standard acid and purified to give the compound of formula XVII . The product was dissolved in HOAc / EtOH and combined with hydrazine monohydrate and heated at a suitable temperature for a suitable time, preferably 60-80 C for 2-4 hours. The mixture was cooled, put into a saturated sodium bicarbonate solution, extracted with an organic solvent, concentrated, and then purified by silica gel chromatography to obtain a compound of the formula XVIII. Compounds of formula (XVII) are oxidized in a number of conventional ways to give compounds of formula (I).
[116] Other compounds of formula I may be prepared by the general methods described above or by analogous methods to the specific methods described in the examples herein. The affinity of the compounds according to the invention for receptors provides a variety of ligands with close proximity and is preferably used for scaffolding provided by a carrier moiety It can be strengthened. The provision of such multi-valent compounds with optimal spacing between sub-structures can significantly improve the binding to the receptor (see, for example, Lee et al., Biochem, 23, 4255 (1984 ) Reference). The multivalency and spacing can be adjusted through the selection of a suitable carrier portion or linker unit. Such moieties include molecular supports that contain complex functional groups capable of reacting with functional groups associated with the compounds of the present invention. Of course, various carriers can be used including various peptides such as proteins such as BSA or HAS, pentapeptides, decapeptides, pentadecapeptides, and the like. The peptides or proteins may contain the intended number of amino acid residues with free amino groups in their side chains, but other functional groups such as sulfhydryl groups or hydroxy groups may also be present in stable connections Can be used to obtain structures.
[117] A compound that strongly modulates, modifies, or inhibits the protein kinase activity associated with receptors VEGF, FGF, CDK complexes, TEK, CHK1, LCK, FAK and other phosphorylase kinases and the like and inhibits angiogenesis and / Are preferred, which are preferred embodiments of the present invention. The invention also relates to methods of modifying or inhibiting protein kinase activity, such as, for example, administering an agent according to the invention to the tissues of mammals. The activity of the compounds according to the invention as modulators of protein kinase activity (i. E., Kinase activity) can be measured by any method commonly used in the art, including in vivo and / or in vitro assays . Suitable examples for an active assay include Parast C., et al., BioChemistry, 37, 16788-16801 (1998); Jeffrey et al., Nature, 376, 313-320 (July 27, 1995); WIPO International Publication No. WO 97/34876; And the methods described in WIPO International Publication No. WO 96/14843. These properties can be evaluated, for example, using one or more of the biological testing methods set forth in the following examples.
[118] The activating agents of the present invention may be formulated into the pharmaceutical compositions described below. The pharmaceutical composition according to the present invention comprises an inert, pharmaceutically acceptable carrier or diluent, with an amount of a compound represented by the general formula I, II, III or IV for effectively modifying, controlling or inhibiting. According to one embodiment of the pharmaceutical composition, the efficacy of the agent according to the invention is provided to obtain an effective benefit, including a modification of the protein kinases. &Quot; Efficacy " refers to the minimal amount by which the effects of protein kinases are modulated. These compositions are prepared in a single dose in an amount suitable for the mode of administration, for example parenteral or oral administration.
[119] The agents of the present invention are administered in conventional amounts by combining a therapeutically effective amount of an agent (e. G., A compound of Formula I) as an active ingredient with pharmaceutical carriers or diluents in accordance with conventional methods. These methods include mixing, granulating, compressing or dissolving the appropriate containing ingredients according to the intended formulation.
[120] The pharmaceutical carrier employed may be solid or liquid. Examples of solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of the liquid carrier include syrup, peanut oil, olive oil, water and the like. Similarly, carriers or diluents include, but are not limited to, those known in the art such as glyceryl monostearate or glyceryl stearate for use with wax, wax, ethylcellulose, hydroxypropylmethylcellulose methylmethacrylate, Or time-release material.
[121] A variety of pharmaceutical forms may also be used. Thus, if a solid carrier is used, the formulation may be tabletted, contained in a hardened gelatin capsule 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 a liquid carrier is 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.
[122] In order to obtain a stable aqueous dosage form, the pharmaceutically acceptable salts of the agents according to the invention are dissolved in aqueous solutions of organic or inorganic acids such as succinic acid or citric acid. If the form of the water-soluble salt can not be used, the agent can be dissolved in a suitable cosolvent or a combination of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohols, propylene glycol, polyethyleneglycol 300, polysorbate 80, glycerin, etc., and have a concentration range of 0-60% . According to an embodiment, the compound of formula I is 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 water-soluble carrier, such as water or an isotonic saline or dextrose solution.
[123] It will be appreciated that the actual amount of addition of the agent used in the composition according to the invention will vary depending on the particular complexity employed, the particular composition formulated, the mode of administration and the particular site, and the disease being treated. Optimal dosages for a given condition of disease can be investigated by those skilled in the art using conventional dose-determination tests based on experimental data of agents. For oral administration, an exemplary daily dosage can be used in the range of about 0.001 to 1000 mg / kg, more preferably 0.001 to 50 mg / kg body weight, depending on the stage of the treatment, which is generally repeatedly administered at appropriate intervals . Administration of the prodrugs is typically administered at a weight level that is chemically equivalent to that of the fully activated form.
[124] The compositions of the present invention are commonly used in the preparation of known pharmaceutical compositions such as, for example, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing, etc.), as described above. The pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers selected from excipients and auxiliaries that aid in the process by which the active compound is made into a pharmaceutically usable preparation .
[125] The appropriate formulation will depend on the chosen route of administration. For injection administration, the agents of the present invention may be formulated as a liquid solution, preferably in dissolved form in physiologically compatible buffers such as Hanks ' s solution, Ringer ' s solution or physiological saline buffer Can be formulated. For transmucosal administration, suitable penetrants that allow passage through the barrier membrane can be used in the formulation. Such infiltrating agents are commonly known in the art.
[126] For oral administration, the present mixtures can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers may be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion to the patient to be treated . Pharmaceutical preparations for oral use can be obtained using a mixture of active inclusion (agonist) and solid dosage forms and, if necessary, further milling the resulting mixture, adding suitable adjuvants, , And can be obtained as tablets or dragee cores. Suitable excipients include fillers such as sugar materials, including lactose, sucrose, mannitol or sorbitol; And cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP), and the like. If desired, crosslinked polyvinylpyrrolidone, agar, or disintegrating agents such as alginic acid or its salts such as sodium alginate may be added.
[127] Dragee cores perform suitable coatings. For this purpose, concentrated sugar solution solutions may be used, which may optionally be selected from the group consisting of geum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions) may contain suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablet or Dragee codings to identify or characterize various other combinations of active agents.
[128] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of a plasticizer such as gelatin and glycerol or sorbitol. Fitted capsules may contain the active ingredient and a filler such as lactose, a binder such as starch, and / or a mixture of 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 can be added. All formulations for oral administration should be appropriate doses for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated by conventional methods.
[129] For administration by intranasal or inhalation, the compositions for use according to the invention may be formulated with suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, It can be easily transported in compressed form (packs) or in the form in which an aerosol spray is emerged from the sprayer. In the case of a compressed aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. Gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mixture of the present compounds and a suitable powder base such as lactose or starch.
[130] The compositions may be formulated for parenteral administration by injection, e. G., Bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, for example, in an ampoule or in a multi-dose container with a preservative. The composition may take the form of a suspension, solution or emulsion by emulsifying or liquid carrier, and may contain formulations such as suspending, stabilizing and / or dispersing agents.
[131] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active agents may 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. Water-soluble injection suspensions may contain substances that increase the viscosity of suspensions, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which may increase the solubility of the present compounds so that a high concentration of solution is produced.
[132] For administration by eye, since the compound of the general formula I, II, III or IV is transported with a pharmaceutically acceptable ophthalmic vehicle, the present compound is kept in contact with the ocular surface for a sufficient time, The present compounds are useful in the treatment of corneal and internal areas of the eye such as anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous fluid, cornea, iris, lens, choroid / It can penetrate into the selera (selera). Pharmaceutically acceptable ocular delivery agents include ointments, vegetable oils, or encapsulating materials. In addition, the compounds of the present invention can be directly injected into the vitreous and aqueous solutions.
[133] In addition, the active ingredient may be in powder form for constitution with a suitable vehicle, e. G. Sterile pyrogen-free water, before use. In addition, the present compounds may be formulated into rectal compositions, such as suppositories or retention enemas, containing conventionally known suppository bases such as cocoa butter or other glycerides.
[134] In addition to the formulations described above, the present compounds may also be formulated as a depot preparation. Such formulations with long lasting effects can be administered by implantation (e. G., Subcutaneously, intramuscularly or intraocularly) or by intramuscular injection. Thus, for example, the present compounds may be formulated with suitable polymeric or hydrophobic materials (such as, for example, emulsions in an acceptable oil) or ion exchange resins, or with substantially greasy, such as sparingly soluble salts ≪ / RTI >
[135] The pharmaceutical carrier for hydrophobic compounds is a cosolvent including benzyl alcohol, a non-polar surfactant, an organic polymer that can be mixed with water, and an aqueous phase. The cooperative system may be a VPD cooperative system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80 and 65% w / v polyethylene glycol 300, and the remaining volume being 100% absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted with a 5% dextran aqueous solution in a ratio of 1: 1. This cosolvent system dissolves hydrophobic compounds, and itself exhibits low toxicity even when administered systemically. Naturally, the ratio of the cosolvent system can vary considerably to the extent that it does not destroy its solubility and toxicity properties. In addition, the homogeneity of the common elements can be varied. For example, other nonpolar surfactants may be used instead of polysorbate 80 provided they have low toxicity. The fraction size of poly (ethylene glycol) can also be varied. Other polymers, such as polyvinyl pyrrolidone, may also be substituted for polyethylene glycol provided they have biological compatibility. Other sugar materials or polysaccharides may also be substituted for dextrose.
[136] In addition, other transport systems for hydrophobic pharmaceutical compounds may also be used. Liposomes and emulsions are well known examples of carriers or carriers for hydrophobic drugs. Certain organic solvents, such as dimethylsulfoxide, may also be used, although generally there is a significant toxicity value. In addition, the present compounds may be delivered using a sustained-release system, such as semipermeable mattresses, of a solid hydrophobic polymer containing a therapeutic agent. A variety of sustained-release materials are well known and established in the art. Sustained-release capsules release compounds from several weeks to over 100 days, depending on their chemical properties. Additional strategies for protein stabilization may be used, taking into account the chemical nature and biological stability of the therapeutic reactants.
[137] In addition, the pharmaceutical compositions may comprise suitable solid or gel-like carriers or excipients. Examples of such carriers or excipients include polymers such as calcium carbonate, calcium phosphate, sugar materials, starches, cellulosic derivatives, gelatin and polyethylene glycol.
[138] Some of the compounds of the present invention may be provided as salts formed with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed by a variety of acids including hydrochloric acid, sulfuric acid, salicylic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like . Salts tend to be more soluble in water soluble or other protonic solvents than the corresponding free-base form.
[139] Although 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 chemical reactions described can be readily adapted to the preparation of numerous other protein kinase inhibitors of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention may be carried out by any means known to those skilled in the art, for example by altering the appropriate protection of the interrupted groups, by altering other suitable reagents known in the art , Or by applying conventional modifications of the reaction conditions. It will also be appreciated that other reactions disclosed herein or known in the art may be applied to produce other compounds of the present invention.
[140] Unless otherwise noted in the following examples, all temperatures are 4 ° C and all parts and percentages are expressed in weight. The reagents were purchased from a manufacturer such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used 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 standard methods known in the art, unless otherwise indicated.
[141] In general, at the ambient temperature (unless otherwise noted), a rubber septum is provided for introducing the substrate and reagent through a syringe into the following reaction apparatus and reaction flask, in which the anhydrous solvent is reacted under a positive pressure of argon or nitrogen or in a drying tube. The glassware was oven-dried and / or heat-dried. Analytical thin layer chromatography (hereinafter referred to as "TLC") was suitably indicated by performing on a supported glass silica gel 60 F254 Analtech 0.25 mm and eluting with a suitable solvent ratio (v / v). The reaction was analyzed by thin layer chromatography and terminated when the starting material was exhausted.
[142] Visualization of the TLC culture was performed by visualizing tip plates with p-anisaldehyde color development reagent or phosphomolybdic acid reagent (containing 20 wt% Aldrich's chemical in ethanol) Respectively. After the reaction volume of the reaction solvent or extraction solvent has been doubled, it is washed with an aqueous solution corresponding to 25% of the volume of the extract unless otherwise indicated. The resulting solution was filtered and on a rotary evaporator prior to evaporation of the solvent under reduced pressure to dryness to put anhydrous Na ₂ SO ₄ and the solvent was removed in vacuum. Property column chromatography (Still et al., J. Org. Chem ., 43, 2923 (1978)) uses Baker grade attribute silica gel (47-61 m) The ratio was from about 20: 1 to 50: 1. The hydrocracking reaction was carried out at the pressure or ambient pressure specified in the examples.
[143] ¹ H-NMR spectra were indicated using a Bruker instrument operating at 300 MHz and ¹³ C-NMR spectra were reported to operate at 75 MHz. NMR spectra were recorded using a solution of CDCl ₃ (reported in ppm) using chloroform in reference standards (7.25 ppm and 77.00 ppm) or CD ₃ OD (3.4, 4.8 ppm and 49.3 ppm) or, if necessary, intrinsically tetramethylsilane ) (0.00 ppm) were purchased and used. Other NMR solvents were used as needed. When the peak redundancy is described, s is a singlet, d is a doublet, t is a triplet, m is a multiplet, br is broadened, dd is a doublet of doublets, and dt is a doublet of triplets. The given coupling constants are expressed in hertz (Hz).
[144] Infrared spectra were expressed as wave number (cm ^-1 ) using a Perkin-Elmer FT-IR spectrometer in neat oil, KBr pellet or CDCl ₃ solution. Mass spectra were obtained using LSIMS or electrospray. All melting points (mp) did not match.
[145] Example 1 (a): Synthesis of 3-E-2- (3,4-dimethoxyphenyl) vinyl] -6- (3-methoxy-4-hydroxy-
[146]
[147] Phenyl] -1H-indazole (-20 mg, 0.461 mmol) was added to a solution of 3- [E / Z- 2- (3,4- dimethoxy- phenyl) vinyl] -6- [3-methoxy- 4- (methoxymethoxy) mmol (theoretical)) was dissolved in 10 ml of tetrahydrofuran (hereinafter referred to as " THF "), treated with 10 ml of water, and then 20 ml of trifluoroacetic acid (hereinafter referred to as "TFA") was added. The reaction mixture was stirred at 23 DEG C for 30 minutes, diluted with 100 mL of toluene, and then the volatile materials were removed under reduced pressure (30 mmHg, 35 DEG C) to obtain 5 mL of a concentrate. To the mixture was further added 100 ml of toluene and concentrated under reduced pressure to obtain a slightly acidic crude product. The crude product was fractionated with ethyl acetate and saturated sodium bicarbonate, and the organic material was separated, dried over sodium sulfate, concentrated, and concentrated under reduced pressure. The residue (~185 mg, 0.461 mmol (theory)), an olefin isomeric mixture, was dissolved in 50 ml of dichloromethane at 23 [deg.] C and 80 mg of iodine was added. The mixture was stirred at 23 < 0 > C for 12 hours. To the mixture was added 10 ml of saturated sodum bicarbonate and 10 ml of 5% water-soluble sodium bisulfite. The mixture was diluted with 200 ml of ethyl acetate, and the organic was washed with 100 ml of saturated sodium bicarbonate, dried over sodium sulfate, concentrated, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica (40 mL, 6: 4 → 7: 3 ethyl acetate / hexanes) and all desired classifications were combined and coagulated and concentrated in a dichloromethane / hexane double layer (1: 93 mg (coupled compound) of solid 3-E-2- (3,4-dimethoxyphenyl) vinyl] -6- (3- methoxy-4-hydroxyphenyl) -1H- R _f sm 0.42, p 0.35 (ethyl acetate-hexane 7: 3); FTIR (thin film) 3324, 1600, 1514, 1463, 1422, 1264, 1137, 1024, 959, 852 cm ^-1 ; _{^{1 H NMR (CDCl 3) δ10.0}} (bs, 1H), 8.08 (d, 1H, J = 8.4Hz), 7.59 (s, 1H), 7.49 (d, 1H, J = 16.6 Hz), 7.45 (dd 1H, J = 1.4,8.4 Hz), 7.34 (d, IH, J = 16.6 Hz), 7.20-7.12 (m, 4H), 7.03 J = 8.2 Hz), 5.68 (bs, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H); ¹ H NMR (CDCl ₃ ) 149.6, 149.5, 146.0, 144.0, 142.6, 140.8, 133.9, 131.4, 130.7, 121.7, 121.4, 120.9, 120.4, 120.2, 118.6, 115.4, 111.7, 110.8, 109.1, 108.2, 56.4 , 56.3, 56.2. HRMS (ES) [m + H] / z yield 403.1658, detected 403.1658. [mH] / z output 401, detection 401.
[148] The starting material was prepared as follows:
[149] (i)
[150]
[151] Add 40.8 g (0.3065 mol, 1 equiv) of 6-aminoindazole to a 2-liter round bottom flask containing a magnetic stirrer rod, add 256 g of ice, add 128 mL of water and drip the flask in an ice bath. After adding 128 mL (1.53 mmol, 5 equiv) of aqueous concentrated HCl to the stirred slurry at 0 ° C, a solution of 23.3 g (0.338 mmol, 1.1 equiv) of NaNO _{2 in} 96 mL of water was added and the mixture was stirred at 0 ° C. for 10 minutes After stirring, KI (61 g, 0.368 mol, 1.2 equiv) is initially added very slowly (initially at less than 100 ml at one time because of sudden release of gas even with a small amount of KI) and later added later (Total travel time 5 minutes). The cooling bath was removed and the reaction mixture was warmed to 40 < 0 > C (gas evolution). When the gas release rate decreased (~ 30 min), the reaction mixture was warmed to 50 < 0 > C for 30 min. After neutralized by cooling the mixture to 23 ℃ and added to 3N NaOH 320㎖ was added to 50% saturated NaHCO ₃ 320㎖. The slurry was dissolved in 800 ml of warm THF, 600 ml (dry) of silica was added, and the mixture was stirred. To the slurry was added 1.2 L of hexane and vacuum filtered through a pad of silica (300 mL) in a large fritted filter. The silica was later washed with 2 L of 40% THF in hexane. The filtrate was combined and concentrated under reduced pressure to obtain a solid. The solid was triturated with ethyl acetate (100 ml), filtered and dried under reduced pressure to give 36.1 g (yield 48%) of 6-iodo-1H-indazole as a light brown solid: R _f cm 0.12, p 0.48 (Hex- EtOAc 1: 1); ¹ H NMR (300 MHz, CDCl ₃ ) 7.9 (s, IH), 7.8 (s, IH), 7.42 (d, IH), 7.33 (d, IH); MS (ES) [m + H] / z yield 245, detect 245. [mH] / z yield 243, detect 243.
[152]
[153] A solution of 7.35 g (30.1 mmol, 1 equiv) of 6-iodo-1H-indazole in 100 mL of THF was cooled to 0 ° C in the presence of argon, and 2.89 g (30.1 mmol, 1 equiv) of sodium t- Respectively. At this time, the color changed from orange to red. 6.60 g (30.1 mmol, 1 equiv) of mesitylenesulfonyl chloride was added and the reaction mixture was removed by warming the reaction mixture to 23 ° C in an ice bath. After 40 minutes the mixture was cooled with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous solution was extracted with three times the total amount of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 12.8 g of 6-iodo-1- (2,4,6-trimethyl-benzenesulfonyl) -1H- : 1 mixture). _{^{1 H NMR (CDCl 3) δ8.51}} (s, 1H), 7.95 (s, 0.66H, main isomer), 7.91 (s, 0.33H, part isomer), 7.47 (d, 0.33H, J = 8.4 Hz) , 7.28 (d, 0.33H, J = 8.4Hz), 7.26 (d, 0.66H, J = 8.9Hz), 7.18 ), 2.15 (s, 3H).
[154]
[155] 5.78 g (13.56 mmol, 1.00 equiv) of 6-iodo-l- (2,4,6-trimethyl- benzenesulfonyl) -lH-indazole and 3-methoxy-4- (methoxymethoxy) benzene- 3.45 g (16.27 mmol, 1.20 equiv) of an acid were dissolved in 15 ml of dioxane and 2.0 ml of water in the presence of argon. 2.83 ml (20.3 mmol, 1.5 equiv) of triethylamine, 2.8 g (20.3 mmol, 1.5 equiv) of potassium carbonate and 476 mg (0.678 mmol, 0.05 equiv) of dichlorobis (triphenylphosphine) palladium were added to the solution. The reaction mixture was heated to 90 < 0 > C for 2 hours and then cooled to 23 < 0 > C. The mixture was separated into 250 ml of ethyl acetate and 150 ml of saturated sodium bicarbonate. The organics were dried over sodium sulfate, concentrated under reduced pressure and dried in a high vacuum for 15 h to give crude 6- (3-methoxy-4-methoxymethoxy-phenyl) -1- 4,6-trimethyl-benzenesulfonyl) -1H-indazole.
[156] 3-Methoxy-4- (methoxymethoxy) benzeneboronic acid was prepared as follows: Prepared in a 100 ml flask by dissolving 50% KOH (20 g KOH, 7 equiv, 20 g ice) in water in the presence of argon. The reaction mixture was stirred rapidly at 0 < 0 > C (maintained in an ice bath), then 50 ml of dichloromethane was added and 10.1 g (50 mmol, 1.00 equiv) of 4-bromo-2-methoxyphenol, methoxymethyl chloride ) (42.5 mmol, 1.05 equiv) and 322 mg (1 mmol, 0.02 equiv) of tetrabutylammonium bromide. The bath was removed and the mixture was slowly warmed to 23 [deg.] C with rapid stirring for 2 hours. The mixture was transferred to a separatory funnel and diluted with 350 mL of dichloromethane and 300 mL of water to aid in this transfer. The organic material (bottom layer in this case) was separated and dried with sodium sulfate, followed by concentration under reduced pressure, followed by purification by ¹ H NMR to obtain 11.9 g of 4-bromo-2-methoxy- 1- (methoxymethoxy) 97%): ¹ H NMR (CDCl ₃ ) 7.0 (s, 3H), 5.13 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H). MS (EI) [m + H] / z yield 235, detected 235.
[157] A solution of 4.80 g (19.4 mmol, 1.00 equiv) of 4-bromo-2-methoxy-1- (methoxymethoxy) benzene dissolved in 35 ml of THF was added to a 50 ml round bottom flask, ). To the flask was added 12.75 mL of n-BuLi (dissolved in hexane, 1.6 M, 20.4 mmol, 1.05 equiv) and the mixture was stirred at -78 <0> C for 40 min. Then 50 mL of THF at -78 deg. C was charged with B (OMe)₃A solution of 22 ml (194 mmol, 10 equiv) was added via a cannula in a second flask. After 20 minutes, the cooling bath was removed, and after 15 minutes (when the ice around the flask started melting), the reaction mixture was stirred for 20 minutes in warm water (50 mL) and stirred for 45 minutes. The mixture was concentrated under reduced pressure to remove most of the THF. The mixture was partitioned between 300 ml of ethyl acetate and 150 ml of water and acidified by adding a small amount of 20% citric acid (~ 10 ml). The organic material was dried over sodium sulfate and concentrated under reduced pressure to obtain a solid. The residue was triturated with 10 ml of ethyl acetate and 5 ml of hexane and filtered to obtain 3.15 g (yield 77%) of 3-methoxy-4- (methoxymethoxy) benzene-fsm 0.59, p 0.18 (ethyl acetate: hexane = 1: 1);^One1 H NMR (CDCl 3₃2H), 4.00 (s, 3H), 3.55 (d, 1H, J = 8 Hz) s, 3H).
[158]
[159] (In the presence of argon) was dissolved in 20 mL of THF &lt; RTI ID = 0.0 &gt; , And a solution of 1 N NaOH (70 ml, gas bubbled with argon for 3 to 5 minutes to remove gas) was added to methanol. The mixture was heated to &lt; RTI ID = 0.0 &gt; 45 C &lt; / RTI &gt; To the mixture was added 50 mL of 1N HCl to neutralize and 200 mL of saturated sodium bicarbonate was added. The product was extracted with 350 ml of ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude 6- (3-methoxy-4-methoxymethoxy-phenyl) -1H-indazole. Purification by silica gel chromatography (500 mL silica, 20% ethyl acetate (1.8 L) dissolved in benzene and 30% ethyl acetate in benzene (1.8 L)) gave 6- (3-methoxy-4- methoxymethoxy-phenyl ) -1H- indazole 1.19g (with a yield of ^{31%): 1 H NMR (} CDCl 3) δ7.80 (s, 1H), 7.69 (d, 1H, J = 8.5 Hz), 7.52 (s, 1H) , 7.29 (d, IH, J = 8.5 Hz), 7.16 (s, IH), 7.13 (s, IH), 7.08 (s, analysis ^{calculated; [m + Cl -] /} z calculated 349, 349 detected.
[160]
[161] 25 mL of dioxane and 14 mL of 3N NaOH were placed in a 100 mL round bottom flask in the presence of argon and 1.19 g (4.18 mmol, 1 equiv.) Of 6- (3-methoxy-4-methoxymethoxy- ). 1.17 g (14.60 mmol, 1.10 equiv) of iodine was added to this mixture in divided portions of not more than 5 times (not more than 10 ml). Iodine (50 mL each) was added several times (4 times or less) until the expected reaction to TLC (3: 7 ethyl acetate / hexane) was complete. To this mixture was added 25 ml of 20% citric acid and acidified, followed by 20 ml of 5% NaHSO ₃ . The mixture was partitioned between 150 ml of ethyl acetate and 100 ml of water. The organic was washed with 80 ml of saturated sodium bicarbonate and 50 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure. Crystallization from 3 ml of ethyl acetate and 7 ml of hexane and purification yielded 1.33 g (yield 78%) of the solid 3-iodo-6- (3-methoxy-4- methoxymethoxy-phenyl) It was _{^{obtained: 1 H NMR (CDCl 3)}} δ10.48 (bs, 1H), 7.62 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.47 (dd, 1H, J = 1.3, 8.5 Hz) , 7.18 (m, 3H), 5.29 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).
[162]
[163] In a 100 mL round bottom flask, 36 mL of THF was added and 921 mg (2.245 mmol, 1.00 equiv) of 3-iodo-6- (3-methoxy-4-methoxymethoxy- (8 min at this stage). 2.5 mL (1.8 M, 4.49 mmol, 2.00 equiv) of PhLi solution was added to the mixture and stirred for 30 minutes. To the mixture was added 3.63 ml (4.71 mmol, 2.1 equiv) of s-BuLi solution, stirred at -78 <0> C for 1 h and then 1.4 ml (18 mmol, 8.0 equiv) of pure DMF was added. It was removed from the cooling bath and slowly warmed to 0 ° C in air. 20 ml of saturated sodium bicarbonate dissolved in ice was added. The product was extracted with 200 mL of ethyl acetate from saturated sodium bicarbonate (75 mL or more), dried over sodium sulfate, concentrated, and concentrated under reduced pressure. Purification by silica gel chromatography (450 mL silica, 4: 6 ethyl acetate / hexanes) afforded 498 mg 6- (3-methoxy-4- methoxymethoxy- phenyl) -1 H- indazole- 71%): Rfsm 0.30, p 0.14 (ethyl acetate-hexane 4: 6);^One1 H NMR (CDCl 3₃1H, J = 8.4 Hz), 6.26 (d, IH, J = 8.4 Hz) d, 1H, J = 8.4 Hz), 7.19 (m, 2H), 5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s,
[164]
[165] 441 mg (1.41 mmol, 1.0 equiv) of 6- (3-methoxy-4-methoxymethoxy-phenyl) -lH- indazole-3-carbaldehyde was dissolved in 15 ml of dichloromethane, Respectively. This mixture was treated with 324 mg (1.48 mmol, 1.05 equiv) of mesitylene sulfonyl chloride and 181 mg (1.48 mmol, 1.05 equiv) of dimethylaminopyridine (DMAP). The mixture was partitioned between water and a 1: 1 ethyl acetate / hexane organic layer. The organic material was dried over sodium sulfate and concentrated under reduced pressure to give a crude material which was purified by silica gel chromatography (50 mL silica, 3: 7 ethyl acetate / hexane) to give 6- (3-methoxy- (Yield 54%) of: R &lt; RTI ID = 0.0 &gt;fcm 0.17, p 0.53 (ethyl acetate-hexane 4: 6);^One1 H NMR (CDCl 3₃1H, J = 8.5 Hz), 7.73 (dd, IH, J = 1.4, 8.4 Hz), 7.3 (m, 3H), 8.41 (s, 3H), 2.74 (s, 3H), 2.74 (s, 3H), 2.40 (s, 3H).
[166]
[167] 1.09 g (2.22 mmol, 4.0 equiv) of finely ground triphenyl (3,4-dimethoxybenzyl) phosphonium bromide was dissolved in 15 ml of THF and cooled to 78 ° C. To this mixture was added 1.04 mL (1.6 M, 1.66 mmol, 3.0 equiv) of n-BuLi to give a red / orange solution. The mixture was warmed to 23 &lt; 0 &gt; C for 1 hour and then added to 5 mL of 0 DEG C THF to a solution of 6- (3-methoxy-4-methoxymethoxy-phenyl) -l- (2,4,6-trimethyl- ) -1H-indazole-3-carbaldehyde (0.554 mmol, 1.0 equiv). The solution was stirred at 0 &lt; 0 &gt; C for 10 min and cooled with saturated sodium bicarbonate. The resulting mixture was partitioned between saturated sodium bicarbonate and ethyl acetate and the organic was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (50 mL silica, 3: 7-> 4: 6 ethyl acetate / hexane) Cis / trans 3- [2- (3,4-Dimethoxy-phenyl) -vinyl] -6- (3- methoxy-4- methoxymethoxy- phenyl) -Benzenesulfonyl) -1H-indazole in the ratio of 2.5: 1 (yield: 83%): Rfsm 0.53, p 0.32 (ethyl acetate-hexane 4: 6);^One1 H NMR (CDCl 3₃(d, 0.3H, J = 8.4Hz), 6.60 (d, 2H), 2.72 (s, 1.8H), 2.67 (s, 4H), 4.00-3.50 (singlets, 2.34 (s, 3 H); MS (ES) [m + H] / z Output 629, Detection 629. Analytical Output; [m-H] / z yield 627, detection 627.
[168]
[169] A 1M solution prepared by dissolving 1.0 g (17.8 mmol) of KOH in 1: 1 water / methanol (total volume 18 ml) in the presence of argon was degassed with argon (5 repetitions). (2, 3-dimethoxy-phenyl) -vinyl] -6- (3-methoxy-4-methoxymethoxy-phenyl) 6-trimethyl-benzenesulfonyl) -1H-indazole (0.461 mmol, 1.0 equiv) was dissolved in 8 mL of THF. 10 ml of 1 M KOH solution (1: 1 water / methanol) was added to the solution, which was then heated to 30 占 폚 and stirred for 7 hours. The reaction mixture was neutralized by the addition of 7 ml of 20% citric acid, and the reaction mixture was separated into 150 ml of ethyl acetate and 100 ml of water. The organic material was separated, dried over sodium sulfate and concentrated under reduced pressure to give cis and trans 3- [2- (3,4-dimethoxy-phenyl) -vinyl] -6- (3-methoxy- Methoxy-phenyl) -1H-indazole: Rfcm 0.46, p1 0.17, p2 0.23 (ethyl acetate-hexane 1: 1);^OneH NMRcisThe isomer (CDCl₃(d, IH, J = 1.9,8.3 Hz), 6.85 (d, IH, J = 12.5 Hz), 6.78 (S, 3H), 3.43 (s, 3H), 3.42 (s, 3H) , 3H). MS (ES) [m + H] / z yield 447, detection 447. Analytical yield; [m-H] / z yield 445, detection 445.
[170] Example 1 (b): 3- (Esteryl) -6- (3-benzyloxy-4-hydroxy-phenyl)
[171]
[172] Example 1 (b) was prepared in the same manner as in Example 1 (a) except that 4-bromo-2-benzyloxy-phenol was used instead of 4-bromo-2-methoxy- 1 (a). Rfsm 0.35, p 0.30 (ethyl acetate-hexane 4: 6);^One1 H NMR (CDCl 3₃(d, 1H, J = 8.6 Hz), 7.63-7.18 (m, 17H), 7.05 (d, 1H, J = 8.2 Hz), 5.19 (s, 2H). MS (CI) [m + H] / z yield 419, detection 419. Analytical yield; [m-H] / z yield 417, detected 417.
[173] Example 1 (c): Synthesis of 3- [E-2- (3,4-dimethoxy-phenyl) vinyl] -6- (3-allyloxy-
[174]
[175] Example 1 (c) was prepared in the same manner as in step (iii) of Example 1 (a) except that 3-allyloxy-4- (methoxymethoxy) ) Benzene- &lt; / RTI &gt; acid in step (a). MS (ESI) [m + H] / z yield 429, detected 429; MS (ESI) [M-H] / z yield 427, detected 427.
[176] Example 2 (a): Synthesis of 3- (naphthalen-2-yl) -6- (3-methoxy-4-hydroxy- phenyl)
[177]
[178] (0.055 mmol) of 6- (4-benzyloxy-3-methoxy-phenyl) -3-naphthalen-2-yl-1H-indazole in 2 ml of ethyl acetate, 2 ml of benzene and 2 ml of methanol Lt; / RTI &gt; To this solution was added 25 mg (10% wt) of palladium on carbon and the reaction vessel was vacuum / refined five times with hydrogen gas. The reaction mixture was stirred at 23 &lt; 0 &gt; C for 3 days and then filtered through a plug of celite. The filtrate was purified by silica gel chromatography and concentrated to give 3- (naphthalene-2-yl) -6- (3-methoxy-4-hydroxy-phenyl) -1H- indazol obtain a sol 8mg (yield 40%): ¹ H NMR _{(CDCl 3) δ10.3 (bs,} 1H), 8.50 (s, 1H), 8.20 (d, 1H, J = 8 Hz), 7.98 (d, 1H, J = 8 Hz), 7.90 (m, 1H) , 7.7-6.8 (m, 9H), 3.98 (s, 3H). MS (ES) [m + H] / z yield 367, detection 367; [mH] / z yield 365, detection 365.
[179] The starting material was prepared as follows:
[180]
[181] 117 mg (0.564 mmol, 6.0 equiv) of 2-bromonaphthalene was dissolved in 0.75 ml of THF and cooled to -78 캜. 226 [mu] L (2.5 M, 6.0 equiv) of n-BuLi was added to the mixture, stirred at -78 [deg.] C for 30 minutes,₂139 mg (0.80 mmol, 8.5 equiv) of the solid was added to warm to 23 [deg.] C (yellow disappears during addition). After 30 minutes, the mixture was added with 60 mg (0.25 mmol) of 6- (4-benzyloxy-3-methoxy-phenyl) -3- iodo-1- (2,4,6- 0.094 mmol, 1 equiv) and Pd (PPh₃)₄(0.005 mmol, 0.05 equiv) was added via cannula and stirred for 16 hours. Saturated sodium bicarbonate was added to the reaction and fractionated into 15 ml of saturated sodium bicarbonate and 15 ml of ethyl acetate. The organics were dried with sodium sulfate and then taken up and concentrated. Purification by silica gel chromatography (1: 9- > 2: 8 ethyl acetate-hexane) gave pure 6- (4-benzyloxy-3-methoxy- , 4,6-trimethyl-benzenesulfonyl) -1H-indazole (yield: 70%): Rfcm 0.4, p 0.4 (ethyl acetate-hexane 3: 7);^One1 H NMR (CDCl 3₃2H), 4.02 (s, 3H), 8.41 (s, 1H), 8.12 ), 2.80 (s, 3H), 2.34 (s, 3H).
[182] The title compound was prepared by the method of Example 1 (a) (step (a)) from 6- (4-benzyloxy-3-methoxy- was prepared in the same manner as in i) to step (v).
[183]
[184] (4-benzyloxy-3-methoxy-phenyl) -3-iodo-l- (2,4,6-trimethyl- benzenesulfonyl) -piperidine was prepared in the same manner as in step (ix) -1H-indazole was modified with 6- (4-benzyloxy-3-methoxy-phenyl) -3-naphthalen-2-yl-1H-indazole. Rfcm 0.40, p 0.17 (ethyl acetate-hexane 3: 7);^One1 H NMR (CDCl 3₃(d, 1H, J = 1.6, 8.4Hz), 7.93 (d, 1H, J = 8.3Hz), 7.88 1H, J = 2.0 Hz), 7.08 (dd, IH), 7.30 (m, 2H) J = 2.1, 8.3Hz), 6.91 (d, 1H, J = 8.3Hz), 5.16 (s, 2H), 3.91 (s, 3H).
[185] Example 2 (b): 3-Phenyl-6- (3-methoxy-4-hydroxy-phenyl)
[186]
[187] Example 2 (b) was prepared in the same manner as in Example 2 (a) except that phenyllithium was used instead of 2-naphthyllithium in 2-bromonaphthalene in step (i) of Example 2 (a) &Lt; / RTI &gt; _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.87 (d, 1H), 7.83 (d, 2H), 7.55-7.27 (m, 5H), 7.01 (m, 2H), 6.80 (d, 1H), 3.83 ( s, 3H). MS (ES) [m + H] / z yield 317, detection 317; [mH] / z yield 315, detection 315.
[188] Example 2 (c): 3- (3,4,5-trimethoxyphenyl) -6- (3-methoxy-4-hydroxy-phenyl)
[189]
[190] Example 2 (c) was prepared in the same manner as in Example 2 (a) except that 3,4,5-trimethoxyphenyl bromide was used instead of 2-bromonaphthalene in the step (i) of Example 2 (a) &Lt; / RTI &gt; Rfsm 0.67, p 0.38 (ethyl acetate-hexane 8: 2);^One1 H NMR (CDCl 3₃1H, J = 8 Hz), 7.10 (m, 4H), 6.92 (d, Hz), 3.90 (s, 9H), 3.85 (s, 3H). MS (ES) [m + H] / z yield 407, detection 407; [m-H] / z yield 405, detection 405.
[191] Example 2 (d): 3- (lH-Indol-2-yl) -6- (3- methoxy-4-hydroxy-phenyl)
[192]
[193] Example 2 (d) was prepared in the same manner as in Example 2 (a) except that 1-phenylsulfonyl-indazole was used instead of 2-bromonaphthalene in the step (i) of Example 2 (a) . Rfcm 0.20, p 0.15 (ethyl acetate-hexane 4: 6);^One1 H NMR (CDCl 3₃8.05 (d, 1H, J = 8.0 Hz), 8.05 (d, 1H, J = 1H, J = 8 Hz), 7.29 (d, 1H, J = 8 Hz), 7.2-7.1 (m, 5H), 6.92 (d, 1H, J = 8 Hz), 5.63 (bs, 1H); MS (ES) [m + H] / z yield 356, detection 356; [m-H] / z yield 354, detection 354.
[194] Example 2 (e): 3- (Benzofuran-2-yl) -6- (3-benzyloxy-4-hydroxy-phenyl)
[195]
[196] Example 2 (e) was prepared in the same manner as in Example 2 (a) except that benzofuran was used instead of 2-bromonaphthalene in the step (i) of Example 2 (a). _{^{1 H NMR (CDCl 3) δ8.21}} (d, 1H, J = 8.0 Hz), 7.60 (m, 3H), 7.30-7.10 (m, 12H), 7.01 (d, 1H, J = 8 Hz), 5.82 (bs, 1 H), 5.15 (s, 3 H).
[197] Example 3: 3- (lH-Indol-2-yl) -6- (3-methoxy-4-hydroxy-phenyl)
[198]
[199] Benzoimidazol-2-yl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1H-indazole was prepared by the same procedure as in Example 1 (a) Yl) -2-methoxy-phenol (3.5 mg, 28%). HRMS (FAB) [m + H] / z yield 357.1351, detected 357.1349.
[200] The starting material was prepared as follows:
[201]
[202] (0.064 mmol, 1 equiv) of 6- (3-methoxy-4-methoxymethoxy-phenyl) -1H-indazole-3-carbaldehyde prepared in step (vi) Was dissolved in 0.7 ml of 1: 1 methanol-water, degassed, and 19 아세 (5 equiv) of acetic acid, 8.3 mg (1.2 equiv.) Of 1,2-diaminobenzene and 18 mg (1.4 equiv.) Of Cooper Was added. The mixture was stirred for 30 minutes, diluted with 3 ml of ethanol and 2 ml of water,₂It was foamed with water vapor to obtain a black precipitate. The mixture was stirred for 12 hours, then filtered and concentrated. Purification by silica gel chromatography (6: 4 ethyl acetate-hexane) gave 3- (lH-benzoimidazol-2-yl) -6- (3- methoxy-4- methoxymethoxy-phenyl) -Indazole (yield 54%): Rfsm 0.39, p 0.24 (ethyl acetate-hexane 6: 4);^One1 H NMR (CDCl 3₃(d, 1H, J = 8 Hz), 7.70 (bs, 2H), 7.58 5.30 (s, 2H), 3.97 (s, 3H), 3.58 (s, 3H); MS (ES) [m + H] / z yield 401, detection 401; [m-H] / z yield 399, detection 399.
[203] Example 4 (a): N- [3- (3-Styryl-lH-indazol-6-yloxy) -phenyl] -benzamide
[204]
[205] 0.09 g (0.17 mmol) of N- [3- (2-benzoyl-3-styryl-1H-indazol-6-yloxy) -phenyl] -benzamide was added to 2 ml of 6N HCl (aqueous) and 3 ml of methanol After dissolution, the mixture was heated to 65 DEG C for about 4 hours, cooled, and then a saturated sodium bicarbonate solution was carefully added. The precipitate was collected by filtration and purified by silica gel chromatography eluting with hexane / EtOAc (1: 1) to give a beige solid of N- [3- (3-styryl-lH-indazol- -Benzamide (yield: 50%). _{^{1 H NMR (DMSO-d 6}} ) δ13.50 (s, 1H), 10.32 (s, 1H), 8.23 (d, 1H, J = 8.7 Hz), 7.92 (d, 2H, J = 6.8 Hz), 7.72 (d, 2H, J = 7.3 Hz), 7.71-7.51 (m, 7H), 7.51-7.47 (m, 3H), 7.30 d, 1H, J = 8.7Hz), 6.86 (dd, 1H, J = 8.2,2.3Hz). _{C 28 H 21 N 3 O 2} · 0.3H ₂ O for analysis calculated: C, 76.97; H, 4.98 ; N, 9.62. Detection: C, 76.94; H, 5.13; N, 9.40.
[206] The starting material was prepared as follows:
[207] (i)
[208]
[209] (38.3 mmol) of 3- (benzhydrylylamino) -phenol, 5.00 g (38.3 mmol) of 3-chloro-cyclohex-2-enone and 5.82 g (42.1 mmol) of potassium carbonate were placed in 150 ml of acetone Refluxed for one day and heated. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / EtOAc (2: 1) to give 8.82 g of 3- [3- (benzhydryl diene-amino) -phenoxy] -cyclohex- Yield: 63%). _{^{1 H NMR (CDCl 3) δ7.78}} (d, 2H, J = 7.0 Hz), 7.50 (d, 1H, J = 7.1 Hz), 7.45 (d, 2H, J = 7.7 Hz), 7.34-7.10 (m 1H, J = 8.0 Hz), 6.69 (d, 1H, J = 8.0 Hz), 6.61 (d, 6.2 Hz), 2.34 (t, 2H, J = 6.2 Hz), 2.06 (m, 2H). Anal. Calcd. For C ₂₅ H ₂₁ NO ₂ .0.2H ₂ O: C, 80.92; H, 5.81; N, 3.78. Detection: C, 81.12; H, 5.81; N, 3.72.
[210] Phenol was prepared as follows: 15.0 g (82.8 mmol) of benzophenone imine and 9.03 g (82.8 mmol) of 3-aminophenol were dissolved in 25 ml of toluene and treated with 3.5 g - Remove H ₂ O from the Dean-Stark trap and heat with reflux. The reaction mixture was cooled and collected by vacuum filtration, and the resulting crystals were washed with hexane and air dried. This gave 17.3 g (76% yield) of 3- (benzhydrylidene-amino) -phenol as a pale yellow solid: ¹ H NMR (CDCl ₃ ) 7.64 (d, 2H, J = 7.1 Hz) (M, 2H), 7.38 (d, 1H, J = 7.1 Hz), 7.34-7.15 , J = 8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J = 7.8 Hz). Anal. Calcd for C ₁₉ H ₁₅ NO: C, 83.49; H, 5.53; N, 5.12. Detection: C, 83.51; H, 5.65; N, 5.03.
[211]
[212] To a solution of 4.37 g (11.89 mmol) of 3- [3- (benzhydrylidene-amino) -phenoxy] -cyclohex-2-enone in 20 ml THF was added at -78 < 1.0 M solution dissolved in THF) was slowly added thereto. After 5 minutes, 1.98 g (11.89 mmol) of trans-cinnamoyl chloride was added all at once and the mixture was stirred for 30 minutes at -78 ° C. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (2x). The combined organic layer was washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / EtOAc (5: 1) to give 3- [3- (benzhydrylidene-amino) -phenoxy] -6- Yl) cyclohex-2-enone (yield: 56%). _{^{1 H NMR (CDCl 3) δ15.69}} (s, 1H), 7.80 (d, 2H, J = 7.1 Hz), 7.63-7.01 (m, 15H), 6.93 (d, 1H, J = 15.6 Hz), 6.75 (d, 1H, J = 7.6 Hz), 6.66 (d, 1H, J = 8.0 Hz), 6.46 (s, (t, 2H, J = 7.2 Hz). Anal. Calcd. For C ₃₄ H ₂₇ NO ₃ : C, 82.07; H, 5.47; N, 2.82. Detection: C, 81.88; H, 5.53; N, 2.81.
[213] (iii)
[214]
[215] (3.64 mmol) of 3- [3- (benzhydrylidene-amino) -phenoxy] -6- (3-phenyl- acryloyl) -cyclohex- ), 2.0 ml (41.23 mmol) of hydrazine hydrate was added, and the mixture was stirred at 75 占 폚 for 25 minutes. After cooling the reaction mixture, a saturated sodium bicarbonate solution was added slowly and extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / EtOAc (1: 1) to give 3- (3-styryl-4,5-dihydro-1 H-indazol- Amine (yield: 45%). _{^{1 H NMR (DMSO-d 6}} ) δ7.55 (d, 2H, J = 7.2 Hz), 7.38 (t, 2H, J = 7.2 Hz), 7.27 (t, 1H, J = 7.2 Hz), 7.05 (m 1H, J = 7.9 Hz), 6.32 (d, 1H, J = 8.0 Hz), 6.31 (s, (t, 2H, J = 8.0 Hz), 2.58 (t, 2H, J = 8.1 Hz). Anal. Calcd for C ₂₁ H ₁₉ N ₃ O 0.3 H ₂ O: C, 75.33; H, 5.90; N, 12.55. Detection: C, 75.46; H, 5.96; N, 12.35.
[216]
[217] 50 mg (0.15 mmol) of 3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) -phenylamine and 54 μl (0.31 mmol) of N, N-diisopropylethylamine After dissolving in 5 mL CH ₂ Cl ₂ and stirring, 36 벤 (0.31 mmol) benzoyl chloride was added. After 15 min the mixture was diluted with CH ₂ Cl ₂ , washed successively with 0.5 N HCl, saturated sodium bicarbonate solution and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane to dissolve and 35 mg (0.15 mmol) of 2,3-diclo-5,6-dicyano-1,4-benzoquinone (DDQ) was added. After 1 h the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with hexane / EtOAc (2: 1) to give N- [3- (2-benzoyl- -Indazol-6-yloxy) -phenyl] -benzamide (90 mg). _{^{1 H NMR (CDCl 3) δ8.13}} (s, 1H), 8.02 (d, 2H, J = 7.0 Hz), 7.94 (d, 1H, J = 8.7 Hz), 7.74 (d, 2H, J = 6.8 Hz ), 7.57-7.19 (m, 17H), 6.84 (d, IH, J = 8.3 Hz).
[218] Example 4 (b): N- [3- (3-Styryl-lH-indazol-6-yloxy) -phenyl] -acetamide
[219]
[220] Example 4 (b) was prepared in the same manner as in Example 4 (a) except that acetic anhydride was used instead of benzoyl chloride in the step (iv) of Example 4 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.08 (bs, 1H), 10.03 (s, 1H), 8.22 (d, 1H, J = 8.7 Hz), 7.72 (d, 2H, J = 7.3 Hz), 7.52 (s, 2H), 7.44-7.27 (m, 6H), 7.01 (s, IH), 6.96 (dd, IH, J = 8.7, 2.1 Hz), 6.78 s, 3H). Anal. Calcd for C ₂₃ H ₁₉ N ₃ O ₂ .0.25 H ₂ O: C, 73.88; H, 5.26; N, 11.24. Detection: C, 74.20; H, 5.57; N, 10.82.
[221] Example 5 (a): 5-Methyl-thiazole-2-carboxylic acid {3- (3-styryl-lH-indazol-
[222]
[223] 5-methyl-thiazole-2-carboxylic acid {3- [1- (5-methyl-thiazole- (0.10 mmol) of potassium carbonate and 50 mg (0.36 mmol) of potassium carbonate were dissolved in methanol, and the mixture was stirred at 23 캜 for 20 minutes. The solution was filtered, diluted with EtOAc and washed with brine (2x). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 5-methyl-thiazole-2-carboxylic acid {3- (3-styryl-1H-indazol-6-yloxy) -phenyl} Was prepared in 47% yield. _{^{1 H NMR (DMSO-d 6}} ) δ13.00 (s, 1H), 10.80 (s, 1H), 8.23 (d, 1H, J = 8.8 Hz), 7.79 (s, 2H), 7.71 (t, 2H, 1H, J = 8.6 Hz), 7.53 (s, 2H), 7.41-7.27 (m, 5H), 7.04 (s, Hz), &lt; / RTI &gt; 2.54 (s, 3H). Analysis for C ₂₆ H ₂₀ N ₄ O ₂ S 揃 1.15 H ₂ O: C, 65.98; H, 4.75; N, 11.84; S, 6.78. Detection: C, 65.99; H, 4.71; N, 11.58; S, 6.76.
[224] The starting material was prepared as follows:
[225]
[226] To a solution of 5-methyl-thiazole-2-carboxylic acid and HATU (o- (2- (4-fluoro- N, N, N ', N'-tetramethyluronium hexafluorophosphate) was treated and treated with the DDQ treatment isolated in step iv) of Example 4 (a) The title compound was prepared from 5-methyl-thiazole-2-carboxylic acid {3- [1- (5-methyl-thiazole- Phenyl} amide. _{^{1 H NMR (DMSO-d 6}} ) δ10.85 (s, 1H), 8.45 (d, 1H, J = 9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 ( m, 5H), 6.96 (d, 1H, J = 8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).
[227] Example 5 (b): 3-Methyl-N- [3- (3-styryl-lH-indazol-6- yloxy) -phenyl] -benzamide
[228]
[229] Example 5 (b) was prepared in the same manner as in Example 5 (a) except that m-tolyl chloride was used in place of 5-methyl-thiazole-2-carboxylic acid and HATU in step (i) . &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ13.04 (s, 1H), 10.28 (s, 1H), 8.23 (d, 1H, J = 8.8 Hz), 7.73-7.30 (m, 14H), 7.05 (s, 1H), 6.99 (d, 1H, J = 8.5 Hz), 6.87 (d, 1H, J = 7.7 Hz), 2.38 (s, 3H). Anal. Calcd. For C ₂₉ H ₂₃ N ₃ O ₂ .0.2 H ₂ O, 0.2 hexane: C, 77.78; H, 5.66; N, 9.01. Detection: C, 77.80; H, 5.84; N, 8.93.
[230] Example 6 (a): N- (3- {3- [2- (4-Chloro-phenyl) -vinyl] -lH-indazol-6- yloxy} -phenyl) -benzamide
[231]
[232] Using as starting materials N- (3- {1-benzoyl-3- [2- (4-chloro-phenyl) -vinyl] -lH-indazol- (3- {3- [2- (4-Chloro-phenyl) -vinyl] -lH-indazol-6-yloxy} -phenyl) -benzamide as a yellowish white solid in the same manner as in Example 5 Was prepared in 72% yield. _{^{1 H NMR (DMSO-d 6}} ) δ13.07 (s, 1H), 10.32 (s, 1H), 8.24 (d, 1H, J = 8.8 Hz), 7.92 (d, 2H, J = 7.1 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.59-7.40 (m, 10H), 7.05 . Anal. Calcd. For C ₂₈ H ₂₀ ClN ₃ O ₂ .04 H ₂ O, 0.15 hexane: C, 71.41; H, 4.75; N, 8.65. Detection: C, 71.62; H, 14.83; N, 8.45.
[233] The starting material was prepared as follows:
[234]
[235] A solution of 3- [3- (benzhydrylidene-amino) -phenoxy] -cyclohex-2-enone and 3- (4-chloro-phenyl) -acryloyl chloride Was prepared in the same manner as in the step (ii) of Example 4 (a). 3- (2- (4-Chloro-phenyl) -vinyl] -4,5-dihydro-4H-pyrazole- Dihydro-lH-indazol-6-yloxy} -phenyl) -phenylamine was prepared in 30% yield. _{^{1 H NMR (DMSO-d 6}} ) δ12.45 (s, 1H), 7.58 (d, 2H, J = 8.5 Hz), 7.43 (d, 2H, J = 8.5 Hz), 5.52 (s, 1H), 5.26 (s, 2H), 2.92 (t, 2H, J = 8.0Hz), 2.58 (t, 2H, J = 8.0Hz). Anal. Calcd. For C ₂₁ H ₁₈ ClN ₃ O 0.75 H ₂ O: C, 66.84; H, 5.21; N, 11.14. Detection: C, 66.73; H, 4.89; N, 11.01.
[236] 3- (4-Chloro-phenyl) -acryloyl chloride was prepared as follows: 2.51 g (13.77 mmol) of 4-chloro-trans-cinnamic acid was dissolved in benzene and 1.1 ml 15.14 mmol) and DMAP were added thereto, followed by heating at reflux for 1.5 hours. The volatiles were removed under reduced pressure and the white residue dissolved in Et ₂ O and concentrated under reduced pressure again to give 2.78 g of 3- (4-chloro-phenyl) -acyl chloride, a white solid: ¹ H NMR (CDCl ₃ ) δ7 J = 8.6 Hz), 6.65 (d, 1H, J = 15.6 Hz), 7.54 (d, 2H, J = 8.6 Hz), 7.44 (d, 2H, J = 8.6 Hz).
[237]
[238] 6-yloxy} -phenylamine was reacted with 4- (3-chloro-phenyl) -vinyl] -4,5-dihydro- (3- {1-benzoyl-3- [2- (4-chloro-phenyl) -vinyl] -lH-indazol-6-yloxy} -phenyl) -benzamide was prepared in the same manner as in (Yield: 85%). _{^{1 H NMR (DMSO-d 6}} ) δ10.37 (s, 1H), 8.43 (d, 1H, J = 8.8 Hz), 8.00-7.39 (m, 21H), 7.34 (d, 1H, J = 8.8 Hz) , 6.93 (d, 1 H, J = 8.8 Hz).
[239] Example 6 (b): N- {3- [3- (2-indolyl) -1H-indazol-6-yloxy] -phenyl} -3-methyl-
[240]
[241] Example 6 (b) was repeated except that 1-SEM-indazole-2-carboxylic acid was used instead of 4-chloro-trans-cinnamic acid in step (i) of Example 6 (a) And was prepared in the same manner as in Example 5 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.19 (s, 1H), 11.59 (s, 1H), 10.29 (s, 1H), 8.23 (d, 1H, J = 8.7 Hz), 7.73-7.38 (m, 1H, J = 7.8 Hz), 7.12 (s, 1H), 7.03 (d, 2H, J = 7.3 Hz), 6.88 (d, HRMS [m + H] / z yield: 459.1821, detected 459.1836.
[242] Example 7: Synthesis of 3- (styryl-lH-indazol-6-yloxy) -phenylamine
[243]
[244] A suspension of 75 mg (0.23 mmol) of 3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) -phenylamine and 90 mg of 5% palladium carbon (Pd / C) C and 4 hours later, 39 mg of 5% Pd / C was further added. After 22 hours, 30 mg of 5% Pd / C was further added and the mixture was filtered after 26 hours. Washed with a catalyst, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / EtOAc (1: 1). The residue was concentrated in an appropriate ratio and triturated with CH ₂ Cl ₂ / hexane to obtain 20 mg (yield 27%) of 3- (styryl-1H-indazol-6-yloxy) -phenylamine as a yellowish white solid. _{^{1 H NMR (DMSO-d 6}} ) δ8.16 (d, 1H, J = 8.5 Hz), 7.71 (d, 2H, J = 6.7 Hz), 7.50 (s, 2H), 7.40 (t, 2H, J = 2H), 5.26 (s, 2H), 7.30 (d, IH, J = 6.5 Hz), 7.06-6.92 (m, 3H) . Anal. Calcd for C ₂₁ H ₁₇ N ₃ O · 0.15 CH ₂ Cl ₂ : C, 74.69; H, 5.13; N, 12.36. Detection: C, 74.64; H, 5.23; N, 12.25.
[245] Example 8 (a): 3- (E-Styryl) -6-phenoxy-1 H-indazole
[246]
[247] A suspension of 200 mg (0.64 mmol) of 3- (Esteril) -6-phenoxy-4,5-dihydro-1H-indazole and 200 mg of 5% Pd / C in 10 ml of tetralin was stirred at 155 ° C And heated for 18 hours. The solution was filtered to remove the catalyst and washed with THF, EtOAc, MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with hexane / EtOAc (2: 1) to obtain 110 mg of 3- (E-styryl) -6-phenoxy-1H- 55%). _{^{1 H NMR (DMSO-d 6}} ) δ6.96 (s, 2H), 7.10 (d, 2H, J = 7.7 Hz), 7.20 (t, 1H, J = 7.1 Hz), 7.30 (t, 1H, J = 7.1 Hz), 7.44 (m, 6H), 7.71 (d, 2H, J = 7.5 Hz), 8.20 (d, 1H, J = 9.2 Hz), 12.90 (s, 1H). Anal. Calcd. For C ₂₁ H ₁₆ N ₂ O · 0.1 H ₂ O: C, 80.28; H, 5.20; N, 8.92. Detection: C, 80.20; H, 5.21; N, 8.93.
[248] The starting material was prepared as follows:
[249] (i) 3.81 g (27.6 mmol) of anhydrous K ₂ CO ₃ powder was added to a solution obtained by mixing 3.00 g (23.0 mmol) of 3-chloro-cyclohex-2-enone and 2.16 g (23.0 mmol) , Refluxed for 18 hours, cooled, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with hexane / EtOAc (4: 1) to give 3-phenoxy-cyclohex-2-enone as a white solid. _{^{1 H NMR (CDCl 3) δ2.10}} (quint, 2H, J = 6.3 Hz), 2.40 (t, 2H, J = 6.2 Hz), 2.68 (t, 2H, J = 6.3 Hz), 5.14 (s, 1H ), 7.05 (d, 2H, J = 7.5 Hz), 7.26 (t, 1H, J = 7.3 Hz), 7.41 (t, 2H, J = 7.6 Hz).
[250] (ii) 301 mg (1.6 mmol) of 3-phenoxy-cyclohex-2-enone was dissolved in 1 ml of THF, and 1.0 M of lithium bis (trimethylsilyl) amide was dissolved in 3.2 ml of THF at a concentration of 1.0 M and stirred The solution was added at -78 &lt; 0 &gt; C. After 15 minutes, 266 mg (1.6 mmol) of cinnamoyl chloride was added in one portion. After 15 minutes, 0.5N HCl was added to the reaction mixture and extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / EtOAc (4: 1) to give 220 mg of 3-phenoxy-6- (3-phenyl-acryloyl) -cyclohex- %). ¹ H NMR (CDCl ₃₎ (enol form) δ2.66 (t, 2H, J = 7.2 Hz), 2.84 (t, 2H, J = 7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H, J = 15.6 Hz), 7.02 (d, 2H, J = 8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m, 3H). HRMS [M + H & lt ^; + & gt ^; ] Output: 319.1334, Detection 319.1340.
[251] (3.55 mmol) of 3-phenoxy-6- (3-phenyl-acryloyl) -cyclohex-2-enone was dissolved in 20 mL HOAc / EtOH (1: 1) followed by hydrazine monohydrate 21 Ml &lt; / RTI &gt; (4.3 mmol). After the reaction was heated at 70 ℃ for 3 hours, cooled and carefully placed carefully to saturated NaHCO ₃ solution, and extracted with EtOAc (2x). Wash the combined organic layer with saturated NaCl solution and concentrated under reduced pressure after drying (MgSO _4). The residue was purified by silica gel chromatography eluting with hexane / EtOAc (2: 1) to give 406 mg of 6-phenoxy-3-styryl-4,5-dihydro-lH-indazole (3) 36%). _{^{1 H NMR (DMSO-d 6}} ) δ2.64 (t, 2H, J = 8.0 Hz), 2.95 (t, 2H, J = 8.0 Hz), 5.46 (s, 1H), 7.04 (AB, 2H, J = 2H), 7.42 (m, 4H), 7.55 (d, 2H, J = 7.7 Hz), 12.44 (s, 1H). Anal. Calcd for C ₂ H ₁₈ N ₂ O 0.2 H ₂ O: C, 79.32; H, 5.83; N, 8.81. Detection: C, 79.36; H, 5.85; N, 8.84.
[252] Example 8 (b): Synthesis of 3- (Esterly) -6- [4- (methoxymethoxy) phenoxy] -1H-indazole
[253]
[254] Example 8 (b) was prepared in the same manner as in Example 8 (a) except that 4- (methoxymethoxy) phenol was used instead of phenol in the step (i) of Example 8 (a). _{^{1 H NMR (DMSO-d 6}} ) δ12.90 (s, 1H), 8.17 (d, 2H, J = 8.8 Hz), 7.71 (d, 2H, J = 7.6 Hz), 7.50 (s, 3H), 7.41 1H, J = 7.6 Hz), 7.31 (d, 1H, J = 7.4 Hz), 7.10 (s, 3H), 6.95 (dd, 1H, J = 8.8, 1.9 Hz), 6.84 , 5.20 (s, 2 H), 3.42 (s, 3 H). Anal. Calcd for C ₂₃ H ₂₀ N ₂ O ₃ : C, 74.17; H, 5.41; N, 7.52. Detection: C, 74.21; H, 5.59; N, 7.46.
[255] Example 8 (c): Synthesis of 3- (E-styryl) -6-phenylsulfanyl-1H-indazole
[256]
[257] Example 8 (c) was prepared in the same manner as in Example 8 (a) except that thiophenol was used instead of phenol in the step (i) of Example 8 (a). _{^{1 H NMR (DMSO-d 6}} ) δ7.29 (d, 1H, J = 8.5 Hz), 7.45-7.59 (m, 9H), 7.67 (s, 2H), 7.86 (d, 2H, J = 7.2 Hz) , 8.35 (d, 1H, J = 8.5 Hz), 13.30 (s, 1H). _{C 21 H 16 N 2 S 3} · 0.25 H ₂ O for analysis calculated: C, 75.76; H, 5.00 ; N, 8.41; S, 9.63. Detection: C, 75.79; H, 4.99; N, 8.16; S, 9.63.
[258] Example 8 (d): 6- (3-Bromo-phenoxy) -3-styryl-lH-indazole
[259]
[260] Example 8 (d) was prepared in the same manner as in Example 8 (a) except that 3-bromophenol was used instead of phenol in the step (i) of Example 8 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.08 (s, 1H), 8.23 (d, 1H, J = 8.8 Hz), 7.72 (d, 2H, J = 7.3 Hz), 7.53 (s, 2H), 7.43 J = 7.2 Hz), 7.09 (s, 1H), 6.98 (d, 1H, J = 8.8 Hz) . Anal. Calcd for C ₂₁ H ₁₅ BrN ₂ O: C, 64.46; H, 3.86; Br, 20.42; N, 7.16. Detection: C, 64.31; H, 3.99; Br, 20.52; N, 7.11.
[261] Example 9 (a): Synthesis of 3- (Esterly) -6- [3-hydroxyphenoxy] -1H-indazole
[262]
[263] 50 mg (0.13 mmol) of 3- (Esteryl) -6- [3- (methoxymethoxy) phenoxy] -1 H- indazole was dissolved in 5 mL of CH ₂ Cl ₂ at -25 ° C and trimethylsilyl bromide 75 [mu] l (0.57 mmol) was added. After 1.5 hours the addition of saturated NaHCO ₃ solution and the product extracted with EtOAc (2x). Wash the combined organic layer with saturated NaCl solution and concentrated under reduced pressure after drying (MgSO _4). The residue was triturated with CH ₂ Cl ₂ / hexane and then eluted with hexane / EtOAc (1: 1) and purified by silica gel chromatography to give a yellowish white solid of 3- (Esterly) -6- [3- Yl] -1H-indazole (yield: 50%). _{^{1 H NMR (DMSO-d 6}} ) δ6.37 (s, 1H), 6.43 (d, 1H, J = 8.1 Hz), 6.50 (d, 1H, J = 8.1 Hz), 6.88 (d, 1H, J = 2H, J = 7.6Hz), 7.44 (s, 1H), 7.92 (s, 1H), 7.64 (d, 2H, J = 7.5 Hz), 8.12 (d, 1H, J = 8.7 Hz), 9.54 (s, 1H), 12.92 (s, 1H). Anal. Calcd. For C ₂₁ H ₁₆ N ₂ O ₂ .0.3 H ₂ O: C, 75.57; H, 5.01; N, 8.39. Detection: C, 75.74; H, 5.11; N, 8.25.
[264] The starting material, 3- (E-styryl) -6- [3- (methoxymethoxy) phenoxy] -1H-indazole, was prepared in the same manner as in Example 8 (b) above.
[265]
[266] _{^{1 H NMR (CDCl 3) δ3.42}} (s, 3H), 5.10 (s, 2H), 6.64 (d, 1H, J = 8.2 Hz), 6.72 (s, 1H), 6.80 (d, 1H, J = 8.3 Hz), 6.98 (s, 1H), 7.00 (d, 1H, J = 8.8 Hz), 7.19-7.38 (m, 5H), 7.53 . Anal. Calcd for C ₂₃ H ₂₀ N ₂ O ₃ : M + H ⁺ : 373.1552, detection 73.1546.
[267] Example 9 (b): Synthesis of 3- (Esteryl) -6- [4-hydroxyphenoxy] -1H-indazole
[268]
[269] Example 9 (b) was repeated except that 3- (E-styryl) -6- [4 (methoxymethoxy) phenoxy] - (methoxymethoxy) phenoxy] -1H-indazole was used in place of the compound of Example 9 (a). _{^{1 H NMR (DMSO-d 6}} ) δ12.95 (s, 1H), 9.58 (s, 1H), 8.33 (d, 1H, J = 9.0 Hz), 7.89 (d, 2H, J = 7.1 Hz), 7.68 (s, 1H), 7.58 (t, 1H, J = 7.3 Hz), 7.48 (d, 1H, J = 7.3 Hz), 7.24 J = 8.8 Hz). HRMS [m + H] / z yield: 329.1290, detected: 329.1293. Anal. Calcd. For C ₂₁ H ₁₆ N ₂ O ₂ .035 H ₂ O: C, 75.36; H, 5.03; N, 8.37. Detection: C, 75.35; H, 5.22; N, 8.24.
[270] Example 10: Preparation of 6- (1-phenyl-vinyl) -3-styryl-1H-indazole
[271]
[272] 16.2 mg (0.0358 mmol) of 6- (1-phenyl-vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was dissolved in 0.6 ml of THF, Butylammonium fluoride (TBAF, dissolved in THF at a concentration of 1M, 0.6 mL) was treated and heated to 60 C in the presence of argon for 4 hours. The mixture was cooled and neutralized with a sufficient amount of saturated sodium bicarbonate. A mixture of these three compounds (analyzed by TLC) was treated with THF-water-THF (1: 1: 2, 4 mL) for 30 minutes. The mixture was diluted with 20 ml of toluene, concentrated and neutralized with a sufficient amount of saturated sodium bicarbonate, and the organic was extracted with ethyl acetate. The organics were dried with sodium sulfate and concentrated to give. Silica gel chromatography (2: 8 ethyl acetate-hexane) to give the 6- (1-Phenyl-vinyl) -3-styryl -1H- indazol obtain a sol 4.6mg (Yield _{40%): R f sm 0.62} , p 0.24 (ethyl acetate-hexane 3: 7); _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.99 (d, 1H, J = 8.5 Hz), 7.60-7.25 (m, 14H), 5.58 (d, 1H, J = 1.1 Hz), 5.56 (d, 1H, J = 1.1 Hz); HRMS [m + H] / z yield: 323.1548, detected: 323.1545.
[273] The starting material was prepared as follows:
[274]
[275] 6-iodoindazole was transformed into 3,6-diiodoindazole (yield: 82%) in the same manner as in the step (v) of Example 1 (a). _{^{1 H NMR (300MHz, CDCl 3}} ) δ10.3 (bs, 1H), 7.90 (s, 1H), 7.52 (dd, 1H, J = 1.2, 8.5 Hz), 7.24 (d, 1H, J = 8.5 Hz) .
[276]
[277] To 755 mg (2.04 mmol) of 3,6-diiodoindazole at 0 占 폚 was added 2.5 g of 50% KOH (dissolved in 2.5 ml of water), 4 ml of dichloromethane was added and tetrabutylammonium bromide (TBABr, 6.6 (SEM-Cl, 397 [mu] l, 2.24 mmol, 1.10 equiv) was added dropwise over 3 minutes. The mixture was stirred rapidly at 0 ° C for 1.5 hours, 20 ml of water and 20 ml of dichloromethane were added to separate organic matters, followed by drying with sodium sulfate and concentration. (1-SEM, 763 mg, 75%; and 2-SEM, 105 mg, 10%): R _f cm 0.08 & _lt; RTI ID _{= 0.0 &} gt; , p 0.34 and 0.27 (ethyl acetate-hexane 1: 9); _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.0 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.24 (d, 1H, J = 8.5 Hz), 5.69 (s, 2H), 3.58 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), -0.1 (s, 9H).
[278]
[279] (0.20 mmol, 2.0 equiv) of 1-bromostyrene was dissolved in 0.75 mL of THF, and the solution was cooled to -78 ° C, treated with 235 μL of t-BuLi (0.40 mmol, 1.70 M, 4.0 equiv) C &lt; / RTI &gt; and then 34 mg (0.25 mmol, 2.5 equiv) of freshly dried zinc chloride was added. The solution was warmed to 23 占 폚 for 25 minutes and then 50 mg (0.10 mmol, 1 equiv.) Of neat 3,6-diiod- 1- [2- (trimethyl-silanyl) -ethoxymethyl] ) and it was added to a mixture of _{Pd (PPh 3) 4 5mg (} 0.004mmol, 0.04 equiv). After 10 minutes, the reaction was completed by TLC monitoring and the reaction was cooled with saturated sodium bicarbonate. The organic was extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography (5:95 ethyl acetate-hexanes) afforded 3-iodo-6- (1-phenyl-vinyl) -1- [2- trimethyl- Indazole (yield 70%): _Rf cm 0.39, p 0.36 (ethyl acetate-hexane 1: 9); ¹ H NMR (300 MHz, CDCl ₃ ) 7.50 (s, 1H), 7.42 (d, 1H, J = 8.4 Hz), 7.33 (m, 5H), 7.22 2H), 5.58 (d, 1H, J = 1.0 Hz), 5.58 (t, 2H, J = J = 8.2 Hz), -0.09 (s, 9H); HRMS (FAB) [m + H] / z yield: 477.0859, Detection: 477.0866.
[280]
[281] Preparation of 6- (1-phenyl-vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole: 23 μl of E-2-bromostyrene mmol, 2.5 equiv) was dissolved in 1.0 mL of THF, cooled to -78 ° C, and 205 μL (0.348 mmol, 5.00 equiv) of t-BuLi was added and heated to -42 ° C for 7 minutes to obtain a dark red mixture. To this solution, 29 mg (0.209 mmol, 3.00 equiv) of neat-dried zinc chloride was added via cannula and stirred for 20 minutes at 23 &lt; 0 &gt; C before adding 3-iodo-6- (1-phenyl- (0.006 mmol, 0.05 equiv) of Pd (PPh ₃ ) ₄ and 33.1 mg (0.0696 mmol, 1.0 equiv) of a neat mixture of 2- (trimethylsilanyl) ethoxymethyl] -1H- Lt; / RTI &gt; via cannula. The solution was stirred for 15 min then saturated sodium bicarbonate was added and extracted with ethyl acetate. The organics were dried with sodium sulfate and then taken up and concentrated. Purification by silica gel chromatography (5:95 ethyl acetate-hexanes; 12 mL silica: and 1:99 ethyl acetate-benzene; 12 mL silica) 16.2 mg (51% yield) of 2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was obtained: R _f sm 0.38, p 0.29 (ethyl acetate-hexane 1: 9); _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.98 (d, 1H, J = 8.4 Hz), 7.62-7.22 (m, 14H), 5.71 (s, 2H), 5.57 (s, 2H), 3.60 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), -0.08 (s, 9H); HRMS (FAB) [m + H] / z yield: 453.2362, Detection: 453.2354.
[282] Example 11: N-methyl-N- (3-styryl-1H-indazol-6-yl) -benzene-
[283]
[284] 237 mg (0.5 mmol) of N-methyl-N- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] ) Was added to 1 M TBAF (10.1 mL, 10.1 mmol) dissolved in THF, followed by addition of 0.34 mL (5.04 mmol, 10 equiv) of ethylenediamine and then to 70 DEG C for 5 hours. The reaction was cooled with saturated NaHCO ₃ and extracted with ₃ x 35 mL EtOAc. After washing in order to accumulate in phase with EtOAc 5x20㎖ H ₂ O and brine and 20㎖ according to embellish dried Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (9: 1 dichloromethane / ethyl acetate) to give 120 mg of N-methyl-N- (3-styryl-1H-indazol-6-yl) (Yield: 70%). R _f sm 0.73, R _f p 0.27 (dichloromethane: ethyl acetate 7: 3); _{^{13 C NMR (75MHz, CDCl 3}} ) δ150.3, 148.8, 147.5, 147.5, 143.9, 143.4, 137.5, 131.1, 130.3, 129.3, 128.9, 128.2, 127.9, 126.7, 121.0, 120.5, 117.0, 116.0, 112.6, 109.8 , 109.0, 98.3, 40.7; LSMS (ESI) [m + H] / z yield: 341, detect 341. Anal. Yield: C, 77.62; H, 5.92; N, 16.46. Detection: C, 76.16; H, 5.88; N, 15.95.
[285] The starting material was prepared as follows:
[286]
[287] 6-nitro-1H-indazole was transformed into 3-iodo-6-nitro-1H-indazole in the same manner as in step (v) of Example 1 (a): FTIR (KBr) 3376, 3076, 2964, 2120, 1739, 1626, 1526, 1439, 1294, 1128, 954 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.28 (s, 1H), 8.05 (s, 1H), 7.66 (d, 1H, J = 8.13 Hz), 7.45 (dd, 1H, J = 8.33, 1.38 Hz) , 7.17 (d, IH, J = 1.01 Hz), 7.14 (s, IH), 7.03 (d, IH, J = 8.04 Hz), 6.89 (s, 2H) 6H), 2.21 (s, 3H), 1.32 (s, 9H). MS (FAB) [m + H] / z yield: 311, Detection: 311. Anal. Yield: C, 69.66; H, 5.85; Detection: C, 69.41; H, 5.98; N, 8.79.
[288]
[289] 3-iodo- [2- (trimethyl-silanyl) -ethoxymethyl] -lH-indazole was obtained in the same manner as in step (ii) of Example 10, Indazole (10.2 g, yield 81%): mp 58 [deg.] C. Analysis calculated: C, 37.24; H, 4.33; N, 10.02. Detection: C, 37.21; H, 4.38; N, 10.00.
[290]
[291] 6-nitro-3-iodide - [2- (trimethyl-chamber not) ethoxymethyl] -1H- indazole 11.0g (26.1 mmol), styryl boronic acid 4.64g (31.4mmol) and Pd (PPh _{3) 4} was added to a solution of toluene (192 mL), methanol (4 mL) and 2N NaOH (aqueous) (32.6 mL, 65.3 mmol) in an argon atmosphere. The heterogeneous mixture was heated to 90 &lt; 0 &gt; C. After 8 hours the solution was diluted with 150 mL of EtOAc and 50 mL of water, then phase separated and the organics were extracted with 2 x 50 mL EtOAc. The organic phase was washed with 50 ml of brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1: 9 EtOAc: Hexane) to give 6-nitro-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H- sol 7.65g (yield 74%) was ^{obtained: 13 C NMR (75MHz, CDCl} 3) δ148.3, 145.0, 141.3, 138.1, 134.2, 130.5, 129.9, 129.8, 129.5, 128.1, 127.4, 123.2, 119.8, 117.8, 108.2, 79.7, 68.5, 19.2, 0.0; MS (FAB) [M + Na] z Calculated: 418, Detected 418. Analysis calculated: C, 63.77; H, 6.37; Detection: C, 64.04; H, 6.29; N, 10.56.
[292]
[293] 8.1 g (20.5 mmol) of 6-nitro-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole were dissolved in 75 ml of DMF under an atmosphere of 23 deg. To the reaction mixture was added 12.9 g (67.7 mmol) of SnCl _2, 1.7 ml (92.2 mmol) of water was added, and the mixture was heated to 50 ° C. After 4 hours 45 ml (135 mmol) of 3N NaOH and 100 ml EtOAc were added in turn. The resulting emulsion was hot filtered through celite and the celite bed was then hot washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a solid. The crude product was purified by silica gel chromatography (2: 8, 7: 3 ethyl acetate: hexane) to obtain a yellow solid, 3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] 6-ylamine (yield: 68%). MS (FAB) [M + Na] / z yield: 366, detected 366.
[294]
[295] (3 mmol) of 3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-ylamine in 6 ml of toluene in an argon atmosphere, (0.13 mmol) of BINAP, 34 mg (0.0375 mmol) of Pd ₂ (dba) ₃ and 1.37 g (4.2 mmol) of Cs ₂ CO ₃ were added. The heterogeneous mixture was heated to 80 占 폚. After 46 h the solution was cooled to 23 [deg.] C and diluted with 20 mL of ethyl acetate (EtOAc) and filtered. 50 ml of water was added to separate the phases and the organic was extracted with 2x50 ml EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 9: 1 hexane: EtOAc) to give (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl- (KBr) 3391, 3059, 2952, 2894, 1614, 1530, 1483, 1346, 1248, 1076, 836, 734 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.86 (s, 1H), 7.83 (s, 1H), 7.65 (dt, 1H, J = 2.21, 5.13 Hz), 7.15-7.41 (m, 5H), 6.93 ( 2H), 3.51 (t, 2H, J = 8.17 Hz), 0.81 (t, 2H, J = 7.96 Hz), -0.15 (s, 9H) ; _{^{13 C NMR (75MHz, CDCl 3}} ) δ149.6, 144.8, 143.5, 142.4, 140.9, 137.3, 131.8, 130.3, 129.0, 128.2, 126.7, 122.8, 122.6, 120.1, 119.3, 116.1, 115.6, 111.4, 98.5, 77.9 , 66.7, 18.0, -1.2; MS (ESI) [M + H] / z yield: 487, detect 487. Anal. Yield: C, 66.64; H, 6.21; N, 11.51. Detection: C, 66.91; H, 6.21; N, 11.44.
[296]
[297] 434 mg (0.89 mmol) of (3-nitro-phenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] After cooling to -5 ° C in an argon atmosphere, 0.42 ml (4.5 mmol) of dimethyl sulfate and 1.8 ml (1.8 mmol) of LiHMDS (dissolved in THF at a concentration of 1 M) were added in turn. After 20 minutes, the reaction was cooled to 2 mL with saturated NH ₄ Cl (aqueous) and extracted with 3 x 20 mL EtOAc. The organic layer was washed with 10 ml of brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. Purification by silica gel chromatography (elution with 9: 1 hexanes: EtOAc) yielded the oil methyl- (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] (KBr) 2951, 2894, 1611, 1528, 1485, 1348, 1248, 1077 cm &lt; ^{-1 &} gt ;; _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.99 (d, 1H, J = 8.67 Hz), 7.77 (t, 1H, J = 2.25 Hz), 7.72 (dd, 1H, J = 0.79, 2.09 Hz), 7.60 (d, 2H, J = 7.22 Hz), 7.26-7.54 (m, 7H), 7.19 (dd, 1H, J = 0.78, 2.41 Hz), 7.07 s, 2H), 3.63 (t, 2H, J = 8.10 Hz), 3.48 (s, 3H), 0.92 (t, 2H, J = 8.10 Hz), -0.04 (s, 9H); _{^{13 C NMR (75MHz, CDCl 3}} ) δ150.2, 149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2, 126.8, 123.1, 122.6, 120.2, 120.0, 119.7, 114.4, 111.4, 104.5, 78.0 , 66.8, 41.1, 18.0, -1.2; LCMS (ESI) [M + H] / z yield: 501, detection 510.
[298]
[299] -Amine was prepared in accordance with the general method of example 11 step &lt; RTI ID = 0.0 &gt; (4-Methoxy- methyl-N- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol- 3-diamine. R _f sm 0.55, R _f p 0.31 (ethyl acetate: hexane 3: 7); FTR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.81 (d, 1H, J = 8.8 Hz), 7.58 (d, 2H, J = 7.21 Hz), 7.26-7.50 (m, 5H), 7.12 (t, 1H, J = 7.93 Hz), 7.01 (d, 1H, J = 1.73 Hz), 6.95 (dd, 1H, J = 1.99,8.85 Hz) , 3.38 (s, 3H), 0.93 (t, 2H, J = 8.13 Hz), -0.04 (s, 9H); _{^{13 C NMR (75MHz, CDCl 3}} ) δ150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3, 130.4, 128.9, 128.0, 126.7, 121.2, 120.6, 117.3, 117.0, 113.1, 110.1, 109.3, 97.5, 77.8 , 66.6, 41.0, 18.0, -1.2; LSMS (ESI) [m + H] / z evolution: 471, detection 471.
[300] Example 12 (a): N- {3- [Methyl- (3-styryl-lH-indazol-6-yl) -amino] -phenyl} -acetamide
[301]
[302] Methyl-N- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -Diamine (34 mg, 0.041 mmol) was suspended in 0.5 ml of CH ₂ Cl ₂ in an argon atmosphere at 23 ° C, followed by the addition of 81 μl (1.0 mmol) of pyridine, 94 μl of Ac ₂ O (1.0 mmol) and DMAP (cat.). The reactants immediately became homogeneous. After 1 hour, TLC analysis (CH ₂ Cl ₂ : EtOAc = 4: 1) showed that all the starting material was consumed. The reaction was quenched with 2 mL saturated NaHCO ₃ (aqueous) and diluted with 15 mL EtOAc, then the organic phase washed with 3 mL brine, taken up and concentrated under reduced pressure with oil. A suspension of ₂ ml of methanol and 83 mg (0.6 mmol) of K ₂ CO ₂ was added. The resulting mixture was stirred in an argon atmosphere at 23 &lt; 0 &gt; C. After 1 hour the reaction was diluted with 15 mL of EtOAc and the organic phase was washed with 3 mL of brine and concentrated under reduced pressure. The crude product was purified by semi-prep HPLC to give 8.4 mg (0.25 mmol) of N- {3- [methyl- (3-styryl- lH- indazol- 6-yl) -amino] -phenyl} Yield 22%). _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.86 (d, 1H, J = 8.68 Hz), 7.58 (d, 1H, J = 7.17 Hz), 7.16-7.45 (m, 7H), 7.15 (d, 1H, J = 8.29 Hz), 6.98 (m, 1H), 6.95 (d, 1H, J = 1.92 Hz), 6.8 (dd, 1H, J = 1.16, 8.05 Hz), 3.37 3H). LCMS (ESI) [M + H] / z analysis 383, detected 383. Analysis calculated: C, 75.37; H, 5.80; N, 14.65. Detection: C, 73.53; H, 6.01; N, 13.73.
[303] Example 12 (b): N- {3- [Methyl- (3-styryl-lH-indazol-6-yl) -amino] -phenyl} -benzamide
[304]
[305] Example 12 (b) was prepared in the same manner as in Example 12 (a), except that benzoyl chloride was used instead of acetic anhydride. LCMS (ESI) [M + H] / z analysis 475, detection 475. Anal. Yield: C (78.36), H (5.44), N (12.60). Detection: C (76.57), H (5.50), N (12.12).
[306] Example 12 (c): {3- [Methyl- (3-styryl-lH-indazol-6-yl) -amino] -phenyl} -carbamic acid benzyl ester
[307]
[308] Example 12 (c) was prepared in the same manner as in Example 12 (a) except that carbobenzoyloxychloride was used instead of acetic anhydride. R _f cm 0.30, R _f p 0.57 (CH ₂ Cl ₂ : EtOAc = 8: 2); LCMS (ESI +) [M + H] / z analysis 475, detection 475. Anal. Yield: C (75.93), H (5.52), N (11.81). Detection: C (75.60), H (5.96), N (10.75).
[309] Example 12 (d): 5-Methyl-thiazole-2-carboxylic acid {3- [methyl- (3-styryl-lH-indazol-
[310]
[311] (0.075 mmol) of the N-methyl-N- (3-styryl-1H-indazol-6-yl) (0.45 mmol) of carboxylic acid were dissolved in 0.375 ml of DMF under an atmosphere of 23 占 폚 argon and HATU (171 mg, 0.45 mmol) was added. After 1 hour, TLC analysis (CH ₂ Cl ₂ : EtOAc = 8: 2) showed that all the starting material was consumed. The reaction was quenched with 2 mL saturated NaHCO ₃ (aqueous), diluted with 15 mL EtOAc, and the organic phase was washed with 3 mL brine, followed by concentration under reduced pressure. To the oil was added ₂ mL of methanol and 62 mg (0.45 mmol) of K ₂ CO ₂ . The resulting mixture was stirred in an argon atmosphere at 23 &lt; 0 &gt; C. After 1 hour, TLC analysis (CH ₂ Cl ₂ : EtOAc = 8: 2) showed that all the starting material was consumed. The reaction was diluted with 15 mL of EtOAc and the organic phase was washed with 3 mL of brine and concentrated to a solid under reduced pressure. The crude product was purified by silica gel chromatography (eluted with CH ₂ Cl ₂ : EtOAc = 85: 15) and semi-prep HPLC to give 5-methyl-thiazole-2-carboxylic acid { - [methyl- (3-styryl-lH-indazol-6-yl) -amino] -phenyl} -amide 9.9 mg (28% yield). R _f sm 0.25, R _f p 0.39 (hexane: EtOAc = 8: 2); LCMS (ESI +) [M + H] / z analysis 466, detection 466. Analysis calculated: C (69.65), H (4.98), N (15.04), S (6.89). Detection: C (69.24), H (5.35), N (13.97), S (5.95).
[312] Example 13: N- [3- (3-Styryl-lH-indazol-6-ylamino) -phenyl] -benzamide
[313]
[314] 6-ylamino} -phenyl) -benzamide was prepared in the same manner as in Example 11, except for using the same procedure as in Example 11 to give N- (3- {3-trimethyl-silanyl) -ethoxymethyl] The title compound was prepared from N- [3- (3-styryl-lH-indazol-6-ylamino) -phenyl] -benzamide. LCMS (ESI) [M + H] / z analysis 431, detection 431. Anal. Yield: C, 78.12; H, 5.15; Detection: C, 77.06; H, 6.91; N, 9.88.
[315] The starting material was prepared as follows:
[316]
[317] (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol- } -Amine was prepared from N- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -ethanone in the same manner as in step (iv) -Benzene-1,3-diamine. LCMS (ESI) [M + H] &lt; &quot; &gt; z analysis 457, detection 457.
[318] (ii)
[319]
[320] 91 mg (0.2 mmol) of N- {3-styryl-1- [2- (trimethyl-silanyl) ethoxymethyl] (1.0 mmol) was dissolved in CH ₂ Cl ₂ , cooled to -5 ° C in an argon atmosphere, and 0.028 ml (0.24 mmol) of benzoyl chloride was added. After 0.5 h, the reaction was quenched with saturated NaHCO ₃ (aqueous) and extracted with ₂ x 5 mL of CH ₂ Cl ₂ . The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give an oil. The crude product was purified by silica gel chromatography (eluting with hexane: EtOAc = 3: 2) to give N- (3- {3-styryl-1- [2- (trimethyl- - indazol-6-ylamino} -phenyl) -benzamide (yield: 96%). R _f sm 0.35, R _f p 0.44 (ethyl acetate: hexane 1: 1); FTR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303, 1248, 1074 cm ^-1 ; LCMS (ESI) [M + H] / z analysis 561, found 561. Anal. Yield: C, 72.82; H, 6.47; N, 9.99. Detection: C, 72.33; H, 6.39; N, 9.81.
[321] Example 14: Methyl-phenyl- (3-styryl-lH-indazol-6-yl)
[322]
[323] Methyl-phenyl- {3-styryl- 1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -amine was prepared in analogy to example 11 from methyl- (3-styryl-lH-indazol-6-yl) -amine. MS (ESI) [M + H] &lt; + &gt; z analysis 326, detection 326.
[324] The starting material was prepared as follows:
[325]
[326] A solution of 1.58 g (4 mmol) of 3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-ylamine in 14 ml of AcOH, cooling the solution mixture to 1.67㎖ HCl in 2 ℃, and the mixture was added a solution prepared by dissolving NaNO ₂ 304mg (4.4mmol) in water for more than 5 minutes 0.5㎖. The dark red solution was stirred for 0.5 hour at 2 캜, and a solution prepared by dissolving 797 mg (4.8 mmol) of KI and 610 mg (2.4 mmol) of I _{2 in} 1 ml of water was added dropwise, and the internal temperature was kept below 5 캜. The reaction was carried out at 2 ° C for 2 hours and then at 23 ° C for 17 hours. The reaction was cooled with 3N NaOH (aqueous), diluted with 50 mL of EtOAc and H ₂ O (15 mL), phase separated and the aqueous solution was extracted with 2 x 15 mL of EtOAc. The organic phase was washed with ₃ x 20 mL of 5% NaHSO ₃ and brine (15 mL), dried over Na ₂ SO ₄ , concentrated and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with hexane: EtOAc = 1: 1) to give 6-iodo-3-styryl-1- [2- (trimethyl- silanyl) -ethoxymethyl] 1H-indazole (yield: 68%). _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.03 (s, 1H), 7.79 (d, 1H, J = 9.0 Hz), 7.30-7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, J = 6.0 Hz), 0.96 (t, 2H, J = 6.0 Hz), 0.0 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4, 119.6, 119.5, 92.9, 78.1, 66.9, 18.0, -1.2; Analysis calculated: C, 52.94; H, 5.29; N, 5.88. Detection: C, 52.66; H, 5.29; N, 5.74.
[327]
[328] Phenyl-3- {3- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole in the same manner as in step (v) -Styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -amine. R _f cm 0.35, R _f p 0.13 (EtOAc: hexane = 1: 9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303, 1248, 1212, 1076, 835, 694 cm ^-1 ; MS (ESI) [M + H] / z analysis 456, detection 456.
[329] Example 15: Preparation of N- [3- (2-benzo [1,3] dioxol-5-yl-vinyl) -lH-indazol-
[330]
[331] Yl] -methyl- (3-nitro-phenyl) -amine was converted to the title compound in step ( vinyl-1H-indazol-6-yl] -N-methyl-benzene-1,3- Diamine. LCMS (ESI) [M + H] / z analysis 385, detection 385. Anal. Yield: C, 71.86; H, 5.24; Detection: C, 70.99; H, 5.60; N, 13.80.
[332] The starting material was prepared as follows:
[333]
[334] In an argon atmosphere 23 ℃ 6-nitro-3-iodide - [2- (trimethyl-chamber not) ethoxymethyl] -1H- indazole 4.2g (10mmol), boronic acid 3.46g (15mmol) and Pd (PPh ₃ ) ₄ was dissolved in 38 ml of 1,4-dioxane and 12.5 ml (25 mmol) of 2N NaOH (aqueous solution). The resulting mixture was heated to 90 &lt; 0 &gt; C. After 2 h, the reaction was diluted with EtOAc (100 mL) and water (70 mL), and the organics were extracted with 2 x 100 mL of EtOAc. The organic phase was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with hexane: EtOAc = 9: 1) to give 3- (2-benzo [1,3] dioxol-5-yl- - [2- (trimethyl-silanyl) -eshmethyl] -1H-indazole in a yield of 94%. FTIR (thin film) 2950, 2898, 1523, 1501, 1483, 1446, 1344, 1249, 1080, 1043, 927 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.56 (dd, 1H, J = 0.68, 1.75 Hz), 8.14 (d, 1H, J = 1.78 Hz), 8.13 (d, 1H, J = 0.67 Hz), 7.50 (d, 1H, J = 1.67 Hz), 7.28 (d, IH, 16.52 Hz), 7.18 J = 8.0 Hz), 6.05 (s, 2H), 5.84 (s, 2H), 3.66 (t, 2H, J = 7.33 Hz), 0.97 ); _{^{13 C NMR (75MHz, CDCl 3}} ) δ148.5, 148.2, 147.0, 143.9, 140.1, 132.7, 131.3, 126.1, 122.3, 121.9, 116.7, 116.5, 108.7, 106.9, 105.7, 101.5, 78.4, 67.2, 17.9, - 1.3; LCMS (ESI) [M + H] &lt; + &gt; z analysis 531, detection 531.
[335]
[336] Vinyl] -6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was used in place of 3- (2-benzo [1,3] dioxol- 1- [2- (trimethyl-silanyl) -ethoxymethyl] -lH-pyrrolo [2,3-d] pyrimidine was obtained in the same manner as in [ Indazol-6-ylamine. ¹ H NMR (300 MHz, CDCl ₃ ) 7.73 (d, IH, J = 8.56 Hz), 7.52 (d, IH, J = 16.57 Hz), 7.18 (D, 1H, J = 1.49 Hz), 6.98 (dd, 1H, J = 1.52, 8.06 Hz), 6.80 (T, 2H, J = 8.33 Hz), 0.04 (t, 2H, J = (s, 9 H); ¹³ C NMR (75 MHz, CDCl ₃ ) 148.3, 147.6, 146.4, 143.4, 143.0, 132.0, 130.8, 122.0, 121.7, 118.8, 116.5, 1.3; LCMS (ESI) [M + H] / z analysis 410, detection 410.
[337]
[338] Vinyl] -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-ylamine was reacted with Yl) -vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] - (2-methyl- Yl} - (3-nitro-phenyl) -amine. ¹³ C NMR (75 MHz, CDCl ₃ ) 150.8, 149.7, 149.1, 146.0, 144.8, 143.6, 142.1, 133.1, 132.7, 131.6, 124.0, 123.8, 123.1, 120.4, 119.5, 117.2, 116.8, 112.6, 109.9, , 102.6, 99.7, 79.1, 67.9, 19.2, 0.0; MS (FAB) [M + H] / z analysis 531, found 531. Anal. Yield: C, 63.38; H, 5.70; N, 10.56. Detection: C, 63.49; H, 5.76; N, 10.42.
[339]
[340] Yl) -vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} - (3-nitro-phenyl) -amine was prepared in the same manner as in step (vi) of Example 11 using {3- (2-benzo [1,3] dioxol- Trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -methyl- (3-nitro-phenyl) -amine. FTIR (KBr) 2952, 2894, 1612, 1529, 1503, 1489, 1446, 1407, 1348, 1306, 1251, 1077, 1039 cm ^-1 ; _{^{13 C NMR (75MHz, CDCl 3}} ) δ150.1, 149.5, 148.4, 147.8, 147.0, 143.5, 142.4, 131.8, 131.5, 129.8, 123.0, 122.49, 121.9, 120.1, 119.5, 118.2, 114.3, 11.3, 108.7, 105.7 , 104.5, 101.4, 78.0, 66.8, 41.0, 17.9, -1.2; MS (FAB) [M + H] / z analysis 545, detection 545. Anal. Yield: C, 63.95; H, 5.92; N, 10.29. Detection: C, 62.63; H, 5.72; N, 9.62.
[341] (v)
[342]
[343] Ylmethyl) - ethoxymethyl] -1H-indazol-6-yl} -methyl (2-benzo [1,3] dioxol-5-yl- (3-nitro-phenyl) -amine was prepared in the same manner as in Example 11 from [3- (2-benzo [1,3] dioxol-5-yl- -Methyl (3-nitro-phenyl) -amine. LCMS (ESI) [M + H] / z analysis 415, detected 415. Analysis calculated: C, 66.66; H, 4.38; N, 13.52. Detection: C, 66.56; H, 4.48; N, 13.35.
[344] Example 16 (a): Preparation of N- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) Phenyl) -benzamide
[345]
[346] Vinyl-1H-indazol-6-yl] -N-methyl-benzene-1,3-diol obtained in Example 15, Diamine was prepared from N- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -Methyl-amino} -phenyl) -benzamide. &Lt; / RTI &gt; LCMS (ESI) [M + H] / z analysis 489, detection 489. Analysis calculated: C, 73.76; H, 4.95; N, 11.47. Detection: C, 73.19; H, 5.09; N, 11.20.
[347] 6-yl] -methyl-amino} - (2-methylsulfanyl) -piperazin-1- Phenyl) -3-methyl-benzamide
[348]
[349] Example 16 (b) was prepared in the same manner as in Example 16 (a), except that m-toluyl chloride was used in place of benzoyl chloride. LCMS (ESI) [M + H] / z analysis 504, detected 504. Analysis calculated: C, 74.09; H, 5.21; N, 11.15. Detection: C, 73.04; H, 5.84; N, 10.29.
[350] 6-yl] -methyl-amino} - (2-methyl-pyridin-2-ylamino) Phenyl) -3-dimethylamino-benzamide
[351]
[352] Example 16 (c) was prepared in the same manner as in Example 16 (a), except that m-dimethylaminobenzoyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M + H] / z analysis 532, detection 532. Anal. Yield: C, 72.30; H, 5.50; N, 13.17. Detection: C, 71.61; H, 5.80; N, 12.75.
[353] 6-yl] -methyl-amino} - (2-methylsulfanyl) -piperazin-1- Phenyl) -3-trifluoromethyl-benzamide &lt; / RTI &gt;
[354]
[355] Example 16 (d) was prepared in the same manner as in Example 16 (a) above except that m-trifluorobenzoyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M + H] / z analysis 557, found 557. Anal. Yield: C, 66.90; H, 4.17; Detection: C, 66.64; H, 4.34; N, 9.82.
[356] Example 16 (e): 3-Acetyl-N- (3 - {[3- (2-benzo [1,3] dioxol-5-yl- -Amino} -phenyl) -benzamide &lt; / RTI &gt;
[357]
[358] Example 16 (e) was prepared in the same manner as in Example 16 (a) above except that m-acetylbenzoyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M + H] / z analysis 531, found 531. Anal. Yield: C, 72.44; H, 4.94; N, 10.56. Detection: C, 55.51; H, 4.21; N, 7.58.
[359] Example 16 (f) Synthesis of 6- [N- (3- (4-tert-butyl-3-hydroxybenzamido) phenyl) Dioxyphenyl) ethenyl] -1H-indazole
[360]
[361] Example 16 (f) was prepared in the same manner as in Example 16 (a), except that 3-tert-butyl-4-hydroxy-benzoic acid, HATU and TEA were used instead of benzoyl chloride. _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.90 (d, 1H, J = 8.91 Hz), 7.83 (d, 1H, J = 2.29 Hz), 7.63 (dd, 1H, J = 8.36, J = 2.31 Hz ), 7.54 (t, IH, J = 1.97 Hz), 7.25-7.43 (m, 4H), 7.14-7.20 (m, 2H), 7.06 (dd, 1H, J = 8.11 Hz, J = 1.55 Hz) (d, 1H, J = 8.93 Hz, J = 1.97 Hz), 6.90 (m, 1H), 6.82 (t, 2H, J = 8.18 Hz), 6.0 (s, 9 H).
[362] Example 17: Phenyl- (3-styryl-lH-indazol-6-yl) -methanone
[363]
[364] Yl) -methanone was reacted with phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] (ESI) [M + H] / z yield 325, detection 325. Analytical calculation: C, &lt; RTI ID = 0.0 &gt;81.46; H, 4.97; N, 8.46 Detection: C, 80.36; H, 5.16; N, 8.51.
[365] The starting material was prepared in the following manner:
[366] (i)
[367]
[368] 143 mg (0.3 mmol) of the 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole prepared in step (i) The solution in 1 mL of THF was cooled to -78 ° C under an argon atmosphere and 0.2 mL (0.315 mmol) of n-BuLi was added dropwise. The mixture was stirred at -78 ° C for 30 minutes, and then a solution of 0.035 ml (0.33 mmol) of benzaldehyde dissolved in 0.5 ml of THF was rapidly added via a cannula. After 0.5 h, the reaction solution was cooled with saturated NH ₄ Cl (aq) and diluted with 10 mL of EtOAc and 3 mL of H ₂ O. After phase separation, the aqueous solution was extracted with 2x10 ml of EtOAc. The residual EtOAc was washed with 5 ml of brine and dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with hexane: EtOAc = 4: 1) to give phenyl- {3-styryl-1- [2- (trimethyl- silanyl) -ethoxymethyl] -6-yl} -methanol (yield 50%). R f sm = 0.72; R f p = 0.39 (hexane: EtOAc = 7: 3); FTIR ( thin film) 3368, 2952, 2893, 1621 , 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835㎝ -1. MS (ESI) [M + H] / z yield 457, detected 457.
[369]
[370] To a solution of phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -methanol in 0.1 ml of dichloromethane (Dess-Martin reagent) 190 mg (0.45 mmol) was added. After the mixture was stirred at 23 DEG C for 1 hour, the solution was diluted with 3 mL of hexane, diluted with Celite, and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluted with hexane: EtOAc = 9: 1) to give phenyl- {3-styryl-1- [2- (trimethyl- silanyl) -ethoxymethyl] 6-yl} -methanone (yield: 79%). R f sm = 0.41; Rf p = 0.63 (hexane: EtOAc = 7: 3); FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm ^-1 . MS (ESI) [M + H] / z yield 455, detected 455.
[371] Example 18: (3-Amino-phenyl) - (3-styryl-lH-indazol-
[372]
[373] (3-amino-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl- ethoxymethyl] -1 H- indazol- ¹ H NMR (300 MHz, CDCl ₃ ): 8.07 (dd, 1H, J), was prepared in accordance with the general method of 2H), 7.46 (d, 2H, J = 12.84 Hz), 7.35 (d, 1H, J = (M, 2H), 7.16-7.13 (m, 2H), 6.91 (ddd, 1H, J = 1.08, 7.89 Hz). LCMS (ESI) z output 340, detection 340.
[374] The starting material was prepared in the following manner:
[375]
[376] Iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -lH-indazol-6-yl} -methanol was prepared in a manner similar to that of Example 17, step (i) (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -methanone. R f sm = 0.71; R f p = 0.25 (hexane: EtOAc = 7: 3); FTIR ( thin film) 3369, 3061, 2952, 2894, 2361, 1620, 1578, 1530, 1478, 1449, 1350, 1308, 1249, 1215, 1080, 961 , 859 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.35 (s, 1H), 8.14 (dd, 1H, J = 1.34, 8.14 Hz), 7.99 (d, 1H, J = 8.38 Hz), 7.76 (d, 1H 1H, J = 7.72 Hz), 7.68 (s, 1H), 7.59-7.30 (m, 8H), 7.21 , 2H, J = 8.30 Hz), 0.90 (t, 2H, J = 8.30 Hz), -0.06 (s, 9H). ^{13 C NMR (75 MHz, CDCl} 3) δ148.5, 145.9, 143.4, 142.4, 141.3, 137.1, 132.7, 132.0, 129.5, 128.9, 128.2, 126.7, 122.6, 122.6, 121.8,121.5, 120.8, 119.6, 107.8, 77.7, 75.4, 66.8, 17.8, -1.3. Analysis calculated: C, 67.04; H, 6.23; N, 8.38. Detection: C, 66.93; H, 6.20; N, 8.41.
[377]
[378] (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol- Yl} -methanol was transformed into (3-nitro-phenyl) - {3-styryl-l- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol- (129 mg, 91%). R f sm = 0.46; Rf = 0.23 (hexane: EtOAc = 7: 3); FTIR (thin film) 3082, 2952, 2894, 1665, 1613, 1532, 1476, 1349, 1298, 1250, 1080, 836, 718 cm ^-1 . LCMS (ESI) [M + H] / z yield 500, detection 500.
[379]
[380] (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H- Yl} -methanone with (3-amino-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol- (102 mg, 84%). LCMS (ESI) [M + H] / z yield 340, detection 340.
[381] Example 19 (a): N- [3- (3-Styryl-lH-indazole-6- carbonyl) -phenyl] -acetamide
[382]
[383] (3-amino-phenyl) - (3-styryl-1H-indazol-6-yl) -methanone prepared in Example 18 was reacted with N- [3- -Styryl-lH-indazole-6-carbonyl) -phenyl] -acetamide (12.2 mg, 78%). R f = 0.16, R f p = 0.35 (CH ₂ Cl ₂ : EtOAc = 8: 2); LCMS (ESI) [M + H] / z yield 382, detect 382. Anal. Yield: C, 75.57; H, 5.02; N, 11.02. Detection: C, 74.32; H, 5.41; N, 10.54.
[384] Example 19 (b): N- [3- (3-Styryl-lH-indazole-6- carbonyl) -phenyl] -benzamide
[385]
[386] Example 19 (b) was prepared in the same manner as in Example 19 (a) except that benzoyl chloride was used instead of acetic anhydride. _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.40 (s, 1H), 8.02 (d, 1H, J = 8.49 Hz), 7.98 (d, 1H, J = 1.01 Hz), 7.95 (s, 1H), 7.95 (s, 1H), 7.83-7.88 (m, 3H), 7.65 (dd, 1H, J = 1.04, 8.48 Hz), 7.29-7.56 (m, 11H). MS (ESI) [M + H] / z yield 444, detected 444. Analysis calculated: C, 78.54; H, 4.77; N, 9.47. Detection: C, 78.01; H, 4.87; N, 9.32.
[387] Example 19 (c): [3- (3-Styryl-lH-indazole-6-carbonyl) -phenyl] -carbamic acid benzyl ester
[388]
[389] Example 19 (c) was prepared in the same manner as in Example 19 (a) except that carboxybenzyloxy chloride was used instead of acetic anhydride. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.37 (d, 1H, J = 8.48 Hz), 7.98 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d , 7.41 (d, 2H, J = 7.44 Hz), 7.61 (d, 2H, J = 1.81 Hz), 7.58 ), 7.31-7.37 (m, 4H), 5.16 (s, 2H); LCMS (ESI) [M + H] / z yield 474, detected 474. Analysis calculated: C, 76.09; H, 4.90; N, 8.87. Detection: C, 73.82; H, 4.93; N, 8.27.
[390] Example 19 (d): 5-Methyl-thiazole-2-carboxylic acid [3- (3-styryl-lH-indazole-6- carbonyl) -phenyl]
[391]
[392] (3-amino-phenyl) - (3-styryl-1H-indazol-6-yl) -methanone was reacted with 5-methyl-thiazole- (3-styryl-lH-indazole-6-carbonyl) -phenyl] -amide. ¹ H NMR (300 MHz, CDCl ₃ ): 8.15 (d, IH, J = 8.49 Hz), 8.09 2H), 7.50-7.58 (m, 3H), 7.50 (d, 1H), 7.75 (d, 1H, J = s, 1 H), 7.42 (t, 3H, J = 8.09 Hz); LCMS (ESI) [M + H] / z yield 456, detection 456.
[393] Example 19 (e): 6- [3- (5-Methylpyridin-3-ylcarboxamido) benzoyl] -3-E-
[394]
[395] Example 19 (e) was prepared in the same manner as in Example 19 (d) except that 5-methyl-thiazole-2-carboxylic acid was used instead of 5-methyl-nicotinic acid. _{^{1 H NMR (300MHz, CDCl 3}} ): δ9.22 (s, 1H), 8.99 (d, 1H, J = 0.59 Hz), 8.67 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H J = 8.32 Hz), 2.97 (dd, 1H, J = 8.3 Hz, J = 0.94 Hz), 7.72 (d, 1H, J = 16.65 Hz), 7.64 7.47 (m, 8H), 6.95 (d, 1H, J = 6.43 Hz), 2.49 (s, 3H). MS (ESI +) [M + H] / z yield 459, detect 459. Anal. Yield: C, 75.97; H, 4.84; N, 12.22. Detection: C, 75.86; H, 4.94; N, 12.10.
[396] Example 19 (f): 6- [3- (Indol-4-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole
[397]
[398] Example 19 (f) was prepared in the same manner as in Example 19 (d), except that 1H-indole-4-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. LCMS (ESI +) [M + H] / z yield 483, detection 483. Anal. Yield: C, 77.16; H, 4.60; N, 11.61. Detection: C, 76.15; H, 4.49; N, 11.31.
[399] Example 19 (g): 6- [3- (Pyridin-2-ylacetamido) benzoyl] -3-E-styryl-1H-indazole
[400]
[401] Example 19 (g) was prepared in the same manner as in Example 19 (d) except that pyridin-2-yl-acetic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.50 (dd, 1H, J = 4.86 Hz, J = 0.91 Hz), 8.37 (d, 1H, J = 8.51 Hz), 8.09 (s, 1H), 7.94 ( d, 1H, J = 7.89Hz), 7.87 (s, 1H), 7.73-7.79 (m, 3H), 7.25-7.60 (m, 10H), 3.86 (s, 2H). MS (ESI) [M + H] / z yield 459, detect 459. Anal. Yield: C, 75.97; H, 4.84; N, 12.22. Detection: C, 74.70; H, 4.83; N, 11.99.
[402] Example 19 (h): 6- [3- (2-Methylpropionamido) benzoyl] -3-E-styryl-1H-indazole
[403]
[404] Example 19 (h) was prepared in the same manner as in Example 19 (a) except that isobutyryl chloride was used instead of acetyl chloride. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.38 (d, 1H, J = 8.13 Hz), 8.08 (t, 1H), 7.96 (s, 1H, J = 7.8 Hz, J = 1.91 Hz), 1H), 7.60 (d, 2H, J = 7.25 Hz), 7.61 (d, , J = 6.82 Hz), 1.1 (d, 6H, J = 6.82 Hz). MS (ESI +) [M + Na] / z yield 432, found 432. Anal. Yield: C, 76.26; H, 5.66; Detection: C, 75.14; H, 5.62; N, 10.08.
[405] Example 19 (i): 6- [3- (2-Acetamido-2-phenylacetamido) benzoyl] -3-E-styryl-1H-indazole
[406]
[407] Example 19 (i) was prepared in the same manner as in Example 19 (d) but using acetylamino-2-phenyl-acetic acid instead of 5-methyl-thiazole-2-carboxylic acid. ¹ H NMR (300 MHz, DMSO-d ₆ ): 13.5 (s, IH), 10.6 (s, IH), 8.66 (d, IH, J = 7.66 Hz), 8.36 ), 8.07 (s, 1H), 7.92 (d, 1H, J = 7.63 Hz), 7.86 (s, 1H), 7.75 (d, 2H, J = 7.33 Hz), 7.29-7.60 (d, 1 H, J = 7.6 Hz), 1.92 (s, 3H). LCMS (ESI +) [M + H] / z yield 515, detect 515. Anal. Yield: C, 74.69; H, 5.09; N, 10.89. Detection: C, 73.01; H, 5.01; N, 10.60.
[408] Example 19 (j): 6- [3- (Pyridin-4-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole
[409]
[410] Example 19 (j) was prepared in the same manner as in Example 19 (d) except that isonicotinic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. Calculated: C, 75.66; H, 4.54; N, 12.60. MS (ESI +) [M + Na] Detection: C, 74.17; H, 4.62; N, 12.31.
[411] Example 19 (k): Synthesis of 6- [3- (pyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole
[412]
[413] Example 19 (k) was prepared in the same manner as in Example 19 (d) except that pyridine-2-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. Calculated: C, 75.66; H, 4.54; N, 12.60. MS (ESI +) [M + Na] Detection: C, 74.17; H, 4.61; N, 12.44.
[414] Example 19 (l): 6- [3- (isoxazol-4-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole
[415]
[416] Example 19 (1) was prepared in the same manner as in Example 19 (d) except that isoxazole-5-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI +) [M + H] / z yield 435, detect 435. Anal. Yield: C, 71.88; H, 4.18; Detection: C, 71.36; H, 4.33; N, 12.47.
[417] Example 19 (m): 6- [3- (6-Chloropyridin-2-ylacetamido) benzoyl] -3-E-styryl-1H-indazole
[418]
[419] Example 19 (m) was prepared in the manner analogous to Example 19 (d), but using 6-chloro-pyridine-2-carboxylic acid instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI &lt; + &gt;) [M + Na] / z yield 501, detection 501.
[420] Example 19 (n): 6- [3- (4-Chloropyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole
[421]
[422] Example 19 (n) was prepared in the same manner as in Example 19 (d) except that 4-chloro-pyridine-2-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI &lt; + &gt;) [M + H] / z yield 479, detection 479. Analysis calculated: C, 70.22; H, 4.00; Detection: C, 70.07; H, 4.09; N, 11.64.
[423] Example 19 (o): 6- [3- (2-Chloropyridin-4-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole
[424]
[425] Example 19 (o) was prepared in the same manner as in Example 19 (d) except that 2-chloro-isonicotinic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI &lt; + &gt;) [M + H] / z yield 479, detected 479.
[426] Example 19 (p): 6- [3- (2-Methylamino-2-phenylacetamido) benzoyl] -3-E-styryl-1H-indazole
[427]
[428] 6 in _{CH 2 Cl 2 2㎖ [3- (} 2-Nt- butoxycarbonyl -N- methylamino) -2-phenyl-acetamido) benzoyl] -3-E- styryl -1H- indazole 115 mg (0.2 mmol) of tetrabutylammonium bromide was dissolved and cooled to 0 deg. C, and 2 ml of TFA was added. After 40 min, the reaction mixture was cooled with saturated NaHCO ₃ (aq) and extracted with CH ₂ Cl ₂ ( ₂ x 10 mL). The organic was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo, and then purified by silica gel chromatography (methanol: dichloromethane = 1: 10) to give 6- [3- Amide) benzoyl] -3-E-styryl-1H-indazole in a yield of 39%. MS (ESI +) [M + H] / z yield 487, detection 487. Anal. Yield: C, 76.52; H, 5.39; N, 11.51. Detection: C, 74.99; H, 5.76; N, 10.89.
[429] The starting material was prepared in the same manner as:
[430] (i) Synthesis of 6- [3- (2- (N-t-butoxycarbonyl-N-methylamino) -2-phenyl-acetamido) benzoyl]
[431]
[432] Benzoyl] -3-E-styryl-lH-indazole was prepared by the same method as described for the synthesis of 5- [3- (2- (Nt-butoxycarbonyl- (D) except that (t-butoxycarbonyl-methyl-amino) -phenyl-acetic acid was used in place of the sol-2-carboxylic acid. MS (ESI &lt; + &gt;) [M + H] / z yield 587, detected 587.
[433] Example 20 (a): 6- (3-Acetamino-phenylsulfanyl) -3-styryl-lH-indazole
[434]
[435] (3-acetamino-phenylsulfanyl) -3-styryl-1H-indazole was prepared by the same procedure for the example 11 with 6- (30 mg, 81%): R f sm = 0.65, R f p = 0.35 (containing 10% methanol in dichloromethane); _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.81 (d, 1H, J = 8.5 Hz), 7.59 (bs, 1H), 7.48-7.0 (m, 13H), 1.98 (s, 3H); HRMS (FAB) [M + Na] / z yield 408.1147, detection 408.1156.
[436] The starting material was prepared as follows:
[437]
[438] To the 9-BBN adduct of 3-phthalamido-thiophenol (1.4 equiv.) Prepared in the same manner as described below, 3.0 ml of 3,6-diiodo-1- [2- (trimethyl-silanyl) - (0.2 equiv) of Pd (dppf) Cl ₂ and 339 mg (1.6 mmol, 3.00 equiv) of potassium phosphate was added to the solution. The reaction mixture was heated at 90 &lt; 0 &gt; C for 9 hours, then cooled and then partitioned into ethyl acetate and saturated sodium bicarbonate. The organic material was dried in the presence of sodium sulfate, concentrated and then purified by silica gel chromatography (ethyl acetate: hexane = 2: 8) to obtain the oil 6- (3-phthalamido-phenylsulfanyl) -1H- indazole 159mg (yield 50%) was ^{obtained: 1 H NMR (300MHz, CDCl} 3): δ7.93 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.5-7.3 (m, 5H), 7.22 (d, 1H), 5.68 (s, 2H), 3.55 (t, 2H, J = 8.2 Hz), 0.87 (t, 2H, J = 8.2 Hz) ); HRMS (FAB) [M + Cs] / z yield 759.9563, detection 759.9571.
[439] The boron reagent was prepared as follows: 1.6 ml (1.0 equiv.) Of a solution of 3-phthalamido-thiophene in a 10 ml Schlenk flask followed by drying under high vacuum and then dissolving 9-BBN in 0.5 M THF, Was added. The mixture was heated at 55 &lt; 0 &gt; C for 2 hours. The volatiles were removed under argon steam at 70 &lt; 0 &gt; C for 1.5 h and the residue was used as is without further manipulation.
[440] (ii)
[441]
[442] (3-phthalamido-phenylsulfanyl) -3-iodo-1H-indazole was synthesized in the same manner as in step (iii) -Styryl-1H-indazole. ¹ H NMR (300 MHz, CDCl ₃ ): 7.93 (m, 3H), 7.78 (m, 2H), 7.7 (s, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.89 (t, 2H, J = 8.2 Hz), -0.06 (s, 9H); HRMS (FAB) [M + Cs] / z yield 736.1066, detect 736.1058.
[443]
[444] 63 mmol (2.0 mmol, 10 equiv) of hydrazine was added to a solution of 121 mg (0.2 mmol) of 6- (3-phthalamido-phenylsulfanyl) -3-styryl-1H-indazole dissolved in 3.5 ml of ethanol. The reaction mixture was stirred at 23 &lt; 0 &gt; C for 45 min and then diluted with saturated sodium bicarbonate and ethyl acetate. The organic material was dried by adding sodium sulfate, followed by concentrating, followed by purification with silica gel chromatography (ethyl acetate: hexane = 3: 7) to obtain an oil 6- (3-aminophenylsulfanyl) (Yield: 90%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.92 (d, IH, J = 8.5 Hz), 7.57 (m, 3H), 7.49 ), 7.23 (dd, 1H, J = 1.5,5.5 Hz), 7.11 (t, 1H, J = 7.9 Hz), 6.79 (m, 2H), 3.60 (bs, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), 0.05 (s, 9H); HRMS (FAB) [M + H] / z yield 474.2035, detection 474.2019.
[445]
[446] (1.0 mmol, 10 equiv) of pyridine and 47 占 퐇 of acetic anhydride were added to a solution of 43.7 mg (0.10 mmol) of 6- (3-aminophenylsulfanyl) -3-styryl-1H-indazole in 0.5 ml of dichloromethane. (0.5 mmol, 5 equiv). The mixture was stirred at 23 &lt; 0 &gt; C for 10 min, then diluted with water, and the product was washed with 30% hexane in ethyl acetate. The organic material was dried by adding 5% citric acid and saturated sodium bicarbonate, followed by concentrating, followed by purification with silica gel chromatography (ethyl acetate: hexane = 3: 7) to obtain an oil 6- (3-acetamido- 3-styryl-1H-indazole (yield: 97%). R _f sm 0.33, R _f p 0.18 (ethyl acetate: hexane = 3: 7); _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s, 2H), 3.62 (t, 2H, J = 8.2 Hz), 2.18 (s , 3H), 0.93 (t, 2H, J = 8.2 Hz), -0.05 (s, 9H). HRMS (FAB) [M + Cs] / z yield 648.1117, detection 648.1098.
[447] Example 20 (b): 6- (3- (Benzoylamido) -phenylsulfanyl) -3-styryl-lH-indazole
[448]
[449] (3- (benzoylamido) -phenylsulfanyl) -3-styryl-1H-indazole was used in place of benzoyl chloride instead of acetic anhydride in step (iv) of Example 20 (a) Prepared in a similar manner to Example 20 (a). FTIR (thin film) 3385, 3169, 2953, 1621, 1581, 1489, 1447, 1349, 1251, 1165, 1071, 959, 906, 870, 817 cm ^-1 . _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.03 (s, 1H), 7.73 (d, 1H, J = 8.5 Hz), 7.63 (m, 2H), 7.47 (m, 1H), 7.42 (t, 1H , J = 1.9Hz), 7.37 (m, 3H), 7.31 (m, 1H), 7.28-6.98 (m, 9H); HRMS (FAB) [M + H] / z yield 448.1484, detection 448.1490.
[450] Example 21: Synthesis of 6- (1- (3-aminophenyl) -vinyl) -3-styryl-1H-indazole
[451]
[452] 1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was prepared in the same manner as in Example 11, except for using 2- To give 6- (1- (3-aminophenyl) -vinyl) -3-styryl-1H-indazole (85 mg, 85% _f sm 0.72, p 0.37 (ethyl acetate: hexane = 1: 1);^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃2H), 7.51 (s, 1H), 7.48 (s, 1H), 7.40 (m, 3H), 7.29 (m, 2H) , 7.15 (m, IH), 6.78 (m, IH), 6.68 (m, 2H), 5.50 (s, 2H), 3.65 (bs, 2H); MS (ES) [M + H] / z yield 338, detected 338; MS (ES) [M-H] / z yield 336, detected 336.
[453] The starting material was prepared in the same manner as:
[454]
[455] 330 mg (0.693 mmol) of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1 H- indazole prepared in step (i) In THF (3.0 mL) was added 0.56 mL (1.5 M, 1.2 equiv) of n-butyl lithium. After 20 minutes, 170 mg of anhydrous zinc chloride was added to the solution, and the mixture was heated to 23 DEG C and stirred for 15 minutes. 1- (3-nitrophenyl) to the mixture of the vinyl triflate 146㎕ (1.05 equiv) and _{Pd (PPh 3) 4 40mg (} 0.05 equiv) was added. The mixture was stirred for 30 minutes and then partitioned into ethyl acetate and saturated sodium bicarbonate, and the organic layer was separated. The organics were dried in the presence of sodium sulfate, concentrated and then purified by silica gel chromatography (ethyl acetate: hexane = 1: 9) and then purified on a second column (1% ethyl acetate / -Nitrophenyl) -vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole in a yield of 52%. FTIR (thin film) 2951, 1616, 1530, 1477, 1488, 1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.26 (t, 1H, J = 1.9 Hz), 8.21 (m, 1H), 8.00 (d, 1H, J = 8.5 Hz), 7.69 (dt, 1H, J 1H), 3.60 (t, 2H, &lt; RTI ID = 0.0 &gt; J = 8.2 Hz), 0.89 (t, 2H, J = 8.2 Hz), -0.05 (s, 9H); _{^{13 C NMR (75MHz, CDCl 3}} ) δ149.9, 149.6, 144.7, 144.5, 142.8, 140.7, 138.6, 135.6, 133.1, 130.7, 130.2, 129.4, 128.0, 124.4, 124.2, 124.1, 123.8, 122.6, 121.2, 118.9 , 111.0, 79.2, 68.0, 19.2, 0.0; HRMS (FAB) [M + Na] / z yield 520.2031, detection 520.2046.
[456]
[457] The title compound was prepared in accordance with the general method of example 11 step (iv) from 6- (1- (3-nitrophenyl) -vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] ) To give 6- (1- (3-aminophenyl) -vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole (140 mg, 95%): Rf cm 0.59, p = 0.46 (ethyl acetate: hexane = 4: 6); FTIR (thin film) 3460, 3366, 3223, 3084, 3028, 2952, 2894, 2246, 1616, 1601, 1581, 1489, 1474, 1448, 1359, 1303, 1249, 1217, 1076, 961, 909, 860, 836, 733, 692 cm &lt; ^{-1 &} gt ;; _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.96 (d, 1H, J = 8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (m, 2H ), 7.30 (m, IH), 7.25 (m, IH), 7.14 (m, IH), 6.77 (m, IH), 6.68 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 151.6, 147.7, 144.6, 143.9, 142.8, 142.4, 138.6, 132.8, 130.6, 130.2, 129.3, 128.0, 124.4, 123.6, 121.9, 121.5, 120.2, 116.4, 116.1, 110.8, 79.0, 67.9, 19.2, 0.0; HRMS (FAB) [M + Na] / z yield 490.2291, detection 490.2302.
[458] Example 22 (a): 6- (1- (3- (5-Methyl-thiazole-2-carboxyamido) -phenyl) -vinyl)
[459]
[460] The procedure of Example 12 (d) was repeated except that 6- (1- (3-aminophenyl) -vinyl) -3-styryl- Vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was obtained (20 mg, 72%); FTIR (thin film) 3271, 1673, 1605, 1585, 1538, 1486, 1428, 1349, 1304, 1090, 960, 907, 871 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ): δ10.7 (bs, 1H), 9.09 (s, 1H), 8.0 (d, 1H), 7.79 (m, 1H), 7.60 (m, 3H), 7.51 (m , 3H), 7.44-7. 15 (m, 7H), 5.59 (s, 2H), 2.54 (s, 3H); _{^{13 C NMR (75MHz, CDCl 3}} ): δ162.2, 157.9, 149.8, 144.4, 142.8, 142.2, 141.9, 141.5, 140.6, 137.63, 137.56, 131.6, 129.5, 129.1, 128.3, 126.9, 125.1, 122.6, 121.2, 120.9, 120.5, 120.2, 119.8, 116.1, 110.2, 12.8; HRMS (FAB) [M + H] / z yield 463.1593, detected 463.1582.
[461] Example 22 (b): 6- (1- (3- (Benzoylamido) -phenyl) -vinyl) -3-styryl-lH-indazole
[462]
[463] Example 22 (b) was performed in the same manner as in Example 22 (a) except that benzoyl chloride was used instead of 5-methyl-thiazole-2-carboxylic acid and HATU; FTIR (thin film) 3243, 1651, 1606, 1580, 1538, 1485, 1447, 1428, 1349, 1307, 1258, 1073, 959, 907 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ): 9.09 (s, 1H), 7.99 (d, 1H, J = 8.5 Hz), 7.78 (m, ), 7.43-7.15 (m, 10H), 5.56 (d, 2H, J = 3.2 Hz); _{^{13 C NMR (75MHz, CDCl 3}} ): δ166.5, 149.7, 144.3, 142.7, 142.1, 140.6, 138.1, 137.6, 135.0, 132.3, 131.6, 129.4, 129.1, 128.3, 127.4, 126.9, 125.0, 122.5, 120.9, 120.8, 120.6, 120.5, 115.9, 110.2; HRMS (FAB) [M + H] / z yield 442.1919, detected 442.1919.
[464] Example 22 (c): 6- (1- (3- (Benzoylamido) -phenyl) -vinyl) -3-styryl-lH-indazole
[465]
[466] Example 22 (c) was carried out in the same manner as in Example 22 (a) except that carbobenzyloxychloride was used instead of 5-methyl-thiazole-2-carboxylic acid and HATU; FTIR (thin film) 3305, 1712, 1606, 1586, 1537, 1487, 1445, 1348, 1216, 1059, 959, 908 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ): 7.99 (d, 1H, J = 8.5 Hz), 7.6-7.0 (m, 18H), 5.55 (s, 2H), 5.19 (s, 2H); _{^{13 C NMR (75MHz, CDCl 3}} ): δ153.9, 149.8, 144.3, 142.7, 142.1, 140.7, 138.2, 137.6, 136.3, 131.7, 129.4, 129.1, 129.0, 128.7, 128.7,128.3, 126.9, 124.0, 122.6, 121.1, 120.8, 120.4, 115.9, 110.1, 67.4; HRMS (FAB) [M + H] / z yield 472.025, detection 472.2026.
[467] Example 23: 6- (1- (3-Acetamido-phenyl) -vinyl) -3-styryl-lH-indazole
[468]
[469] 3-styryl-1- [2-trimethylsilanyl-ethoxymethyl] -1H-indazole was prepared by the same method as in Example 11, except that 6 (1- (3-acetamido- - (1- (3-acetamido-phenyl) -vinyl) -3-styryl-1H-indazole; FTIR (thin film) 3252, 1667, 1606, 1557, 1486 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ): δ10.4 (bs, 1H), 7.91 (d, 1H, J = 8.5 Hz), 7.5-7.0 (m, 13H), 5.47 (s, 2H), 2.10 (s , 3H); [MH] / z yield 378, detected 378. MS (ES) [M + H] / z yield 380, detection 380;
[470] The starting material was prepared in the following manner:
[471]
[472] Trimethylsilanylethoxymethyl] -1H-indazole was prepared by the same method as in Example 12 (a), except that 6 (1- (3-aminophenyl) - (1- (3-acetamido-phenyl) -vinyl) -3-styryl-1- [2-trimethylsilanylethoxymethyl] -1H-indazole; R _f sm 0.42, p 0.26 (ethyl acetate: hexane = 4: 6); FTIR (thin film) 3305, 3059, 2952, 1667, 1608, 1585, 1555, 1486, 1448, 1433, 1369, 1306, 1249, 1076, 912, 859, 836, 748,^-One;^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃J = 8.5 Hz), 7.7-7.4 (m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, J = 7.8 Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 t, 2H, J = 8.2 Hz), -0.02 (s, 9H);¹³C NMR (75 MHz, CDCl3₃): δ 169.8, 150.9, 144.6, 143.5, 142.8, 142.0, 139.4, 138.6, 132.9, 130.3, 129.3, 127.9, 125.6, 124.2, 123.7, 122.0, 121.3, 121.0, 117.1, 110.8, 68.0, 25.8, 19.1, 0.0; HRMS (FAB) [M + Na] / z yield 532.2396, detected 532.2410.
[473] Example 24 (a): 4- [3- (1-H-Benzoimidazol-2-yl) -1H-indazol-6-yl] -2- methoxy-
[474]
[475] Phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] - (2-methoxy- 326 mg (0.43 mmol) of 3- {1- [2- (trimethyl-silanyl) ethoxymethyl] -1-H-indazole was dissolved in 4.5 ml of TBAF (1 M concentration in THF, ) And 0.6 ml (8.9 mmol) of ethylenediamine were mixed and refluxed for 40 hours. The reaction solution was diluted with ethyl acetate / THF (40 mL / 5 mL) and washed with H ₂ O (20 mL) and brine (20 mL). The organics were dried (MgSO ₄ ), concentrated in vacuo and purified by silica gel chromatography (60% THF / hexanes) and then precipitated with chloroform to give 4- [3- (1-H-benzoimidazol- -Yl) -1H-indazol-6-yl] -2-methoxy-5-methyl-phenol as a colorless oil. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.62 (s, 1H), 13.05 (br s, 1H), 9.01 (s, 1H), 8.50 (d, 1H, J = 8.4 Hz), 7.62 ( (s, 3H), 7.27-7.20 (m, 3H), 6.85 (s, 1H). Analysis _{(C 22 H 18 N 4 O} 2 · 1.3H 2 O) C, H, N calculated: C, 67.10; H, 5.27 ; N, 14.23. Detection: C, 67.30; H, 5.27; N, 14.11.
[476] The starting material was prepared in the following manner:
[477]
[478] Preparation of 2-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-benzoimidazole
[479] To a solution of 5.029 g (20.25 mmol) of 1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-benzoimidazole (Witten et al., J. Org. Chem., 51, 1891-1894 (1986)) was cooled to -78 占 폚, and a solution of 30 ml of THF in which n-butyllithium (dissolved in hexane at a concentration of 2.5 M, 12.2 ml) In the presence of a drop for 12 minutes drops. After stirring at -78 ° C for 25 minutes, the flask was heated to 0 ° C for 10 minutes and then cooled to -78 ° C again. The solution was then added via cannula to a second flask containing a solution of iodine (25.7 g, 101 mmol) in 50 mL of THF at -78 ° C. (~ 5 min), then the cooling bath was removed and continued for 30 min Followed by stirring. The reaction mixture was partitioned between 500 ml of ethyl acetate and 100 ml of water. The organic layer was washed with aqueous saturated sodium metabisulfite (2 x 100 mL) to clear the deep iodine color, dried (MgSO ₄ ), concentrated in vacuo and purified by flash chromatography (10% to 50% ethyl acetate / hexanes) (Yield 63%) of the yellow solid 2-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-benzoimidazole. _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J = 8.1 Hz), 0.92 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H). Anal. (C ₁₃ H ₁₉ IN ₂ OS) C, H. Calculated: C, 41.71; H, 5.12; I, 33.90; Detection: C, 41.90; H, 5.09; I, 34.00; N, 7.37.
[480]
[481] Preparation of 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- (trimethyl-stannanyl) -1-H-indazole: 3-Iodo- 10.0 g (23.9 mmol) of [2- (trimethylsilanyl) ethoxymethyl] -1-H-indazole and 10.0 g (30.5 mmol) of hexamethylditin were placed in a flask refined with argon and dried 300 mg (0.26 mmol) of Tetrakis (triphenylphosphine) -palladium (0) was added and stirred. After refluxing in the presence of argon for 2.5 hours, the mixture was cooled to 23 ° C and 60 ml The organic material was washed with 20 mL of 0.1N HCl and 20 mL of brine, dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (3% to 8% ethyl acetate-hexane) nitro-1- [2-ethoxy-methyl (trimethyl-chamber not)] -3- (trimethyl-stent Oh carbonyl). -1-H- indazole obtain the 7.70g (yield 71%) ¹ H NMR (300MHz _{, CDCl 3): δ8.53 (d} , 1H, J = 1.8 Hz), 8.0 2H), 3.58 (t, 2H, J = 8.1 Hz), 0.90 (t, 2H, J = 8.7 Hz), 7.81 (d, (C ₁₆ H ₂₇ N ₃ O ₃ SiSn) C, H, N. Calcd .: C, 42.13 (s, 9H) H, 5.97; N, 9.21. Detection: C, 42.39; H, 6.01; N, 9.26.
[482] (iii)
[483]
[484] Ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H-benzoimidazol- - yl} -1-H-indazole: A solution of 6-nitro-l- [2- (trimethyl-silanyl) -ethoxymethyl] -3- (trimethyl- (17.4 mmol) of 3-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-1-H- benzimidazole and 313 mg 1.64 mmol) were placed in a refined argon flask and reacted with 150 ml of dry THF. Tetrakis (triphenylphosphine) -palladium (0) was added and stirred, then refluxed in the presence of argon for 23 hours, then cooled and adsorbed directly onto silica gel (~ 16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate-hexanes) afforded 6-nitro-l- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (Trimethyl-silanyl) -ethoxymethyl] -1-H-benzoimidazol-2-yl} -1-H-indazole in a yield of 82%. _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.91 (d, 1H, J = 9.0 Hz), 8.59 (d, 1H, J = 1.8 Hz), 8.22 (dd, 1H, J = 8.7, 1.8 Hz), 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 7.92-7.89 (m, 1H), 7.66-7.62 0.94 (t, 2H, J = 8.1 Hz), 0.86 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C ₂₆ H ₃₇ N ₅ O ₄ Si ₂ ) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Detection: C, 57.60; H, 6.81; N, 12.82.
[485] (iv)
[486]
[487] Ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H-benzoimidazol- -Yl} -1-H-indazole To a solution of 12.0 g (63.3 mmol) of tin (II) chloride in DMF / H ₂ O (160 ml / Ylmethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H- benzoimidazol- g (13.3 mmol) of sodium hydroxide was added thereto, followed by stirring at 50 占 폚 for 2.5 hours, followed by cooling to 0 占 폚. Slowly adding saturated sodium bicarbonate to precipitate the precipitated material , Concentrated in vacuo and dissolved in 100 ml of ether. The insoluble material was removed by filtration, and 50 ml of ether was poured. The filtrate was washed with 50 ml of brine, dried (MgSO ₄ ), concentrated in vacuo, and purified by silica gel chromatography (25% ethyl acetate / A yellowish waxy solid, 6-amino-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -H-benzoimidazol-2-yl} -1-H-indazole (6.0 g, 89%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.40 (d, 1H, J = 9.0 Hz), 7.89-7.86 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.31 (m, 2H) 2H), 3.63 (br s, 2H), 3.65-3.55 (m, 2H), 6.78 (s, (S, 9H), 0.93 (t, 2H, J = 8.1 Hz), 0.85 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C ₂₆ H ₂₉ N ₅ O ₂ Si ₂ ) C, H, N. Calculate: C, 61.26; H, 7.71; N, 13.74. Detection: C, 61.18; H, 7.65; N, 13.82.
[488]
[489] Ethyl-3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H-benzoimidazol- -Yl} -1H-indazole: To a solution of 6-amino-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) ] -1-H- benzo imidazol-2-yl} a stirred solution of the -1H- indazole 500mg (0.98mmol) in acetic acid in a 1.5㎖ 0 ℃ then diluted with H ₂ O then H ₂ O 1.0㎖ 250 [mu] L (~ 3 mmol) of concentrated HCl was added to 300 [mu] l. A solution of 90 mg (1.3 mmol) of sodium nitrate in 300 μl of H ₂ O was added, followed by stirring for 8 minutes. A solution prepared by dissolving 250 mg (1.3 mmol) of potassium iodide in 10 mg of iodine and 250 μl of H ₂ O was added, For 30 minutes with stirring. The reaction was diluted with 25 mL of H ₂ O and extracted with ethyl acetate (2 x 20 mL). The organics were washed with 10 ml of saturated sodium metabisulfite solution and brine (10 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- (2-pyridinylmethyl) 316 mg (yield: 52%) of [2- (trimethyl-silanyl) -ethoxymethyl] -1-H- benzoimidazol-2-yl} -1H- indazole was obtained. _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.45 (d, 1H, J = 9.0 Hz), 8.05 (s, 1H), 7.91-7.88 (m, 1H), 7.67-7.62 (m, 2H), 7.38 2H, J = 8.1 Hz), 7.35 (m, 2H), 7.37 (s, 2H) = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C ₂₆ H ₃₇ IN ₄ O ₂ Si ₂ ) C, H, N. Calculate: C, 50.31; H, 6.01; N, 9.03. Detection: C, 50.55; H, 6.08; N, 9.00.
[490]
[491] Preparation of [2- (4-bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl- silane: Phenol (see chien-Hsun et al., Syn. Lett. , 12, 1351-1352 (1997)) was added to 100 ml of dry CH ₂ Cl ₂ at 23 ° C and stirred. After addition of 6.05 ml (34.6 mmol) of DIEA, 5.6 ml (31.7 mmol) of 2- (trimethylsilyl) ethoxymethyl chloride was added and the mixture was stirred for 1 hour. The solution was then washed with H ₂ O, 0.1N HCl, saturated NaHCO ₃ and brine and washed with each 25㎖. The organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (6% ethyl acetate / hexanes) afforded 9.06 mg (0.24 mmol) of [2- (4-bromo-2-methoxy-5-methyl-phenoxymethoxy) Yield: 91%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.06 (s, 1H), 7.02 (s, 1H), 5.24 (s, 2H), 3.84 (s, 3H), 3.79 (t, 2H, J = 8.4 Hz ), 2.31 (s, 3H), 0.96 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H).
[492]
[493] Preparation of 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-bromonic acid: [2- (4-Bromo- 2.6 g (7.5 mmol) of methyl-phenoxymethoxy-ethyl] -trimethylsilane were added to 10 ml of dry THF in the presence of argon at -78 DEG C. N-Butyllithium (3.75 ml, dissolved in hexane to a concentration of 2.5 M , 9.36 mmol) was added dropwise, followed by stirring for 30 minutes, and then 8.4 ml (75 mmol) of trimethylborate dissolved in 15 ml of THF in the presence of argon at -78 ° C was added via a cannula to the flask. the reaction was stirred at -78 ℃ 30 minutes and then allowed to warm to 0 and then cooled to ℃ H ₂ O 20㎖, acidified with 0.1N HCl and extracted with ethyl acetate (2x25㎖). organics were washed with brine 20㎖ after drying to a (Na ₂ SO ₄₎ and concentrated in vacuo. purification (20% to 50% ethyl acetate / hexane) was purified by silica gel chromatography as a white solid, 5-methoxy-2-methoxy .-4- [2- (trimethyl-chamber not) -ethoxy-methoxy] -phenyl-boronic acid to give the 1.11mg (yield ^{47%) 1 H NMR (300MHz} , CDCl 3): δ7.78 (s, 1H 2H, J = 8.4 Hz), 7.10 (s, 1H), 5.36 (s, 2H), 3.93 8.4 Hz), 0.01 (s, 9H) analysis _{(C 14 H 25 BO 5 Si} -H 2 O) C, H. calculated: C, 57.15; H, 7.88 detection:.. C, 56.89; H , 7.87.
[494]
[495] Phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] - (2-methoxy- Preparation of 3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H-benzamidazol-2-yl} -1- - (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H- benzoimidazol- (0.68 mmol) of 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl- ) Was added to a flask refined with argon containing a mixture of 5 ml of benzene, 330 ㎕ of H ₂ O and 1 ml of methanol, and the mixture was stirred. Tetrakis (triphenylphosphine) palladium (0) was added to the reaction mixture, and the mixture was refluxed in the presence of argon for 16 hours and stirred. After cooling the reaction was diluted with 23 ℃ 20㎖ ether, and concentrated in the resultant product was washed with H ₂ O and 10㎖ 10㎖ brine, dried (Na ₂ SO ₄₎ vacuum. Purification by silica gel chromatography (15% ethyl acetate / hexanes) afforded 6- {5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] 1- [2- (trimethyl-silanyl) -ethoxymethyl] -1-H-benzimidazol-2-yl} - 1-H-indazole (yield: 89%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.68 (d, 1H, J = 8.4 Hz), 7.93-7.90 (m, 1H), 7.67-7.63 (m, 1H), 7.54 (s, 1H), 7.38 2H), 5.39 (s, 2H), 3.89 (s, 3H), 6.99 (s, 2H), 3.86 (t, 2H, J = 8.4 Hz), 3.69-3.58 (m, 4H), 2.22 (s, 9H), -0.05 (s, 9H), -0.15 (s, 9H). Anal. (C ₄₀ H ₆₀ N ₄ O ₅ Si ₃ ) C, H, N. Calculated: C, 63.12; H, 7.95; N, 7.36. Detection: C, 63.22; H, 7.93; N, 7.46.
[496] Example 24 (b): 4- [3- (1-H-Benzoimidazol-2-yl)
[497]
[498] Instead of 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic acid in step (viii) 4- [3- (1-H-benzoimidazol-l-yl) -ethanone was obtained in the same manner as in Example 24 (a) 2-yl) -1-H-indazol-6-yl] -3-methyl-phenol. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.60 (s, 1H), 12.99 (br s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J = 8.4 Hz), 7.72 ( 1H, J = 8.1 Hz), 6.73-6.67 (m, 2H), 7.52 (br s, , &Lt; / RTI &gt; 2.20 (s, 3H). Anal (C ₂₁ H ₁₆ N ₄ O 0.7 H ₂ O) C, H, N. Calculated: C, 71.45; H, 4.97; N, 15.87. Detection: C, 71.44; H, 4.96; N, 15.77.
[499] 2-Methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic acid is prepared as follows:
[500]
[501] Methyl-phenol was prepared from [2- (4-bromo-2-methoxy-5-methyl-phenoxymethoxy) Bromo-3-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane (yield 86%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.39 (d, 1H, J = 8.7 Hz), 6.93 (d, 1H J = 2.7 Hz), 6.75 (dd, 1H, J = 8.7, 2.7 Hz), 5.16 (s, 2H), 3.74 (t, 2H, J = 8.4 Hz), 2.36 (s, 3H), 0.95 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H). Analysis _{(C 13 H 21 BrO 2 Si} ) C, H. calculated: C, 49.21; H, 6.67 . Detection: C, 49.33; H, 6.67.
[502]
[503] The title compound was prepared from 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxyamine from 4- [2- (4- bromo-3- methyl- phenoxymethoxy) 2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic acid (52% yield) was prepared by the procedure described above. _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.15 (d, 1H, J = 8.1 Hz), 6.98-6.92 (m, 2H), 5.29 (s, 2H), 3.78 (t, 2H, J = 8.4 Hz ), 2.78 (s, 3H), 0.98 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H). Analysis _{(C 13 H 23 BO 4 Si} · H 2 O) C, H. calculated: C, 59.10; H, 8.01 . Detection: C, 59.07; H, 8.08.
[504] Example 24 (c): 4- [3- (1-H-Benzoimidazol-2-yl)
[505]
[506] Chloro-2-methyl-phenyl) -acetic acid was used in the method of Example 24 (a) (viii) instead of 5-methoxy- 4- [3- (l- (3-methyl-lH-imidazol-1-ylmethyl) -phenyl] -acetic acid was prepared in the same manner as in Example 24 (a) Yl-1H-indazol-6-yl] -2-chloro-5-methyl-phenol. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.61 (s, 1H), 13.00 (br s, 1H), 10.22 (s, 1H), 8.51 (d, 1H, J = 8.4 Hz), 7.64 ( 2H), 7.50 (s, 1H), 7.26-7.21 (m, 4H), 6.95 (s, 1H), 2.19 (s, 3H).
[507] 5-Chloro-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic acid is prepared as follows:
[508]
[509] 6.68 g (46.9 mmol) of 2-chloro-5-methyl-phenol was mixed with 200 ml of acetonitrile, 8.5 g (47.8 mmol) of bromosuccinimide was added and the reaction was stirred for 45 minutes Respectively. The solution was concentrated in vacuo and redissolved in 100 mL of chloroform. The organics were washed with 50 ml of saturated NaHCO ₃ and 50 ml of brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (8% ethyl acetate / hexane) gave 7.98 g (yield 77%) of 4-bromo-3-chloro-5-methyl-phenol as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ): 7.47 (s, IH), 6.91 (s, IH), 5.52 (br s, IH), 2.32 (s, 3H). Anal. (C ₇ H ₆ ClBrO · 0.1H ₂ O) C, H. Output: C, 37.66; H, 2.80. Detection: C, 37.57; H, 2.82.
[510] (ii)
[511]
[512] The above process of making [2- (4-bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl- silane from 4- bromo- To give [2- (4-bromo-2-chloro-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane (yield: 83%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.51 (s, 1H), 7.09 (s, 1H), 5.26 (s, 2H), 3.79 (t, 2H, J = 8.4 Hz), 2.35 (s, 3H ), 0.95 (t, 2H, J = 8.4 Hz), 0.02 (s, 9H). Anal. (C ₁₃ H ₂₀ ClBrO ₂ Si) C, H-Calculate: C, 44.39; H, 5.73. Detection: C, 45.08; H, 5.91.
[513]
[514] Methoxy-2-methyl-4- [2- (trimethyl-silanyl) - &lt; / RTI &gt; -Phenyl-boronic acid was prepared by the procedure described above to give 5-chloro-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] %). _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.11 (s, 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H, J = 8.4 Hz), 2.76 (s, 3H ), 0.98 (t, 2H, J = 8.4Hz), 0.01 (s, 9H). Anal. (C ₁₃ H ₂₂ BClO ₄ Si.H ₂ O) C, H. yield: C, 52.28; H, 6.75. Detection: C, 51.98; H, 6.84.
[515] Example 24 (d): 3-1 H-Benzoimidazol-2-yl-6- (4-hydroxy-2-methoxyphenyl)
[516]
[517] Example 24 (d) was prepared in the same manner as in step (vi) of Example 24 (a) except that 4-bromo-3-methoxy-phenol Carreno et al., Syn. Lett., 11, 1241-42 (1997)). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.52 (s, 1H), 12.98 (s, 1H), 9.63 (s, 1H), 8.44 (d, 1H, J = 8.4 Hz), 7.72 (d J = 6.9 Hz), 7.61 (s, 1H), 7.50 (d, 1H, J = 6.9 Hz), 7.36 (dd, 1H, J = 8.4, 1.5 Hz), 7.18-7.22 , 6.55 (d, IH, J = 2.1 Hz), 6.48 (dd, IH, J = 8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [m + H] / z yield 357, detect 357; [mH] / z yield 355, detect 355.
[518] Example 24 (e): 3-1H-Benzoimidazol-2-yl-6- (2-ethyl-
[519]
[520] Example 24 (e) was prepared in the same manner as in step (vi) of Example 24 (a) except that 4-bromo-3-methoxy-phenol was used instead of 4-bromo-2-methoxy- (Yield: 80%) was prepared by the method for the synthesis of 4-bromo-3-ethyl-phenol (prepared as described in Carreno et al., Syn. Lett., 11, 1241-42 (a). ¹ H NMR (300 MHz, DMSO-d ₆ ): 13.66 (s, 1H), 13.02 (s, 1H), 9.43 1H, J = 6.9 Hz), 7.53 (d, IH, J = 6.9 Hz), 7.44 (s, IH), 7.18-7.25 (d, 1H, J = 2.1 Hz), 6.66 (dd, 1H, J = 8.1, 2.1 Hz), 2.50 (q, 2H, J = 7.5 Hz), 1.04 (t, MS (ES) [m + H] / z yield 355, detect 355; [mH] / z yield 353, detect 353.
[521] Example 24 (f): 3-1H-Benzoimidazol-2-yl-6- (2,4-dihydroxyphenyl)
[522]
[523] (0.13 mmol) of 6- (2-methoxy-4-hydroxyphenyl) -3-1H-benzoimidazol-2-yl-1H-indazole prepared in Example 24 (d) was added pyridinium chloride 0.5 g, and the mixture was heated at 180 DEG C for 2 hours. The reaction was quenched with 15 mL saturated NaHCO ₃ and extracted with EtOAc (2 x 20 mL). The organics were dried (Na ₂ SO ₄ ), concentrated in vacuo and then purified by silica gel chromatography (60% THF / hexanes) to give 3-1H-benzoimidazol-2-yl- -Dihydroxyphenyl) -1H-indazole (yield: 59%). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.49 (s, 1H), 12.94 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H, J = (M, 2H), 7.50 (d, 1H, J = 6.9Hz), 7.43 (dd, 1H, J = 8.4,1.2Hz), 7.16-7.23 d, 1 H, J = 2.1 Hz), 6.35 (dd, 1H, J = 8.4, 2.1 Hz). MS (ES) [m + H] / z yield 343, detect 343; [mH] / z yield 341, detect 341.
[524] Example 24 (g): 3-1H-Benzoimidazol-2-yl-6- (2-phenoxy-4-hydroxyphenyl)
[525]
[526] Example 24 (g) was prepared in the same manner as in Example 24 (c) except that 3-phenoxy-phenol was used instead of 2-chloro-5-methyl-phenol in step (i). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.54 (s, 1H), 12.95 (s, 1H), 9.78 (s, 1H), 8.43 (d, 1H, J = 8.4Hz), 7.67-7.72 (m, 2H), 7.49 (dd, 1H, J = 6.3, 2.1 Hz), 7.43 (d, 2H, J = 8.4 Hz), 7.33 (t, 2H, J = 7.5 Hz), 7.17-7.22 2H), 6.96-7.07 (m, 3H), 6.72 (dd, 1H, J = 8.4, 2.1Hz), 6.40 (d, 1H, J = 2.1Hz). MS (ES) [m + H] / z yield 419, detect 419; [mH] / z yield 417, detect 417.
[527] Example 24 (h): 3-1 H-Benzoimidazol-2-yl-6- (2- (2-methoxyethyl) -4- hydroxyphenyl)
[528]
[529] Example 24 (h) was prepared in the same manner as in step (vii) except for using {2- [4-bromo-2-methoxy-5-methyl-phenoxymethoxy) -Methyl-3- (2-methoxy-ethyl) -phenoxymethoxy] -ethyl} -trimethyl-silane was used as the starting material. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.60 (s, 1H), 13.01 (s, 1H), 9.44 (s, 1H), 8.49 (d, 1H, J = 8.4Hz), 7.73 (br 1H, J = 8.1 Hz), 6.78 (d, 1H, J = 8.1 Hz), 7.51 (br s, 2H, J = 7.2 Hz), 3.70 (d, 2H, J = ). M / z yield 385, detect 385; [mH] / z yield 383, detect 383.
[530] The starting material was prepared as follows:
[531]
[532] (2-hydroxy-ethyl) -phenol was obtained by replacing 3- (2-hydroxy-ethyl) -phenol by the same procedure as in the step (i) of Example 24 (c) Was prepared in 88% yield. _{^{1 H NMR (300MHz, CDCl 3}} ): δ9.56 (s, 1H), 7.29 (d, 1H, J = 8.7Hz), 6.74 (d, 1H, J = 3.0Hz), 6.55 (dd, 2H, J = 8.7, 3.0 Hz), 4.71 (t, 1H, J = 5.4 Hz), 3.52-3.59 (m, 2H), 2.73 (t, 2H, J =
[533]
[534] Bromo-3- (2-hydroxy-ethyl) -phenol prepared in step (vi) of Example 24 (a) above was substituted for 2- [2-bromo-5- / RTI &gt; ethoxy-methoxy) -phenyl] was prepared in 65% yield. _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.43 (d, 1H, J = 8.7Hz), 6.97 (d, 1H, J = 3.0Hz), 6.82 (dd, 1H, J = 8.7, 3.0Hz), 2H, J = 6.6 Hz), 1.42 (t, 1H, J = 6.6 Hz), 3.74 (t, 2H, J = = 6.6 Hz), 0.94 (t, 2H, J = 8.4 Hz), -0.01 (s, 9H).
[535]
[536] Preparation of {2- [4-bromo-3- (2-methoxy-ethyl) -phenoxymethoxy] -ethyl} -trimethyl- A solution in which 1.35 g (24 mmol) of potassium hydroxide was dissolved in 16 ml of DMSO was added to 1.9 g (6.0 mmol) of diethyl azodicarboxylate, 1.12 ml (118 mmol) of iodomethane was added to 16 Lt; / RTI &gt; The reaction was diluted with 50 mL water and extracted with ether (2 x 40 mL). Organics were washed with brine 40㎖, dried (Na ₂ SO _4), concentrated in vacuo and then purified by silica gel chromatography (10% ether / hexane) to give a clear oil of {2- [4-Bromo-3- ( Methoxy-ethyl) -phenoxymethoxy] -ethyl} -trimethyl-silane (1.28 g). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.40 (d, 1H, J = 8.7Hz), 6.96 (d, 1H, J = 3.0Hz), 6.80 (dd, 1H, J = 8.7, 3.0Hz), 2H), 3.74 (t, 2H, J = 8.4 Hz), 3.60 (t, 2H, J = 7.2 Hz), 3.37 (s, 0.95 (t, 2H, J = 8.4 Hz), -0.01 (s, 9H).
[537] Example 24 (i): 3-1 H-Benzoimidazol-2-yl-6- (2- (2-hydroxyethyl) -4-hydroxyphenyl)
[538]
[539] (0.26 mmol) of 3-1H-benzoimidazol-2-yl-6- (2- (2-methoxyethyl) -4-hydroxyphenyl) -1H-indazole prepared in Example 24 (h) Was dissolved in 20 mL of EtOAc and cooled to -78 &lt; 0 &gt; C in the presence of argon. Boron tribromide was added dropwise and stirred at room temperature for 3 hours. The solution was diluted with 60 mL of EtOAc, washed with 20 mL each of saturated NaHCO ₃ and brine, and the organics were dried (NaHCO ₃ ) and concentrated in vacuo. The residue was purified by silica gel chromatography (THF) to obtain 56 mg of 3-1H-benzoimidazol-2-yl-6- (2- (2-hydroxyethyl) -4-hydroxyphenyl) -1H- Yield: 59%). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J = 8.4Hz), 7.71 (br 1H, J = 8.4 Hz), 6.77 (d, 1H, J = 8.1 Hz), 7.51 (br s, 2H, J = 2.1 Hz), 6.69 (dd, 1H, J = 8.1, 2.1 Hz), 4.57 (br s, Hz). MS (ES) [m + H] / z yield 371, detect 371; [mH] / z yield 369, detect 369.
[540] Example 24 (j): 3-1H-Benzoimidazol-2-yl-6- (2,6-dimethyl-
[541]
[542] Example 24 (j) used 4-bromo-3,5-dimethyl-phenol instead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi) Was prepared in a similar manner to Example 24 (a). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.57 (s, 1H), 12.99 (s, 1H), 9.22 (s, 1H), 8.52 (d, 1H, J = 8.4Hz), 7.72 (d 1H, J = 6.6 Hz), 7.51 (d, IH, J = 6.6 Hz), 7.31 (s, IH), 7.16-7.25 (s, 2 H), 1.93 (s, 6 H). MS (ES) [m + H] / z yield 355, detect 355; [mH] / z yield 353, detect 353.
[543] Example 24 (k): 3-1H-Benzoimidazol-2-yl-6- (2-methylsulfanyl-4-hydroxyphenyl)
[544]
[545] Example 24 (k) was prepared in the same manner as in Example 24 (c) except that 3-methylsulfanyl-phenol was used instead of 2-chloro-5-methyl-phenol in step (i) &Lt; / RTI &gt; ^{1 H NMR (300MHz, DMSO-} d 6): δ13.59 (s, 1H), 12.98 (s, 1H), 9.64 (s, 1H), 8.48 (d, 1H, J = 8.4Hz), 7.71 (br 1H, J = 8.4 Hz), 6.76 (d, 1H, J = 2.1 Hz), 6.65 (dd, 1H, J = 8.4, 2.1 Hz), 2.34 (s, 3H). Calculated 373, [372] [mH] / z yield 371, detected 371. MS (ES) [m + H]
[546] The starting material was prepared in the following manner:
[547]
[548] Preparation of 3-methylsulfanyl-phenol 5.0 g (39.7 mmol) of 3-hydroxythiophenol and 6.03 g (43.6 mmol) of potassium carbonate were added to 80 ml of acetone and the mixture was stirred at 0 ° C. 2.5 mL (40 mmol) of iodomethane was added dropwise to the mixture, and the mixture was stirred for 45 minutes. The solution was diluted with 150 mL H ₂ O and extracted with EtOAc (2 x 100 mL). The organics were washed with 100 ml brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography (25% EtOAc / hexanes) to give 5.08 g of a clear oil, 3-methylsulfonyl- %). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.15 (t, 1H, J = 8.1Hz), 6.82 (d, 1H, J = 8.1Hz), 6.74 (t, 1H, J = 1.8Hz), 6.60 ( dd, 1H, J = 8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).
[549] Example 24 (l): 3-1 H-Benzoimidazol-2-yl-6- (2- (ethoxymethyl) -5-methoxy-
[550]
[551] Example 24 (1) was prepared in analogy to example 24 a) by replacing [2- (4-bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethylsilane in step (vii) The title compound was prepared in the same manner as in Example 24 (a), except that [2- (4-bromo-5-ethoxymethyl-2-methoxy- phenoxymethoxy) -ethyl] -trimethyl- silane was used. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.63 (s, 1H), 12.99 (s, 1H), 9.15 (s, 1H), 8.50 (d, 1H, J = 8.4Hz), 7.73 (dd J = 6.6, 2.1 Hz), 7.59 (s, 1H), 7.51 (dd, 1H, J = 6.6, 2.1 Hz), 7.32 (d, 1H, J = 8.4 Hz), 7.19-7.24 2H), 6.94 (s, IH), 6.91 (s, IH), 4.22 (s, 2H), 3.81 = 6.9 Hz). MS (ES) [m + H] / z yield 415, detected 415.
[552] The starting material was prepared in the following manner:
[553]
[554] 3-formyl-2-methoxy-phenol (Hazlet et al., J. Org. Chem., 27 (1991)) was prepared in the same manner as in step (vi) , 3253-55 (1962)) to give 2-bromo-4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -benzaldehyde in 79% yield. _{^{1 H NMR (300MHz, CDCl 3}} ): δ10.16 (s, 1H), 7.68 (s, 1H), 7.07 (s, 1H), 5.28 (s, 2H), 3.94 (s, 3H), 3.77 (t , 2H, J = 8.4 Hz), 0.94 (t, 2H, J = 8.4 Hz), -0.03 (s, 9H).
[555] (ii)
[556]
[557] Preparation of [2- (4-bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy) -ethyl] -trimethyl-silane: 275 mg (7.2 mmol) of sodium borohydride were added to a solution of Was added to a solution of 1.3 g (3.6 mmol) of 2-bromo-4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -benzaldehyde in 10 minutes. After 30 min, the reaction was diluted with 40 mL H ₂ O and extracted with EtOAc (2 x 30 mL). Organics washed with brine 30㎖, dry (Na ₂ SO ₄₎ and concentrated in vacuo to transparent after five days of [2-bromo-4-methoxy-5- (2-trimethylsilanyl chamber not-ethoxy-methoxy) - Phenyl] -methanol (1.31 g). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.29 (s, 1H), 7.05 (s, 1H), 5.27 (s, 2H), 4.66 (d, 2H, J = 6.6Hz), 3.87 (s, 3H ), 3.79 (t, 2H, J = 8.4Hz), 1.92 (t, 1H, J = 6.6Hz), 0.96 (t, 2H, J = 8.4Hz), 0.01 (s, 9H).
[558] The crude benzyl alcohol prepared above was added to a solution of 800 mg (14.4 mmol) of potassium hydroxide in 8 ml of DMSO and stirred. 580 ml (7.2 mmol) of iodine ethane was added to the reaction mixture, followed by stirring for 16 hours, followed by dilution with 30 ml H ₂ O and extraction with ether (2 x 30 ml). The organics were washed with 20 ml brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and then purified by silica gel chromatography (15% EtOAc / hexanes) to give a clear oil, [2- (4- Methoxy-phenoxymethoxy) -ethyl] -trimethyl-silane (yield: 92%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.79 (t 2H, J = 8.4 Hz), 3.58 (q, 2H, J = 6.9 Hz), 1.26 (t, 3H, J = 6.9 Hz), 0.95 9H).
[559] Example 24 (m): 3-1 H-benzoimidazol-2-yl-6- (2-hydroxymethyl) -4-ethoxy-5-methoxy-
[560]
[561] Example 24 (m) was prepared in analogy to example 24 a) by replacing [2- (4-bromo-2-methoxy-5-methyl-phenoxymethoxy) The title compound was prepared in the same manner as in Example 24 (a) except that [2- (2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy) -ethyl] -trimethyl- silane was used. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.64 (s, 1H), 13.00 (s, 1H), 8.50 (d, 1H, J = 8.4Hz), 7.73 (d, 1H, J = 8.4Hz 1H, J = 8.4,1.2Hz), 7.19-7.24 (m, 2H), 7.15 (s, 1H), 7.62 2H, J = 6.9 Hz), 3.80 (s, 1H), 6.91 (s, 3H), 1.37 (t, 3H, J = 6.9 Hz). MS (ES) [m + H] / z yield 415, detected 415.
[562] The starting material was prepared in the following manner:
[563]
[564] Preparation of 4-bromo-2-methoxy-5- (2-trimethylsilanylethoxymethyl) -phenol: [2-Bromo-4-methoxy-5- (2-trimethylsilanyl- 2-methoxy-5- (2-trimethylsilanyl-ethoxymethyl) -methoxy) -phenyl] -methanol was prepared via a SEM-migration prepared from phenyl ring to benzyl alcohol over a period of one week or longer. ) -Phenol. &Lt; / RTI &gt; _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.04 (s, 1H), 7.01 (s, 1H), 5.54 (s, 1H), 4.77 (s, 2H), 4.57 (s, 2H), 3.88 (s , 3H), 3.68 (t, 2H, J = 8.4Hz), 0.97 (t, 2H, J = 8.4Hz), 0.02 (s, 9H).
[565]
[566] Preparation of [2- (2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy) -ethyl] -trimethyl-silane: 4-Bromo-2-methoxy- (3.53 mmol) was mixed with a solution of 790 mg (14.1 mmol) of potassium hydroxide in 8 ml of DMSO. 565 ml (7.1 mmol) of iodine ethane was added to the reaction mixture, followed by stirring for 16 hours, followed by dilution with 30 ml H ₂ O and extraction with ether (2 x 30 ml). Organic material is a clear oil of [2- 30㎖ then washed with brine, dried (Na ₂ SO ₄₎ and concentrated in vacuo (2-bromo-5-ethoxy-4-methoxy-benzyloxy methoxy) ethyl ] -Trimethyl-silane (yield: 91%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.02 (s, 1H), 6.98 (s, 1H), 4.78 (s, 2H), 4.60 (s, 2H), 4.09 (q, 2H, J = 6.6Hz 2H, J = 8.4 Hz), 3.86 (s, 3H), 3.69 (t, 2H, J = ).
[567] Example 24 (n): 3-1 H-Benzoimidazol-2-yl-6- (2- (hydroxymethyl) -5-methoxy-4-hydroxy-phenyl)
[568]
[569] Example 24 (n) was prepared from 6- [5-methoxy-2-methyl-4- (2- trimethylsilanylethoxymethoxy) -phenyl] -l- (2- trimethylsilanylethoxymethyl) -6- [5-methoxy-2-hydroxymethyl-4-methyl-1H-indazol- - (2-trimethylsilanyl-ethoxymethyl) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [1- Benzoimidazol-2-yl] -1H-indazole was used in place of the compound obtained in Example 24 (a). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.59 (s, 1H), 12.95 (s, 1H), 9.05 (s, 1H), 8.49 (d, 1H, J = 8.4Hz), 7.72 (dd (D, 1H, J = 6.3, 2.1 Hz), 7.60 (s, 1H), 7.51 2H), 7.02 (s, IH), 6.87 (s, IH), 5.02 (t, IH, J = 5.4 Hz), 4.32 (d, 2H, J = 5.4 Hz), 3.80 MS (ES) [m + H] / z yield 387, detect 387; [mH] / z yield 385, detect 385.
[570] The starting material was prepared in the following manner:
[571] (i)
[572]
[573] Preparation of 4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanyl-benzaldehyde: To a solution of 2-bromo-4-methoxy- Benzylaldehyde (3.36 g, 9.3 mmol) was placed in a refined flask in the presence of argon and mixed with 60 ml of dry toluene. To this mixture was added 500 mg (0.45 mmol) of tetrakis (triphenylphosphine) palladium (0) and the mixture was stirred at 100 ° C for 23 hours. The reaction was cooled and concentrated in vacuo and then purified by silica gel chromatography (5% EtOAc / hexanes) to give 4-methoxy-5- (2-trimethylsilanylethoxymethoxy) (Yield: 67%) of stannyl-benzaldehyde. _{^{1 H NMR (300MHz, CDCl 3}} ): δ9.81 (dd, 1H, J = 3.0, 0.9Hz), 7.66 (t, 1H, J = 6.6Hz), 7.21 (t, 1H, J = 9.0Hz), 2H, J = 8.4 Hz), 0.25 (t, 9H, J = 26.7 Hz), 0.98 (t, 2H, J = -0.01 (s, 9H).
[574]
[575] Preparation of 4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanyl-phenyl] -methanol: Methoxy) -2-trimethylstannyl-benzaldehyde (2.36 g, 5.3 mmol) were dissolved in methanol (30 ml), and the mixture was stirred at 0 ° C. 400 mg (10.6 mmol) of sodium borohydride was added to the mixture, and the mixture was stirred for 1 hour. The solution was diluted with 60 mL H ₂ O and extracted with EtOAc (2 x 50 mL). The organic was washed with 50 ml brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a clear oil, [4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2- trimethylstannanyl -Phenyl] -methanol (yield: 91%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.18 (t, 1H, J = 6.9Hz), 7.03 (t, 1H, J = 9.3Hz), 5.27 (s, 2H), 4.58-4.63 (m, 2H 2H, J = 8.4 Hz), 0.31 (t, 2H), 3.89 (s, 3H) , J = 27.3 Hz), 0.01 (s, 9H).
[576]
[577] (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [1 - [2- (trimethylsilanyl) ethoxymethyl] -1H-benzoimidazol-2-yl] -1H- Yl} -1H-indazole (Example 24 (a), step (v)) was added to a solution of (2- 282 mg (0.63 mmol) of [4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannylphenyl] -methanol was placed in 8 ml of dioxin, At &lt; RTI ID = 0.0 &gt; 98 C &lt; / RTI &gt; The reaction was cooled and diluted with EtOAc. The organics were washed with brine and saturated NaHCO ₃ , dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography (20% EtOAc / hexanes) to give pale yellow oil, 6- [5-methoxy- - (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [1- -1H-benzoimidazol-2-yl] -1H-indazole (yield: 60%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.70 (d, 1H, J = 8.4Hz), 7.89-7.92 (m, 1H), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H) , 6.91 (s, 2H), 6.91 (s, 2H), 6.91 (s, , 4H), 0.83-1.04 (m, 6H), 0.03 (s, 9H), -0.04 (s, 9H), -0.13 (s, 9 Hz).
[578] Example 24 (o): 3-1H-Benzoimidazol-2-yl-6- (3-hydroxyphenyl)
[579]
[580] Example 24 (o) was prepared in a similar manner to 6- (3-methoxy-phenyl) -3-trifluoromethyl-benzoimidazol- -3-lH-benzoimidazol-2-yl-lH-indazole was used as the starting material. The above 6- (3-methoxy-phenyl) -3-1H-benzoimidazol-2-yl-lH-indazole is obtained in step (viii) Was prepared in the same manner as in Example 24 (f) except that 3-methoxy-phenylboronic acid was used instead of 3-methoxy-phenylamino) -ethoxymethoxy] -phenylboronic acid. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1H, J = 8.4Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 (t, 1H, J = 7.8Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, J = 8.1,1.5Hz). MS (ES) [m + H] / z yield 327, detected 327; MS (ES) [mH] / z yield 325, detected 325.
[581] Example 24 (p): 3-1 H-Benzoimidazol-2-yl-6- (2-methoxy-3-hydroxyphenyl)
[582]
[583] Example 24 (p) Example 24 (e) was prepared in the same manner as Zristoff et al., Supra instead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi) al., Tet. Prepared by the same method as in Example 24 (a) except that 3-bromo-2-methoxy-phenol prepared by Lett., 25, 3955-58 (1984) was used. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.60 (s, 1H), 12.97 (s, 1H), 9.37 (s, 1H), 8.52 (d, 1H, J = 8.4 Hz), 7.69-7.74 (m, 2H), 7.51 (dd, 1H, J = 7.8,1.8Hz), 7.43 (dd, 1H, J = 8.4,1.2Hz), 7.19-7.24 = 7.8 Hz), 6.85-6.93 (m, 2H), 3.50 (s, 3H). MS (ES) [m + H] / z yield 357, detect 355; [mH] / z yield 357, detect 355.
[584] Example 25 (a): 3- (3H-imidazo [4,5- c] pyridin-2-yl) -6- (4-hydroxy-
[585]
[586] 3- [3- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -l- (2-trimethylsilanylethoxymethyl) (0.11 mmol) was added to a solution of TBAF (1 M in THF, 1.25 mL, 1.2 mL) at 0 &lt; 0 & ) And 150 ml (2.2 mmol) of ethylenediamine, and the mixture was stirred at 68 캜 for 48 hours. The reaction solution was concentrated in vacuo and purified by silica gel chromatography (2: 1 EtOH / EtOAc) and then precipitated with acetonitrile to give 3- (3H-imidazo [4,5-c] pyridin- -Yl) -6- (4-hydroxy-2-methoxyphenyl) -1H-indazole in a yield of 53%. ¹ H NMR (300 MHz, DMSO-d ₆ ): 13.70 (s, IH), 13.49 (br s, IH), 9.62 J = 8.7 Hz), 8.34 (d, IH, J = 5.7 Hz), 7.64 (s, IH), 7.57 (br s, IH), 7.39 J = 8.1 Hz), 6.55 (d, 1H, J = 2.1 Hz), 6.49 (dd, 1H, J = 8.1, 2.1Ha), 3.74 (s, 3H). MS (ES) [m + H] / z yield 358, detect 358; [mH] / z yield 356, detect 356.
[587] The starting material was prepared in the following manner:
[588]
[589] Preparation of 3- (1,1-dimethoxy-methyl) -6-iodo-1- (2-trimethylsilanylethoxymethyl) -1H-indazole: (2.69 mmol) of iodo-3-styryl- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was added to 40 mL of CH ₂ Cl ₂ / methanol And stirred at -78 ° C. The ozone was treated until the reaction turned blue and then purified with argon. 4 ml of methyl sulfide was added to the mixture, and the mixture was warmed to room temperature for 4 hours and stirred. The mixture was concentrated in a vacuum state and placed in 10 ml of trimethyl orthoformate containing 0.8 g of Amberlyst 15 (wet) oxide ion exchange resin. The mixture was stirred for 1 hour to prepare a mixture of acetal and aldehyde . The resin was filtered off to give a solution which was concentrated in vacuo and then purified by silica gel chromatography to give 3- (l, l-dimethoxy-methyl) -6-iodo-1- (2-trimethylsilanyl- 1H-indazole (yield: 92%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.98 (s, 1H), 7.68 (d, 1H, J = 8.4Hz), 7.48 (dd, 1H, J = 8.4, 1.2Hz), 5.77 (s, 1H 2H), 3.53 (t, 2H, J = 8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J = 8.4 Hz), -0.06 (s, 9H).
[590]
[591] Methoxy-4- (2-trimethylsilanylethoxymethoxy) -phenyl] -1- (2-trimethylsilanyl-ethoxy) Methyl) -1H-indazole: 1.06 mg (2.37 mmol) of 3- (1,1-dimethoxy-methyl) -6-iodo-1- (2-trimethylsilanyl- ethoxymethyl) (3.32 mmol) of 2-methoxy-4- (trimethylsilanylethoxymethoxy) -phenylboronic acid and 352 mg (1.4 mmol) of sodium carbonate were dissolved in 15 ml of benzene, 3 ml of methanol and 1 ml of water And the mixture was stirred in a flask refined with argon containing a mixed solution. 220 mg (0.19 mmol) of tetrakis (triphenylphosphine) palladium (0) was added to the reaction mixture, and the mixture was refluxed for 16 hours and stirred. The reaction was then cooled and diluted with 70 ml of ether. The organics were washed with H ₂ O and brine (10 mL each), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc / Hexane) gave the pale yellow oil, 3- (l, l-dimethoxy-methyl) -6- [2-methoxy- Ethoxy) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole in a yield of 82%. _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.91 (d, 1H, J = 8.4Hz), 7.64 (s, 1H), 7.37 (dd, 1H, J = 8.4, 1.2Hz), 7.29 (d, 1H 2H, J = 8.4 Hz), 6.71-6.77 (m, 2H), 5.82 (s, 2H, J = 8.4 Hz), 3.46 (s, 6H), 1.00 (t, 2H, J = 8.4 Hz), 0.88 , 9H).
[592]
[593] (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde (2-methoxy-4- (2-trimethylsilanylethoxymethoxy) -phenyl] -1- (2-methoxycarbonylmethoxy) (1.92 mmol) were added to 20 mL of 1% TFA / CH ₂ Cl ₂ , and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give a clear oil, 6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde (yield: 100%). ¹ H NMR (300 MHz, CDCl ₃ ): 10.27 (s, 1H), 8.28 (d, 1H, J = 8.4 Hz), 7.73 2H), 5.28 (s, 2H), 3.78-3.84 (m, 5H), 3.61 (t, 2H) 2H, J = 8.1 Hz), 0.89-1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H).
[594]
[595] 3- [3- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -l- (2-trimethylsilanylethoxymethyl) Yl] -1H-indazole: 6- [2-Methoxy-4- (2-trimethyl 320 mg (0.61 mmol) of 3,4-diamino-benzenesulfonyl chloride were added to a solution of 4-amino-3-methyl-isoxazol- 68 mg (0.62 mmol) of pyridine and 23 mg (0.73 mmol) of sulfur were mixed in 2 ml of dry DMF and stirred at 90 占 폚 for 16 hours in the presence of argon. The reaction solution was cooled and diluted with 20 mL of EtOAc. The organics were washed with saturated NaHCO ₃ and brine (15 mL each), dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography (75% to 100% EtOAc / hexanes) Methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) -phenyl] -1- (2- trimethylsilanylethoxymethyl) -3- [3- Imidazo [4,5-c] pyridin-2-yl] -1H-indazole (yield: 21%). ¹ H NMR (300 MHz, CDCl ₃ ): 10.69 (br s, 1H), 9.21 (s, 1H), 8.63 (dd, 1H, J = 8.4, 0.3 Hz), 8.50 1H), 7.74 (s, 1H), 7.47 (br s, 1H), 7.57 (dd, 1H, J = 8.7, 1.2Hz), 7.33 2H), 5.80 (s, 2H), 5.29 (s, 2H), 3.78-3.85 (m, 5H), 3.63 (t, 1H, J = 8.1Hz), 0.89-1.04 , 9H), -0.06 (s, 9H).
[596] Example 25 (b): Synthesis of 3- [6- (2-morpholin-4-yl-ethylcarbamoyl) -1H-benzoimidazol- Hydroxyphenyl) -1H-indazole &lt; / RTI &gt;
[597]
[598] Example 25 (b) was prepared in the same manner as in Example 25 (a) except that 3,4-diamino-N- (2-morpholin-4-yl-ethyl) - &lt; / RTI &gt; benzamide. &Lt; RTI ID = 0.0 &gt; ^{1 H NMR (300MHz, DMSO-} d 6): δ13.61 (s, 0.5H), 13.59 (s, 0.5H), 13.22 (s, 0.5H), 13.18 (s, 0.5H), 9.59 (s, 1H), 7.53 (d, 0.5H), 7.71-7.79 (m, 1.5H), 7.63 (s, 1H), 8.35-8.46 1H, J = 8.7 Hz), 7.38 (d, 1H, J = 8.7 Hz), 7.21 J = 8.4, 2.1 Hz), 3.75 (s, 3H), 3.58 (t, 4H, J = 4.5 Hz), 3.42 (q, 2H, J = 6.0 Hz), 2.43-2.51 (m, 6H). MS (ES) [m + H] / z yield 513, detect 513; [mH] / z yield 511, detect 511.
[599] 3,4-Diamino-N- (2-morpholin-4-yl-ethyl) -benzamide is prepared in the following way:
[600]
[601] Preparation of 3,4-diamino-N- (2-morpholin-4-yl-ethyl) -benzamide: 5 g (32.9 mmol) of 3,4-diaminobenzoic acid, 5.2 mmol (39.4 mmol) of triethylamine, 9.2 ml (66 mmol) of triethylamine and 0.40 g (3.3 mmol) of DMAP were placed in 80 ml of dry DMF and mixed at 0 ° C. 9.45 g (49.3 mmol) of EDC was added to the reaction solution, followed by stirring at room temperature for 24 hours. Concentrated in vacuo and then purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ , 0.2% NH ₄ OH) to give light brown solid 3,4-diamino-N- (2-morpholin- -Ethyl) -benzamide (yield: 31%). ^{1 H NMR (300MHz, DMSO-} d 6): δ7.72 (t, 1H, J = 5.4Hz), 7.02 (d, 1H, J = 1.8Hz), 6.92 (dd, 1H, J = 8.1, 1.8Hz 2H), 4.55 (br s, 2H), 3.55 (t, 4H, J = 4.8 Hz), 3.29 (q, 2H, J = 7.2 Hz), 2.36-2.43 (m, 6H).
[602] Example 25 (c): 3- [6- (4-Methylpiperazin-l-yl) -lH-benzoimidazol- 1H-indazole
[603]
[604] Example 25 (c) was prepared in the same manner as in Example 25 (a) except that 4- (4-methyl-piperazin-1-yl) -benzene- The title compound was prepared in the same manner as in Example 25 (a) except that diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)) was used. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.51 (s, 0.33H), 13.38 (s, 0.67H), 12.66 (s, 0.33H), 12.59 (s, 0.67H), 9.58 (s, 1H), 8.42 (d, 0.33H, J = 8.4 Hz), 8.41 (d, 0.67H, J = 8.4 Hz), 7.59 J = 1.5 Hz), 6.48 (dd, IH, J = 8.4 Hz), 7.92 (d, 2H), 3.74 (s, 3H), 3.12 (br s, 4H), 2.50 (br s, 4H), 2.22 (s, 3H). MS (ES) [m + H] / z yield 455, detect 455; [mH] / z yield 453, detect 453.
[605] Example 25 (d): 3- [4- (4-Methylpiperazin-l-yl) -lH-benzoimidazol- 1H-indazole
[606]
[607] Example 25 (d) was prepared in the same manner as in step (iv) of Example 25 (a) except that 3- (4-methyl-piperazin-1-yl) The title compound was prepared in the same manner as in Example 25 (a) except that diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)) was used. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.41 (br s, 1H), 12.79 (br s, 1H), 9.60 (br s, 1H), 8.37 (d, 1H, J = 8.4Hz), 1H, J = 8.4Hz), 7.03-7.07 (m, 2H), 6.46-6.56 (m, 3H), 7.60 (d, , 3.75 (s, 3H), 3.62 (brs, 4H), 2.62 (brs, 4H), 2.28 (s, 3H). MS (ES) [m + H] / z yield 455, detect 455; [mH] / z yield 453, detect 453.
[608] Example 25 (e): 3-Imidazol-2-yl-6- (2-methoxy-4-hydroxyphenyl)
[609]
[610] Example 25 (e) was prepared from 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) -phenyl] -l- (2-trimethylsilanylethoxymethyl) Imidazo [4,5-c] pyridin-2-yl] -1H-indazole in place of 3- [3- (2- trimethylsilanylethoxymethoxy) (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanylethoxymethyl) -3-imidazol- Was used in place of &lt; RTI ID = 0.0 &gt; ^{1 H NMR (300MHz, DMSO-} d 6): δ13.10 (s, 1H), 12.59 (s, 1H), 9.56 (s, 1H), 8.27 (d, 1H, J = 8.4Hz), 7.53 (s 1H), 7.25 (dd, 1H, J = 8.4, 1.2 Hz), 7.13-7.20 (m, 3H), 6.54 Hz), &lt; / RTI &gt; 3.73 (s, 3H). MS (ES) [m + H] / z yield 307, detected 307.
[611] The starting material was prepared in the following manner:
[612]
[613] 0.4 mmol (3.5 mmol) of Glyoxal (40 wt% H ₂ O) was added to a solution of 6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) 420 mg (0.8 mmol) of 28% aqueous ammonia and 0.6 ml of 28% aqueous ammonia were dissolved in THF (8 ml) / MeOH (1 ml) 8 ml), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to in vacuo and re-dissolved in CHCl ₃ 50㎖. The organics were washed with H ₂ O and brine (25 mL each), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc / hexanes) gave a clear oil, 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) -phenyl] -Trimethylsilanylethoxymethyl) -3-imidazol-2-yl-1H-indazole (yield: 27%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 10.03 (s, 1H), 8.48 (d, 1H, J = 8.4 Hz) ), 7.29-7.48 (m, 2H), 7.13 (d, IH, J = 1.5 Hz), 6.73-6.78 (m, 2H), 5.73 (s, 2H), 5.28 (s, 2H), 3.78-3.86 m, 5H), 3.60 (t, 2H, J = 8.4Hz), 0.88-1.03 (m, 4H), 0.33 (s, 9H), -0.05 (s, 9H).
[614] Example 25 (f): 3- [4- (2-Hydroxyethylsulfanyl) -lH-benzoimidazol-2-yl] -6- (2-methoxy- Indazole
[615]
[616] Example 25 (f) was prepared in the same manner as in Example 25 (a) except that 2- (2,3-diamino-phenylsulfanyl) -ethanol was used instead of 3,4-diaminopyridine in Step (iv) And was prepared in the same manner as in Example 25 (a). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.51 (s, 1H), 13.02 (s, 1H), 9.59 (s, 1H), 8.45 (d, 1H, J = 8.4Hz), 7.61 (s J = 2.4 Hz), 6.48 (dd, 1H, J = 8.1, 2.4 Hz), 4.96 (m, 2H), 7.32-7.40 (m, 2H), 7.11-7.23 (s, 3H), 3.65 (br s, 2H), 3.33 (t, 2H, J = 6.9Hz). MS (ES) [m + H] / z yield 455, detection 455; MS (ES) [mH] / z yield 431, detection 431.
[617] The starting material was prepared in the following manner:
[618]
[619] Preparation of 2- (3-amino-2-nitro-phenylsulfanyl) -ethanol To a mixture of 1.12 g (6.5 mmol) of 3-chloro-2-nitro- aniline, 0.60 ml (8.6 ml) of 2-mercaptoethanol mmol) and 0.99 g (7.1 mmol) of potassium carbonate were added to dry DMF (15 ml), and the mixture was stirred at 130 캜 for 4 hours. The reaction solution was cooled and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc / hexanes) gave 1.29 g (93% yield) of 2- (3-amino-2-nitro-phenylsulfanyl) -ethanol as a light red solid. ^{1 H NMR (300MHz, DMSO-} d 6): δ7.20 (t, 1H, J = 8.1Hz), 6.80 (s, 2H), 6.73 (dd, 1H, J = 8.4, 0.9Hz), 6.63 (dd 2H, J = 6.0 Hz), 2.98 (t, 2H, J = 6.0 Hz).
[620] Preparation of 2- (2,3-diamino-phenylsulfanyl) -ethanol To a solution of 1.02 g (4.8 mmol) of 2- (3-amino-2-nitro- phenylsulfanyl) -ethanol in 25 ml of EtOAc was added 10% Pd C was reduced for 6 hours by hydrogenation using 45 psi of H ₂ in a solution of 180 mg. The reaction solution was filtered through celite, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (EtOAc) to obtain 762 mg of a pale yellow solid, 2- (2,3-diamino-phenylsulfanyl) %). _{^{1 H NMR (300MHz, CDCl 3}} ): δ6.98 (dd, 1H, J = 7.5, 1.5Hz), 6.60-6.72 (m, 2H), 3.65 (t, 2H, J = 5.7Hz), 3.55 (br s, 5H), 2.91 (t, 2H, J = 5.7 Hz).
[621] Example 25 (g): 3- (5-Methylcarbamoyl-1H-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxyphenyl)
[622]
[623] Example 25 (g) was prepared in the same manner as in Example 25 (a) except that 3,4-diamino-N-methyl-benzamide (Kumar, et al., J . Med. Chem., 27, 1083-89 (1984)). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.59 (s, 0.5H), 13.55 (s, 0.5H), 13.21 (s, 0.5H), 13.14 (s, 0.5H), 9.60 (s, 2H), 8.26 (s, 0.5H), 8.03 (s, 0.5H), 7.71-7.79 (m, 1.5H), 7.63 1H, J = 8.4 Hz), 7.35-7.40 (m, 1H), 7.21 (d, , 2.4Hz), 3.75 (s, 3H), 2.82 (d, 1.5H, J = 1.5Hz), 2.81 (d, 1.5H, J = 1.5Hz). MS (ES) [m + H] / z yield 414, detection 414; MS (ES) [mH] / z yield 412, detection 412.
[624] Example 25 (h): 3- (5-Dimethylamino-1 H-benzoimidazol-2-yl) -6- (2- methoxy-4-hydroxy-
[625]
[626] Example 25 (h) was prepared in the same manner as in Example 25 (a) except that 3,4-diamino-N, N-dimethyl-aniline (Cazaux et al., Can. J. Chem., 71, 1236-46 (1993)), was used. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.36 (s, 1H), 12.51 (br s, 1H), 9.58 (s, 1H), 8.42 (d, 1H, J = 8.4Hz), 7.59 ( 1H, J = 8.1 Hz), 6.87 (br d, 2H, J = 8.1 Hz), 7.31 (dd, ), 6.55 (d, IH, J = 2.1 Hz), 6.48 (dd, IH, J = 8.1, 2.1 Hz), 3.73 (s, 3H), 2.92 (s, 6H). MS (ES) [m + H] / z yield 400, detect 400; MS (ES) [mH] / z yield 398, detect 398.
[627] Example 25 (i): 3- (5-Aminosulfonyl-lH-benzoimidazol-2-yl) -6- (2-methoxy-
[628]
[629] Example 25 (i) was prepared in analogy to Example 25 (a) except that 3,4-diamino-benzenesulfonamide was used instead of 3,4-diaminopyridine in step (iv) of Example 25 (a) Were prepared in the same manner. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.67 (s, 0.5H), 13.64 (s, 0.5H), 13.39 (s, 0.5H), 13.35 (s, 0.5H), 9.60 (s, (D, 0.5H, J = 1.5 Hz), 7.99 (d, 0.5H, J = 1.5 Hz), 7.86 (M, 3H), 6.55 (d, 1H, J = 2.1Hz), 6.49 (d, 1H, J = 8.4 Hz), 7.62-7.72 , 1 H, J = 8.4, 2.1 Hz), 3.75 (s, 3H). MS (ES) [m + H] / z yield 436, detection 436; MS (ES) [mH] / z yield 434, detected 434.
[630] Example 25 (j): 3- (4-Methylcarbamoyl-1H-benzoimidazol-2-yl) -6- (2-methoxy-
[631]
[632] Example 25 (j) was prepared in the same manner as in Example 25 (a) except that 2,3-diamino-N-methyl-benzamide was used in place of 3,4-diaminopyridine in Step (iv) was prepared in the same manner as in a). ¹ H NMR (300 MHz, DMSO-d ₆ ): 13.71 (s, 1H), 13.46 (s, 1H), 9.85 (br d, 1H, J = 4.8 Hz), 9.61 1H, J = 8.4 Hz), 7.89 (dd, 1H, J = 7.5, 1.2 Hz), 7.66-7.72 (m, 2H), 7.47 1H, J = 7.8 Hz), 7.23 (d, IH, J = 8.1 Hz), 6.56 , 3H), 3.10 (d, 3H, J = 1.8 Hz). MS (ES) [m + H] / z yield 414, detection 414; MS (ES) [mH] / z yield 412, detection 412.
[633] 2,3-Diamino-N-methyl-benzamide is prepared in the following manner:
[634]
[635] (9.9 mmol) of 2-amino-3-nitro-benzoic acid and 1.33 g (19.8 mmol) of methylamine hydrochloride were dissolved in dry CH ₂ Cl ₂ 30 ml) / DMF (5 ml), and the mixture was stirred at 0 ° C. 2.83 g (14.8 mmol) of EDC and 4.92 ml (27.7 mmol) of DIEA were added to the reaction solution, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (8% MeOH / CHCl ₃₎ to yield a yellow solid 2-amino -N- methyl-3-nitro-benzamide to give the 1.42g (yield 74%). ¹ H NMR (300 MHz, DMSO-d ₆ ): 8.58 (br s, 1H), 8.23 (br s, 2H), 8.15 J = 8.1, 1.8 Hz), 6.68 (t, 1H, J = 8.1 Hz), 2.76 (d, 3H, J = 4.5 Hz).
[636] (7.2 mmol) of 2-amino-N-methyl-3-nitro-benzamide was placed in 25 ml of EtOAc and treated with 250 mg of 10% Pd-C and 250 mg of H ₂ with 50 psi of hydrogenation for 5 hours. Of the reaction solution was filtered through celite and the solvent removed in vacuo, and purified by silica gel chromatography (10% MeOH / CHCl ₃₎ light yellow solid of 2,3-diamino -N- methyl-benzamide 1.08mg (Yield: 91%). ¹ H NMR (300 MHz, CDCl ₃ ): 6.87 (dd, 1H, J = 7.8,1.5Hz), 6.76 (dd, 1H, J = 7.8,1.5Hz) ), 6.14 (br s, 4H), 4.28 (br s, 4H), 2.95 (d, 3H, J = 5.1 Hz).
[637] Example 26: Synthesis of 6- (4-hydroxy-3-methoxyphenyl) -3- [E-2- (4-glycylamino-phenyl) -ethenyl]
[638]
[639] Example 26 was prepared in the same manner as in Example 1 (a) using the starting material described below. ¹ H NMR (300 MHz, CDCl ₃ ): 8.29 (d, IH), 7.80 (m, 5H), 7.58 (m, 3H), 7.38 , 4.00 (s, 3H), 3.42 (s, 2H); LCMS (100% area) Rt = 3.44 min, (pos) [M + H] / z yield 415.1.
[640] The starting material is prepared in the following manner:
[641]
[642] (3-methoxy-4-methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] The compound prepared in step (v) was prepared in the same manner as in step (ii) of Example 10. _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.71 (s, 1H), 7.55 (m, 2H), 7.33 (m, 1H), 7.20 (m, 2H), 5.82 (s, 2H), 5.33 (s 2H), 4.02 (s, 3H), 3.64 (t, 2H), 3.59 (s, 3H), 0.95 (t, 2H), -0.03 (s, 9H).
[643]
[644] Methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was prepared in the same manner as in Example 11 (Iii): R _f sm 0.41, p 0.35 (ethyl acetate: hexane = 2: 8); _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.12 (d, 1H), 7.73 (s, 1H), 7.62 (m, 2H), 7.51 (m, 2H), 7.46 (m, 2H), 7.38 (m 3H), 3.62 (s, 3H), 3.82 (s, 3H), 0.98 (t, 2H) 2H), -0.02 (s, 9H).
[645] (iii)
[646]
[647] Methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was prepared from 3- was prepared in the same manner as in step (i) of ^{(a): 1 H NMR (} 300MHz, CDCl 3): δ10.33 (s, 1H), 8.34 (d, 1H), 7.82 (s, 1H), 7.65 ( 3H), 3.51 (s, 3H), 0.98 (s, 3H), 5.00 (s, 2H) , 2H), -0.02 (s, 9H).
[648]
[649] Methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was prepared from 3- (4-nitrostyryl) -6- Step (ii) of Example 33 (a) was performed except that 4-nitrobenzyltriphenylphosphonium bromide and lithium hexamethyldisilazide were used instead of 2-picolyltriphenylphosphonium chloride-potassium hydride. Was prepared in the same manner as LCMS (100% area) Rt = 6.89 min, (pos) [M + H] / z yield 562.4, detection 562.4.
[650]
[651] (3-methoxy-4-methoxymethoxy-phenyl) -1H-indazole was prepared in the same manner as in Example 11, except that FTIR (thin film) 3335, 3178, 2954, 1592, 1512, 1338, 1257, 1136, 1257, 1136, 987 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.22 (d, 2H, J = 8.8Hz), 8.02 (d, 1H, J = 8.5Hz), 7.70 (d, 2H, J = 8.8Hz), 7.58 ( (s, 3H), 7.45 (dd, 1H, J = 1.3, 8.5 Hz), 7.20 (m, 4H), 7.26 % area) Rt = 5.13 min, (pos) [M + H] / z yield 432.1, detection 432.1.
[652]
[653] (3-methoxy-4-methoxymethoxy-phenyl) -1H-indazole was prepared in a manner similar to that of Example 11, step (iv): R _f sm 0.39, p 0.26 (ethyl acetate: hexane = 6: 4); FTIR (thin film) 3366, 3210, 2954, 1608, 1517, 1465, 1412, 1259, 1157, 1077, 989, 912 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.11 (d, 1H), 7.63 (s, 1H), 7.50-7.15 (m, 8H), 6.71 (d, 2H), 5.36 (s, 2H), 3.97 (s, 3H), 3.61 (s, 3H); LCMS (100% area) Rt = 4.40 min, (pos) [M + H] / z yield 402.2, detection 402.2.
[654]
[655] 90 mg (0.224 mmol) of 3- (4-aminostyryl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1H-indazole was redissolved in 2 ml of dichloromethane, (1.12 mmol, 5 equiv), DMAP (3 equiv) and HATU 426 mg (5 equiv). The mixture was stirred for 30 minutes and then partitioned between ethyl acetate and water. The organic material was concentrated, dissolved in 5 ml of methanol, and treated with 100 mg of potassium carbonate. The mixture was heated at 50 &lt; 0 &gt; C for 3 days. The product was further partitioned with ethyl acetate and water to concentrate the organics and purify with silica (109 mg, 66%): _Rf cm 0.32, p 0.46 (ethyl acetate: hexane = 6: 4); _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.18 (bs, 1H), 8.03 (d, 1H, J = 8.1Hz), 7.56 (m, 5H), 7.40 (m, 3H), 7.20 (m, 3H ), 5.29 (s, 2H), 5.20 (s, 3H), 3.98 (s, 3H), 3.96 (d, 2H), 3.54
[656] Example 27 (a): 6-Phenyl-3-E-styryl-1H-indazole
[657]
[658] 345 mg (0.81 mmol) of 6-phenyl-3-styryl-1- [2- (trimethyl-silanyl) ethoxymethyl] -1H-indazole was dissolved in TBAF (dissolved in THF at a concentration of 1 M, (8.1 mmol) of ethylene diamine, and the mixture was heated at 70 DEG C for 2 hours. The solution was poured into 200 mL of brine and extracted with ethyl acetate (3 x 30 mL). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. ¹ H NMR (300 MHz, CDCl ₃ ): 8.10 (d, 1H). 1H-NMR (CDCl3) , J = 8.5 Hz); HRMS (FAB) [M + H] / z yield 297.1392, detection 297.1393. Analytical Output C (85.10), H (5.44), N (9.45). Detection: C (85.10), H (5.46), N (9.43).
[659] The starting material is prepared in the following manner:
[660]
[661] 476 mg (1.0 mmol) of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) ethoxymethyl] -lH-indazole prepared in step (i) of Example 14 was dissolved in dioxane ) (3㎖, removing the gas to sonic treatment and foaming _{argon), Pd (PPh 3) 4} 23mg (0.05mmol), phenylboronic 1.25㎖, the acid of 302mg (2.5mmol) and Na ₂ CO ₃ (2M aqueous solution, and Deg.] Was heated at 90 &lt; 0 &gt; C for 2 h, then the solution was diluted with 100 ml ethyl acetate and washed with brine (2 x 20 ml). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The filtrate was purified by silica gel chromatography to obtain a brown oil of 6-phenyl-3-styryl-1 - to give the [2-ethoxymethyl (trimethyl chamber not)] -1H- indazole 345mg (yield 81%): ¹ H NMR _{(300MHz, CDCl 3): δ8.09} (dd, 1H, J = 8.5, 0.7Hz), 7.75 (s, 1H), 7.70 (d, 1H, J = 7.0Hz), 7.64-7.58 (m, 2H) 2H), 7.50-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 J = 8.3 Hz), 1.12 (t, 2H, J = 8.3 Hz).
[662] Example 27 (b): 6- (3-Methoxyphenyl) -3-E-styryl-1H-indazole
[663]
[664] Example 27 (b) was prepared in the same manner as in Example 27 (a) except that 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step (i) of Example 27 (a). ^{1 H NMR (300MHz, MeOH-} d 4): δ8.16 (d, 1H, J = 8.4Hz), 7.70 (s, 1H), 7.67-7.61 (m, 2H), 7.60-7.43 (m, 3H) , 7.43-7.33 (m, 3H), 7.32-7.21 (m, 3H), 6.99-6.92 (m, 1H), 3.88 (s, 3H). HRMS (FAB) [M + Na] / z yield 349.1317, detected 349.1342. Calculating analyzed by _{0.1H 2 O C (80.50),} H (5.59), N (8.55). Detection: C (80.44), H (5.49), N (8.55).
[665] Example 27 (c): 6- (4-Methoxyphenyl) -3-Esteryl-lH-indazole
[666]
[667] Example 27 (c) was prepared in the same manner as in Example 27 (a) except that 4-methoxyphenylboronic acid was used instead of phenylboronic acid in step (i) of Example 27 (a). ^{1 H NMR (300MHz, DMSO-} d 6): δ13.20 (s, 1H), 8.23 (d, 1H, J = 8.4Hz), 7.76-7.64 (m, 1H), 7.76-7.64 (m, 5H) , 7.54 (s, IH), 7.50-7.37 (m, 3H), 7.33-7.25 (m, IH), 7.07 (d, 2H, J = 8.8Hz), 3.82 (s, 3H). HRMS (FAB) [M + H] / z yield 327.1497, detect 327.1502. Analytical Output C (80.96), H (5.56), N (8.58). Detection: C (80.71), H (5.42), N (8.47).
[668] Example 27 (d): Synthesis of naphth-l-yl-3-E-styryl-lH-indazole
[669]
[670] Example 27 (d) was prepared in the same manner as in Example 27 (a) except that 1-naphthaleneboronic acid was used instead of phenylboronic acid in the step (i) of Example 27 (a). ^{1 H NMR (300MHz, DMSO-} d 6): δ10.11 (s, 1H), 8.45 (d, 1H, J = 8.41), 7.97-7.87 (m, 3H), 7.66-7.37 (m, 13H), 7.35-7.28 (m, 1 H). HRMS (FAB) [M + Na] / z yield 369.1368, detected 369.1359. Analytical Output C (86.68), H (5.32), N (8.19). Detection: C (86.52), H (5.32), N (8.19).
[671] Example 27 (e): 6-Pyridin-3-yl-3-E-styryl-lH-indazole
[672]
[673] Example 27 (e) was prepared in the same manner as in Example 27 (a) except that 3-pyridinoboronic acid was used instead of phenylboronic acid in step (i) of Example 27 (a). ^{1 H NMR (300MHz, MeOH-} d 4): δ8.97 (s, 1H), 8.63 (d, 1H, J = 4.8Hz), 8.30 (d, 1H, H = 8.5 Hz), 8.27 (d, 1H (M, 2H), 7.40-7.32 (m, 2H), 7.72 (d, 1H). HRMS (FAB) [M + H] / z yield 298.1344, detection 298.1356. Calculated C (79.58), H (5.18), N (13.92) analyzed with 0.25 H ₂ O. Detection: C (79.53), H (5.16), N (13.80).
[674] Example 27 (f): 6-Pyridin-4-yl-3-E-styryl-1H-indazole
[675]
[676] Example 27 (f) was prepared in the same manner as in Example 27 (a) except that 4-pyridineboronic acid was used instead of phenylboronic acid in step (i) of Example 27 (a). ^{1 H NMR (300MHz, MeOH-} d 4): δ8.69 (bs, 2H), 8.30 (d, 1H, J = 8.5 Hz), 7.96 (s, 1H), 7.87 (d, 2H, J = 5.6Hz ), 7.75-7.68 (m, 3H), 7.68-7.50 (m, 2H), 7.50-7.42 (m, 2H), 7.40-7.31 (m, HRMS (FAB) [M + H] / z yield 298.1344, detection 298.1357. Calculating analyzed by _{0.3H 2 O C (79.34),} H (5.19), N (13.88). Detection: C (79.14), H (5.08), N (13.84).
[677] Example 27 (g): 6-Indole-4-yl-3-E-styryl-1H-indazole
[678]
[679] Example 27 (g) was prepared in the same manner as in Example 27 (a) except that 4-indoleboronic acid was used instead of phenylboronic acid in step (i) of Example 27 (a). ^{1 H NMR (300MHz, MeOH-} d 4): δ8.25 (d, 1H, J = 8.5 Hz), 7.85 (s, 1H), 7.75-7.67 (m, 3H), 7.67-7.52 (m, 2H) , 7.52-7.42 (m, 3H), 7.39-7.22 (m, 4H), 6.72 (d, 1H, J = 3.2 Hz). HRMS (FAB) [M + H] / z yield 336.1501, detected 336.1506. Calculating analyzed by _{0.3H 2 O C (78.97),} H (5.36), N (12.01). Detection: C (78.95), H (5.20), N (12.03).
[680] Example 27 (h): 6- [3-Ethoxy-4-hydroxyphenyl] -3-E-styryl-1H-indazole
[681]
[682] Example 27 (h) was prepared in the same manner as in Example 27 (a) except that 3-ethoxy-4- (2-trimethylsilanylethoxymethoxy) benzeneboronic acid was used instead of phenylboronic acid in Step (i) And was prepared in the same manner as in Example 27 (a). ¹ H NMR (300 MHz, CDCl ₃ ): 8.10 (d, IH, J = 8.7 Hz), 7.74 (s, IH), 7.74-7.16 ), 4.27 (q, 2H, J = 14.0 Hz), 1.54 (t, 3H, J = 14.0 Hz). HRMS (FAB) [M + H] / z yield 357.1603, detected 357.1611. Calculating analyzed by _{0.2H 2 O C (76.73),} H (5.71), N (7.78). Detection: C (76.72), H (5.91), N (7.63).
[683] The starting material was prepared as follows:
[684]
[685] Bromo-2-ethoxy-phenol (Smith et al., Soc. Pl., 1877-78 (1992)) was prepared in the same manner as in step (vi) ¹ H NMR (300 MHz, CDCl ₃ ): 7.82 (d, 1H, J = 8.0 Hz), 2H, J = 8.8 Hz), 7.72 (s, 1H), 7.31 (d, 1H, J = 8.1 Hz) 1.54 (t, 2H, J = 14.0 Hz), 0.99 (t, 2H, J = 16.8 Hz), 0.03 (s, 9H).
[686] Example 27 (i) Synthesis of 6- [3- (2-hydroxyethoxy) -4-hydroxyphenyl] -3-E-styryl-1H-indazole
[687]
[688] Example 27 (i) was prepared in the same manner as in step (i) - (iii) of Example 24 (c) except that in step (i) of Example 27 (a) 3- [2- (trimethylsilanylethoxymethoxy) - [alpha] -D-glucopyranosyloxy-phenol , prepared from 2- ethoxy] -4- (2-trimethylsilanyl chamber not-ethoxy-methoxy) -, except for using benzene boronic acid, which was prepared in the same manner as in example ^{27 (a) 1 H NMR (} 300MHz, DMSO-d 6). (d, 1H, J = 8.7 Hz), 7.73-7.17 (m, 11H), 6.92 (73.37), H (5.35), N (7.41), calculated for trifluoroacetic acid, Detection: C (73.11), H (5.33), N (7.39).
[689] Example 27 (j): 6- (3,4-Dimethoxyphenyl) -3-E-styryl-1H-indazole
[690]
[691] Example 27 (j) was prepared in the same manner as in Example 27 (a) except that 3,4-dimethoxyphenylboronic acid was used instead of phenylboronic acid in step (i) of Example 27 (a) . ^{1 H NMR (300MHz, DMSO-} d 6): δ8.01 (d, 1H, J = 8.1 Hz), 7.51-7.05 (m, 11H), 6.86 (d, 1H, J = 8.0 Hz), 3.58 (s , &Lt; / RTI &gt; 3H), 3.65 (s, 3H). HRMS (FAB) [M + H] / z yield 357.1598, detect 357.1508. Calculating analyzed by _{0.2H 2 O C (76.73),} H (5.71), N (7.78). Detection: C (76.45), H (5.70), N (7.68).
[692] Example 27 (k): 6- (2-Methoxypyridin-5-yl) -3-E-
[693]
[694] (2-methoxypyridin-5-yl) -3 - ((E) -styryl) (2-methoxypyridin-5-yl) -3-E-styryl-1H-indazole. _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.53 (d, 1H, J = 2.1 Hz), 8.15 (d, 1H, J = 9.2 Hz), 7.97 (dd, 1H, J = 2.6, 8.6Hz), 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, J = 8.6 Hz). HRMS (FAB) [M + H] / z yield 328.1450, detect 328.1462. Analytical Output C (77.04), H (5.23), N (12.83). Detection: C (77.00), H (5.28), N (12.65).
[695] The starting material was prepared as follows:
[696]
[697] 5-Bromo-2-methoxy pyridine 2.00g (6.10mmol), hexamethyl ditin (hexamethylditin) 1.15g (6.10mmol) and _{Pd (PPh 3) 4 0.28g (} 0.24mmol) in dioxane and a solution mixture of 10 Ml, degassed, and refluxed for 16 hours. The mixture in the 6-iodine -3 - ((E) - styryl) -1- (2-trimethylsilanyl chamber not-ethoxymethyl) -1H- indazole was added to 2.90g (6.10mmol) and Pd (PPh _{3) 4} was added and the reaction mixture was refluxed for 16 hours. The mixture was diluted with 150 mL of ethyl acetate and washed with 30 mL of brine. The organic material was dried over MgSO ₄ , concentrated under reduced pressure, and purified by silica gel chromatography to obtain 6- (2-methoxypyridin-5-yl) -3 ((E) -styryl) -1- Silanyl-ethoxymethyl) -1H-indazole (yield: 40%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ8.51 (d, 1H, J = 2.5 Hz), 8.50 (d, 1H, J = 9.1 Hz), 7.93 (dd, 1H, J = 2.5, 8.6Hz), 2H), 3.63 (t, 2H, J = 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 8.3 Hz), 0.93 (t, 2H, J = 8.3 Hz), -0.03 (s, 9H).
[698] Example 28 (a): 6- (3-Hydroxyphenyl) -3-E-styryl-1H-indazole
[699]
[700] 100 mg (0.3 mmol) of 6- (3-methoxyphenyl) -3-E-styryl-1H-indazole prepared in Example 27 (b) was cooled to -78 ° C and BBr ₃ (CH ₂ Cl ₂ Gt; 1 M &lt; / RTI &gt; concentration, 1.8 mL, 1.8 mmol). The solution was allowed to stand at -78 占 폚 for 15 minutes, then heated to 0 占 폚 and left for 3 hours. The solution was added with 10 mL of saturated aqueous sodium hydrogen carbonate, and then diluted with 50 mL of ethyl acetate. The organic layer was washed with 20 ml of brine, concentrated under reduced pressure and then purified by silica gel chromatography to obtain 55 mg (yield 59%) of 6- (3-hydroxyphenyl) -3-E-styryl-1H- . ^{1 H NMR (300MHz, MeOH-} d 4): δ8.16 (d, 1H, J = 8.5Hz), 7.71-7.62 (m, 3H), 7.61-7.44 (m, 3H), 7.43-7.35 (m, 2H), 7.33-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.85-6.79 1H, J = 8.4 Hz), 7.73 (d, 2H, J = 7.3), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 2H, J = 8.6 Hz).
[701] Example 28 (b): 6- (4-Hydroxyphenyl) -3-E-styryl-1H-indazole
[702]
[703] 6- (4-methoxyphenyl) -3-E-styryl-1H-indazole prepared in Example 27 (c) was treated in the same manner as in Example 28 (a) -3-E-styryl-1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, J = 8.4 Hz), 7.73 (d, 2H, J = 7.3 Hz ), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d, 2H, J = 8.6 Hz). HRMS (FAB) [M + Na] / z yield 313.1341, detection 313.1347. Calculating analyzed by _{0.5H 2 O C (78.48),} H (5.33), N (8.72). Detection: C (78.35), H (5.26), N (8.49).
[704] Example 28 (c): 6- (2-Hydroxypyridin-5-yl) -3-E-styryl-1H-indazole
[705]
[706] 6- (2-methoxypyridin-5-yl) -3-E-styryl-1H-indazole prepared in Example 27 (k) Hydroxypyridin-5-yl) -3-E-styryl-1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.22 (d, 1H, J = 8.4 Hz), 7.96 (dd, 2H, J = 2.6, 9.65 Hz), 7.81 (d, 1H, J = 2.0 Hz ), 7.74-7.30 (m, 9H), 6.50 (d, 1H, J = 9.4 Hz). HRMS (FAB) [M + H] / z yield 314.1293, detect 314.1280. C (72.69), H (4.86), N (12.59) analyzed with 0.1 trifluoroacetic acid. Detection: C (72.77), H (4.81), N (12.65).
[707] Example 28 (d): 6- (3,4-Dihydroxyphenyl) -3-E-styryl-1H-indazole
[708]
[709] 6- (3,4-dimethoxyphenyl) -3-Esteryl-1H-indazole prepared in Example 27 (j) was treated in the same manner as in Example 28 (a) Dihydroxyphenyl) -3-E-styryl-1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ9.09 (br s, 1H), 9.07 (br s, 1H), 8.20 (d, 1H, J = 8.5), 7.73 (d, 2H, J = 7.5 1H, J = 8.2 Hz), 7.56 (d, 2H, J = 10.1 Hz), 7.53 (s, 1H), 7.43-7.29 6.86 (d, 1 H, J = 8.2 Hz). HRMS (FAB) [M + H] / z yield 329.1290, detect 329.1274. Calculating analyzed by _{1.0H 2 O C (66.79),} H (4.73), N (7.15). Detection: C (66.54), H (4.56), N (7.36).
[710] Example 29 (a): 6-Pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl]
[711]
[712] (2-trimethylsilanyl-ethoxymethyl) -1H-indazole was reacted with 6-pyrid-4-yl-3- pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1H-indazole in the same manner as in (a). _{^{1 H NMR (300MHz, CDCl 3}} ): δ13.55 (s, 1H), 8.68 (dd, 2H, J = 4.6, 1.6Hz), 8.21 (d, 1H, J = 8.5 Hz), 7.96 (s, 1H 2H), 7.81 (dd, 2H, J = 4.5, 1.6 Hz), 7.66 (dd, 1H, J1 = 8.5, 1.4 Hz), 7.58 -7.32 (m, 1 H). MS (FAB) [M + H] / z yield 366, detection 366. Calculated C (63.40), H (3.83), N (11.09) as analyzed by 0.7H ₂ O. Detection: C (63.63), H (3.75), N (10.83).
[713] The starting material was prepared as follows:
[714]
[715] 1.20 g (5 mmol) of 2,6-dichlorobenzyl bromide were mixed with 1.66 g (10 mmol) of triethyl phosphite and heated at 150 ° C for 2 hours. The reaction mixture was distilled at 160 DEG C under reduced pressure (10 mmHg) to remove residual triethylphosphite to obtain 1.46 g (yield: 100%) of diethyl 2,6-dichloro-benzoylphosphonic acid as a transparent liquid phase, &Lt; / RTI &gt; _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.33-7.28 (m, 2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, J = 22.4Hz) , 1.27 (t, 6H, J = 7.0 Hz).
[716]
[717] A solution of 2.13 g (5.0 mmol) of 6-pyrid-4-yl-3-E-styryl-1- (2-trimethylsilanylethoxymethyl) -1H- Lt; RTI ID = 0.0 &gt; -78 C &lt; / RTI &gt; for 15 minutes. The solution was bubbled with argon for 10 minutes at -78 &lt; 0 &gt; C and 1.46 ml (20 mmol) of dimethylsulfoxide were added. The solution was allowed to warm to room temperature and then allowed to stand for 2 hours, then purified with 300 ml of brine and extracted with ethyl acetate (3 x 100 ml). The organic was dried over MgSO ₄ , evaporated under reduced pressure and then purified by silica gel chromatography to obtain 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazol- 2.2 g (yield 75%) of the aldehyde was obtained. _{^{1 H NMR (300MHz, CDCl 3}} ): δ10.39 (s, 1H), 8.75 (d, 2H, J = 1.6 Hz), 8.45 (d, 1H, J = 2.8 Hz), 7.91 (s, 1H), (S, 2H), 3.63 (t, 2H, J = 2.7 Hz), 0.93 (t, 2H, J = 2.8 Hz), 0.00 (s, 9H).
[718]
[719] A solution of 582 mg (2.0 mmol) of (2,6-dichlorobenzyl) phosphinic acid diethyl ester dissolved in 15 ml of DMF was cooled to 0 占 폚 and treated with 160 mg of NaH (60% dissolution in mineral oil, 4.0 mmol). The solution was allowed to stand at 0 ° C for 30 minutes and then treated with 353 mg (1.0 mmol) of 6-pyridin-4-yl-1- (2-trimethylsilanyl- ethoxymethyl) -1H-indazole-3-carbaldehyde Respectively. The solution was allowed to warm to room temperature over 1 hour and then left at room temperature for 2 hours. The solution was poured into 250 ml of brine and extracted with ethyl acetate (3 x 80 ml). The organic material was dried over MgSO ₄ , concentrated under reduced pressure and purified by silica gel chromatography to obtain a yellow oil, 6-pyrid-4-yl-3-E- [2- (2,6- dichlorophenyl) (2-trimethylsilanylethoxymethyl) -1H-indazole (yield: 67%). _{^{1 H NMR (300MHz, CDCl 3}} ): δ7.72 (dd, 2H, J = 4.6, 1.5Hz), 8.16 (d, 1H, J = 8.5 Hz), 7.84 (s, 1H), 7.62 (ss, 2H 1H, J = 8.5, 1.5 Hz), 7.39 (d, 1H, J = 8.1 Hz), 7.18-7.12 (m, 3.64 (t, 2H, J = 8.3 Hz), 0.92 (t, 2H, J = 8.3 Hz), 0.00 (s, 9H).
[720] Example 29 (b): 6-Pyrid-4-yl-3-E- [2- (3-methylphenyl) -ethenyl]
[721]
[722] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-methylphenyl) ethenyl] -1H-indazole. ¹ H NMR (300 MHz, MeOH-d ₄ ): 8.88 (d, 1H, J = 6.7 Hz), 8.41-8.35 8.6, 1.6 Hz), 7.67-7.48 (m, 4H), 7.35 (t, 1H, J = 7.6Hz), 7.22-7.17 (m, 1H), 4.88 (s, 3H). MS (FAB) [M + H ] / z calculated 312, detection 312. 0.2H ₂ O, calculated by analysis with acetic acid to 1.1 trifluoromethyl C (63.27), H (4.23 ), N (9.54). Detection: C (63.08), H (4.18), N (9.80).
[723] Example 29 (c): 6-Pyrid-4-yl-3-E- [2- (4- chlorophenyl) ethenyl]
[724]
[725] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-methylphenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.40 (s, 1H), 8.67 (dd, 2H, J = 4.6, 1.6Hz), 8.33 (d, 1H, J = 8.5 Hz), 7.92 (s 2H), 7.78 (d, 2H, J = 8.5 Hz), 7.67-7.56 (m, 3H) . Calculating analyzed by _{0.15H 2 O C (71.81),} H (4.31), N (12.56). Detection: C (71.85), H (4.26), N (12.48).
[726] Example 29 (d): 6-Pyrid-4-yl-3-E- [2- (biphenyl-4-yl) ethenyl]
[727]
[728] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (biphenyl-4-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.40 (s, 1H), 8.68 (d, 2H, J = 4.6, 1.5Hz), 8.35 (d, 1H, J = 8.5Hz), 7.93 (s 1H), 7.87-7.79 (m, 4H), 7.73 (d, 4H, J = 8.1 Hz), 7.66-7.60 (m, 3H), 7.45 (m, 2H), 7.41-7.34 (m, MS (FAB) [M + H ] / z calculated 374, a detection output 374. 0.20H analyzed by _{2 O C (82.82), H} (5.19), N (11.15). Detection: C (82.82), H (5.19), N (11.16).
[729] Example 29 (e): 6-Pyrid-4-yl-3-E- [2- (3-methoxyphenyl) ethenyl]
[730]
[731] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-methoxyphenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.39 (s, 1H), 8.67 (d, 2H, J = 5.3 Hz), 8.33 (d, 2H, J = 8.5Hz), 7.92 (s, 1H ), 7.81 (dd, 2H, J = 4.6,1.5Hz), 7.65-7.54 (m, 3H), 7.35-7.28 (m, 3H), 3.83 (s, 3H). MS (FAB) [M + H ] / z calculated 328, 328. detection calculation was analyzed in _{0.20 H 2 O C (76.20)} , H (5.30), N (12.70). Detection: C (76.17), H (5.34), N (12.65).
[732] Example 29 (f): 6-Pyrid-4-yl-3-E- [2- (pyrid-2- yl) ethenyl]
[733]
[734] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (pyrid-2-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.68 (dd, 2H, J = 4.5, 1.6 Hz), 8.62 (d, 1H, J = 3.8 Hz), 8.33 (d, 1H, J = 8.5Hz ), 7.99 (d, 1H, J = 16.4 Hz), 7.94 (s, 1H), 7.86-7.78 (m, 3H), 7.73-7.57 (m, 3H), 7.32-7.26 (m, Calculating analyzed by _{0.05H 2 O C (76.26),} H (4.75), N (18.72). Detection: C (76.22), H (4.79), N (18.76).
[735] Example 29 (g): 6-Pyrid-4-yl-3-E- [2- (3-fluorophenyl) ethenyl]
[736]
[737] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-fluorophenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.40 (s, 1H), 8.68 (dd, 2H, J = 4.5 1.6Hz), 8.34 (d, 1H, J = 8.4Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J1 = 4.5, 1.6 Hz), 7.74-7.52 (m, 5H), 7.49-7.40 (m, 1H), 7.16-7.07 (m, 1H). MS (FAB) [M + H] / z yield 316, detection 316. Anal. Yield C (76.17), H (4.48), N (13.33). Detection: C (76.07), H (4.53), N (13.36).
[738] Example 29 (h): 6-Pyrid-4-yl-3-E- [2- (2- fluorophenyl) ethenyl]
[739]
[740] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (2-fluorophenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.43 (s, 1H), 8.66 (dd, 2H, J = 4.5, 1.6Hz), 8.23 (d, 1H, J = 8.2Hz), 7.98-7.90 (m, 2H), 7.80 (dd, 2H, J = 4.5,1.7Hz), 7.73-7.54 (m, 3H), 7.40-7.31 (m, 1H), 7.30-7.21 (m, 2H). MS (FAB) [M + H] / z yield 316, detection 316. Anal. Yield C (76.17), H (4.48), N (13.33). Detection: C (76.12), H (4.51), N (13.29).
[741] Example 29 (i): 6-Pyrid-4-yl-3-E- [2- (3- chlorophenyl) ethenyl]
[742]
[743] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-chlorophenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.42 (s, 1H), 8.68 (dd, 2H, J = 4.5, 1.6Hz), 8.35 (d, 1H, J = 8.1Hz), 7.92 (s 1H), 7.86 (s, 1H), 7.82 (dd, 2H, J = 4.5, 1.7 Hz), 7.74-7.51 (m, 4H), 7.43 (t, 1H, J = 7.8Hz), 7.37-7.21 m, 1H). MS (FAB) [M + H] / z yield 332, detection 332. Anal. Yield C (72.40), H (4.25), N (12.67). Detection: C (72.52), H (4.28), N (12.57).
[744] Example 29 (j): 6-Pyrid-4-yl-3-E- [2- (2-methylthiazol-4-yl) ethenyl]
[745]
[746] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (2-methylthiazol-4-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.38 (s, 1H), 8.67 (dd, 2H, J = 4.5, 1.6Hz), 8.25 (d, 1H, J = 8.5Hz), 7.92 (s 1H), 7.81 (dd, 2H, J = 4.5, 1.6 Hz), 7.70-7.50 (m, 4H), 2.72 (s, 3H). MS (FAB) [M + H] / z yield 319, detection 319. 0.15 Calculated C (65.51), H (4.25), N (16.70) analyzed with trifluoroacetic acid. Detection: C (65.56), H (4.37), N (16.53).
[747] Example 29 (k): 6-Pyrid-4-yl-3-E- [2- (naphthalen-2-yl) ethenyl]
[748]
[749] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (naphthalen-2-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ13.40 (s, 1H), 8.68 (dd, 2H, J = 4.6, 1.4Hz), 8.39 (d, 1H, J = 8.5Hz), 8.17 (s (Dd, 1H, J = 8.5, 1.4 Hz), 7.60 (s, 2H) 7.46 (m, 4H). MS (FAB) [M + H] / z yield 348, detected 348. Calculated C (67.10), H (3.89), N (9.00) analyzed with 1.05 trifluoroacetic acid. Detection: C (67.20), H (3.93), N (9.05).
[750] Example 29 (1): 6-Pyrid-4-yl-3-E- [2- (2,3- difluorophenyl) ethenyl]
[751]
[752] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (2,3-difluorophenyl) ethenyl] -1H-indazole. _{^{1 H NMR (300MHz, CDCl 3}} + MeOH-d 4): δ8.68 (d, 2H, J = 5.6 Hz), 8.02 (d, 1H, J = 8.5 Hz), 7.70 (s, 1H), 7.58 ( dd, 2H, J = 4.8, 1.5Hz), 7.57-7.39 (m, 3H), 7.38-7.31 (m, 1H), 7.06-6.96 (m, 2H). MS (FAB) [M + H] / z yield 334, detected 334. Calculated C (69.08), H (4.23), N (12.08) as analyzed by 0.80 H ₂ O. Detection: C (68.77), H (3.93), N (11.85).
[753] Example 29 (m): 6-Pyrid-4-yl-3-E- [2- (3,5- difluorophenyl) ethenyl]
[754]
[755] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3,5-difluorophenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, MeOH-} d 4): δ8.69 (d, 2H, J = 6.3 Hz), 8.34 (d, 1H, J = 8.5 Hz), 7.97 (s, 1H), 7.97 (d, 2H 1H, J = 6.3 Hz), 7.71 (d, 1H, J = 10.0 Hz), 7.62 (s, 1H). MS (ES) [M + H] / z yield 334, detected 334. Anal. Yield C (72.06), H (3.93), N (12.61). Detection: C (72.20), H (4.01), N (12.58).
[756] Example 29 (n): 6-Pyrid-4-yl-3-E- [2- (biphenyl-3- yl) ethenyl]
[757]
[758] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (biphenyl-3-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.68 (d, 2H, J = 6.1 Hz), 8.39 (d, 1H, J = 8.5), 8.04 (s, 1H), 7.92 (s, 1H) , 7.82 (d, 2H, J = 6.2Hz), 7.79-7.37 (m, 11H). MS (ES) [M + H] / z yield 374, detected 374. Anal. Yield C (83.62), H (5.13), N (11.25). Detection: C (83.47), H (5.08), N (11.32).
[759] Example 29 (o): 6-Pyrid-4-yl-3-E- [2- (2,6- difluorophenyl) ethenyl]
[760]
[761] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (2,6-difluorophenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, MeOH-} d 4): δ8.69 (d, 2H, J = 6.3 Hz), 8.21 (d, 1H, J = 8.6 Hz), 7.97 (s, 1H), 7.88 (d, 2H (D, IH, J = 8.6 Hz), 7.65 (d, IH, J = 17.1 Hz), 7.40-7.35 7.13-7.08 (m, 2H). MS (ES) [M + H ] / z calculated 334, a detection output 334. analyzed by _{0.1 H 2 O C (71.67)} , H (3.97), N (12.54). Detection: C (71.37), H (3.90), N (12.31).
[762] Example 29 (p): 6-Pyrid-4-yl-3-E- [2- (3- trifluoromethoxyphenyl) ethenyl] -1H-
[763]
[764] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-trifluoromethoxyphenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.84 (d, 2H, J = 6.4 Hz), 8.43 (d, 1H, J = 8.5Hz), 8.19 (d, 2H, J = 6.4 Hz), 8.07 (s, 1 H), 7.81-7.27 (m, 5 H), 7.78 (s, 1 H). Calculated C (55.76), H (3.05), N (8.48) as analyzed by 1.0 trifluoroacetic acid. MS (ES) [M + H] Detection: C (55.84), H (3.09), N (8.45).
[765] Example 29 (q): 6-Pyrid-4-yl-3-E- [2- (benzimidazol-2- yl) ethenyl]
[766]
[767] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (benzimidazol-2-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.69 (d, 2H, J = 6.1 Hz), 8.25 (d, 1H, J = 8.5 Hz), 8.03 (d, 1H, J = 16.7 Hz), 1H), 7.97 (s, 1H), 7.84 (d, 2H, J = 6.2), 7.72 (d, 1H, J = 8.5 Hz), 7.60-7.57 , 7.22-7. 19 (m, 2H). Calculated C (52.77), H (3.08), N (12.31) analyzed with 2.0 trifluoroacetic acid and 0.2 H ₂ O. MS (ES) [M + H] Detection: C (52.59), H (3.17), N (12.18).
[768] Example 29 (r): 6-Pyrid-4-yl-3-E- [2- (3,4-methylene dioxyphenyl) ethenyl]
[769]
[770] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3,4-methylenedioxyphenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6): δ8.67 (d, 2H, J = 6.1 Hz), 8.30 (d, 1H, J = 8.5 Hz), 7.89 (s, 1H), 7.81 (d, 2H (D, 1H, J = 6.1 Hz), 7.61 (d, 1H, J = 9.9 Hz), 7.46-7.42 ), 6.05 (s, 2H). MS (ES) [M + H] / z yield 342, Detection 342. Anal. Yield C (73.89), H (4.43), N (12.31). Detection: C (73.74), H (4.52), N (12.40).
[771] Example 29 (s): 6-Pyrid-4-yl-3-E- [2- (2,5-difluorophenyl) ethenyl]
[772]
[773] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (2,5-difluorophenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, MeOH-} d 4): δ8.53 (d, 2H, J = 6.0 Hz), 8.03 (d, 1H, J = 8.5 Hz), 7.60 (d, 2H, J = 6.2 Hz), 7.56-7.35 (m, 3H), 7.34-7.26 (m, 1H), 7.03-6.93 (m, 1H), 6.90-6.81 (m, 1H). MS (ES) [M + H] / z yield 334, detected 334. Calculated C (70.91), H (4.05), N (12.37) analyzed with 0.30 H ₂ O. Detection: C (70.97), H (4.17), N (12.37).
[774] Example 29 (t): 6-Pyrid-4-yl-3-E- [2- (lH-pyrrol-
[775]
[776] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (lH-pyrrol-2-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, MeOH-} d 4): δ8.60 (d, 2H, J = 6.3Hz), 8.13 (d, 1H, J = 8.5Hz), 7.86 (s, 1H), 7.79 (d, 2H (D, 1H, J = 16.7 Hz), 6.87 (d, 1H, J = 6.82 (m, 1H), 6.40-6.35 (m, 1H), 6.16 (t, 1H, J = 2.9Hz). Calculated C (72.07), H (6.21), N (16.05) analysis with 0.5 ethyl acetate, 0.3 tetrahydrofuran, 0.1 hexane, 0.1 ethylenediamine, . Detection: C (71.95), H (6.20), N (15.76).
[777] The starting material is prepared in the following manner:
[778]
[779] (i) A solution of 9.5 g (100 mmol) of 1H-pyrrole-2-carbaldehyde and 500 ml of THF was cooled in a cooling bath. To the reaction mixture, 19.2 g (200 mmol) of Bu ^t ONa was added and stirred at 0 ° C for 1 hour. Then 32.7 mg (150 mmol) of MtsCl was added and the mixture was warmed to room temperature and left at room temperature for 2 hours. To this solution was added 100 ml of saturated aqueous NH ₄ Cl and 2 l of brine was added. The mixture was extracted with EtOAc (3 x 300 mL). The resulting organic layer was concentrated under reduced pressure and then dried in MgSO _4. The oil thus obtained was purified by silica gel chromatography to obtain 15.7 g (yield: 57%) of 1- (2,4,6-trimethyl-benzenesulfonyl) -1H-pyrrole-2-carbaldehyde as a light yellow oil . _{^{1 H NMR (CDCl 3):}} δ9.50 (s, 1H), 7.79-7.74 (m, 1H), 7.12 (dd, 1H, J = 3.7, 1.8Hz), 6.95 (s, 2H), 6.38 (t , 1H, J = 3.4 Hz), 2.50 (s, 6H), 2.30 (s, 3H).
[780]
[781] (20 mmol) of LiBH ₄ at room temperature was added to a solution of 2.77 g (10 mmol) of 1- (2,4,6-trimethyl-benzenesulfonyl) -1H- And then left at room temperature for 1 hour. To this mixture was added 10 ml of methanol, 600 ml of brine was added, and the mixture was extracted with EtOAc (3 x 200 ml). The resulting organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The oil thus formed was purified by silica gel column to obtain 2.43 g (yield 87%) of [1- (2,4,6-trimethyl-benzenesulfonyl) -1 H- pyrrol-2-yl] . _{^{1 H NMR (CDCl 3):}} δ7.17 (dd, 1H, J = 3.3, 1.8 Hz), 6.99 (s, 2H), 6.28-6.23 (m, 1H), 6.18 (t, 1H, J = 3.3 Hz ), 4.42 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).
[782]
[783] (iii) To a solution of 1.4 g (5.0 mmol) of [1- (2,4,6-trimethyl-benzenesulfonyl) -1H-pyrrol-2-yl] -methanol in 25 ml of CHCl ₃ was cooled in a cooling bath . Then 1.1 ml (15 mmol) of SOCl ₂ was slowly added. The solution was warmed to room temperature, then left to stand for another 45 minutes and then concentrated under reduced pressure to obtain 1.5 g of a brown solid, 2-chloromethyl-1- (2,4,6-trimethyl-benzenesulfonyl) ). _{^{1 H NMR (CDCl 3):}} δ7.28 (dd, 1H, J = 3.3, 1.7Hz), 6.98 (s, 2H), 6.38-6.34 (m, 1H), 6.19 (t, 1H, J = 3.4 Hz ), 4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).
[784] Example 29 (u): 6-Pyrid-4-yl-3-E- [2- (3-methylcarbamoylmethoxyphenyl) ethenyl]
[785]
[786] 6-pyridm-4-yl-l- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was prepared in the same manner as in Example 29 (a) Yl-3-E- [2- (3-methylcarbamoylmethoxyphenyl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, MeOH-} d 4): δ8.68 (d, 2H, J = 5.9 Hz), 8.51 (br s, 1H), 8.37 (d, 1H, J = 8.5 Hz), 8.19 (s, 1H), 7.93 (s, 1H), 7.87 (d, 1H, J = 7.7 Hz), 7.85 m, 3 H), 7.51 (t, 1 H, J = 7.6 Hz). MS (ES) [M + H ] / z calculated 355, a detection output 355. analyzed by 0.4 trifluoroacetic _{acid, 0.50 H 2 O C (69.67} ), H (4.98), N (14.26). Detection: C (69.78), H (5.18), N (14.08).
[787] Example 30 (a) Synthesis of 6- [3-benzamidophenoxy] -3-E- [2- (thien-2-yl) ethenyl]
[788]
[789] Example 30 (a) was prepared in the same manner as in Example 6 (a) except that (E) -3-thiophen-2-yl-pyridine was used instead of 3- (4- chlorophenyl) acryloyl chloride in step (i) The title compound was prepared in the same manner as in Example 6 (a) except that acryloyl chloride was used. _{^{1 H NMR (DMSO-d 6}} ): δ13.05 (s, 1H), 10.33 (s, 1H), 8.19 (d, 1H, J = 8.8 Hz), 7.92 (d, 2H, J = 6.9 Hz), 1H, J = 8.1 Hz), 7.20 (d, 1H, J = 16.5 Hz), 7.65-7.49 (m, 6H), 7.40 J = 16.5 Hz), 7.10 (m, 1H), 7.04 (s, 1H), 6.98 (d, 1H, J = 8.8 Hz), 6.86 (s, 1H, J = 9.8 Hz). Analysis for C ₂₆ H ₁₉ N ₃ O ₂ S 0.6H ₂ O: C, 69.65; H, 4.54; N, 9.37; S, 7.15. Detection: C, 69.77; H, 4.45; N, 9.52; S, 7.02.
[790] Example 30 (b): 6- [3- (1-Acetylpiperidin-4-ylcarboxamido) phenoxy] -3-E- [2- (4- chlorophenyl) ethenyl] Indazole
[791]
[792] Example 30 (b) was prepared in the same manner as in Example 6 (a) except that 1-acetyl-piperidine-4-carboxylic acid and HATU were used in place of benzoyl chloride in step (ii) &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) (J = 8.6 Hz) · 7.76, (d, J = 8.6 Hz), 7.53 (d, J = 6.2 Hz), 7.46 (d, J = 8.4 Hz), 7.37 (m J = 7.7 Hz), 4.38 (m, 1H), 3.85 (m, 1H), 3.09 (d, J = 2H), 1.99 (s, 3H), 1.77 (m, 2H), 1.55 (m, 1H), 1.37 (m, 1H). Anal. Calcd. For C ₂₉ H ₂₇ ClN ₄ O ₃ .1.3H ₂ O: C, 64.69; H, 5.54; N, 10.41. Detection: C, 64.64; H, 5.51; N, 10.23.
[793] Example 30 (c): Synthesis of 6- [3-benzamidophenoxy] -3-E- [2- (fur-2-yl) ethenyl]
[794]
[795] Example 30 (c) was prepared in the same manner as in (E) -3-furan-2-yl-acryloyl chloride (Collect, Czech. , 52, 409-24 (1987)) was prepared in the same manner as in Example 6 (a). _{^{1 H NMR (DMSO-d 6}} ): δ13.00 (s, 1H), 10.32 (s, 1H), 8.14 (d, 1H, J = 8.8 Hz), 7.91 (d, 2H, J = 7.0 Hz), 2H, J = 16.7 Hz), 7.04 (s, 1H), 6.98 (d, 1H), 7.70 (s, 1H), 7.70-7.51 1H, J = 8.7 Hz), 6.86 (d, 1H, J = 8.0 Hz), 6.65 (s, 1H, finely separated), 6.60 (s, 1H, finely separated). Anal. Calcd. For C ₂₆ H ₁₉ N ₃ O ₂ .0.7H ₂ O: C, 71.94; H, 4.74; N, 9.68. Detection: C, 72.17; H, 4.83; N, 9.44.
[796] Example 30 (d): 6- [3- (Indol-4-ylcarboxamido) phenoxy] -3-E-
[797]
[798] Example 30 (d) was prepared in the same manner as in Example 30 (a) except that 3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) (A), except that 1H-indole-4-carboxylic acid was used in place of benzoic acid, instead of benzoic acid, in the same manner as in Example 6 Respectively. ¹ H NMR (DMSO-d ₆ ) 揃 12.99 (s, 1H), 11.33 (s, 1H), 10.24 (s, 1H), 8.22 (d, 1H, J = 8.7 Hz), 7.72-7.38 ), 7.30 (d, IH, J = 7.1 Hz), 7.19 (m, 2H), 7.04 (m, 3H), 6.82 (m, 2H). Anal. Calcd for C ₃₀ H ₂₂ N ₄ O ₂ .6H ₂ O: C, 74.86; H, 4.86; N, 11.64. Detection: C, 74.90; H, 5.01; N, 11.33.
[799] Example 30 (e): 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol-5-yl) -carboxamido) phenoxy] Sol
[800]
[801] Example 30 (e) was prepared in the same manner as in Example 30 (a) except that 3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) (1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used in place of benzoic acid, instead of 2-chloro- 6 (a).
[802] Example 31 (a): 6- [3-Benzamidophenoxy] -3-E- [2- (pyridin-2- yl) ethenyl] -1H-indazole
[803]
[804] To a solution of 6- [3-benzamidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -4,5-dihydro-1H-indazole 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (386 mg, 1.7 mmol) was added to a solution of 492 mg (1.13 mmol) The reaction mixture was stirred for 30 minutes at room temperature was added the following, a saturated NaHCO ₃ solution and EtOAc. The layers were separated and re-extracted with EtOAc, and the resulting organic layer was successively washed with saturated NaHCO ₃ and saturated NaCl solution, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel eluting with CH ₂ Cl ₂ / EtOAc: MeOH (1: 1: 0.1). The oil obtained above was triturated from EtOAc / hexane to give the tan solid 6- [3- Benzimidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole. _{^{1 H NMR (DMSO-d 6}} ) δ13.12 (s, 1H), 10.30 (s, 1H), 8.60 (d, 1H, J = 3.8 Hz), 8.22 (d, 1H, J = 8.8 Hz), 7.93 (m, 3H), 7.82 (t, 1H, J = 7.7Hz), 7.68-7.49 (m, 7H), 7.40 1H), 7.03 (s, 1H), 7.03 (d, 1H, J = 8.7 Hz), 6.87 (d, 1H, J = 8.1 Hz, finely separated). Anal. Calcd for C ₂₇ H ₂₀ N ₄ O ₂ .065 EtOAc: C, 72.59; H, 5.19; N, 11.44. Detection: C, 72.34; H, 5.11; N, 11.82.
[805] The starting material was prepared in the following way:
[806]
[807] To a solution of 4.00 g (10.9 mmol) of 3- [3- (benzhydrylidene) -amino) -phenoxy] -cyclohex-2-enone in 20 ml of THF was added LiHMDS (dissolved in 1.0 M in THF (E) -3-pyridin-2-yl-acryloyl chloride hydrochloride was added thereto, followed by stirring at -78 ° C for 30 minutes. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (3x). The resulting organic layer was concentrated under reduced pressure and washed with a saturated NaCl solution, dried over MgSO _4. The residue was purified by flash chromatography on silica gel eluting with hexane / EtOAc (2: 1). Concentrate under reduced pressure and redissolved in EtOH / HOAc (1: 1, 8 mL). To the solution was added 3.4 mL (70.0 mmol) of hydrazine hydrate at 80 占 폚. After 15 minutes, the reaction of all starting materials was complete, saturated NaHCO ₃ was carefully added to the reaction mixture and extracted with EtOAc (2x). The resulting organic layer was washed with a saturated NaCl solution, dried over MgSO _4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with CH ₂ Cl ₂ / MeOH (9: 1) to give 6- (3-aminophenoxy) -3-E- [2- (pyridin- Ethenyl] -4,5-dihydro-1H-indazole (yield: 19%). _{^{1 H NMR (DMSO-d 6}} ) δ12.51 (s, 1H), 8.57 (d, 1H, J = 3.8 Hz), 7.78 (t, 1H, J = 7.8 Hz), 7.51 (m, 2H), 7.25 1H), 7.05 (m, 2H), 6.35 (d, IH, J = 7.9 Hz, finely separated), 6.32 2H), 2.95 (t, 2H, J = 8.2 Hz), 2.60 (t, 2H, J = 8.2 Hz); 5.54 (s, 1H). MS [m + H] / z calculated 331, _{detection: 331. C 20 H 18 N 4} O · 0.15H ₂ O for analysis calculated: C, 72.12; H, 5.54 ; N, 16.82. Detection: C, 72.11; H, 5.55; N, 16.61.
[808]
[809] 2.42 g (6.36 mmol) of HATU and 1.8 ml (12.71 mmol) of NEt ₃ were added to a solution of 350 mg (1.06 mmol) of dihydroaniline and 776 mg (6.36 mmol) of benzoic acid in 15 ml of DMF. The reaction mixture was heated at 50 &lt; 0 &gt; C for 1 hour, cooled, and cooled with ice / saturated NaCl solution. The ppt was condensed by vacuum filtration, washed with H ₂ O and air dried. The filter cake was added to 650 mg of K ₂ CO ₃ and 1 ml of H ₂ O and redissolved in 10 ml MeOH / THF (1: 1). After 1 h, saturated NaCl was added to the reaction mixture and extracted with EtOAc (2x). The resulting organic layer was washed with saturated NaCl, dried over MgSO _4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with CH ₂ Cl _{2 /} EtOAc / MeOH ( _{1: 1:} 1) to give 6- [3-benzamidophenoxy] -3-E- [2- Pyridin-2-yl) ethenyl] -4,5-dihydro-1H-indazole (yield: 72%). _{^{1 H NMR (DMSO-d 6}} ) δ12.58 (bs, 1H), 10.34 (s, 1H), 8.57 (d, 1H, J = 3.8 Hz), 7.95 (d, 2H, J = 6.8 Hz), 7.81 (M, 2H), 7.63-7.50 (m, 6H), 7.40 (t, 1H, J = 8.1 Hz), 7.25 2H, J = 8.1 Hz), 2.64 (t, 2H, J = 8.1 Hz). Anal. Calcd for C ₂₇ H ₂₂ N ₄ O ₂ .0.1 CH ₂ Cl ₂ : C, 73.48; H, 5.05; N, 12.65. Detection: C, 73.48; H, 5.05; N, 12.48.
[810] Example 31 (b): 6- [3 - ((1,5-Dimethyl-1H-pyrazol-3- Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[811]
[812] Example 31 (b) was prepared in analogy to Example 31 (a), but using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid instead of benzoic acid in step (ii) . &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ13.13 (s, 1H), 10.07 (s, 1H), 8.60 (d, 1H, J = 4.3 Hz), 8.21 (d, 1H, J = 8.7 Hz), 7.93 (d, IH, J = 16.3 Hz), 7.82 (t, IH, J = 7.4 Hz), 7.69 (m, 3H), 7.56 (s, IH), 7.01 (d, IH, J = 8.7 Hz), 6.80 (m, IH), 6.52 (s, IH), 3.81 (s, 3H), 2.29 Anal. Calcd. For C ₂₆ H ₂₂ N ₆ O ₂ .0.1 CH ₂ Cl ₂ /0.1 hexane: C, 68.58; H, 5.09; N, 17.97. Detection: C, 68.26; H, 5.25; N, 17.61.
[813] Example 31 (c): 6- [3 - ((5-methylsulfonylthien-2-yl) carboxyamido) -phenoxy] -3-E- [2- (pyridin- ) Ethenyl] -1H-indazole &lt; / RTI &gt;
[814]
[815] Example 31 (c) was prepared in the same manner as in Example 31 (a), except that 5-methylsulfonyl-thiophene-2-carboxylic acid was used instead of benzoic acid in the step (ii) of Example 31 (a) &Lt; / RTI &gt; ¹ H NMR (DMSO-d ₆ ) 13.17 (s, IH), 10.58 (s, IH), 8.61 (d, IH, J = 4.0 Hz), 8.24 (d, 1H, J = 4.1 Hz), 7.97-7.79 (m, 3H), 7.68 (d, 1H, J = 7.8 Hz), 7.60-7.48 1H, J = 8.7 Hz), 7.28 (m, 1H), 7.10 (s, 1H, finely separated), 7.00 (s, 3 H). Anal. Calcd for C ₂₆ H ₂₀ N ₄ O ₄ S ₂ .4O EtOAc: C, 60.07; H, 4.24; N, 10.15; S, 11.62. Detection: C, 60.22; H, 4.48; N, 10.05;
[816] Example 31 (d): 6- [3 - ((l-Ethyl-3-methyl-lH-pyrazol- 5- yl) -carboxyamido) -phenoxy] Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[817]
[818] Example 31 (d) was prepared in analogy to Example 31 (a) except that 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used instead of benzoic acid in step (ii) was prepared in the same manner as in a). _{^{1 H NMR (DMSO-d 6}} ) δ13.15 (s, 1H), 10.18 (s, 1H), 8.61 (d, 1H, J = 3.7 Hz), 8.22 (d, 1H, J = 8.8 Hz), 7.94 (d, IH, J = 16.3 Hz), 7.82 (t, IH, J = 7.5 Hz), 7.67 1H, J = 7.9 Hz), 6.78 (s, 1H), 4.38 (d, 1H, J = (q, 2H, J = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). Anal. Calcd. For C ₂₇ H ₂₄ N ₆ O ₂ .6 EtOAc: C, 68.25; H, 5.61; N, 16.24. Detection: C, 68.28; H, 5.88; N, 16.01.
[819] Example 31 (e): Synthesis of 6- [3- ((1-methylimidazol-2-yl) -carboxamido) -phenoxy] -3-E- [2- (pyridin- / RTI &gt; &lt; RTI ID = 0.0 &gt;
[820]
[821] Example 31 (e) was prepared in the same manner as in Example 31 (a), except that 1-methyl-1H-imidazole-2-carboxylic acid was used instead of benzoic acid in the step (ii) &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ13.13 (s, 1H), 10.47 (s, 1H), 8.60 (d, 1H, J = 3.9 Hz), 8.21 (d, 1H, J = 8.7 Hz), 7.93 (d, IH, J = 16.3 Hz), 7.82 (t, IH, J = 7.6 Hz), 7.65 (m, 3H), 7.56 1H, J = 8.1 Hz), 7.28 (m, 1H), 7.04 (m, 3H), 6.84 (d, Anal. Calcd. For C ₂₅ H ₂₀ N ₆ O ₂ .0.4 H ₂ O: C, 67.49; H, 4.80; N, 18.65. Detection: C, 67.68; H, 4.73; N, 18.94.
[822] Example 31 (f): 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol- 2-dimethyl-1H-imidazol-4-yl) ethenyl] -1H-indazole
[823]
[824] Example 31 (f) was prepared in the same manner as in step (i) of Example 31 (a) except that (E) -3- (1,2-benzyloxycarbonylamino) Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used in place of benzoic acid in step (ii) Was prepared in the same manner as in Example 31 (a). ¹ H NMR (DMSO-d ₆ ) 12.82 (s, IH), 10.17 (s, IH), 8.05 (d, IH, J = 8.8 Hz), 7.58 (s, 1H), 7.38 (t, 1H, J = 8.1 Hz), 7.25 (s, 2H), 7.20 2H), 6.85 (d, 1H, J = 8.7 Hz), 6.78 (s, 3H), 1.29 (t, 3H, J = 7.0 Hz). Anal. Calcd for C ₂₇ H ₂₇ N ₇ O ₂ .1.0 H ₂ O 0.3 EtOAc: C, 64.39; H, 6.02; N, 18.64. Detection: C, 64.52; H, 5.98; N, 18.52.
[825] Example 32 (a): 6- [3-Benzamidophenoxy] -3-E- [2- (1H-imidazol-4-yl) ethenyl]
[826]
[827] To a solution of 6- (3-benzamidophenoxy) -3-E- [2- (1- (2-trimethylsilanyl-ethoxy) (6.0 mmol) of TBAF dissolved in THF and 0.26 ml (3.86 mmol) of ethylenediamine were added to a solution prepared by dissolving 213 mg (0.39 mmol) of 1H-indazole in THF after the reaction solution was cooled, diluted with EtOAc, and washed repeatedly with sat NaHCO ₃ solution. Organic layer is concentrated under reduced pressure and dried MgSo _4. The residue was purified by flash chromatography on silica gel eluting with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.2). The oil thus obtained was triturated with EtOAc / hexane to obtain 65 mg (yield: 40%) of AG13853. ¹ H NMR (DMSO-d ₆ ) 12.90 (s, 1H), 12.35 (s, 1H), 10.32 1H, J = 6.8 Hz), 7.81 (s, 1H), 7.64-7.49 (m, 5H), 7.42-7.31 6.85 (d, 1 H, J = 8.1 Hz). _{C 25 H 19 N 5 O 2} · 0.7 analysis of the H ₂ O · 0.4 EtOAc calculated: C, 68.07; H, 5.07 ; N, 14.92. Detection: C, 67.93; H, 4.89; N, 15.06.
[828] The starting material was prepared according to the procedure described in step (i) of Example 31 (a) from (E) -3- {1- (2-trimethylsilyl) -Methanesulfonyl-benzoyl) -ethoxymethyl) -lH-imidazol-4-yl] -acryloyl chloride hydrochloride was used as the starting material.
[829] Example 32 (b): 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol-5-yl) carboxyamido) phenoxy] 4-yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[830]
[831] Example 32 (b) was prepared analogously to example 32 (a) except for using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid instead of benzoic acid in step (ii) was prepared in the same manner as in a). ¹ H NMR (DMSO-d ₆ ) 12.89 (s, IH), 12.37 (s, IH), 10.18 (s, IH), 8.07 , 7.58 (d, IH, J = 8.3 Hz), 7.49 (s, IH), 7.44-7.32 (m, 3H), 7.28 = 8.9 Hz), 6.86 (d, 1H, J = 8.6 Hz), 6.78 (s, 1H), 4.38 (q, 2H, J = 7.1 Hz), 2.19 = 7.1 Hz). _{C 25 H 23 N 7 O 2} · 0.8 H 2 O / 0.1 Analysis of the EtOAc calculated: C, 63.99; H, 5.37 ; N, 20.57. Detection: C, 63.72; H, 5.12; N, 20.25.
[832] Example 32 (c): 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol-5-yl) carboxyamido) phenoxy] Imidazol-4-yl) ethenyl] -1H-indazole
[833]
[834] Example 32 (c) was prepared from (E) -3- [1- (2-trimethylsilanyl) -ethoxymethyl) -1H-imidazol- ] -Acryloyl chloride hydrochloride instead of (E) -3- [2-methyl-1- (2-trimethylsilanyl) -ethoxymethyl) -1H-imidazol- Hydrochloride was used as the starting material in Example 32 (b). ¹ H NMR (DMSO-d ₆ ) 12.85 (bs, IH), 11.80 (bs, IH), 10.18 (s, IH), 8.05 1H, J = 8.4 Hz), 7.48 (s, 1H), 7.39 (t, 1H, J = 8.2 Hz), 7.33-7.05 2H, J = 7.1 Hz), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (s, t, 3H, J = 7.1 Hz). Anal. Calcd for C ₂₆ H ₂₅ N ₇ O ₂ .0.9 H ₂ O .4 EtOAc: C, 63.87; H, 5.83; N, 18.89. Detection: C, 63.64; H, 5.76; N, 18.85.
[835] Example 33 (a): 6- [2- (Methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-4-yl) ethenyl]
[836]
[837] Example 33 (a) was prepared in the same manner as in Example 33 (a) except that 6- [2- (methylcarbamoyl) -phenylsulfanyl] -3- E- E- [2- (pyridin- Nonyl) ethoxymethyl] -1H-indazole in a similar manner to Example 11. R _f sm 0.8, p 0.15 (ethyl acetate); ^{1 H NMR (300MHz, DMSO-} d 6) δ13.45 (s, 1H), 8.72 (d, 1H, J = 3.9 Hz), 8.47 (m, 1H), 8.31 (d, 1H, J = 8.5 Hz) , 8.06 (d, IH, J = 16.4 Hz), 7.92 (dt, IH, J = 1.7,7.6 Hz), 7.78 1H, J = 16.5 Hz), 7.61 (dd, 1H, J = 1.7,7.2 Hz), 7.45-7.36 (m, 3H), 7.31 2.89 (d, 3H, J = 4.6 Hz); ^{13 C NMR (75MHz, DMSO-} d 6) δ167.8, 154.8, 149.5, 141.9, 141.8, 137.0, 136.8, 135.4, 132.5, 130.2, 130.0, 129.2, 127.7, 126.1, 125.4, 123.5, 122.5, 122.4, 121.6 , 120.2, 114.5; LCMS (100% area) Rt = 3.5min (pos) [M + H] / z calculated 387, detection 387. 0.1 H ₂ O, calculated analyzed by 0.1 EtOAc C (67.78), H (4.82), N (14.11 ), S (8.08). Detection: C (67.78), H (4.77), N (14.06), S (8.08).
[838] The starting material was prepared as follows:
[839] (i)
[840]
[841] (62.9 mmol) of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -lH-indazole prepared in step (1) Was dissolved in 375 mL of dichloromethane and cooled to -42 째 C in an acetonitrile-dry ice bath. The mixture was then ozone foamed for 45 minutes (1 L / min, 60 V, 1.8 Amps). The standard indicator does not change transparently due to the background color of the solution. The reaction progress was monitored by TLC (EtOAc: Hex = 1: 9) to avoid excess oxidation. The reaction was stopped by adding ozone and argon was flushed through the flask. 30 ml of dimethyl sulfide was added to the reaction mixture, followed by heating to 23 占 폚. The mixture was stirred for 4 hours and then concentrated under reduced pressure. The oil was discharged through a high vacuum for 16 hours. The residue was redissolved in 15 mL of dichloromethane and then diluted with 100 mL of hexane to crystallize the undesired product. The mixture was filtered and the filtrate was concentrated. The residue was redissolved in 250 mL of Hex-EtOAc (8: 2), treated with 50 mL of silica, filtered and concentrated. 24.17 g (purity to 95% by NMR, yield: 6-iodo-3-carboxyaldehyde-1- [2- (trimethyl- 91%). R _f sm 0.34, p0.29 (ethyl acetate: hexane = 1: 9); _{^{1 H NMR (300MHz, CDCl 3}} ) δ10.25 (s, 1H), 8.09 (s, 1H), 8.05 (d, 1H), 7.80 (d, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 0.93 (t, 2H), 0.0 (s, 9H).
[842] (ii)
[843]
[844] 24.0 g (59.7 mmol) of 6-iodo-3-carboxyaldehyde-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was dissolved in 350 ml of THF and cooled to -5 ° C. To the solution was added 45.7 g (100 mmol, 1.68 equiv) of 2-picolyltriphenylphosphonium chloride-potassium hydride in solid form and stirred for 45 minutes. To the mixture was added 20 mL of 3N HCl followed by the addition of 50 mL of saturated aqueous sodium bicarbonate to a pH of 6. The residue of THF was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic was washed with saturated aqueous sodium bicarbonate and water, and the organic layer was separated with sodium sulfate, dried, and concentrated under reduced pressure. The filtrate was purified by silica gel chromatography (2 L silica eluting with 20 to 30% ethyl acetate-hexane at 20 to give 6-iodo-3-E- [2- (pyridin- 18.9 g (yield 66%) of [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole was obtained: R _f cm 0.52, p 0.25 (ethyl acetate: hexane = 2: 8); ¹ H NMR (300 MHz, CDCl ₃ ) 8.64 (s, IH), 8.00 (d, IH, J = 0.7 Hz), 7.87 1H, J = 8.5 Hz), 7.69 (td, 1H, J = 7.7,1.8Hz), 7.55 (d, 1H, J = 16.4 Hz), 7.55 J = 7.9 Hz), 7.18 (dd, 1H, J = 1.1, 4.8 Hz), 5.70 (s, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.90 , -0.04 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 156.8, 151.2, 144.2, 143.6, 138.0, 132.3, 132.2, 124.4, 124.0, 123.8, 123.7, 123.5, 120.7, 94.1, 79.4, 68.1, 19.17, 0.0.
[845] (iii)
[846]
[847] 13.7 g (41.9 mmol) of cesium carbonate was added to a 200 ml round-bottomed flask and the salt was dried under a high vacuum using a heating gun. Catalyst _{[Pd (dppf) Cl 2 -CH} 2 Cl 2] 1.37g (1.68mmol, 0.1equiv) and 6-iodine -3-E- [2- butenyl-1-on (pyridin-2-yl) [2- (Trimethyl-silanyl) -ethoxymethyl] -1H-indazole were added and dissolved in 71 ml of DMF and mixed. To this mixture was added 4.62 ml (33.5 mmol, 2.0 equiv) of methyl thiosalicylate and the flask was heated at 85 캜 for 4.5 hours. The mixture was cooled to 23 [deg.] C and then partitioned into 350 ml of ethyl acetate and 300 ml of 50% -saturated aqueous sodium bicarbonate. The organics were washed with 10% sodium bisulfite, dried over sodium sulfate, concentrated in vacuo. The filtrate was purified by silica gel chromatography (500 mL silica, eluting with 30 to 40% ethyl acetate-hexane to give 6 - [(2-methoxycarbonylphenyl) sulfonyl] -3-E- [2- (Yield: 74%): R _f cm 0.52, p 0.19 (ethyl) ethyl] -1- [2- (trimethyl- Acetate: hexane = 3: 7); FTR (thin film) 2950, 2887, 2356, 1713, 1585, 1464, 1433, 1250, 1076, 837 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.70 (d, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.99 (d, 1H, J = 16.4 Hz), 7.90 (s, 1H) 1H), 7.88 (d, 1H), 7.76 (d, 1H, J = 16.4 Hz), 7.62 5.80 (s, 2H), 4.01 (s, 3H), 3.78 (t, 2H), 0.96 (t, 2H), -0.03 (s, 9H); _{^{13 C NMR (75MHz, CDCl 3}} ) δ168.3, 156.8, 151.2, 144.3, 144.2, 143.2, 138.0, 133.8, 133.6, 132.5, 132.4, 129.9, 129.3, 128.5, 126.0, 124.7, 124.6, 123.8, 123.5, 118.3 , 79.4, 68.2, 53.7, 19.2, 0.0; LCMS (100% area) Rt = 4.4 min, (pos) [M + H] / z yield 518.2, detection 518.2.
[848] (iv)
[849]
[850] 1- [2- (trimethyl-silanyl) -ethoxymethyl] - 1 - [2- (2- 120 mg of THF, 120 ml of methanol, 120 ml of water and 15.9 g (115 mmol, 7.0 equiv.) Of potassium carbonate were added to 8.50 g (16.4 mmol) of 1- The mixture was heated to 67 DEG C and stirred for 22 hours. The mixture was cooled and the remaining solvent was removed without further reaction. The residue was partitioned between 300 ml of ethyl acetate and 250 ml of water. The aqueous solution was acidified with 20% citric acid (~ 70 ml) at pH 5 and water was drained. The organic layer was washed with 50 ml of water and 100 ml of hexane added to aid precipitation of the crystals forming the ethyl acetate layer. The solid was filtered and dried to give 6 - [(2-carboxyphenyl) sulfanyl] -3- E- E- [2- (pyridin- 2- yl) ethenyl] -1- [2- (trimethyl- (Yield 91%) of the title compound: R _f sm 0.67, p 0.41 (ethyl acetate: hexane = 8: 2); ¹ H NMR (300 MHz, CDCl ₃ ) 8.60 (m, 1H), 8.10 (d, 1H, J = 8.4 Hz), 8.04 (dd, 1H, J = 1.7,7.7 Hz) J = 16.5 Hz), 7.83 (s, 1H), 7.70 (dt, 1H, J = 1.7, 7.7 Hz), 7.59 (d, , 7.38 (dd, 1H, J = 1.3, 8.4 Hz), 7.22-7.10 (m, 3H), 6.80 0.85 (t, 2H, J = 8.8. 1 Hz), -0.1 (s, 9H).
[851] (v)
[852]
[853] 1- [2- (trimethyl-silanyl) -ethoxymethyl] -lH-pyrrolo [2,3-e] 820 mg (1.63 mmol) of indazole were dissolved in 5 ml of DMF and treated with methylamine (2 M in THF, 4.1 ml, 8.13 mmol, 50 equiv) and HATU 929 mg (2.44 mmol, 1.5 equiv.). The mixture was stirred for 30 minutes and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate to separate the organic layer. The organics were dried over sodium sulfate, concentrated under reduced pressure and then purified by silica gel chromatography (50 mL silica, eluted with 60-70% ethyl acetate-hexanes) to give solid 6 - [(2- methylcarbamoyl) phenylsulfanyl] 795 mg (yield 94%) of 3 - E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) -ethoxymethyl] _f cm 0.35, p 0.23 (ethyl acetate: hexane = 6: 4); FTR (thin film) 3306, 2951, 1643, 1606, 1601, 1587, 1563, 1469, 1433, 1410, 1303, 1249, 1217, 1075, 836 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 8.70 (m, IH), 8.06 (d, IH, J = 8.4 Hz), 7.94 1H, J = 7.9Hz), 7.70-7.60 (m, 3H), 7.52 (d, 3.62 (t, 2H), 3.00 (d, 2H), 0.93 (t, 2H), -0.05 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 179.7, 169.9, 156.8, 151.1, 144.2, 143.0, 138.1, 136.1, 135.4, 133.2, 132.2, 132.1, 130.2, 128.5, 127.2, 124.7, 124.1, 123.8, , 68.1, 28.2, 19.2, 0.0; LCMS (100% area) Rt = 4.15 min, (pos) [M + H] / z yield 517.2, detection 517.2.
[854] Example 33 (b): 6- [2- (2-Methylquinol-6-ylcarbamoyl) phenylsulfanyl] -3- E- E- [2- (pyridin- 1H-indazole
[855]
[856] Example 33 (b) was prepared in the same manner as in Example 33 (a) except that 6-amino-2-methylquinoline was used in place of methylamine in the step (v) of Example 33 (a). _{^{1 H NMR (300MHz, CDCl 3}} ) δ10.2 (bs, 1H), 8.64 (m, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.98-7.80 (m, 4H), 7.69 ( dt, 1H, J = 1.7,7.7Hz), 7.55-7.40 (m, 7H), 7.25-7.16 (m, 3H), 2.71 (s, 3H).
[857] Example 33 (c): 6- [2- (Phenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[858]
[859] Example 33 (c) was prepared in the same manner as in Example 33 (a) except that aniline was used instead of methylamine in the step (v) of Example 33 (a). ^{1 H NMR (300MHz, DMSO-} d 6) δ13.35 (s, 1H), 10.53 (s, 1H), 8.67 (m, 1H), 8.22 (d, 1H, J = 7.5 Hz), 7.99 (d, 1H, J = 16.4Hz), 7.85 (dt, 1H, J = 1.8, 7.6Hz), 7.80-7.55 (m, 5H), 7.45-7.10 (m, 9H); LCMS (100% area) Rt = 3.86 min, (pos) [M + H] / z yield 449.1, detection 449.1. 0.41 H ₂ O, C (71.13), H (4.60), N (12.29), S (7.03). Detection: C (71.04), H (4.62), N (12.31), S (7.01).
[860] Example 33 (d): 6- [2- (3-Chlorophenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[861]
[862] Example 33 (d) was prepared in the same manner as in Example 33 (a) except that 3-chloroaniline was used instead of methylamine in the step (v) of Example 33 (a). ¹ H NMR (300 MHz, CDCl ₃ ) 8.53 (m, 1H), 7.92 (d, 1H, J = 1.7, 7.7 Hz), 7.64-7.56 (m, 2H), 7.51-7.43 (m, 3H), 7.35-7.28 (m, 4H), 7.19-7.12 (m, 3H), 7.02 (m, 1H); LCMS (100% area) Rt = 3.98 min, (pos) [M + H] / z yield 483.1, detection 483.1. Calculated C (66.40), H (4.05), N (11.47), S (6.57) analyzed with 0.3 H ₂ O. Detection: C (66.36), H (4.08), N (11.49), S (6.55).
[863] Example 33 (e): 6- [2- (3-Cyclopropylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] -1H-
[864]
[865] Example 33 (e) was prepared in the same manner as in Example 33 (a) except that cyclopropylamine was used instead of methylamine in the step (v) of Example 33 (a). ^{1 H NMR (300MHz, DMSO-} d 6) δ13.45 (s, 1H), 8.73 (d, 1H, J = 3.9 Hz), 8.56 (d, 1H, J = 4.3 Hz), 8.31 (d, 1H, (D, 1H, J = 8.5 Hz), 8.08 (d, 1H, J = 16.4 Hz), 7.91 , 7.57 (m, 1H), 7.40 (m, 3H), 7.30 (d, 1H, J = 8.4 Hz), 7.20 2H), 0.65 (m, 2H); LCMS (100% area) Rt = 3.51 min, (pos) [M + H] / z yield 413.1, detection 413.1.
[866] Example 33 (f): 6- [2- (2,2,2-Trifluoroethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- - Indazole
[867]
[868] Example 33 (f) was prepared in the same manner as in Example 33 (a), except that 2,2,2-trifluoroethylamine was used in place of methylamine in the step (v) of Example 33 (a) . ^{1 H NMR (300MHz, DMSO-} d 6) δ13.5 (s, 1H), 9.29 (t, 1H, J = 6.3 Hz), 8.74 (m, 1H), 8.37 (d, 1H, J = 8.3 Hz) J = 7.9 Hz), 7.75-7.65 (m, 3H), 7.55 (d, 1H, J = 7.40 (m, 3H), 7.33 (d, IH), 7.22 (d, IH), 4.22 (m, 2H); LCMS (100% area) Rt = 3.70 min, (pos) [M + H] / z yield 455.1, detection 455.1.
[869] Example 33 (g): Synthesis of 6- [2- (carboxy) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] -1H-lH-indazole, tetrabutylammonium salt
[870]
[871] Example 33 (g) was prepared in a manner similar to that of Example 33 (a) except that step (v) of Example 33 (a) was omitted: R _f sm 0.41, p 0.0 (ethyl acetate: hexane = 8: 2); ^{1 H NMR (300MHz, DMSO-} d 6) δ8.75 (m, 1H), 8.25 (d, 1H, J = 8.6 Hz), 8.05 (d, 1H, J = 16.4 Hz), 7.88 (dt, 1H, (M, 2H), 7.16 (m, 2H), 6.70 (m, 1H), 3.30 (m, 8H), 1.70 ), 1.42 (m, 8H), 1.05 (t, 12H); LCMS (100% area) Rt = 3.24 min, (pos) [M + H (oxide only)] / z yield 374.1, detection 374.1. Calculated C (72.07), H (8.21), N (9.09), S (5.20) as analyzed by 0.1 H ₂ O. Detection: C (72.04), H (8.29), N (9.06), S (5.12).
[872] Example 33 (h): Synthesis of 6- [2- (3-chlorophenylcarbamoyl) phenylsulfanyl] -3-Z- [2- (pyridin- 2- yl) ethenyl]
[873]
[874] Example 33 (h) was prepared following the same reaction as in Example 33 (d). This compound is separated or purified, but is characterized in that it is detected as an isomer under the analytical conditions of Example 33 (d). _{^{1 H NMR (300MHz, CDCl 3}} ) · 8.82 (m, 1H), 8.31 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.61 (t, 1H, J = 2.0 Hz), (D, 1H, J = 1.5, 8.1 Hz), 7.08 (m, 1H), 7.43 (d, 1H, J = 8.0 Hz) ), 6.98 (d, 1H, J = 13.0 Hz), 6.66 (d, 1H, J = 13.1 Hz); LCMS (100% area) Rt = 4.40 min, (pos) [M + H] / z yield 483.1, detection 483.1. Calculated C (66.40), H (4.05), N (11.47), S (6.57) analyzed with 0.3 H ₂ O. Detection: C (66.36), H (4.08), N (11.49), S (6.55).
[875] Example 34: Synthesis of 6- [2 - ((RS- (trans-2-phenylcyclopropyl) carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- Indazole
[876]
[877] Example 34 was prepared analogously to Example 33 (g), but using trans-2-phenylcyclopropylamine instead of methylamine in step (v) of Example 33 (a) FTR (thin film) 1704, 1638, 1584, 1559, 1530, 1497, 1460, 1430, 1339, 1306, 1269, 1223, 1152, 1086, 1061, 966, 844 cm ^-1 ; _{^{1 H NMR (300MHz, CDCl 3}} ) δ13.3 (s, 1H), 8.71 (d, 1H, J = 4.4 Hz), 8.61 (d, 1H, J = 3.9 Hz), 8.20 (d, 1H, J = J = 7.8 Hz), 7.96 (d, 1H, J = 16.4 Hz), 7.81 (dt, , 7.37-7.25 (m, 5H), 7.21-7.08 (m, 5H), 3.01 (m, 1H), 2.03 (m, 1H), 1.25 (m, 2H); LCMS (100% area) Rt = 3.72 min, (pos) [M + H] / z yield 489.2, detection 489.2. Calculated C (70.86), H (5.17), N (10.75), S (6.15) as analyzed by 0.6 MeOH, 0.16 CH ₂ Cl ₂ . Detection: C (70.87), H (5.18), N (10.75), S (5.96).
[878] Example 35 (a): Synthesis of 6- [2- (n-propylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[879]
[880] (0.1112 mmol) of 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] , Treated with 11 μl (0.1335 mmol) of n-propylamine, and stirred at room temperature. Analysis by HPLC after 15 minutes showed that all of the starting materials were consumed. The reaction mixture was concentrated under reduced pressure by rotary evaporation to obtain a solid. This solid was filtered and sonicated with CH ₂ Cl ₂ to give a high purity suspension. CH ₂ Cl ₂ to give 40 mg (yield: 80%) of 6- [2- (n-propylcarbamoyl) -phenylsulfanyl] -3-E- [2- (pyridin- 87%). _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.41 (t, J = 6.2 Hz, 1H), 8.19 (d, J = 8.5 Hz 1H), 7.94 (m, 3H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (t, J = 8.7 Hz, J = 6.0 Hz, 2H), 7.30 (m, 3H), 7.18 (d, J = 8.3 Hz, 1H), 3.20 6.0 Hz, 3H). Anal. Calcd for C ₂₄ H ₂₂ N ₄ OS (1.5 H ₂ O · 0.8 DMF): C, 63.41; H, 6.17; N, 13.45; Detection: C, 63.37; H, 5.68; N, 13.44; S, 6.32.
[881] The starting material was prepared in the following manner:
[882]
[883] A solution of the tetrabutylammonium salt of 6- (2-carboxyphenylsulfanyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole (615 mg, 1.0 mmol) (1.1 mmol) of pyridine and 206 (1.2 eq) of pentafluorophenyltrifluoroacetate were treated at room temperature under an argon atmosphere. Analysis by HPLC after 45 minutes showed that most of the carboxylic acids did not react. Thus, 89 [mu] l (1.1 mmol) of pyridine and 206 [mu] l (1.2 eq) of pentafluorophenyltrifluoroacetate were added. After 15 minutes, the starting material was consumed by HPLC analysis. The reaction mixture was concentrated by evaporation under high vacuum, and the crystals collected by filtration were pulverized with CH ₂ Cl ₂ (~ ₁ mL) and further dried with flowing CH ₂ Cl ₂ . The mass of clear yellow crystals was 336 mg. The remaining filtrate was concentrated to give additional solid 70mg was purified by flash chromatography (10% acetonitrile / CH ₂ Cl ₂ eluted at 80% acetonitrile / CH ₂ Cl _2). The total amount of 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H- )to be. _{^{1 H NMR (CDCl 3) δ10.22}} (1H, bs), 8.66 (1H, d, J = 4.5 Hz), 8.28 (2H, dd, J = 7.7, 1.5 Hz), 8.15 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 16.2 Hz), 7.79 (1H, s), 7.15-7.75 (7H, m), 6.92 (1H, d, J = 8.1 Hz).
[884] Example 35 (b): Synthesis of 6- [2- (i-propylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[885]
[886] Example 35 (b) was prepared in the same manner as in Example 35 (a) except that isopropylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.30 (s, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.26 (d, J = 7.34 Hz, 1H), 8.19 (d, J = 8.3 Hz (D, J = 7.7 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.80 (m, 1H), 7.30 (m, 3H), 7.18 (d, J = 8.5 Hz, 1H), 7.08 6.6 Hz, 6H). Analysis for C ₂₄ H ₂₂ N ₄ OS 1.7 H ₂ O: C, 64.75; H, 5.75; N, 12.59; S, 7.20. Detection: C, 64.79; H, 5.36; N, 12.74;
[887] Example 35 (c): 6- [2- (Cyclobutylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[888]
[889] Example 35 (c) was prepared in the same manner as in Example 35 (a) except that cyclobutylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.62 (m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 7.94 (m, 2H), 7.80 (dt, J = (M, 3H), 7.17 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 4.36 (septet, J = 8.1 Hz, 1H), 2.22 (m, 2H), 2.03 (m, 2H), 1.67 (m, 2H). Anal. Calcd for C ₂₅ H ₂₂ N ₄ OS (0.5 H ₂ O, 0.9 DMF): C, 66.36; H, 5.89; N, 13.69; Detection: C, 66.21; H, 5.78; N, 13.82; S, 6.36.
[890] Example 35 (d): 6- (2-Carbamoylphenylsulfanyl) -3-E- [2- (pyridin-2- yl) ethenyl]
[891]
[892] Example 35 (d) was prepared in the same manner as in Example 35 (a) except that ammonia was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ8.60 (d, J = 4.9 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.94 (m, 3H), 7.81 (dt, J = 1.7, 1H), 7.60 (m, 4H), 7.48 (bs, IH), 7.25 (m, 4H), 7.0 (m, 1H). Analysis for C ₂₁ H ₁₆ N ₄ OS · 0.25 H ₂ O: C, 66.91; H, 4.41; N, 14.86; S, 8.51. Detection: C, 66.99; H, 4.40; N, 15.10;
[893] Example 35 (e): Synthesis of 6- [2 - ((1-methylpyrrol-2-ylhydrazidecarbamoyl) phenylsulfanyl] -3- E- E- [2- (pyridin- -1H-indazole
[894]
[895] Example 35 (e) was prepared in the same manner as in Example 35 (a) except that 1-methylpyrrol-2-yl hydrazide was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.34 (s, 1H), 10.25 (s, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.95 (m, 3H), 7.57 (d, J = 16.0 Hz, 1H), 7.43-7.18 (m, 2H), 7.07 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 3.4 Hz, 2H), 6.07 (t, J = 3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calcd for C ₂₇ H ₂₂ N ₆ O ₂ S 0.6 H ₂ O: C, 64.17; H, 4.63; N, 16.63; S, 6.34. Detection: C, 64.24; H, 4.48; N, 16.56; S, 6.28.
[896] Example 35 (f): Synthesis of 6- [2 - ((2-fluorobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Sol
[897]
[898] Example 35 (f) was prepared in the same manner as in Example 35 (a) except that 2-fluorobenzylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.99 (t, J = 5.8 Hz, 1H), 8.61 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 8.5 Hz , 7.94 (d, J = 16.2 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H) (t, J = 7.9 Hz, 1H), 7.31 (m, 4H), 7.15 (m, 4H), 4.51 (d, J = 5.7 Hz, 2H). Anal. Calcd. For C ₂₈ H ₂₁ FN ₄ OS 0.25 H ₂ O: C, 69.33; H, 4.47; N, 11.55; S, 6.61. Detection: C, 69.32; H, 4.41; N, 11.58; S, 6.59.
[899] Example 35 (g): 6- [2 - ((4-methoxybenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Sol
[900]
[901] Example 35 (g) was prepared in the same manner as in Example 35 (a) except that 4-methoxybenzylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.19 (d, J = 8.3 Hz , 7.95 (d, J = 16.3 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H) (m, 5H), 7.18 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.72 Analysis for C ₂₉ H ₂₄ N ₄ O ₂ S 0.6 H ₂ O: C, 69.19; H, 5.05; N, 11.13; S, 6.37. Detection: C, 69.12; H, 4.85; N, 11.24; S, 6.35.
[902] Example 35 (h): Synthesis of 6- [2 - ((5-methylpur-2-yl) methylcarbamoyl) phenylsulfanyl] -3- E- E- [2- (pyridin- / RTI &gt; &lt; RTI ID = 0.0 &gt;
[903]
[904] Example 35 (h) was prepared in the same manner as in Example 35 (a) except that 5-methylpyr-2-ylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.88 (t, J = 5.3 Hz, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.19 (d, J = 8.3 Hz , 7.95 (d, J = 16.3 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H) (m, 4H), 7.18 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.1 Hz, 3H). Analysis for C ₂₇ H ₂₂ N ₄ O ₂ S 0.4 H ₂ O: C, 68.45; H, 4.85; N, 11.83; S, 6.77. Detection: C, 68.35; H, 4.80; N, 11.85; S, 6.68.
[905] Example 35 (i): 6- [2- (Benzyloxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[906]
[907] Example 35 (i) was prepared in the same manner as in Example 35 (a) except that O-benzylhydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 11.64 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 16.3 Hz, 1H), 7.81 (m, 2H), 7.50-7.24 (m, 9H), 7.17 (t, J = 8.5 Hz, 2H), 4.94 (s, 2H). _{C 28 H 22 N 4 O 2} S · 0.8 H ₂ O for analysis calculated: C, 68.22; H, 4.83 ; N, 11.37; S, 6.50. Detection: C, 68.08; H, 4.65; N, 11.41; S, 6.47.
[908] Example 35 (j): 6- [2- (Allyloxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] -1H-
[909]
[910] Example 35 (j) was prepared in the same manner as in Example 35 (a) except that O-allyl hydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.32 (s, 1H), 11.56 (s, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 16.5 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.56 (m, 2H), 7.48-7.24 (D, J = 6.0 Hz, 1H), 7.16 (m, 2H), 6.00 1H). Anal. Calcd for C ₂₄ H ₂₀ N ₄ O ₂ S (0.2 H ₂ O, 0.2 CH ₂ Cl ₂ ): C, 65.35; H, 4.96; N, 12.10; Detection: C, 65.24; H, 4.50; N, 12.56;
[911] Example 35 (k): 6- [2- (Isopropoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] -1H-indazole
[912]
[913] Example 35 (k) was prepared in the same manner as in Example 35 (a) except that O-isopropylhydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.30 (s, 1H), 11.33 (s, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 16.5 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.55 (m, 2H), 7.48-7.24 J = 6.7 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H). 4.12 (septet, J = 5.7 Hz, Analysis for C ₂₄ H ₂₂ N ₄ O ₂ S (0.4 H ₂ O, 0.7 CH ₂ Cl ₂ ): C, 59.67; H, 4.91; N, 11.27; Detection: C, 59.61; H, 4.81; N, 11.42; S, 6.45.
[914] Example 35 (l): Synthesis of 6- [2 - ((4-aminobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[915]
[916] Example 35 (1) was prepared in the same manner as in Example 35 (a) except that 4-aminobenzylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.78 (t, J = 6.0 Hz, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.19 (d, J = 8.1 Hz , 7.95 (dt, J = 16.3 Hz, 1H), 7.85 (bs, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, (m, 2H), 7.51 (m, 3H), 7.19 (d, J = 8.7 Hz, , 6.51 (d, J = 8.5 Hz, 2H), 4.29 (d, J = 6.0 Hz, 2H) .C 28 H 23 N 5 OS · 0.6 H ₂ O analysis of the calculated: C, 68.86; H, 4.99 ; N, 14.34; S, 6.57. Detection: C, 68.83; H, 4.80; N, 14.16; S, 6.52.
[917] Example 35 (m): 6- [2 - ((Thein) -2-ylhydra map) carbamoyl) phenylsulfanyl] -3- E- E- [2- (pyridin- -1H-indazole
[918]
[919] Example 35 (m) was prepared in the same manner as in Example 35 (a) except that thien-2-yl hydrazide was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.49 (bs, 1H), 10.64 (s, 1H), 10.47 (s, 1H), 8.66 (d, J = 4.0 Hz, 1H), 8.22 (d, J = (M, 2H), 7.09 (d, J = 8.1Hz, 1H), 7.00 (m, 2H), 8.08-7.82 d, J = 3.4 Hz, 2H), 6.07 (t, J = 3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calcd for C ₂₆ H ₁₉ N ₅ O ₂ S ₂ .1.5 H ₂ O: C, 59.52; H, 4.23; N, 13.35; S, 12.22. Detection: C, 59.56; H, 4.42; N, 13.33; S, 11.75.
[920] Example 35 (n): Synthesis of 6- [2- (N ² - (pyrid- ² -ylhydrazino) carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- ] -1H-indazole
[921]
[922] Example 35 (n) was prepared in the same manner as in Example 35 (a) except that 2-hydrazinopyridine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 10.30 (s, 1H), 8.60 (d, J = 4.4 Hz, 1H), 8.48 (s, 1H), 8.21 (d, J = J = 4.9 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H) , 7.62-7.47 (m, 3H), 7.40 (m, 2H), 7.31-7.12 (m, 3H), 6.73 (m, 2H). Anal. Calcd for C ₂₆ H ₂₀ N ₆ OS 0.3 H ₂ O: C, 66.45; H, 4.42; N, 17.88; S, 6.82. Detection: C, 66.33; H, 4.50; N, 17.78; S, 6.60.
[923] Example 35 (o): 6- [2- (N-Hydroxy-N-methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Sol
[924]
[925] Example 35 (o) was prepared in the same manner as in Example 35 (a) except that N-methylhydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.24 (s, 1H), 9.94 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 16.2 Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.65 -7.24 (m, 6H), 7.16 (d, J = 8.5 Hz, 1H), 3.24 (bs, 1H). Anal. Calcd for C ₂₂ H ₁₈ N ₄ O ₂ S (0.5 H ₂ O, 0.3 CH ₂ Cl ₂ ): C, 61.29; H, 4.52; N, 12.82; Detection: C, 61.24; H, 4.33; N, 12.67; S, 7.34.
[926] Example 35 (p): 6- [2 - ((pyrid-4-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- Indazole
[927]
[928] Example 35 (p) was prepared in the same manner as in Example 35 (a) except that 4-aminomethylpyridine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (bs, 1H), 9.07 (t, J = 6.8 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.48 (d, J = 5.0 Hz J = 8.7 Hz, 1H), 7.95 (d, J = 16.4 Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.68-7.52 , 7.42 (m, 2H), 7.39-7. 31 (m, 3H), 7.27 (m, 1H), 7.20-7.10 (m, 2H), 4.48 (d, J = 6.2 Hz, 2H).
[929] Example 35 (q): Synthesis of 6- [2 - ((2-methylphenylhydra map) carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[930]
[931] Example 35 (q) was prepared in the same manner as in Example 35 (a), except that 2-methylphenyl hydrazide was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.43 (bs, 1H), 10.45 (s, 1H), 10.28 (s, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 1H), 7.69 (m, 1H), 7.60 (d, J = 16.4 Hz, 1H) , 7.50-7.22 (m, 8H), 7.07 (d, J = 7.7 Hz, 1H), 2.45 (s, 3H).
[932] Example 35 (r): 6- [2- (Methoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[933]
[934] Example 35 (r) was prepared in the same manner as in Example 35 (a) except that O-methylhydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.32 (s, 1H), 11.60 (s, 1H), 8.60 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.95 J = 7.9 Hz, 1H), 7.56 (m, 2H), 7.47 (dd, J = 7.4, 1.7Hz, 1H), 7.43-7.24 (m, 3H), 7.17 (m, 2H), 3.72 (s, 3H) .C analysis of the _{22 H 18 N 4 O 2 s} · 0.6 CH 2 Cl 2 calculated : C, 59.86, H, 4.27, N, 12.36, S, 7.07. Detection: C, 59.94; H, 4.40; N, 12.00; S, 6.80.
[935] Example 35 (s): Synthesis of 6- [2 - ((cyclopropyl) methoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[936]
[937] Example 35 (s) was prepared in the same manner as in Example 35 (a) except that O-cyclopropylhydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.38 (s, 1H), 11.51 (s, 1H), 8.64 (d, J = 3.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 16.4 Hz, 1H), 7.86 (m, 2H), 7.63-7.52 (m, 2H), 7.49-7.29 1H), 1.10 (m, 1H), 0.53 (m, 2H), 0.27 (m, 2H). _{C 25 H 22 N 4 O 2} S · 1.6 H ₂ O for analysis calculated: C, 63.70; H, 5.39 ; N, 11.89; S, 6.80. Detection: C, 63.58; H, 4.95; N, 11.71; S, 6.66.
[938] Example 35 (t): 6- [2- (n-Propoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[939]
[940] Example 35 (t) was prepared in the same manner as in Example 35 (a) except that On-propylhydroxyamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 11.48 (s, 1H), 8.60 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 16.2 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.60-7.52 (m, 2H), 7.49-7.24 J = 6.4 Hz, 2H), 1.62 (m, 4H), 7.17 (m, 2H), 3.84 (t, J = 6.6 Hz, 2H). Anal. Calcd for C ₂₄ H ₂₂ N ₄ O ₂ S (0.5 H ₂ O, 0.25 CH ₂ Cl ₂ ): C, 63.21; H, 5.14; N, 12.16; Detection: C, 63.15; H, 5.13; N, 12.17; S, 6.99.
[941] Example 35 (u): Synthesis of 6- [2- (allylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[942]
[943] Example 35 (u) was prepared in the same manner as in Example 35 (a) except that allylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.60 (m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 16.3 Hz, 3H), 7.79 (m, 3H), 7.37-7.23 (m, 3H), 7.17 (d, J = 8.5Hz, 1H), 7.60 5.07 (m, 1H), 5.87 (m, 1H), 5.25 (dq, J = 17.33, 1.9 Hz, 1H), 5.09 (dq, J = 10.2, 1.9 Hz, 1H), 3.87 (m, 2H). Anal. Calcd for C ₂₄ H ₂₀ N ₄ OS 揃 0.8 CH ₂ Cl ₂ : C, 62.00; H, 4.53; N, 11.66; S, 6.67. Detection: C, 62.08; H, 4.73; N, 11.99; S, 6.66. MALDIFTMS (MH ^&lt; ⁺ & gt ^; ) yield 413.1431, detected 413.1449.
[944] Example 35 (v): 6- [2- (Cyclopropylmethyl-carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[945]
[946] Example 35 (v) was prepared in the same manner as in Example 35 (a) except that cyclopropylmethylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.30 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.48 (t, J = 5.3 Hz, 1H), 8.17 (d, J = 8.7 Hz , 7.90 (d, J = 16.4 Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.67-7.5 (m, 4H), 7.33-7.23 1H, J = 8.3 Hz, 1H), 7.06 (m, 1H), 3.13 (t, J = 6.2Hz, 2H), 1.00 (m, 1H), 0.41 (m, Analysis for C ₂₅ H ₂₂ N ₄ OS 揃 0.5 CH ₂ Cl ₂ : C, 65.30; H, 4.94; N, 11.95; S, 6.84. Detection: C, 65.10; H, 4.93; N, 12.04; S, 6.82. MALDIFTMS (MH ^&lt; ⁺ & gt ^; ) yield 427.1587, detected 427.1605.
[947] Example 35 (w): 6- [2- (Cyanomethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] -1H-indazole
[948]
[949] Example 35 (w) was prepared in the same manner as in Example 35 (a) except that aminoacetonitrile was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.35 (s, 1H), 9.19 (t, J = 5.3 Hz, 1H), 8.60 (t, J = 4.8 Hz, 1H), 8.20 (d, J = 8.7 Hz 1H), 7.94 (d, J = 16.4 Hz, 3H), 7.79 (dt, J = 1.7, 7.5 Hz, 1H), 7.70-7.50 (m, 4H), 7.41-7.23 d, J = 8.3 Hz, 1H), 7.06 (d, J = 6.6 Hz, 1H), 4.32 (d, J = 5.5 Hz, 2H). MALDIFTMS (MH ^&lt; ⁺ & gt ^; ) yield 412.1227, detection 412.1215.
[950] Example 35 (x): 6- [2- (Ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[951]
[952] Example 35 (x) was prepared in the same manner as in Example 35 (a) except that ethylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ8.60 (d, J = 4.0 Hz, 1H), 8.40 (t, J = 6.2 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94 (m (M, 3H), 7.30 (d, J = 1.7, 7.5 Hz, 1H), 7.68-7.44 Hz, 1H), 7.06 (m, 1H), 3.24 (m, 2H), 1.11 (t, J = 7.0 Hz, 3H). Anal. Calcd for C ₂₃ H ₂₀ N ₄ OS (1.75 H ₂ O, 1.0 DMF): C, 61.82; H, 6.09; N, 13.87; Detection: C, 61.58; H, 5.66; N, 13.96; S, 5.93. MALDIFTMS (MH ^&lt; ⁺ & gt ^; ) yield 401.1431, detection 401.1417.
[953] Example 35 (y): 6- [2- (Thiazol-2-ylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[954]
[955] Example 35 (y) was prepared in the same manner as in Example 35 (a) except that 2-aminothiazole was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.32 (s, 1H), 12.67 (s, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 16.3 Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.65 -7.51 (m, 3H), 7.49-7. 34 (m, 2H), 7.26 (m, 2H), 7.18 (m, 2H). Anal. Calcd for C ₂₄ H ₁₇ N ₄ OS ₂ .0.75 H ₂ O: C, 61.45; H, 3.98; N, 14.93; Detection: C, 61.35; H, 4.10; N, 14.96; S, 13.68.
[956] Example 35 (z): Synthesis of 6- [2- (2- (ethoxy) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[957]
[958] Example 35 (z) was prepared in the same manner as in Example 35 (a) except that 2-ethoxyethylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.30 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.45 (t, J = 6.2 Hz, 1H), 8.18 (d, J = 8.5 Hz J = 7.7 Hz, 1H), 7.60-7.45 (m, 3H), 7.36-7.23 (m, (m, 3H), 7.17 (d, J = 8.3 Hz, 1H), 7.07 (m, 1H), 3.50 (m, 6H), 1.10 (d, J = 7.0 Hz, 3H). _{C 25 H 24 N 4 O 2} S · 0.5 CH 2 Cl ₂ for analysis calculated: C, 62.89; H, 5.17 ; N, 11.50; S, 6.58. Detection: C, 62.45; H, 5.33; N, 11.25;
[959] Example 35 (aa): 6- [2 - ((3-methoxybenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Sol
[960]
[961] Example 35 (aa) was prepared in the same manner as in Example 35 (a) except that 3-methoxybenzylamine was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.30 (s, 1H), 8.97 (t, J = 5.5 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.18 (d, J = 8.7 Hz J = 7.9 Hz, 1H), 7.60-7.51 (m, 3H), 7.80 (d, J = J = 6.6 Hz, 2H), 7.38-7.15 (m, 5H), 7.08 (m, 3.71 (s, 3 H). Analysis for C ₂₉ H ₂₄ N ₄ O ₂ S 0.4 H ₂ O: C, 60.25; H, 4.50; N, 17.57; S, 8.04. Detection: C, 60.14; H, 4.47; N, 17.42; S, 8.00.
[962] Example 35 (bb): 6- [2 - ((Pyr-2-yl) methylcarbamoyl) phenylsulfanyl] -3- E- E- 1H-indazole
[963]
[964] Example 35 (bb) was prepared in the same manner as in Example 35 (a) except that 2-aminomethylfuran was used instead of n-propylamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.31 (s, 1H), 8.93 (d, J = 5.7 Hz, 1H), 8.60 (d, J = 4.3 Hz), 8.19 (d, J = 8.0 Hz, 1H ), 7.93 (d, J = 16.5 Hz, 1H), 7.80 (dt, J = 1.9,7.4 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.59-7.48 (m, 4H), 7.37-7.24 (m, 3H), 7.18 (d, J = 9.2 Hz, 1H), 7.06 1H), 4.44 (d, J = 5.3 Hz, 2H). Anal. Calcd for C ₂₆ H ₂₀ N ₄ O ₂ S (0.1 H ₂ O, 0.75 CH ₂ Cl ₂ ): C, 62.02; H, 4.22; N, 10.82; Detection: C, 61.58; H, 4.30; N, 10.55; S, 6.12.
[965] Example 35 (cc): 6- [2- (2-Propynylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[966]
[967] Example 35 (cc) was prepared in the same manner as in Example 35 (a) except that propargylamine was used instead of propylamine (76%). ¹ H NMR (300 MHz, CDCl ₃ ) 8.56 (m, IH), 7.96 (d, IH, J = 8.6 Hz), 7.81 2H), 4.20 (m, 2H), 2.20 (t, 1H, &lt; RTI ID = 0.0 & , J = 2.6 Hz). LCMS (100% area) Rt = 3.36 min, (pos) [M + H] / z yield 411.1, detection 411.1. Analytical yield for 0.2 H ₂ O, 0.17 DMF, 1.2 dichloromethane, C (58.44), H (4.19), N (11.05), S (6.07). Detection: C (58.18), H (4.11), N (10.98), S (6.05).
[968] Example 35 (dd): 6- [2- (Ethoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[969]
[970] Example 35 (dd) was prepared in the same manner as in Example 35 (a) except that ethoxyamine was used instead of propylamine. _{^{1 H NMR (300MHz, CDCl 3}} ) δ11.60 (s, 1H), 8.71 (d, 1H, J = 7.9 Hz), 8.30 (d, 1H, J = 8.5 Hz), 8.05 (d, 1H, J = (Dd, 1H, J = 1.8, 7.3 Hz), 7.76 (d, 1H, J = 7.8 Hz) , 7.52-7.36 (m, 3H), 7.28 (m, 2H), 4.06 (q, 2H, J = 7.0 Hz), 1.31 (t, 2H, J = 7.0 Hz). LCMS (100% area) Rt = 3.28 min, (pos) [M + H] / z yield 417.1, detection 417.1. 0.2 H ₂ O, C (65.53), H (4.98), N (13.05), S (7.48). Detection: C (65.66), H (4.91), N (12.75), S (7.44).
[971] Example 35 (ee): 6- [2- (2-Methyl-2-propenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Sol
[972]
[973] Example 35 (ee) was prepared in the same manner as in Example 35 (a), except that 2-methylallylamine was used instead of propylamine. ¹ H NMR (300 MHz, CDCl ₃ ) 8.56 (m, 1H), 7.98 (d, 2H), 6.72 (m, 1H), 4.89 (s, 1H, &lt; RTI ID = 0.0 & ), 4.81 (s, 1H), 3.90 (d, 2H, J = 5.5 Hz), 1.71 (s, 3H). LCMS (100% area) Rt = 3.37 min, (pos) [M + H] / z yield 427.1, detection 427.1. Analytical yield for 0.7 H ₂ O, 0.1 dichloromethane, C (67.35), H (5.31), N (12.52), S (7.16). Detection: C (67.55), H (5.39), N (12.35), S (7.15).
[974] Example 35 (ff): 6- [2 - ((3-Fluorobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- Sol
[975]
[976] Example 35 (ff) was prepared in the same manner as in Example 35 (a), except that 3-fluorobenzylamine was used instead of propylamine. _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.60 (m, 1H), 7.97 (d, 1H, J = 8.5 Hz), 7.86 (d, 1H, J = 16.4 Hz), 7.70 (m, 2H), 7.51 (m, 2H), 7.33 (m, 4H), 7.18 (m, 2H), 7.11 (dd, Hz); LCMS (100% area) Rt = 3.55 min, (pos) [M + H] / z yield 481.1, detection 481.1. Analytical yield for 0.7 H ₂ O, 0.5 dichloromethane, C (63.91), H (4.40), N (10.46), S (5.99). Detection: C (63.80), H (4.34), N (10.34), S (5.98).
[977] Example 35 (gg): 6- [2- (2- (Methylamino) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[978]
[979] Example 35 (gg) was prepared in the same manner as in Example 35 (a) except that N-methylethylenediamine was used instead of propylamine. ¹ H NMR (300 MHz, CDCl ₃ ) 8.60 (m, 1H), 7.98 (d, 2H), 3.45 (t, 2H), 2.69 (t, 2H, &lt; RTI ID = 0.0 & ), 2.15 (bs, 3H); LCMS (100% area) Rt = 3.16 min, (pos) [M + H] / z yield 430.1, detection 430.1. Analytical calculation for 0.2 H ₂ O, 0.6 dichloromethane, 0.06 hex (Hex), C (61.28), H (5.24), N (14.31), S (6.55). Detection: C (61.26), H (5.14), N (14.22), S (6.56).
[980] Example 35 (hh): 6- [2- (2- (thien-2-yl) ethylcarbamoyl) phenylsulfanyl] -3- E- E- [2- (pyridin- - Indazole
[981]
[982] Example 35 (hh) was prepared in the same manner as in Example 35 (a) except that 2- (2-aminoethyl) thiophene was used instead of propylamine. ¹ H NMR (300 MHz, CDCl ₃ ) 8.56 (m, 1H), 7.98 (d, 2H), 6.72 (m, IH), 6.63 (m, IH), 7.63 (m, IH) ), 6.52 (m, 1 H), 3.45 (q, 2H), 3.00 (t, 2H). Analytical yield for 0.5 H ₂ O, 0.7 dichloromethane, C (65.35), H (4.69), N (11.26), S (12.82). Detection: C (65.49), H (4.80), N (11.21), S (12.77).
[983] Example 35 (ii): 6- [2- (Aminocarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2- yl) ethenyl]
[984]
[985] Example 35 (ii) was prepared in the same manner as in Example 35 (a) except that hydrazine was used instead of propylamine. ^{1 H NMR (300MHz, DMSO-} d 6) δ13.3 (s, 1H), 9.57 (s, 1H), 8.54 (d, 1H, J = 3.9 Hz), 8.14 (d, 1H, J = 8.5 Hz) 1H, J = 7.9 Hz), 7.50 (m, 2H), 7.40 (dd, 1H, J = 1H, J = 1.8,7.1 Hz), 7.3-7.1 (m, 4H), 7.0 (m, 1H); LCMS (100% area) Rt = 0.55 min, (pos) [M + H] / z yield 388.1, detection 388.1. 0.1 DMF, 0.55 EtOAc, 0.12 Tol (NMR) and 0.15 H ₂ O analysis of the calculated, C (63.98), H ( 5.15), N (15.63), S (7.02). Detection: C (63.99), H (5.07), N (15.75), S (6.89).
[986] Examples 35 (jj) to 35 (nn) can be produced in the same manner as in Example 35 (a).
[987] Example 35 (jj)
[988]
[989] Example 35 (kk)
[990]
[991] Example 35 (II)
[992]
[993] Example 35 (mm)
[994]
[995] Example 35 (nn)
[996]
[997] Example 36 (a): Synthesis of 6- [2- (N ² - (1-methylimidazol-2-ylmethylidene) hydrazino) carbonyl) phenylsulfanyl] -3-E- [2 - (pyridin-2-yl) ethenyl] -1H-indazole
[998]
[999] Example 36 (a) was prepared by treating a solution prepared by dissolving 29 mg (0.258 mmol, 2.5 equiv) of 1-methyl-2-imidazolecarboxyaldehyde in 40 mg (0.103 mmol) of the compound prepared in Example 35 (ii) ^{were: 1 H NMR (300MHz, DMSO} -d 6) δ8.60 (m, 2H), 8.31 (s, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.98 (d, 1H), (M, 2H), 7.63 (m, 2H), 7.40 (m, 3H), 7.30 (s, 3 H); LCMS (100% area) Rt = 4.0 min, (pos) [M + H] / z yield 480.2, detection 480.2. Analytical yield for 1.45 H ₂ O, C (61.76), H (4.76), N (19.39), S (6.34). Detection: C (61.78), H (4.67), N (19.34), S (6.39).
[1000] Example 36 (b): Synthesis of 6- [2- (N ² - (pyridin- ² -ylmethylidene) hydrazino) carbonyl) 2-yl) ethenyl] -1H-indazole
[1001]
[1002] Example 36 (b) was prepared in the same manner as in Example 36 (a) except that 2-pyridylcarboxyaldehyde was used instead of 1-methyl-2-imidazolecarboxaldehyde: ¹ H NMR (300 MHz, CDCl 3 _{3) δ8.57 (m, 2H)} , 8.45 (m, 2H), 8.22 (d, 1H), 8.10 (s, 1H), 7.93 (d, 1H), 7.83 (d, 1H), 7.8-7.1 ( m, 11H); LCMS (100% area) Rt = 4.0 min, (pos) [M + H] / z yield 477.1, detection 477.1. Analytical yield for 0.85 H ₂ O, C (65.93), H (4.45), N (17.09), S (6.52). Detection: C (66.02), H (4.42), N (16.95), S (6.38).
[1003] Example 36 (c): 6- [2- (N 2 - ( 2,2,2-trifluoro-butylidene) hydrazino) carbonyl) phenylsulfanyl peonil] -3-E- [2- (pyridin- Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[1004]
[1005] Example 36 (c) was prepared in a manner similar to that of Example 36 (a) except that trifluoroacetaldehyde was used instead of 1-methyl-2-imidazolecarboxaldehyde: ¹ H NMR (300 MHz, DMSO- d ₆ ) 8.70 (m, 1H), 8.25 (m, 1H), 8.02 (d, 1H), 7.90 (dt, 1H), 7.80-7.20 (m, 10H); LCMS (100% area) Rt = 5.64 min, (pos) [M + H] / z yield 468.1, detection 468.0. Analytical yield for 0.75 H ₂ O, C (57.39), H (3.67), N (14.56), S (6.67). Detection: C (57.44), H (3.67), N (14.56), S (6.67).
[1006] Example 37 (a): Synthesis of 6- [6-fluoro-2- (ethoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1007]
[1008] Example 37 (a) was prepared in a manner similar to that of Example 35 (a) except that the following starting materials were prepared using ethoxyamine instead of propylamine: ¹ H NMR (300 MHz, CDCl ₃ ) 1H), 7.80 (d, IH), 7.80 (d, IH), 7.80 (d, 1H, J = 16.4 Hz), 7.40 (t, 1H), 7.36 (d, 2H), 1.19 (t, 3H). LCMS (100% area) Rt = 4.85 min, (pos) [M + H] / z yield 435.1, detect 435.1, (neg) [MH] / z yield 433.1, detect 433.1. Analytical yield for 0.35 H ₂ O, 0.07 EtOAc, C (62.56), H (4.57), N (12.54), S (7.17). Detection: C (62.61), H (4.55), N (12.49), S (7.11).
[1009] The starting material was prepared as follows:
[1010]
[1011] To a solution of 1.07 g (5.75 mmol) of ethyl-2,3-difluorobenzoate in 10 ml of DMF was treated 896 mg (11.5 mmol, 2.0 equiv) of sodium sulfide at 23 ° C. The mixture was stirred for 10 hours in the presence of argon. The solution was diluted with 50 mL of ethyl acetate, 50 mL of water and 5 mL of 10% citric acid. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure to obtain 3-fluoro-2-mercapto-benzoic acid ethyl ester: ¹ H NMR (300 MHz, CDCl ₃ ) (T, 1H), 7.38 (m, 1H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt = 4.53 min, (pos) [M + H] / z yield 201.0, detection 200.9.
[1012]
[1013] The thioether was prepared in the same manner as in step (iii) of Example 33 (a) except that 3-fluoro-2-mercapto-benzoic acid ethyl ester was used instead of thiosalicylate (320 mg , 39%): FTIR (thin film) 2952, 1727, 1607, 1586, 1564, 1469, 1433, 1366, 1292, 1249, 182, 1141, 1074, 836 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 8.62 (m, 1H), 7.90 (d, 1H, J = 2H, J = 7.1 Hz), 3.56 (t, 2H, J &lt; RTI ID = 0.0 &gt; = 8.2 Hz), 1.30 (t, 3H, J = 7.1 Hz), 0.88 (t, 2H, J = 8.2 Hz), -0.06 (s, 9H); LCMS (100% area) Rt = 4.44 min, (pos) [M + H] / z yield 549.2, detection 549.2.
[1014] (iii)
[1015]
[1016] The carboxylic acid was prepared in the same manner as in the step (iv) of Example 33 (a) (303 mg, 99%): FTIR (thin film) 2953, 2496, 1715, 1643, 1607, 1567, 1470, 1434, 1300, 1250, 1221, 1075, 967, 932, 836 cm &lt; ^{-1 &} gt ;; _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.81 (m, 1H), 7.87 (m, 2H), 7.79 (m, 3H), 7.65 (m, 2H), 7.56 (m, 1H), 4.40 (m, 1H), 7.30 (m, 1H), 7.00 (dd, 1H, J = 1.4, 8.5 Hz), 5.58 (s, 2H), 3.59 (t, 2H, J = 8.2 Hz) = 8.2 Hz), 0.93 (t, 2H, J = 8.2 Hz), -0.01 (s, 9H); LCMS (100% area) Rt = 10.47 min, (pos) [M + H] / z yield 522.2, detection 522.2.
[1017]
[1018] This salt was prepared in a manner similar to that of Example 33 (g): ¹ H NMR (300 MHz, DMSO-d ₆ ) 13.2 (s, 1H), 8.68 = 8.5 Hz), 7.98 (d, 1H, J = 16.4 Hz), 7.88 (dt, 1H, J = 1.8,7.6 Hz), 7.73 = 16.4 Hz), 7.43-7.32 (m, 3H), 7.20 (m, 2H), 7.07 (t, 1H), 3.23 (m, 8H), 1.68 (t, 12 H).
[1019] (v)
[1020]
[1021] The pentafluorophenyl ester was prepared in the same manner as in step (i) of Example 35 (a): LCMS (100% area) Rt = 10.53 min, (pos) [M + H] / z yield 558.1 558.1.
[1022] Example 37 (b): Synthesis of 6- [6-fluoro-2- (cyclopropylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1023]
[1024] Example 37 (b) was prepared in a manner similar to that of Example 37 (a) except that cyclopropylamine was used instead of ethoxyamine: ¹ H NMR (300 MHz, DMSO-d ₆ ) 8.42 (m, 2H), 7.15 (m, 4H), 6.86 (d, IH), 7.80 (d, IH) ), 2.58 (m, 1H), 0.42 (m, 2H), 0.23 (m, 2H). LCMS (100% area) Rt = 4.91 min, (pos) [M + H] / z yield 431.1, detect 431.1, (neg) [MH] / z yield 429.1, detect 429.2. Analytical yield for 0.55 H ₂ O, C (65.46), H (4.60), N (12.72), S (7.28). Detection: C (65.52), H (4.58), N (12.64), S (7.06).
[1025] Example 37 (c): Synthesis of 6- [6-fluoro-2- (isopropoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Sol
[1026]
[1027] Example 37 (c) was prepared in a manner similar to that of Example 37 (a) except that isopropoxyamine was used instead of ethoxyamine: ¹ H NMR (300 MHz, CDCl ₃ ) 9.50 (bs, 1H (M, 4H), 7.20 (m, 4H), 8.47 (m, 1H), 7.72 (m, 1 H), 1.07 (d, 6 H); LCMS (100% area) Rt = 4.90 min, (pos) [M + H] / z yield 449.1, detection 449.1. Analytical calculation for 0.1 DMF, 0.3 H ₂ O, C (63.28), H (4.87), N (12.45), S (6.95). Detection: C (63.22), H (4.84), N (12.37), S (6.91).
[1028] Example 37 (d): Synthesis of 6- [6-fluoro-2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1029]
[1030] Example 37 (d) was prepared in a manner similar to that of Example 37 (a) except that methylamine was used instead of ethoxyamine: ¹ H NMR (300 MHz, DMSO-d ₆ ) 8.37 (m, 1H ), 8.18 (m, IH), 7.87 (d, IH), 7.67 (d, IH, J = 16.4 Hz), 7.59 (m, 4 H), 6.85 (d, 1 H), 2.49 (d, 3 H); LCMS (100% area) Rt = 4.63 min, (pos) [M + H] / z yield 405.1, detect 405.2, (neg) [MH] / z yield 403.1, detect 403.1. Analytical yield for 0.2 DMF, 0.3 CH ₂ Cl ₂ (nmr), 0.3 H ₂ O, C (61.13), H (4.39), N (13.07), S (7.13). Detection: C (61.08), H (4.35), N (13.14), S (7.22).
[1031] Example 38 (a): Synthesis of 6- [2- (2-methylquinol-6-ylcarbamoyl) phenylsulfanyl] -3-E- (2-styryl)
[1032]
[1033] Example 38 (a) was prepared in a manner similar to that of Example 33 (b) except that step (i) and step (ii) of Example 33 (b) were omitted: ¹ H NMR (300 MHz, CDCl ₃ 2H), 7.34-7.16 (m, 9H), 7.13 (d, IH), 7.83 (d, IH) , &Lt; / RTI &gt; 1H), 7.07 (d, 1H), 2.60 (s, 3H). LCMS (100% area) Rt = 3.87 min, (pos) [M + H] / z yield 513.1, detection 513.2.
[1034] Example 38 (b): Synthesis of 6- [2 - ((4-piperidin-1-yl-3- trifluoromethylphenyl) carbamoyl) phenylsulfanyl] - Indazole
[1035]
[1036] Example 38 (b) was prepared in the same manner as in Example 38 (a), except that 3-trifluoromethyl-4-piperazin-l-yl-phenylamine was used instead of 6-amino- It was ^{prepared: 1 H NMR (300MHz, CDCl} 3) δ8.75 (s, 1H), 7.95 (d, 1H), 7.77 (m, 2H), 7.69 (s, 1H), 7.55 (m, 3H), 7.40 -7.25 (m, 9H), 7.20 (d, IH), 3.00 (m, 4H), 2.83 (m, 4H). LCMS (100% area) Rt = 3.94 min, (pos) [M + H] / z yield 600.2, detection 600.2. Analytical Output for 0.1 Hex (nmr), 1.4 H ₂ O, C (63.71), H (5.12), N (11.06), S (5.06). Detection: C (63.67), H (5.06), N (10.98), S (5.00).
[1037] Example 39 (a): 6- [2- (Methylcarbamoyl) phenylamino] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1038]
[1039] (E) -2-pyridin-2-yl-vinyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol- (0.07820 mmol), ethylenediamine (21 μl, 0.3128 mmol) and 1M TBAF (0.63 ml, 0.6256 mmol) dissolved in THF was stirred for 2 hours at 90 ° C. in an oil bath. The crude product was diluted with 50 mL of ethyl acetate, extracted with 1 M sodium bicarbonate solution (2 x 20 mL), brine (5 x 20 mL), dried over magnesium sulfate, filtered and concentrated to a solid. This solid was dissolved in THF and concentrated to an oil which was then precipitated and triturated with CH ₂ Cl ₂ / Et ₂ O. The powder was filtered, and Et ₂ O was poured. The solid was dried under high vacuum to give 20 mg (yield 70%) of the solid. _{^{1 H NMR (DMSO-d 6}} ) δ12.91 (bs, 1H), 9.86 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.52 (m, 1H), 8.08 (d, J = J = 7.9 Hz, 1H), 7.51 (dt, J = 7.9 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 2.79 (d, J = 7.9 Hz, 1H), 7.47-7.34 (m, 2H) J = 4.7 Hz, 3 H). Anal. Calcd. For C ₂₂ H ₁₉ N ₅ O 0.5 CH ₂ Cl ₂ : C, 65.61; H, 4.89; N, 17.00. Detection: C, 65.52; H, 5.08; N, 16.78.
[1040] The starting material was prepared as follows:
[1041]
[1042] 193 mg (0.4 mmool) of 6-iodo-3-carboxyaldehyde-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole prepared in step (ii) ₁₈ mg (0.02 mmol) of Pd ₂ (dba) ₃ , 212.3 mg (0.08 mmol) of K ₃ PO _4, (1.0 mmol) dissolved in 1.0 mL of dry DME was purged with argon (3X) to make it in a vacuum state, followed by stirring in an 80 DEG C oil bath for 3 days under an argon atmosphere. The product was purified and then _{25% CH 3 CN / CH 2} " chromatography Tron" radial chromatography eluted with Cl ₂ and filtered through a plug (plug) of SiO _2, eluting with ethyl acetate. The mass of the purified fraction was 42 mg. An additional 120 mg of product was further collected with ~ 90% purification. (E) -2-pyridin-2-yl-vinyl) -1- (2-trimethylsilanylethoxymethyl) -1H- indazol- The total amount of amide was 162 mg (~ 81%).
[1043] Example 39 (b): 6- [2- (Prop-2-ynylcarbamoyl) phenylamino] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1044]
[1045] Example 39 (b) was prepared in the same manner as in Example 39 (a) except that propargylamine was used instead of methylamine. _{^{1 H NMR (CDCl 3) δ9.50}} (s, 1H), 8.64 (d, J = 4.5 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 16.4 Hz, 1H J = 1.5, 7.2 Hz, 1H), 7.70 (dt, J = 1.7, 7.5 Hz, 1H), 7.57 (d, J = 16.3 Hz, 1H), 7.52-7.43 , 7.26 (m, 3H), 7.34 (ddd, J = 1.0, 4.9, 7.5 Hz, 1H), 7.09 (dd, J = 1.7, 9.0 Hz, 1H), 6.85 ), 6.33 (bs, 1H), 4.24 (dd, J = 2.6, 5.3 Hz, 2H), 2.30 (t, J = 5.5 Hz, 1H). Anal. Calcd. For C ₂₄ H ₁₉ N ₅ O 0.25 CH ₂ Cl ₂ : C, 70.24; H, 4.74; N, 16.89. Detection: C, 70.72; H, 4.96; N, 16.55.
[1046] Example 40 (a): 6- (3-Amino-benzoyl) -3-E- [2- (pyridin- 2- yl) ethenyl]
[1047]
[1048] Example 40 (a) was prepared in the same manner as in Example 11. ^{1 H NMR (300MHz, DMSO-} d 6) δ13.5 (s, 1H), 8.62 (d, 1H, J = 3.86 Hz), 8.34 (d, 1H, J = 8.5 Hz), 8.01 (d, 1H, (M, 3H), 7.29 (qd, 1H, J = 7.39 Hz, J = 8.3 Hz), 7.87 (s, 1H, J = 0.98 Hz), 7.21 (t, 1H, J = 7.77), 7.00 (t, 1H, J = 1.86 Hz), 6.90 (dt, 1H, J = 6.15 Hz, J = 1.40 Hz) 1H), &lt; / RTI &gt; 5.40 (bs, 2H). Calculated: C, 74.10; H, 4.74; N, 16.46. MS (ESI +) [M + H] Detection: C, 72.72; H, 4.87; N, 16.02.
[1049] The starting material was prepared as follows:
[1050] (i)
[1051]
[1052] 8.22 g (60 mmol) of m-amino-phenylboronic acid were dissolved in 60 ml of dimethylformamide under argon atmosphere at 23 DEG C and 10 ml (72 mmol) of triethylamine and 0.366 g (3 mmol) of 4- (dimethylamino) . The solution was heated to 50 &lt; 0 &gt; C. 4-nitro-phenyl ester carbonate 20.4 g (72 mmol) of 2-trimethylsilyl-ethyl ester was added for 5 hours in 4 g portions at a time for 18 hours. After 44 hours, 3.4 g (12 mmol) of carbonic acid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester was added and 1.7 ml (12 mmol) of triethylamine was added. After 63 hours, the reaction mixture was concentrated to an oil and purified by silica gel chromatography eluting with 3-7 to 7-3 ethyl acetate-hexanes to give (3-bromo-phenyl) -carbamic acid 2-triethylsilanyl - ethyl ester (yield 48%); R _f cm 0.067, p 0.33 (ethyl acetate: hexane = 1: 1); _{^{1 H NMR (300MHz, CD 3}} OD) δ7.64 (s, 1H), 7.49 (d, 1H, J = 8.94 Hz), 7.26 (m, 2H), 4.23 (t, 2H, J = 8.28 Hz), 1.06 (t, 2H, J = 8.21 Hz), 0.72 (s, 9H). MS (ESI) [M + Na] / z calc. 304, detection 304.
[1053]
[1054] 7.1 g (14.8 mmol) of 6-iodo-3 - ((E) -2-pyridin-2-yl- (Triphenylphosphine) palladium (II) (312 mg, 0.44 mmol) and potassium carbonate (6.13 g, 44.4 mmol) were added to a solution of 2-trimethylsilanyl- ) And 2.1 ml (14.8 mmol) of triethylamine were placed in 60 ml of anisole and heated to 80 ° C under an atmosphere of carbon monoxide. After 24 hours, 2.1 ml (14.8 mmol) of triethylamine was further added. After 33 h, analysis by thin layer chromatography (ethyl acetate: hexane = 7: 3) showed complete reaction. After cooling the reaction mixture to 23 ℃ and then diluted with saturated NaHCO ₃ and ethyl acetate 300㎖. After phase separation, the aqueous solution was extracted with ethyl acetate (2 x 100 mL). Wash the ethyl acetate accumulates in 100㎖ with brine, filtered and dried in Na ₂ SO _4, and concentrated. Purification by silica gel chromatography provided a yellow glassy product (3- {1- [3- (2-pyridin-2-yl-ethyl) -1- (2- trimethylsilanylethoxymethyl) -Yl] -methanoyl} -phenyl) -carbamic acid 2-trimethylsilanyl-ethyl ester (yield: 79%). _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.65 (d, 1H, J = 3.93 Hz), 8.10 (d, 1H, J = 8.54 Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 1H, J = 16.33 Hz), 7.82 (s, 1H), 7.66-7.77 (m, 3H), 7.61 (t, 2H, J = 6.79 Hz), 1.00 (t, 2H, J = t, 2H, J = 8.13 Hz), 0.04 (s, 9H), 0.0 (s, 9H). MS (ESI &lt; + &gt;) [M + H] / z yield 615, detected 615.
[1055] Example 40 (b): 6- (3-Amino-4-methyl-benzoyl) -3-E- [2- (pyridin- 2- yl) ethenyl]
[1056]
[1057] Example 40 (b) was prepared in the same manner as in Example 40 (a) except that 4-methyl-3-amino-phenylboronic acid was used instead of m-amino- 40 (a). ¹ H NMR (DMSO-d ₆ ) 13.6 (s, 1H), 8.62 (d, 1H, J = 3.81 Hz), 8.33 (D, 1H, J = 16.36 Hz), 7.85 (d, 1H, J = 7.80 Hz) 1H), 7.57 (dd, 1H, J = 8.47 Hz, J = 1.2 Hz), 7.29 6.90 (dd, 1H, J = 7.59 Hz, J = 1.65 Hz), 5.16 (bs, 1H), 2.16 (s, 1H). MS (ESI +) [M + H] / z yield 355, detect 355. Calcd. C, 74.56; H, 5.12; N, 15.81. Detection: C, 73.86; H, 5.25; N, 15.34.
[1058] The starting material was prepared as follows:
[1059]
[1060] A mixture of 3.34 g (18.45 mmol) of 4-methyl-3-nitro-phenylboronic acid and 334 mg of 10% Pd / C in 30 ml of MeOH was subjected to hydrogenation at 23 ° C. After 22 hours, the reaction mixture was filtered through celite and concentrated to give 2.53 g (yield 91%) of 3-amino-4-methylphenylboronic acid. ^{1 H NMR (300MHz, DMSO-} d 6) δ7.21 (s, 1H), 7.08 (d, 1H, J = 7.5 Hz), 6.92 (d, 1H, J = 7.46 Hz), 4.81 (bs, 2H) , 2.09 (s, 3 H). MS (ESI) [M + H] / z yield 152, Detection 152.
[1061] Example 40 (c): 6- (5-Amino-2,4-dimethyl-benzoyl) -3-E- [2- (pyridin- 2- yl) ethenyl]
[1062]
[1063] Example 40 (c) was prepared in the same manner as in Example 40 (a) except that 2,4-dimethyl-3-amino-phenylboronic acid was used instead of m-amino- The title compound was prepared in the same manner as in Example 40 (a). ¹ H NMR (DMSO-d ₆ ) 8.62 (d, 1H, J = 3.78 Hz), 8.32 (d, 1H, J = 8.48 Hz), 7.99 (D, 1H, J = 7.68 Hz, J = 1.8 Hz), 7.80 2H), 2.12 (s, 3H), 2.10 (s, 2H), 7.62 (d, 1H, J = 16.36 Hz), 7.29 , 3H). LCMS (ESI +) [M + H] / z yield 369, detected 369. Analysis calculated: C, 74.98; H, 5.47; N, 15.21. Detection: C, 73.85; H, 5.56; N, 14.49.
[1064] The starting material was prepared as follows:
[1065]
[1066] 2,4-dimethylphenylboronic acid was prepared in the same manner as in step (vii) of Example 24 (a), except that 2,4-dimethylbromobenzene was used as a starting material. _{^{1 H NMR (CD 3 OD)}} δ7.13 (d, 1H, J = 7.43 Hz), 7.00 (s, 1H), 6.97 (d, 1H, J = 7.49 Hz), 2.28 (s, 3H), 2.28 ( s, 3H). LCMS (ESI &lt; + &gt;) [M + H] / z yield 151,
[1067]
[1068] 1 ml of fuming nitric acid cooled to -40 占 폚 was added to 1 ml of TFA. The mixture was gradually warmed to -35 DEG C and 150 mg (1 mmol) of 2,4-methylphenylboronic acid was added in one portion. After 1 hour, the ice was added and the heterogeneous mixture was filtered. The solid produced above was suspended in Et ₂ O and extracted with 1 mL of 3 N NaOH (aq) and extracted with 2 mL of water. The aqueous phase was acidified with 1 mL of 3N HCl (aq) and the remainder extracted with EtOAc (3 x 5 mL). Highly organics washed with brine and concentrated decanted and dried by Na ₂ SO ₄ to 2,4-dimethyl-5-nitro-phenyl boronic acid to give 93mg (yield 47%). LCMS (ESI &lt; + &gt;) [M + H] / z yield 196, detected 196.
[1069]
[1070] 3-Amino-4,6-dimethylphenylboronic acid was prepared in the same manner as in step (i) of Example 40 (b). _{^{1 H NMR (CD 3 OD)}} δ6.83 (s, 2H), 6.64 (s, 1H), 2.17 (s, 3H), 2.13 (s, 3H).
[1071] Example 41 (a): 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol- 5- ylcarbamoyl) -Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[1072]
[1073] To a solution of 323 mg (2.1 mmol, 2.1 equiv) of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid in 5 ml of DMF in the presence of 23 ° C argon was added 365 디 (2.1 mmol, 2.1 equiv), 798 mg HATU (2.1 mmol, 2.1 equiv) and DMAP (cat). To this solution was added 340 mg (1 mmol, 1 equiv) of 6- (3-amino-benzoyl) -3-E- (2-pyridin- Was added. The reaction was subjected to HPLC (where mono and bis acrylic compounds were formed) until all starting material was consumed (~ 2 hours). The reaction mixture was cooled with saturated NaHCO ₃ , then diluted with water and extracted with ethyl acetate. EtOAc stagnant was filtered and concentrated, the oil is washed with water, brine, dried over Na ₂ SO _4. The oil was redissolved in 10 mL of methanol and 290 mg (2.1 mmol, 2.1 equiv) of K ₂ CO ₃ was added followed by stirring at 23 ° C. until all of the bis-acrylic compound was consumed (~30 min). The reaction mixture was concentrated to an oil and then partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Ethyl) -3-methyl-lH-pyrazol-5-yl) carboxyamido) was obtained by silica gel chromatography (eluting with 1: 1 to 8: 2 ethyl acetate: dichloromethane) -Benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole. ^{1 H NMR (300MHz, DMSO-} d 6) δ13.6 (s, 1H), 10.3 (s, 1H), 8.62 (d, 1H, J = 3.88 Hz), 8.38 (d, 1H, J = 8.51 Hz) , 8.20 (s, 1H), 8.12 (td, 1H, J = 7.58 Hz, J = 1.78 Hz), 8.02 (d, 1H, J = 16.36 Hz), 7.93 J = 7.61 Hz, J = 1.7 Hz), 7.70 (d, 1H, J = 7.78 Hz), 7.65 (d, 1H, J = 16.23 Hz), 7.65-7.53 , 4.43 (q, 2H, J = 7.07 Hz), 2.21 (s, 3H), 1.31 (t, 3H, J = 7.07 Hz). MS (ESI +) [M + H] / z yield 477, detection 477. Anal. Yield: C, 70.57; H, 5.08; N, 7.64. Detection: C, 70.46; H, 5.11; N, 17.61.
[1074] Example 41 (b): 6- [3- (Pyridin-4-ylcarboxamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1075]
[1076] Example 41 (b) was prepared in the same manner as in Example 41 (a) except that isonicotinic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. _{^{1 H NMR (300MHz, CD 3}} OD) δ8.74 (d, 2H, J = 6.04 Hz), 8.56 (d, 1H, J = 4.14 Hz), 8.27 (m, 2H), 8.05 (dt, 1H, J = 7.97 Hz, J = 1.64 Hz), 8.02 (s, IH), 7.95 (d, IH, J = 16.55 Hz), 7.83-7.91 (m, 3H), 7.73 (m, 2H), 7.56-7.67 , &Lt; / RTI &gt; 3H), 7.32 (m, 1H). MS (ESI +) [M + H] / z yield 446, detect 446. Anal. Yield: C, 72.80; H, 4.30; Detection: C, 71.59; H, 4.43; N, 15.33.
[1077] Example 41 (c): crotonylamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole
[1078]
[1079] Example 41 (c) was prepared in the same manner as in Example 41 (a) except that crotonic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole- Respectively. ^{1 H NMR (300MHz, DMSO-} d 6) δ13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J = 3.81 Hz), 8.37 (d, 1H, J = 8.49 Hz) (Dd, 1H, J = 7.67Hz, J = 1.78Hz), 7.70 (d, 1H, J = 7.88Hz) (d, 1H, J = 7.85 Hz), 7.65 (d, 1H, J = 16.40 Hz), 7.63 (dd, 1H, J = 8.43 Hz, J = 1.23 Hz), 7.47-7.56 (dd, J = 15.21, J = 1.68 Hz), 1.87 (d, 3H, J = 6.9 Hz) 6.89 Hz). MS (ESI &lt; + &gt;) [M + H] / z yield 409, detected 409. Analysis calculated: C, 73.51; H, 4.94; Detection: C, 72.15; H, 4.97; N, 13.39.
[1080] Example 41 (d): Synthesis of 6- [3- (idol-4-ylcarboxamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1081]
[1082] Example 41 (d) was prepared in the same manner as in Example 41 (a) except that 1H-indole-4-carboxylic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole- . LCMS (ESI &lt; + &gt;) [M + H] / z yield 484, detected 484.
[1083] Example 41 (e): 6- [3 - ((5-acetylthien-2-yl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- Indazole
[1084]
[1085] Example 41 (e) was prepared analogously to Example 41 (a) but using 5-acetyl-thiophene-2-carboxylic acid instead of 2-ethyl- . &Lt; / RTI &gt; ^{1 H NMR (300MHz, DMSO-} d 6) δ13.6 (s, 1H), 10.6 (s, 1H), 8.63 (d, 1H, J = 3.83 Hz), 8.39 (d, 1H, J = 8.51 Hz) , 8.02 (d, 1H, J = 16.42 Hz), 8.20 (s, (d, 1H, J = 4.01 Hz), 7.94 (s, 1H), 7.83 (td, 1H, J = 7.69 Hz, J = 1.78 Hz), 7.59-7.65 J = 7.40 Hz, J = 0.96 Hz), 2.58 (s, 3H). Calculated: C, 68.28; H, 4.09; N, 11.37; S, 6.51. MS (ESI +) [M + H] Detection: C, 66.07; H, 4.34; N, 10.91; S, 6.14.
[1086] Example 41 (f): 6- [3- (3,5-Difluorophenylacetamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1087]
[1088] Example 41 (f) was prepared analogously to Example 41 (a), but using (3,5-difluoro-phenyl) acetic acid instead of 2-ethyl-5-methyl-2H-pyrazole- . &Lt; / RTI &gt; ^{1 H NMR (300MHz, DMSO-} d 6) δ13.6 (bs, 1H), 10.5 (s, 1H), 8.62 (d, 1H, J = 4.02 Hz), 8.36 (d, 1H, J = 8.51 Hz) , 8.05 (s, 1H), 8.01 (d, IH, J = 16.38 Hz), 7.93 (d, IH, J = 7.88 Hz), 7.90 (Dd, 1H, J = 8.45 Hz, J = 1.15 Hz), 7.48-7.57 (d, (m, 2H), 7.15-7.31 (m, 5H), 3.77 (s, 2H). MS (ESI &lt; + &gt;) [M + H] / z yield 495, detected 495.
[1089] Example 41 (g): 6- [3 - ((5-Methyl-lH-pyrazol-3- yl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- ] -1H-indazole
[1090]
[1091] Example 41 (g) was prepared in analogy to Example 41 (e) except for using 5-methyl-2H-pyrazole-3-carboxylic acid instead of 2-ethyl- was prepared in the same manner as in a). ^{1 H NMR (300MHz, DMSO-} d 6) δ13.6 (bs, 1H), 13.0 (bs, 1H), 10.3 (bs, 1H), 8.63 (d, 1H, J = 3.95 Hz), 8.37 (d, 1H, J = 8.66 Hz), 8.36 (s, 1H), 8.16 (d, 1H, J = 7.55 Hz), 8.02 1H, J = 7.61 Hz, J = 1.73 Hz), 7.70 (d, 1H, J = 7.82 Hz), 7.65 1.12 Hz), 7.52 (m, 2H), 7.29 (m, 1H), 6.50 (s, 1H), 2.29 (s, 3H). MS (ESI &lt; + &gt;) [M + H] / z yield 449, detection 449. Anal. Yield: C, 69.63; H, 4.49; Detection: C, 68.53; H, 4.95; N, 17.47.
[1092] Example 41 (h): Synthesis of 6- [3 - ((2-RS-trans-methylcyclopropyl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- - Indazole
[1093]
[1094] Example 41 (h) was prepared in the same manner as in Example 41 (a), except that 2-methyl-cyclopropanecarboxylic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole- . R _f sm 0.32, R _f p 0.42 (ethyl acetate: dichloromethane = 8: 2). ¹ H NMR (300 MHz, DMSO-d ₆ ) 隆 13.6 (s, 1H), 10.4 (s, 1H), 8.62 (dd, 1H, J = 4.75 Hz, J = 0.96 Hz), 8.36 J = 8.47 Hz), 8.06 (t, 1H, J = 1.67 Hz), 8.01 (d, 1H, J = 16.37 Hz), 7.90 (m, 2H), 7.83 (D, 1H, J = 8.47 Hz, J = 1.32 Hz), 7.71 (d, 1H, J = J = 7.69 Hz), 7.45 (dt, 1H, J = 7.68 Hz, J = 1.50 Hz), 7.29 (dq, 1H, J = 7.41 Hz, J = 1.04 Hz), 1.51 1H), 1.09 (d, 3H, J = 5.93), 1.01 (m, 1H), 0.65 (m, 1H). Calculated: C, 73.92; H, 5.25; N, 13.26. MS (ESI +) [M + H] Detection: C, 71.41; H, 5.56; N, 13.27.
[1095] Example 41 (i): 6- [3 - ((1,5-Dimethyl-1H-pyrazol-3-yl) carboxamido) benzoyl] -3- E- E- [2- (pyridin- Ethenyl] -1H-indazole
[1096]
[1097] Example 41 (i) was prepared in the same manner as in Example 41 (1) except that 1,5-dimethyl-1H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- 41 (a). ¹ H NMR (300 MHz, DMSO-d ₆ ) 13.6 (s, IH), 10.2 (s, IH), 8.63 (d, IH, J = 3.87 Hz), 8.37 , 8.13 (dd, 1H, J = 7.43 Hz, J = 1.96 Hz), 8.02 (d, 1H, J = 16.35 Hz), 7.92 (dd, 1H, J = 7.68 Hz, J = 1.79 Hz), 7.70 (d, 1H, J = 7.84 Hz), 7.65 , 7.52 (m, 2H), 7.29 (m, 1H), 6.55 (s, 1H), 3.83 (s, 3H), 2.30 (s, 3H). Calculated: C, 70.12; H, 4.79; N, 18.17. MS (ESI +) [M + H] Detection: C, 69.59; H, 4.88; N, 17.86.
[1098] Example 41 (j) 6- [3 - ((3-Methylpyridin-4-yl) carboxyamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Indazole
[1099]
[1100] Example 41 (j) was prepared in the same manner as in Example 41 (a) except that 3-methyl-isonicotinic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid . ^{1 HNMR (300MHz, DMSO-d} 6) δ13.6 (s, 1H), 10.7 (s, 1H), 8.62 (dd, 1H, J = 4.72 Hz, J = 0.86 Hz), 8.57 (s, 1H), (D, 1H, J = 7.27 Hz, J = 1.99 Hz), 8.02 (d, 1H, J = (d, 1H, J = 16.37 Hz), 7.93 (s, 1H), 7.83 (td, 1H, J = 7.69 Hz, J = 1.79 Hz), 7.70 1H, J = 16.27 Hz), 7.55-7.65 (m, 3H), 7.48 (d, 1H, J = 4.89 Hz), 7.30 (qd, 1H, J = 7.39 Hz, J = 1.02 Hz) 3H). MS (ESI &lt; + &gt;) [M + H] / z yield 460, detection 460.
[1101] Example 41 (k): 6- [3- (Cyclopropylcarbamoylido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1102]
[1103] Example 41 (k) was prepared in the same manner as in Example 41 (a) except that cyclopropanecarboxylic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. _{^{1 H NMR (CDCl 3 /MeOD)δ8.52(d,}} 1H, J = 3.9 Hz), 8.09 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.85-7.80 (m, 3H) , 7.71-7.63 (m, 2H), 7.55-7.48 (m, 3H), 7.39 (1H, t, J = 7.8 Hz), 7.16 (1H, qd, J = 6.3, 1.5 Hz), 1.62-1.57 , &Lt; / RTI &gt; 1H), 1.25-1.84 (m, 2H), 0.87-0.81 (m, 2H). _{HRMS (MALDI) C 25 H 20} N 4 O 2 [M + H +] / z calculated 409.1659, 409.1660 detected.
[1104] Example 41 (l): To a solution of 6- [3 - ((2-RS-trans-phenylcyclopropyl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- - Indazole
[1105]
[1106] Example 41 (1) was prepared in analogy to example 41, except (1S, 2S) -2-phenyl-cyclopropanecarboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole- (a). ¹ H NMR (CDCl _{3 /} MeOD) 8.60 (d, IH, J = 4.2 Hz), 8.17 (d, IH, J = 8.4 Hz), 8.02 (s, 2H), 7.63-7.56 (m, 3H), 7.47 (t, 1H), 7.32-7.12 (m, 5H), 2.60-2.54 (m, 1H), 1.69 (q, 1H, J = 4.8Hz), 1.37-1.32 (m, 1H). HRMS C ₃₁ H ₂₄ N ₄ O ₂ [M + H ⁺ ] / z yield 485.1993, detection 485.1995.
[1107] Example 41 (m): 6- [3 - ((3-methylisoxazol-5-yl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- ] -1H-indazole
[1108]
[1109] Example 41 (m) was prepared analogously to Example 41 (a) except that 3-methyl-isooxazole-5-carboxylic acid was used instead of 2-ethyl- ). &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ10.95 (1H, s), 8.68 (1H, d, J = 4.2 Hz), 8.44 (d, 1H, J = 8.7 Hz), 8.35 (s, 1H), 8.21 1H, J = 7.5, 1.8 Hz), 7.76-7.64 (m, 6H), 8.08 (d, 7.37-7.33 (m, 1 H), 6.72 (s, 1 H), 3.36 (s, 3 H). HRMS (MALDI) C ₂₆ H ₁₉ N ₅ O ₃ [M + H ⁺ ] / z yield 450.1561, detection 450.1570.
[1110] Benzoyl] -3-E- [2- (pyridine-2-carbonyl) amino] 2-yl) ethenyl] -1H-indazole
[1111]
[1112] Example 41 (n) was prepared using 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid instead of 2-ethyl-5-methyl-2H-pyrazole- Was prepared in the same manner as in Example 41 (a). _{^{1 H NMR (CDCl 3 /MeOD)δ8.59(d,}} 1H, J = 4.8 Hz), 8.14 (d, 1H, J = 8.4 Hz), 8.08-8.04 (m, 1H), 7.98-7.56 (m, 1H), 7.75 (t, 1H, J = 7.8,1.8 Hz), 7.68 (dd, 1H, J = 8.4 Hz), 7.61-7.56 7.25-7.21 (m, 1 H), 6.75 (s, 1 H), 4.12 (s, 3 H), 1.30 (s, 9 H). HRMS (MALDI) C ₃₀ H ₂₈ N ₆ O ₂ [M + H ⁺ ] / z yield 505.2347, detected 505.2353.
[1113] Example 41 (o): 6- [3 - ((5-chlorothien-2-yl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- -1H-indazole
[1114]
[1115] Example 41 (o) was prepared analogously to Example 41 (a) but using 5-chloro-thiophene-2-carboxylic acid instead of 2-ethyl- . &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ10.58 (s, 1H), 8.68 (d, 1H, J = 4.2 Hz), 8.43 (d, 1H, J = 8.5 Hz), 8.22 (s, 1H), 8.15 (dd, 1H, J = 7.5,2.0 Hz), 8.08 (d, 1H, J = 16.4 Hz), 8.00-7.98 (m, 3H), 7.88 (td, 1H, J = 7.7, 1.9 Hz) 7.62 (m, 4H), 7.33 (d, 2H, J = 4.1 Hz). HRMS (MALDI) C ₂₆ H ₁₇ N ₄ O ₂ CIS [M + H ⁺ ] / z yield 485.0843, detection 485.0853.
[1116] Example 41 p: 6- [3 - ((1,3-Dimethyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3- E- E- [2- (pyridin- Ethenyl] -1H-indazole
[1117]
[1118] Example 41 (p) was prepared in the same manner as in Example 41 (2) except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- 41 (a). _{HPLC: R t 3.90min (100%} area). _{^{1 H NMR (CDCl 3) δ8.52}} (d, 1H, J = 4.8 Hz), 8.10 (d, 1H, J = 8.4 Hz), 7.98 (d, 1H, J = 8.1 Hz), 7.93 (s, 1H 1H, J = 7.8 Hz), 7.16 (dd, 1H, J = 7.1 Hz), 7.88-7.80 (m, 3H), 7.71-7.62 , 4.8 Hz). HRMS (MALDI) C ₂₇ H ₂₂ N ₆ O ₂ [M + H ⁺ ] / z yield 463.1877, detection 465.1889.
[1119] Example 41 (q): 6- (3-Fluoropyridin-4-yl) / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1120]
[1121] Example 41 (q) was prepared in analogy to Example 41 (a) but using 2-chloro-6-methyl-isonicotinic acid instead of 2-ethyl-5-methyl-2H-pyrazole- &Lt; / RTI &gt; _{HPLC:. R t 4.11min (100} % area). _{^{1 H NMR (DMSO-d 6}} ) δ10.77 (s, 1H), 8.68 (d, 1H, J = 3.9 Hz), 8.44 (d, 1H, J = 8.4 Hz), 8.28 (s, 1H), 8.21 (dd, 1H, J = 6.9, 2.1 Hz), 8.08 (d, 1H, J = 16.2 Hz), 7.98 (s, 1H), 7.92-7.64 , 4.8 Hz), 2.61 (s, 3H).
[1122] Benzoyl] -3-E- [2- (pyridin-3-yl) -carbamic acid ethyl ester. 2-yl) ethenyl] -1H-indazole
[1123]
[1124] Example 41 (r) was prepared in analogy to example 5, but using 5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid instead of 2-ethyl- Prepared in a similar manner to Example 41 (a). ¹ H NMR (DMSO-d ₆ ) 10.29 (s, 1H), 8.58 (d, 1H, J = 3.9 Hz), 8.33 (dd, 1H, J = 7.5,1.5 Hz), 7.61 (d, 1H, J = 16.5 Hz), 7.87 (s, 1H), 7.78 (td, 1H, J = 5.4, 2.1 Hz), 7.60-7.49 1H, J = 6.9 Hz), 1.69 (q, 2H, J = 7.2 Hz), 0.77 (t, Hz). HRMS (MALDI) C ₂₈ H ₂₀ ClN ₅ O ₂ [M + H ⁺ ] / z yield 491.2190, detection 491.2203.
[1125] Example 41 (s): Synthesis of 6- [3- (4-t-butylbenzamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1126]
[1127] Example 41 (s) was prepared in the same manner as in Example 41 (a) except that 4-tert-butyl-benzoic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole- Respectively. _{HPLC:. R t 4.67min (100} % area). ^{1 H NMR (DMSO) · 10.45} (s, 1H), 8.44 (d, 1H, J = 8.4 Hz), 8.32 (s, 1H), 8.22 (d, 1H, J = 7.5 Hz), 8.07 (d, 1H 1H, J = 7.7,1.5Hz), 7.69-7.59 (m, 7H), 7.38 (dd, 1H, 13.5, 5.1 Hz), 7.99-7.95 (m, , &Lt; / RTI &gt; 1.36 (s, 9H).
[1128] Benzoyl] -3-E- [2- (pyridin-2-yl) -2-methyl- Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[1129]
[1130] Example 41 (t) was prepared in the same manner as described in example 41 except that 2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- Prepared in a similar manner to Example 41 (a). _{HPLC:. R t 4.11min (100} % area). ^{1 H NMR (DMSO) δ10.46 (} s, 1H), 8.74 (t, 1H, J = 5.1 Hz), 8.48 (d, 1H, J = 8.4 Hz), 8.28 (s, 1H), 8.22 (t, 1H, J = 5.4, 2.1 Hz), 8.15-8.01 (m, 3H), 7.39 (td, 1H, J = 7.8, 1.8 Hz), 7.82-7.63 7.7, 1.5 Hz), 6.14-6.02 (m, 2H), 5.22-5.03 (m, 4H), 2.38 (s, 3H). HRMS (MALDI) C ₂₉ H ₂₄ N ₆ O ₂ [M + H ⁺ ] / z yield 489.2034, detection 489.2035.
[1131] Example 41 (u): Synthesis of (6- (3-fluoro-6-methoxypyridin-4-yl) / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1132]
[1133] Example 41 (u) was prepared in analogy to Example 41 (a), except that 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid was used instead of 2-Chloro-6-methoxy- Were prepared in the same manner. _{HPLC:. R t 4.37min (100} % area). _{^{1 H NMR (DMSO-d 6}} ) δ10.74 (s, 1H), 8.68 (d, 1H, J = 3.6 Hz), 8.44 (d, 1H, J = 8.4 Hz), 8.28 (s, 1H), 8.20 (d, 1H, J = 6.6,2.4 Hz), 8.07 (d, 1H, J = 16.2 Hz), 7.98 (s, 1H), 7.89 (td, 1H, J = 7.7, 1.8 Hz), 7.77-7.62 m, 6H), 7.38 (s, IH), 7.35 (dd, IH, J = 6.9, 1.8 Hz), 3.98 (s, 3H).
[1134] Example 41 (v): 6- [3 - ((3-Ethyl- 1 -methyl-1 H-pyrazol-5- yl) carboxyamido) Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[1135]
[1136] Example 41 (v) was prepared in analogy to Example 41 (a), except that 2-chloro-6-methoxy-isonicotinic acid was used instead of 5-ethyl- Were prepared in the same manner. _{HPLC:. R t 4.16min (100} % area). _{^{1 H NMR (DMSO-d 6}} ) δ10.44 (s, 1H), 8.73 (d, 1H, J = 3.0 Hz), 8.78 (d, 1H, J = 8.7 Hz), 8.30 (s, 1H), 8.23 (t, 1H, J = 6.9 Hz), 8.14-8.03 (m, 2H), 7.93 (t, 1H, 6.9 Hz), 7.82-7.63 , 7.01 (s, IH), 4.12 (s, IH), 2.68 (q, 2H, 7.8 Hz), 1.30 (t, 3H, J = 7.5 Hz). _{HRMS (MALDI) C 28 H 24} N 6 O 2 [M + H +] / z calculated 477.2034, 477.2054 detected.
[1137] Example 41 w: 6- [3 - ((2-Chloropyridin-4-yl) carboxyamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl] Indazole
[1138]
[1139] Example 41 (w) was prepared in the same manner as in Example 41 (a) except that 2-chloro-isonicotinic acid was used instead of 5-ethyl-2-methyl-2H-pyrazole- . _{HPLC:. R t 3.99min (100} % area). _{^{1 H NMR (DMSO-d 6}} ) δ10.88 (s, 1H), 7.33 (d, 2H, J = 4.8 Hz), 8.49 (d, 1H, J = 8.4 Hz), 8.33 (s, 1H), 8.26 (t, 1H, J = 6.9, 3.0 Hz), 8.12-7.91 (m, 5H), 7.82-7.63 (m, 5H), 7.40 (t, 1H, J = 4.8 Hz).
[1140] Example 41 (x): 6- [3 - ((l-Isopropyl-3-methyl-lH-pyrazol- 5- yl) carboxyamido) -Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[1141]
[1142] Example 41 (x) was prepared using 2-isopropenyl-5-methyl-2H-pyrazole-3-carboxylic acid instead of 5-ethyl- Was prepared in the same manner as in Example 41 (a). _{HPLC:. R t 4.19min (100} % area). ^{1 H NMR (DMSO) δ10.46 (} s, 1H), 8.72 (t, 1H, J = 4.80 Hz), 8.48 (d, 1H, J = 9.0 Hz), 8.31 (s, 1H), 8.21 (td, 1H, J = 9.6,2.1 Hz), 8.15-7.98 (m, 2H), 7.96-7.84 (m, 1H), 7.82-7.65 (m, 5H), 7.42-7.38 1H), 5.64-5.38 (m, IH), 2.32 (s, 3H), 1.48 (d, IH, J = 6.6 Hz). HRMS (MALDI) C ₂₉ H ₂₆ N ₆ O ₂ [M + H ⁺ ] / z yield 491.2190, detection 491.2194.
[1143] Example 41 (y): 6- [3- (Isopropoxycarbonylamino) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1144]
[1145] Example 41 (y) was prepared in the same manner as in Example 41 (a) except that isopropyl chloroformate was used instead of 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid. _{^{1 H NMR (DMSO-d 6}} ) δ9.97 (s, 1H), 8.72 (t, 2H, J = 4.8 Hz), 8.47 (d, 1H, J = 8.7 Hz), 8.34-7.96 (m, 3H) 2H, J = 7.5, 1.2 Hz), 8.01-7.87 (m, 2H), 7.82-7.69 (m, 2H), 7.52 (dt, 6.6 Hz), 2.02 (m, 1H), 1.02 (d, 6H, J = 6.6 Hz). HRMS (MALDI) C ₂₆ H ₂₄ N ₄ O ₃ [M + H ⁺ ] / z yield 441.1921, detected 441.1937.
[1146] Example 41 (z): 6- [3 - ((4-Clopyridin-2-yl) carboxyamido) benzoyl] -3- E- E- [2- (pyridin- Indazole
[1147]
[1148] Example 41 (z) was prepared in analogy to example 41 (a), except that 4-chloro-pyridine-2-carboxylic acid was used instead of 5-ethyl- Were prepared in the same manner. _{HPLC:. R t 4.40min (100} % area). _{^{1 H NMR (DMSO-d 6}} ) δ10.99 (s, 1H), 8.72 (d, 1H, J = 5.4 Hz), 8.63 (d, 1H, J = 3.9 Hz), 8.44 (s, 1H), 8.38 (d, IH, J = 8.4 Hz), 8.25 (dt, IH, J = 6.6, 2.4 Hz), 8.16 (s, 1H), 7.86-7.80 (m, 2H), 7.72-7.58 (m, 5H), 7.29 (dd, 1H, J = 6.9, 6.0 Hz).
[1149] Example 41 (aa): 6- [3- (pyridin-2-yl-carboxyamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1150]
[1151] Example 41 (aa) was prepared in the same manner as in Example 41 (a) except that pyridine-2-carboxylic acid was used in place of 5-ethyl-2-methyl-2H-pyrazole- Respectively. ^{1 H NMR (300MHz, DMF-} d 6) δ10.9 (s, 1H), 8.74 (m, 1H), 8.63 (dd, 1H, J = 4.78 Hz, 0.94 Hz), 8.46 (s, 1H), 8.38 (dd, 1H, J = 7.73 Hz, J = 1.04 Hz), 8.07 (dd, 1H, J = 7.17 Hz, J = 2.05 Hz) 1H, J = 7.56 Hz, J = 1.67 Hz), 8.02 (d, 1H, J = 16.28 Hz), 7.95 7.66 (m, 4H), 7.30 (qd, 1H, J = 7.40 Hz, J = 1.02 Hz). MS (ESI +) [M + H ^& lt ^{; +} & gt ^; ] / z yield 446, detected 446.
[1152] Example 41 (bb): 6- [3- (3-Methoxybenzamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1153]
[1154] Example 41 (bb) was prepared in the same manner as in Example 41 (a) except that 3-methoxy-benzoic acid was used instead of 5-ethyl-2-methyl-2H-pyrazole- . _{^{1 H NMR (DMSO-d 6}} ) δ10.50 (s, 1H), 8.67 (d, 1H, J = 3.9 Hz), 8.46 (d, 1H, J = 8.7 Hz), 8.33 (s, 1H), 8.22 (d, 1H, J = 7.8,1.8), 8.08 (d, 1H, J = 15.0 Hz), 8.00 (s, 1H), 7.78-7.54 (m, 8H), 7.51 7.38-7.33 (m, 1H), 7.23 (dd, 1H, J = 7.5, 1.5 Hz), 3.90 (s, 3H). HRMS (MALDI) C ₂₉ H ₂₂ N ₄ O ₃ [M + H ⁺ ] / z yield 475.1765, detection 475.1763.
[1155] Example 41 (cc): 6- [3- (Phenoxyamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1156]
[1157] Example 41 (cc) was prepared in the same manner as in Example 41 (a) except that phenyl chloroformate was used instead of 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid. ^{mp 212-217 ℃, 1 H NMR (} 300MHz, DMSO-d 6) δ13.63 (s, 1H), 10.51 (s, 1H), 8.62 (d, 1H, J = 4.3 Hz), 8.36 (d, 1H , J = 8.6Hz), 8.04-7.81 (m, 5H), 7.71-7.40 (m, 7H), 7.31-7.22 (m, 4H). ESIMS m / z 461 [M + H] &lt; ⁺ &gt;. Anal. Calcd for C ₂₈ H ₂₀ N ₄ O ₃ x 0.3 H ₂ O (465.9 g mol ^-1 ): C, 72.18; H, 4.46; N, 11.33. Detection: C, 72.41; H, 4.63; N, 11.57.
[1158] Example 41 (dd): 6- [3- (3,3-Dimethylacrylamido) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1159]
[1160] Example 41 (dd) was prepared in the same manner as in Example 41 (a) except that 3,3-dimethyl acrylic acid was used instead of 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid . ^{1 H NMR (300MHz, DMSO-} d 6) δ13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J = 3.81 Hz), 8.37 (d, 1H, J = 8.49 Hz) (Dd, 1H, J = 7.67Hz, J = 1.78Hz), 7.70 (d, 1H, J = 7.88Hz) (d, IH, J = 7.85 Hz), 7.63 (dd, IH, J = 8.43 Hz, J = 1.23 Hz), 7.47-7.56 0.99 Hz), 6.82 (m, 1H, J = 6.9 Hz), 5.85 (s, 1H), 2.12 (s, 3H), 1.85 (s, 3H). MS (ESI +) [M + H] / z yield 409, detected 409. Analysis for C ₂₆ H ₂₂ N ₄ O ₂ x 0.33 TBME: C, 73.54; H, 5.80; N, 12.41. Detection: C, 73.26; H, 5.76; N, 12.36.
[1161] Example 41 ee: 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol- 5- yl) carboxyamido) Pyridin-2-yl) ethenyl] -1H-indazole
[1162]
[1163] Example 41 (ee) was performed in the place of 6- (3-amino-benzoyl) -3- E- E- [2-pyridin-2- yl) ethenyl] -1H-indazole prepared in Example 40 Except that the 6- (3-amino-4-phenyl-benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole prepared in Example 40 (b) The title compound was prepared in the same manner as in Example 41 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.6 (s, 1H), 9.94 (s, 1H), 8.62 (d, 1H, J = 3.8 Hz), 8.36 (d, 1H, J = 8.51 Hz), 8.01 (d, IH, J = 16.36 Hz), 7.91 (s, IH), 7.84 (dd, 1H, J = 7.66 Hz, J = 1.74 Hz) 7.9 Hz), 7.64 (d, 1H, J = 16.45 Hz), 7.62 (m, 2H), 7.50 (d, 1H, J = 7.83 Hz), 7.29 (q, 2H, J = 7.06 Hz), 2.36 (s, 3H), 2.21 (s, 3H), 1.30 (t, 3H, J = 7.09 Hz). MS (ESI +) [M + H] / z yield 491, detection 491. Anal. Yield: C, 71.00; H, 5.34; N, 17.13. Detection: C, 70.80; H, 5.38; N, 17.00.
[1164] Example 41 (ff): 6- [3 - ((1-Allyl-3-methyl-lH-pyrazol- 5- yl) carboxyamido) Pyridin-2-yl) ethenyl] -1H-indazole
[1165]
[1166] Example 41 (ff) was repeated except that 2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- The title compound was prepared in the same manner as in Example 41 (ee). _{^{1 H NMR (DMSO-d 6}} ) δ13.6 (s, 1H), 9.98 (s, 1H), 8.62 (d, 1H, J = 4.60 Hz), 8.36 (d, 1H, J = 8.46 Hz), 8.01 (d, 1H, J = 16.37 Hz), 7.91 (s, 1H), 7.83 (td, 1H, J = 7.69 Hz, J = 1.77 Hz), 7.78 1H, J = 7.78 Hz), 7.59-7.70 (m, 3H), 7.50 (d, 1H, J = 8.01 Hz), 7.29 (qd, 1H, J = 7.46 Hz, J = 1.02 Hz), 6.86 1H), 5.95 (m, 1H), 4.93-5.10 (m, 4H), 2.34 (s, 3H), 2.22 (s, 3H). LCMS (ESI &lt; + &gt;) [M + H] / z yield 503, detected 503. Analysis calculated: C, 71.70; H, 5.21; Detection: C, 70.98; H, 5.42; N, 15.94.
[1167] Example 41 (gg): 6- (3-Acetamido-4-methylbenzoyl) -3-E- [2- (pyridin- 2- yl) ethenyl]
[1168]
[1169] Example 41 (gg) was prepared in the same manner as in Example 41 (ee) except that acetyl chloride was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (CD ₃ OD) 8.57 (d, 1H, J = 4.90 Hz), 8.13 (d, 1H, J = 8.49 Hz), 7.99 ), 7.89 (d, 1H, J = 1.46 Hz), 7.86 (td, 1H, J = 7.64 Hz, J = 1.73 Hz), 7.73 (d, 1H, J = 7.05 Hz), 7.62-7.69 ), 7.65 (d, 1H, J = 16.48 Hz), 7.44 (d, 1H, J = 7.97 Hz), 7.32 (qd, 1H, J = 7.44 Hz, J = 1.03 Hz) 2.18 (s, 3 H). LCMS (ESI +) [M + H] / z yield 397, detection 397. Analysis calculated: C, 72.71; H, 5.08; Detection: C, 72.29; H, 5.09; N, 13.98.
[1170] Example 41 (hh): 6- [3 - ((1,3-Dimethyl-1H-pyrazol-5-yl) carboxyamido) 2-yl) ethenyl] -1H-indazole
[1171]
[1172] Example 41 (hh) was prepared in the same manner as in Example &lt; RTI ID = 0.0 &gt; 41 (ee). HPLC R _t: 3.92min. (100% area). ¹ H NMR (DMSO) δ 10.02 (s, 1H), 8.74 (d, 1H, J = 3.6 Hz), 8.49 , 8.03 (s, 1H), 7.96-7.93 (m, 2H), 7.84-7.72 (m, 4H), 7.63 (d, 6.95 (s, IH), 4.11 (s, IH), 2.48 (s, IH), 2.32 (s, IH).
[1173] Example 41 (ii): 6- [3 - ((1-n-propyl-3-methyl-1H-pyrazol- 5- yl) carboxyamido) - (pyridin-2-yl) ethenyl] -1H-indazole
[1174]
[1175] Example 41 (ii) was repeated except that 5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- The title compound was prepared in the same manner as in Example 41 (ee). ¹ H NMR (DMSO-d ₆ ) 10.29 (s, 1H), 8.58 (d, 1H, 3.9 Hz), 8.33 1H, J = 5.4,2.1 Hz), 7.96 (d, 1H, J = 16.5 Hz), 7.87 2H, J = 6.9 Hz), 7.28 (d, 1H, J = 6.9, 1.8 Hz), 4.32 (t, 2H, J = 6.90 Hz) = 7.2 Hz), 0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) C ₃₀ H ₂₆ N ₆ O ₂ [M + H ⁺ ] / z yield 505.2347, detected 505.2343.
[1176] Example 41 (jj): 6- [3 - ((3-Ethyl- 1 -methyl-1 H-pyrazol-5- yl) carboxyamido) Pyridin-2-yl) ethenyl] -1H-indazole
[1177]
[1178] Example 41 (jj) was prepared in analogy to example 5, but using 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid instead of 2-ethyl- The title compound was prepared in the same manner as in Example 41 (ee). ¹ H NMR (DMSO-d ₆ ) 10.78 (s, 1H), 9.43 (d, 1H, J = 3.0 Hz), 9.15 1H, J = 6.9, 5.7), 7.93-7.89 (m, 1H), 7.72-7.69 (m, 2H), 8.52-8.30 (s, 3H), 3.39 (q, 2H, J = 7.8 Hz), 3.17 (s, 3H), 2.10 (t, 3H, J = 7.5 Hz). HRMS (MALDI) C ₂₉ H ₂₆ N ₆ O ₂ [M + H ⁺ ] m / z yield 491.2190, detect 491.2211.
[1179] Example 41 (kk): 6- [3- ((l-Isopropyl-3-methyl-lH-pyrazol- 5- yl) carboxyamido) (Pyridin-2-yl) ethenyl] -1H-indazole
[1180]
[1181] Example 41 (kk) was prepared in the same manner except that 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid was used instead of 2- And was prepared in the same manner as in Example 41 (ee). _{HPLC:. R t 4.11min (100} % area). _{^{1 H NMR (DMSO-d 6}} ) δ9.99 (s, 1H), 8.68 (d, 1H, J = 3.6 Hz), 8.42 (d, 1H, J = 8.7 Hz), 8.07 (d, 1H, J = 2H), 7.77-7.65 (m, 4H), 7.56 (d, 1H, J = 7.8 Hz), 7.37-7.33 (m, (S, 3H), 2.42 (s, 3H), 1.42 (d, 6H, J = 6.6Hz). _{(C 30 H 28 N 6 O} 2 · 0.2H 2 O) Analysis calculated: C, 5.63; N, 16.54 . Detection C, 70.57; H, 5.70; N, 16.35.
[1182] Example 41 (11): 6- [2,4-Dimethyl-5 - ((1-ethyl-3-methyl-1H-pyrazol- 5- yl) carboxyamido) benzoyl] -3- - (pyridin-2-yl) ethenyl] -1H-indazole
[1183]
[1184] Example 41 (11) was prepared in analogy to example 40, but using in place of 6- (3-amino-benzoyl) -3-E- [2- (pyridin- (2- (pyridin-2-yl) ethenyl] -1H-indazole prepared in Example 40 (c) Was prepared in the same manner as in Example 41 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.6 (s, 1H), 9.82 (s, 1H), 8.63 (d, 1H, J = 3.84 Hz), 8.35 (d, 1H, J = 8.54 Hz), 8.00 (dd, 1H, J = 16.37 Hz), 7.83 (s, 1H), 7.83 (td, 1H, J = 7.65, J = 1.82 Hz), 7.69 1H, J = 8.52 Hz, J = 1.36 Hz), 7.62 (d, 1H, J = 16.34 Hz), 7.35 (S, 3H), 2.19 (s, 3H), 1.27 (t, 2H) 3H, J = 7.15 Hz). LCMS (ESI &lt; + &gt;) [M + H] / z yield 505, detected 505.
[1185] Example 41 (mm): 6- [2,4-Dimethyl-5- ((l, 3-dimethyl- lH-pyrazol- 5- yl) carboxyamido) benzoyl] -3- E- Pyridin-2-yl) ethenyl] -1H-indazole
[1186]
[1187] Example 41 (mm) was prepared in the same manner as in Example (2) except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- 41 (11). _{^{1 H NMR (DMSO-d 6}} ) δ13.6 (s, 1H), 9.81 (s, 1H), 8.62 (d, 1H, J = 3.81 Hz), 8.35 (d, 1H, J = 8.6 Hz), 8.00 (d, 1H, J = 16.36 Hz), 7.83 (dt, 1H, J = 7.65 Hz, J = 1.8 Hz), 7.8 1H, J = 8.53 Hz, J = 1.36 Hz), 7.62 (d, 1H, J = 16.35 Hz), 7.36 (s, (S, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H). LCMS (ESI +) [M + H] / z yield 491, detection 491. Analysis calculated: C 71.00; H, 5.34; N, 17.13. Detection: C, 70.69; H, 5.57; N, 16.26.
[1188] Example 41 (nn): 6- (5-Acetamido-2,4-dimethylbenzoyl) -3-E- [2- (pyridin- 2- yl) ethenyl]
[1189]
[1190] Example 41 (nn) was prepared in the same manner as in Example 41 (II) except that acetyl chloride was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. _{^{1 H NMR (DMSO-d 6}} ) δ13.6 (bs, 1H), 9.34 (s, 1H), 8.62 (d, 1H, J = 4.15 Hz), 8.33 (d, 1H, J = 8.6 Hz), 7.86 (d, IH, J = 16.36 Hz), 7.83 (td, IH, J = 7.71 Hz, J = 1.82 Hz), 7.81 1H, J = 1.38 Hz), 7.62 (d, 1H, J = 16.46 Hz), 7.48 (s, ), 2.27 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H). LCMS (ESI &lt; + &gt;) [M + H] / z yield 411, detection 411.
[1191] Examples 41 (oo) to 41 (III) can be produced in the same manner as in Example 41 (a).
[1192] Example 41 (oo)
[1193]
[1194] Example 41 (pp)
[1195]
[1196] Example 41 (qq)
[1197]
[1198] Example 41 (rr)
[1199]
[1200] Example 41 (ss)
[1201]
[1202] Example 41 (tt)
[1203]
[1204] Example 41 (uu)
[1205]
[1206] Example 41 (vv)
[1207]
[1208] Example 41 (ww)
[1209]
[1210] Example 41 (xx)
[1211]
[1212] Example 41 (yy)
[1213]
[1214] Example 41 (zz)
[1215]
[1216] Example 41 (aaa)
[1217]
[1218] Example 41 (bbb)
[1219]
[1220] Example 41 (ccc)
[1221]
[1222] Example 41 (ddd)
[1223]
[1224] Example 41 (eee)
[1225]
[1226] Example 41 (fff)
[1227]
[1228] Example 41 (ggg)
[1229]
[1230] Example 41 (hhh)
[1231]
[1232] Example 41 (iii)
[1233]
[1234] Example 41 (jjj)
[1235]
[1236] Example 41 (kkk)
[1237]
[1238] Example 41 (III)
[1239]
[1240] Example 42 (a): 6- (3-Benzamidobenzoyl) -3-E- [2- (pyridin-2- yl) ethenyl] -1H-indazole
[1241]
[1242] Example 42 (a) was prepared from 6- (3-benzamidobenzoyl) -3-E- [2- (pyridin- 2- yl) ethenyl] -1- (2- trimethylsilanylethoxymethyl) 1H-indazole as starting materials (0.58 g, 80.6%). HPLC 4.13 min (98% area). _{^{1 H NMR (CDCl 3) δ8.66}} (d, 1H, J = 4.1 Hz), 8.24 (d, 1H, J = 8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7.98 (m, 4H) , 7.83 (t, 2H, J = 7.1 Hz), 7.72-7.53 (m, 7H), 7.30 (qd, 1H, J = 5.2, 1.1 Hz). _{HRMS (MALDI) C 28 H 20} N 4 O 2. [M + H & lt ^; + & gt ^; ] / z yield 445.1664, detection 445.1659. Anal (C ₂₆ H ₁₉ N ₅ O ₂ 0.2 EtOAc): C, 75.87; H, 4.78; N, 12.39.
[1243] The starting material was prepared as follows:
[1244]
[1245] (8.40 mmol) of 6-iodo-3 - ((E) -styryl) -1- (2-trimethylsilanylethoxymethyl) -1 H- indazole prepared in step (i) (Triphenylphosphine) palladium dichloride, 288 mg (1.0 mmol) of TBACl and 1.54 ml (16.8 mmol) of 2-butanol in 48 ml of anisole under argon atmosphere, And 3.48 g (25.2 mmol) of potassium carbonate. The mixture was stirred for 100 hours under an atmosphere of carbon monoxide at 80 ° C. The residue was diluted with 400 mL of EtOAc and extracted with saturated NaCl (2 x 150 mL), saturated NaHCO ₃ (2 x 50 mL) and water (2 x 50 mL), and the organic layer was then filtered through 20 mL silica gel . The filtrate was concentrated in vacuo to give a yellow oil. Purification by flash chromatography (hexane: EtOAc = 7: 3) gave a concentrated yellow oil, 6- (3-aminobenzoyl) -3 - ((E) -styryl) -1- (2-trimethylsilanyl- (Yield: 61%) of the title compound was obtained. _{^{1 H NMR (CDCl 3) δ8.84}} (dd, 1H, J = 8.70, 0.90 Hz), 8.02 (s, 1H), 7.77 (dd, 1H, J = 8.40, 1.50 Hz), 7.62-7.59 (m, 2H), 7.40 (t, 2H, J = 7.20 Hz), 7.38-7.24 (m, 4H), 7.22-7.19 (m, 3H), 6.98 (dq, 1H, J = 8.30, 0.90 Hz), 3.83 , 2H), 3.61 (t, 2H, J = 8.10 Hz), 0.91 (t, 2H, J = 7.20 Hz), -0.17 (s, 9H).
[1246] (ii)
[1247]
[1248] 3.22 g (6.87 mmol) of 6- (3-aminobenzoyl) -3 - ((E) -styryl) -1- (2-trimethylsilanyl- ethoxymethyl) -1H-indazole in 10 ml of methylene chloride under an argon atmosphere. mmol) were dissolved and stirred, 0.95 ml (8.37 mmol) of benzoyl chloride and 0.67 ml (3.22 mmol) of pyridine were added. After 2 h the solution was diluted with 100 mL EtOAc and washed with sat. NaCl (2 x 50 mL), citric acid (1M, 2.5 pH, 2 x 50 mL) and (50: 50) NaHCO ₃ / water (1 x 50 mL). The organic layer was dried over Na ₂ SO ₄ and filtered through 20 mL silica. The organic layer was concentrated in vacuo to give a yellow solid as the product. Purification by flash chromatography on silica eluting with hexane: EtOAc (7: 3) gave the yellow 6- (3-benzamidobenzoyl) -3 - ((E) -styryl) Silanyl-ethoxymethyl) -1H-indazole (yield: 85.1%). _{^{1 H NMR (CDCl 3) δ8.19}} (d, 1H, J = 8.7 Hz), 8.16 (s, 1H), 8.11-8.10 (m, 2H), 8.03-7.93 (m, 3H), 7.82 (dd, 1H, J = 8.4,1.2 Hz), 7.70-7.67 (m, 3H), 7.64-7.54 (m, 5H), 7.48 (t, 2H, J = 14.1 Hz), 7.39 ).
[1249]
[1250] 2.35 g (4.07 mmol) of 6- (3-benzamidobenzoyl) -3 - ((E) -styryl) -1- (2-trimethylsilanylethoxymethyl) -1 H- indazole was dissolved in methylene chloride 45.6 And the resulting solution was cooled to -45 DEG C in an acetonitrile / solid carbon carbon dioxide bath. The ozone was then foamed through the solution at a rate of 1.5 lpm, 60 amps for 15 minutes. The reaction mixture was cooled by the addition of 2.5 ml of hydrogen sulfide and then warmed to 25 &lt; 0 &gt; C. And concentrated under vacuum to remove methylene chloride. The residue was purified via silica eluting with hexane: EtOAc (7: 3) to give white light bubbles of 6- (3-benzamidobenzoyl) -l- (2- trimethylsilanylethoxy-methyl) Indazole-3-carboxyaldehyde (yield: 85%). HPLC 3.78 min. (100% area); _{^{1 H NMR (DMSO-d 6}} ) δ10.77 (s, 1H), 10.42 (s, 1H), 8.46-8.39 (m, 2H), 8.31 (dt, 1H, J = 6.0, 1.8 Hz), 8.19 ( 2H, J = 6.0, 1.2 Hz), 7.70-7.64 (m, 5H), 5.81 (s, 2H), 3.68 (t, 2H, J = 6.9 Hz), 0.98 (t, 2H, J = 6.7 Hz), 0.02 (s, 9H).
[1251]
[1252] To a solution of 2.23 g (4.91 mmol) of 2-picolyltriphenylphosphonium chloride w / sodium hydride in 5 mL anhydrous THF refined in argon was added 6- (3-benzamidobenzoyl) -1- (2.46 mmol) of 2-trimethylsilanyl-ethoxy-methyl) -1H-indazole-3-carboxyaldehyde was added to the solution, and the mixture was stirred at 0 ° C for 1 hour and CH ₃ COOH / MeOH : 1, 1 ml). The reaction mixture was diluted with 100 mL EtOAc and partitioned between saturated NaCl (1 x 50 mL) and saturated NaHCO ₃ (2 x 50 mL), then the organic layer was dried over Na ₂ SO ₄ ( ₂ x 50 mL) and washed with 20 mL silica plug (3: / Cis mixture). Purification via a 4 mm silica rotor eluting with hexane / EtOAc (1: 1) and concentration to a yellow solid gave 6- (3-benzamidobenzoyl) -3- E- E- [2- (pyridin- Yl) ethenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole in a yield of 62%. _{^{1 H NMR (CDCl 3) δ8.62}} (d, 1H, J = 4.1 Hz), 8.22 (d, 1H, J = 8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7.98 (m, 4H) 2H), 7.83 (t, 2H, J = 7.1 Hz), 7.72-7.53 (m, 7H), 7.30 (qd, = 6.9 Hz), 0.98 (t, 2H, J = 6.7 Hz), 0.02 (s, 9H).
[1253] Example 42 (b): 6- (3-Benzamidobenzoyl) -3- (1H-benzoimidazol-2-yl)
[1254]
[1255] Example 42 (b) was prepared in the same manner as in Example 42 (a) except that step (iv) of Example 42 (a) was changed to the following: Step (iii) of Example 42 ), 0.011 g (0.11 mmol) of 1,2-diaminobenzene, 0.4 g (0.1201 mmol) of elemental sulfur (USP grade) and 2 ml of anhydrous DMF was added to the aldehyde prepared in After heating, the mixture was cooled to 25 deg. The reaction mixture was diluted with 10 mL of ethyl acetate and washed with saturated NaCl (1 x 10 mL), NaHCO ₃ (1 x 10 mL), water (10 mL), dried over NaSO ₄ and filtered through a 0.22 μm teflon filter to yield yellow And concentrated to an oil. And purified by radioactive chromatography, which was precipitated with 2 mL of methylene chloride and hexane (2 mL) to give an intermediate product as a white precipitate. ¹ H NMR (acetone _{-d 6) δ8.81 (d, 1H} , J = 8.6), 8.30-8.25 (m, 2H), 8.11 (s, 1H), 8.02-7.99 (m, 2H), 7.79 (td , 2H, J = 12.2, 1.2 Hz), 7.63-7.47 (m, 7H), 7.28-7.40 (m, 2H). HRMS (MALDI) m / z C 28 H 19 N 5 O 2. [M + H +] / z calculated 458.1617, 458.1632 detected.
[1256] Example 42 (c): 6- (3-Benzamidobenzoyl) -3-E- [2- (2-methylthiazol-4-yl) ethenyl-
[1257]
[1258] Example 42 (c) was prepared in the same manner as in Example 42 (a) except that 4- (2-methylthiazyl) -methyltriphenylphosphonium chloride was used instead of 2-picolyltriphenylphosphonium chloride in Step (iv) Was prepared in a manner similar to that of Example 42 (a). ^{1 H NMR (DMSO) δ8.11-8.01 (} m, 4H), 7.92 (d, 2H, J = 6.9 Hz), 7.76-7.71 (m, 2H), 7.65-7.62 (m, 1H), 7.56-7.48 (m, 5 H), 7.15 (s, 1 H), 2.81 (s, 3 H). HRMS (MALDI) C ₂₇ H ₂₀ N ₄ O ₂ S [M + H ⁺ ] / z: Calculated (M + H ⁺ ) 465.1380, found 465.1373.
[1259] Example 42 (d): 6- (3-Benzamidobenzoyl) -3- (3H-imidazo [4,5- c] pyridin-
[1260]
[1261] Example 42 (d) was prepared in the same manner as in Example 42 (b) except that 1,2-diamine-2-pyridine was used instead of 1,2-diamine benzene. HPLC: 3.88 min (95% area); ¹ H NMR (DMSO-d ₆ ) 10.62 (s, IH), 8.83 (d, IH, J = 8.4 Hz), 8.53 (s, IH), 8.43 J = 6.9, 1.8 Hz), 8.15 (d, 1H, J = 12.9 Hz), 8.11-8.10 (m, 2H), 7.91 (d, 1H, J = 9.0 Hz), 7.72-7.65 7.43 (dd, 1 H, J = 6.3, 4.8 Hz). HRMS (MALDI) m / z C ₂₇ H ₁₈ N ₆ O ₂ yield (M + H ⁺ ) 459.1564, detected 459.1558. Anal. Calcd for C ₂₇ H ₁₈ N ₆ O ₂ .04 CH ₂ Cl ₂ : C, 66.83; H, 3.85; N, 17.07. Detection: C, 66.93; H, 4.04; N, 16.68.
[1262] Example 42 (e): 6- (3-Benzamidobenzoyl) -3-E- [N- (4H-1,2,4- triazol-4- yl) iminomethyl]
[1263]
[1264] Example 42 (e) was carried out except that 2-picolyltrifosphonium chloride and potassium hydride were added at 23 &lt; 0 &gt; C and 4-amino-1,2,4 triazole and PPTS were added at 80 & The title compound was prepared in the same manner as in Example 42 (a). HPLC R _t : 4.05 min (96% area); _{^{1 H NMR (DMSO-d 6}} ) δ10.58 (s, 1H), 9.53 (s, 1H), 9.40 (s, 2H), 8.56 (d, 1H, J = 8.4 Hz), 8.38 (s, 1H) , 8.26 (dt, 1H, J = 7.2, 2.1Hz), 8.13 (s, 1H), 8.08-8.05 (m, 2H), 7.73-7.67 (m, 5H). HRMS (MALDI) C ₂₄ H ₁₇ N ₇ O ₂ [M + H ⁺ ] / z: Calculated 436.1516, Detected 436.1510. Anal. Calcd. For C ₂₄ H ₁₇ N ₇ O ₂ .0.4 hexane: C, 66.18; H, 4.67; N, 20.47. Detection: C, 65.78; H, 4.87; N, 20.47.
[1265] Example 43: 6- (3-Benzamidobenzoyl) -3-E- [2- (2-formamidophenyl) ethenyl] -1H-indazole
[1266]
[1267] Example 43 was prepared from 6- (3-benzamidobenzoyl) -3-E- (2-formamidophenyl) ethenyl- 1- (2-trimethylsilanylethoxymethyl) -1H- (18 mg, 36%) as a white solid. HPLC R _t : 4.19 min. _{^{1 H NMR (CDCl 3) δ8.43-7.92}} (m, 6H), 7.68-7.49 (m, 4H), 7.39-7.36 (m, 3H), 7.32-7.21 (m, 2H), 7.09-7.00 (m , &Lt; / RTI &gt; 2H), 6.91-6.84 (m, 1H). HRMS (MALDI) C ₃₀ H ₂₂ N ₄ O ₃ [M + Na] / z: Calculated 509.1590, Detected 509.1580. Anal. Calcd for C ₃₀ H ₂₂ N ₄ O ₃ .0.3 H ₂ O: C, 73.25; H, 4.63; N, 11.39. Detection: C, 73.10; H, 4.58; N, 11.28.
[1268] The starting material was prepared as follows:
[1269]
[1270] (2-trimethylsilanyl-ethoxy-methyl) -1H-indazole-3-carboxyaldehyde prepared in step (iii) of Example 42 (a) The procedure of Example 42 (a) was repeated except that (2-nitrobenzyl) triphenylphosphonium bromide monohydrate was used instead of 2-picolyltriphenylphosphonium chloride in the step (iv) of Example 42 (a) Was changed to 6- (3-benzamidobenzoyl) -3-E- (2-nitrophenyl) -ethyl- 1- (2-trimethylsilanylethoxymethyl) -1H-indazole %). ¹ H NMR (CDCl ₃ ) 8.15-7.93 (m, 5H), 7.89-7.86 (m, 3H), 7.54-7.41 (m, 6H), 7.36-7.35 (m, 2H), 7.21-7.18 , 2H), 7.03-6.91 (m, 1H), 3.64-3.46 (m, 2H), 0.96-0.79 (m, 2H), -0.06 (s, 9H).
[1271]
[1272] To a solution of 0.19 g of 6- (3-benzamidobenzoyl) -3-E- (2-nitrophenyl) -ethenyl-1- (2-trimethylsilanylethoxymethyl) -1H- 0.27 g (1.40 mmol) of SnCl ₂ and 0.037 ml (1.87 mmol) of water were treated and stirred at 50 ° C for 3 hours. The reaction was cooled with 0.5 ml of 3N NaOH at 25 &lt; 0 &gt; C and the precipitate was filtered off with celite. The solution was partitioned with 50/50 saturated NaHCO ₃ / water (2 × 30 mL) and the organic layer was filtered through a silica plug to give a yellow oil, 6- (3-benzamidobenzoyl) -3-E- ) Eethenyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole (yield: 92%).
[1273] The product was used without further purification.
[1274]
[1275] 0.17 g (0.28 mmol) of 6- (3-benzamidobenzoyl) -3-E- (2-aminophenyl) ethenyl- 1- (2-trimethylsilanylethoxymethyl) Chloride (3 mL). 0.12 g (0.56 mmol) of formafluorophenyl ester of formic acid was added dropwise to the solution. After 3 h the reaction mixture was diluted with 40 mL EtOAc and washed with 50/50 NaHCO ₃ (2 x ₃₀ mL) and the organic layer was filtered through a silica plug. The residue hexane _{/ EtOAc / CH2Cl 2 (1:} 1: 1) to a clear oil of 6-through silica purified by chromatography eluting with radiation (3-benz amido-benzoyl) -3-E- (2- formaldehyde Amidophenyl) ethenyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole (yield: 40%). _{^{1 H NMR (CDCl 3) δ8.48-8.36}} (m, 1H), 8.20-7.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26-7.01 (m (M, 2H), 0.95-0.87 (m, 2H), -0.05 (s, 9H), 6.82 (t, 1H, J = 14.2 Hz).
[1276] Example 44: Preparation of 6- (3-aminobenzoyl) -3-E- [N- (pyrrol- l-yl) -iminomethyl]
[1277]
[1278] Example 44 was prepared in the same manner as in Example 12 from the starting material prepared in the following manner. R _f sm 0.6, p 0.5 (ethyl ^{acetate): 1 H NMR (300MHz,} CDCl 3) δ8.8 (s, 1H), 8.5 (d, 1H), 7.95 (s, 1H), 7.75 (d, 1H) , 7.45-7.3 (m, 7H), 7.2 (m, 1H), 6.40 (s, 2H).
[1279] The starting material is prepared as follows:
[1280]
[1281] (0.66 mmol, 1.3 equiv) of 1-aminopyrrole and 204 mg (0.507 mmol) of the aldehyde prepared in step (i) of Example 33 (a) were placed in 2 ml of toluene and stirred. To the mixture was added 1 mg of PPTS and heated to 80 DEG C for 1 hour. The mixture was cooled and then partitioned between 2: 8 ethyl acetate-hexane and water. The organic material was dried over sodium sulfate, concentrated under reduced pressure. The product was crystallized from 0.5 ml of dichloromethane and 2 ml of methanol (215.7 mg 91%): ¹ H NMR (300 MHz, C ₆ D ₆ ) 8.71 (s, ), 8.08 (s, IH), 7.75 (d, IH, J = 8.5 Hz), 6.35 (s, 2H), 5.85 (s, 2H).
[1282]
[1283] The iodide 535mg (1.15mmol, 1 equiv), 3- amino-phenyl boronic acid 236mg (1.72mmol, 1.5 equiv), PdCl 2 (PPh 3) 2 24mg (0.034mmol, 0.03 equiv) and a mixture of potassium carbonate Was dissolved in 6.7 ml of anisole in the presence of carbon monoxide (1 atm). The mixture was heated to 80 &lt; 0 &gt; C for 14 hours, then cooled, and partitioned between ethyl acetate and water. The organics were washed with saturated aqueous sodium bicarbonate, water, brine and the organic layer was separated. The organic material was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50 mL silica, eluting with 3: 7 ethyl acetate-hexane in 2: 8) to give 331 mg (63% yield) of solid aniline product: R _f sm 0.60, p 0.21 (ethyl acetate: hexane ^{= 3: 7): 1 H} NMR (300MHz, CDCl 3) δ8.75 (s, 1H), 8.51 (d, 1H, J = 8.4 Hz), 8.06 (s, 1H), 7.76 (dd, 1H, J 2H), 3.84 (m, IH), 6.31 (t, 1H, J = 2.3 Hz) 2H), 3.60 (t, 2H, J = 8.2 Hz), 0.91 (t, 2H, J = 8.2 Hz), -0.08 (s, 9H). LCMS 4.98 min (pos) [M + H] / z yield 460, detection 460.
[1284] Example 45 (a) Synthesis of 6- [3- (indol-4-ylcarboxamido) benzoyl] -3-E- [N- (pyrrol- 1 -yl) iminomethyl]
[1285]
[1286] Example 45 (a) was prepared in the same manner as in Example 12 (d) except that indole-4-carboxylic acid was used instead of 5-methyl-thiazole- &Lt; / RTI &gt; R _f sm 0.0, p 0.2 (ethyl acetate-benzene ^{1: 3): 1 H NMR} (300MHz, DMSO-d 6) δ9.84 (s, 1H), 8.92 (s, 1H), 8.66 (s, 1H) 2H), 7.66 (d, 1H, J = 8.5 Hz), 7.52-7.40 (m, 4H), 7.27 7.07 (m, 5 H), 6.83 (s, 1 H), 6.21 (s, 2 H).
[1287] Example 45 (b): 6- (3-Benzamidobenzoyl) -3-E- [N- (pyrrol-1-yl) iminomethyl] -1H-indazole
[1288]
[1289] Example 45 (b) was prepared in the same manner as in Example 12 (d), except that benzyl chloride was used instead of 5-methyl-thiazole-2-carboxylic acid and HATU starting from Example 44. . _{^{1 H NMR (300MHz, CDCl 3}} ) δ11.9 (bs, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H, J = 8.4 Hz), 7.99 (s, 1H) , 7.9-7.8 (m, 4H), 7.65 (d, 1H, J = 8.4 Hz), 7.48 (t, 2H, J = 7.8 Hz), 7.42-7.35 Hz), 6.28 (t, 2H, J = 2.2 Hz).
[1290] Example 46: Synthesis of 6- [N- (3-aminophenyl) amino] -3-E-styryl-1H-indazole
[1291]
[1292] Example 46 was prepared in the same manner as in the step (i) of Example 13 from the starting material prepared in the following manner. ¹ H NMR (300 MHz, DMSO-d ₆ ) 12.6 (s, IH), 8.07 (s, IH), 7.97 (d, IH, J = 8.73 Hz), 7.69 1H), 7.40 (m, 4H), 7.28 (m, IH), 7.06 (d, IH, J = 1.49 Hz), 6.44 1H, J = 7.88 Hz, J = 1.26 Hz), 5.01 (bs, 2H).
[1293]
[1294] The compound prepared in the step (v) of Example 11 was transformed into 6- [N- (3-nitrophenyl) amino] -3-E-styryl-1H-indazole in the same manner as in Example 12 above. _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.0 (m, 2H), 7.77 (m, 1H), 7.64 (d, 2H, J = 7.86 Hz), 7.41-7.56 (m, 6H), 7.33 (m, 2H), 7.08 (d, 1 H, J = 8.67 Hz). MS (ESI &lt; + &gt;) [M + H] / z yield 357, detection 357. Calcd .: C, 70.77; H, 4.53; Detection: C, 69.18; H, 4.51; N, 15.30.
[1295] Example 47: 6- [N- (3-Benzamido-4-fluorophenyl) amino] -3-E-
[1296]
[1297] (2-trimethylsilanyl-ethoxymethyl-3-E-styryl-1H-indazole was reacted with 6- [N- (3-benzamido-4- fluorophenyl) and in the same manner 6- [N- (3- benz amido-4-fluorophenyl) amino] -3-E- styryl was -1H- indazol sol ^{transformation. 1 H NMR (300MHz, DMSO} -d 6) (d, 1H, J = 8.78), 7.98 (d, 2H, J = 6.87 Hz), 7.69 (d, 1H), 8.08 2H, J = 7.27 Hz), 7.48-7.61 (m, 4H), 7.45 (s, 2H), 7.40 (t, 2H, J = 7.28 Hz), 7.53-7.30 , 7.53-7.30 (m, 2H), 7.07 (d, IH, J = 1.55 Hz), 7.03 (m, IH), 6.95 (dd, IH, J = 8.79 Hz, J = 1.85 Hz) [M + H] / z yield 449, detection 449. Calcd .: C, 74.98; H, 4.72; N, 12.49. Detection: C, 74.29; H, 4.76;
[1298] The starting material was prepared as follows:
[1299]
[1300] To a solution of 3.12 g (20 mmol) of 2-fluoro-5-nitro-phenylamine in 20 ml of dichloromethane in the presence of 23 ° C argon was added 1.94 ml (24 mmol) of pyridine and 2.8 ml (24 mmol) of benzoyl chloride. A white precipitate was formed after 45 minutes. The reaction mixture was concentrated in vacuo, diluted with water, filtered and then re-suspended in methanol to give 4.86 mg (yield 93%) of N- (2-fluoro-5-nitro- ). _{^{1 H NMR (300MHz, CDCl 3}} ) δ9.48 (dd, 1H, J = 6.8 Hz, J = 2.81 Hz), 8.17 (bs, 1H), 8.03 (m, 1H), 7.92 (m, 2H), 7.52 -7.65 (m, 3 H), 7.31 (d, 1 H, J = 9.2 Hz).
[1301]
[1302] A solution prepared by dissolving 4.86 g (18.7 mmol) of N- (2-fluoro-5-nitro-phenyl) -benzamide and 486 mg of 10% PD / C in 80 ml of THF-MeOH mixed at a ratio of 1: Lt; / RTI &gt; After 2.5 h, the reaction mixture was filtered through celite and concentrated to give 3.92 g (91% yield) of N- (5-amino-2-fluoro-phenyl) -benzamide. MS (ESI &lt; + &gt;) [M + H] / z yield 231, detected 231.
[1303]
[1304] 6- [N- (3-benzamido-4-fluorophenyl) -amino] -1- (2-trimethylsilanylethoxymethyl- The procedure of Example 48 (a) was repeated except that the compound prepared using as starting material in step 14 (i) and N- (5-amino-2-fluoro-phenyl) was prepared in the same manner as in ^{iii). 1 H NMR (300MHz} , CDCl 3) δ8.38 (dd, 1H, J = 6.84 Hz, J = 2.73 Hz), 8.09 (d, 1H, J = 3.08 Hz), 7.86 1H), 7.08 (dd, 1H, J = 10.48 Hz), 7.08 (m, 3H), 7.48-7.61 (m, 5H), 7.28-7.45 (T, 2H, J = 8.32 Hz), 0.06 (s, 2H), 3.62 , 9H). MS (ESI +) [M + H] / z Output 579, Detection 579. Analytical Output: C, 70.56; H, 6.10; N, 9.68. Detection: C, 20.26; H, 6.08;
[1305] Example 48 (a): 6- [N- (5- ((1-Ethyl-3-methyl-1H- pyrazol- 5- yl) carboxyamido) -2-fluoro-4- -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole
[1306]
[1307] Example 48 (a) was prepared in the same manner as in Example 41 (a) from the starting material prepared as follows. _{^{1 H NMR (300MHz, CD 3}} OD) δ8.54 (d, 1H, J = 4.8 Hz), 7.95 (d, 1H, J = 9.49 Hz), 7.84 (td, 1H, J = 7.71 Hz, J = 1.78 1H, J = 7.45 Hz), 7.70 (d, 1H, J = 7.95 Hz), 7.53 (d, 1H, J = 16.59 Hz) 2H, J = 1.07 Hz), 7.11 (d, 1H, J = 11.8), 7.03-7.06 (m, 2H), 6.71 ), 2.26 (s, 3H), 1.38 (t, 3H, J = 7.11 Hz). MS (ESI &lt; + &gt;) [M + H] / z yield 496, detect 496. Analysis calculated: C, 67.86; H, 5.29; Detection: C, 66.24; H, 5.50; N, 18.61.
[1308] The starting material was prepared as follows:
[1309]
[1310] A mixture of 1.0 g (5 mmol) of 1-fluoro-5-methyl-2,4-dinitro-benzene and 200 mg of 10% Pd / C in 20 ml of MeOH was hydrogenated at 23 ° C for 24 hours. The reaction mixture was filtered through celite and concentrated. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1) to obtain 613 mg of 4-fluoro-6-methyl- benzene-1,3-diamine (yield: 87%).
[1311]
[1312] (0.1 mmol) of DMAP and 0.35 ml (2 mmol) of DIEA were added to a solution of 566 mg (2 mmol) of carbonic acid 4-nitro-phenyl ester 2-trimethylsilanylethyl ester in 4 ml of DMF at 23 & And 4-fluoro-6-methyl-benzene-1,3-diamine were added. The solution was heated to 50 &lt; 0 &gt; C for 48 hours. Cooling the reaction mixture with saturated Na / HCO ₃ (aq) and extracted with EtOAc (3x20㎖). After removing the EtOAc by in vacuo and re-dissolve the residue in _{Et 2 O 3N NaOH (aq)} , washed with water, brine, dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with ethyl acetate: hexane = 2: 8-7: 3) to give 2-trimethylsilanyl-ethyl ester (5-amino-4-fluoro- 160 mg (Yield 28%). MS (ESI &lt; + &gt;) [M + H] / z yield 634, detected 634.
[1313]
[1314] 224 mg (0.47 mmol) of 6-iodo-3 - ((E) -2-pyridin-2-yl-vinyl )- 1- (2- trimethylsilyan- ethoxymethyl) 160 mg (0.56 mmol) of 2-trimethylsilanyl-ethyl ester, 214 mg (0.66 mmol) of Cs ₂ CO ₃ , PdCl ₂ (PPh ₃ ) ₂ (0.0059 mmol) and BINAP (10 mg, 0.0176 mmol) was added 0.5 mL of toluene. The mixture was heated to 80 &lt; 0 &gt; C for 16 hours. The reaction mixture was cooled to 23 [deg.] C, then diluted with 20 mL water and extracted with EtOAc (3 x 50 mL). After the organics are washed with water 30㎖, 30㎖ brine and dried over Na ₂ SO ₄ and concentrated by filtration, the foam (foam). The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain {4-fluoro-2- - trimethylsilanylethoxymethyl) -1H-indazol-6-ylamino] -phenyl} -carbamic acid 2-trimethylsilanyl-ethyl ester 98 mg (Yield 33%). TLC (hexane: ethyl acetate = 7: 3) R _f sm 0.42, R _f p 0.23. _{^{1 H NMR (CDCl 3) δ8.64}} (dd, 1H, J = 4.79 Hz, J = 0.86 Hz), 7.94 (d, 1H, J = 8.71 Hz), 7.91 (bs, 1H), 7.86 (d, 1H 1H, J = 16.41 Hz), 7.69 (dd, 1H, J = 7.91 Hz), 7.17 (dd, 1H, J = 8.67 Hz, J = 1.89 Hz), 6.93 (d, 1H, J = 11.2 Hz), 6.25 (bs, 1H) 2H, J = 8.53 Hz), 5.95 (d, 1H, J = 1.97 Hz), 5.70 (s, 2H), 4.25 , 1.04 (t, 2H, J = 8.54 Hz), 0.9 (t, 2H, J = 8.25 Hz), 0.05 (s, 9H), 0.0 (s, 9H). ¹³ C NMR (CDCl ₃ , 75 MHz) δ 156.0, 154.4, 149.8, 142.9, 142.8, 142.5, 136.6, 132.1, 130.1, 130.5, 128.7, 128.5, 124.3, 122.2, 122.0, 121.8, 118.2, 117.3, 117.0, 115.1 , 95.2, 77.6, 77.4, 66.5, 63.7, 17.9. 17.2, -1.3. FTIR cm ^-1 : 3326, 2947, 1716, 1617, 1534, 1514, 1244, 1057. MS (ESI +) [M + H] / z yield 634, detection 634.
[1315]
[1316] The aniline was prepared in the same manner as in Example 11. _{^{1 H NMR (300MHZ, CD 3}} OD) δ8.54 (m, 1H), 7.91 (dd, 1H, J = 8.74 Hz, J = 0.58 Hz), 7.83 (td, 1H, J = 7.72 Hz, J = 1.79 1H, J = 7.43 Hz), 7.80 (d, 1H, J = 16.52 Hz), 7.69 (d, J = 1.07 Hz), 6.94-6.99 (m, 2H), 6.83 (d, 1H, J = 11.98 Hz), 6.82 (d, 1H, J = 7.49 Hz), 2.15 (s, 3H). MS (ESI &lt; + &gt;) [M + H] / z yield 360, detection 360.
[1317] Example 48 (b): 6- [N- (5 - ((1,3-Dimethyl-1H-pyrazol- 5- yl) carboxyamido) -2-fluoro-4- -E- [2- (pyridin-2-yl) ethenyl] -1H-indazole
[1318]
[1319] Example 48 (b) was prepared in analogy to example (b) except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used instead of 2-ethyl- 48 (a). ^{1 H NMR (300MHz, DMSO-} d 6) δ12.8 (s, 1H), 9.71 (s, 1H), 8.59 (m, 1H), 8.11 (s, 1H), 8.00 (d, 1H, J = 8.75 1H, J = 7.88 Hz), 7.49 (d, IH, J = 16.37 Hz), 7.80 J = 16.38 Hz), 7.34 (d, 1H, J = 8.16 Hz), 7.26 (m, 1H), 7.21 (s, 1 H), 6.79 (s, 1 H), 3.98 (s, 3 H), 2.20 (s, 3 H), 2.19 MS (ESI +) [M + H] / z yield 482, detection 482. Analysis calculated: C, 67.35; H, 5.02; Detection: C, 66.83; H, 5.25; N, 19.68.
[1320] Example 49 (a): Synthesis of 6- [N- (3 - ((1,3-dimethyl-1H-pyrazol-5- yl) carboxyamido) -4-fluoro-phenyl) - [2- (pyridin-2-yl) ethenyl] -1H-indazole
[1321]
[1322] Example 49 (a) was prepared in a manner similar to that of Example 48 (a) except for the following parts: 2-Ethyl-5-methyl-2H-pyrazole- -Dimethyl-2H-pyrazole-3-carboxylic acid; (5-Amino-2-fluoro-phenyl) -carbamic acid prepared in step (iii) instead of 2-trimethylsilanyl- -Phenyl) -carbamic acid 2-trimethylsilanyl-ethyl ester and using biphenyl-2-yl-dicyclohexylphosphine as the ligand with DME as the solvent. ¹ H NMR (300 MHz, CD ₃ OD) 12.7 (s, IH), 9.94 (s, IH), 8.48 1H), 7.87 (d, 1H, J = 16.37 Hz), 7.80 (d, 1H, J = 7.63 Hz, J = 1.81 Hz) 2H), 6.96 (dd, 1H, J = 8.81 Hz, J = 1.82 (m, 2H) Hz), 6.85 (s, 1 H), 4.0 (s, 3 H), 2.20 (s, 3 H). MS (ESI &lt; + &gt;) [M + H] / z yield 468, detect 468. Anal. Yield: C, 66.80; H, 4.74; Detection: C, 66.01; H, 4.72; N, 20.81.
[1323]
[1324] (54 mmol) of 2-trimethylsilanylethanol was added to a solution of 9.82 g (54 mmol) of 1-fluoro-2-isocyanato-4-nitro-benzene in 40 ml of THF at 23 DEG C under an argon atmosphere. Was added. The mixture was stirred for 11 hours and then heated to 50 &lt; 0 &gt; C for 2 hours. Cooled to 23 ℃ the reaction mixture with saturated NaHCO ₃ (aq) and extracted with EtOAc (3x100㎖). The combined ethyl acetate was washed with 1 N HCl (aq) (2 x 90 mL), water (90 mL), brine (90 mL), dried over Na ₂ SO ₄ , filtered and concentrated to a yellow solid. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 2: 8) to obtain 12.3 g (yield 77%) of (2-fluoro-5-nitro- phenyl) -carbamic acid 2-trimethylsilanyl- ethyl ester. _{^{1 H NMR (300MHz, CDCl 3}} ) δ9.06 (dd, 1H, J = 6.89 Hz, J = 2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J = 8.67 Hz), 1.06 (t, 2H, J = 8.67 Hz), 0.05 (s, 9H). LCMS (ESI-) [M + H] / z yield 299, detected 299.
[1325] (ii)
[1326]
[1327] (10 mmol) of 2-trimethylsilanyl-ethyl ester and 300 mg of 10% Pd / C in 30 ml of methanol was hydrogenated at 23 [deg.] C . The mixture was stirred for 24 hours, then filtered through celite and concentrated to give 2.62 g (yield: 97%) of (2-trimethylsilanylethyl) ethyl ester of (5-amino-2-fluoro- phenyl) -carbamic acid. _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.52 (m, 1H), 6.85 (dd, 1H, J = 10.8 Hz, J = 8.69 Hz), 6.73 (bs, 1H), 6.28 (m, 1H), 4.27 (t, 2H, J = 8.57 Hz), 3.0-4.4 (bs, 2H), 1.06 (t, 2H, J = 8.58 Hz), 0.07 (s, 9H).
[1328] Example 49 (b): 6- [N- (3 - ((1,3-Dimethyl-1H-pyrazol-5- yl) carboxyamido) -4-methylphenyl) amino] -3- - (pyridin-2-yl) ethenyl] -1H-indazole
[1329]
[1330] Example 49 (b) was prepared in the same manner as in step (a) of Example 49 (a) except that 1-methyl-2-isocyanato-4-nitro -Benzene as starting materials. _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.59 (m, 1H), 8.35 (s, 1H), 8.00 (d, 1H, J = 8.73 Hz), 7.87 (d, 1H, J = 16.38 Hz), 7.80 (d, 1H, J = 16.35 Hz), 7.26 (m, 1H), 7.19 (m, 1H) (Dd, 1H, J = 8.79 Hz, J = 1.80 Hz), 7.09 (d, 6.81 (bs, 1 H), 4.00 (s, 3 H), 2.20 (s, 3 H), 2.18 (s, 3 H). LCMS (ESI &lt; + &gt;) [M + H] / z yield 464, detected 464.
[1331] Example 49 (c): 6- [N- (3-Acetamido-4-fluorophenyl) amino] -3- E- E- [2- (pyridin- 2- yl) ethenyl]
[1332]
[1333] Example 49 (c) was prepared in the same manner as in Example 49 (a) except that acetic anhydride was used instead of 2,5-dimethyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (300 MHz, CD ₃ OD) 8.44 (m, 1H), 7.82 (d, 1H), 7.70 (m, 3H), 7.55 ), 7.19 (m, IH), 7.03 (s, IH), 6.94 (m, IH), 6.87 (m, 2H), 2.11 (s, 3H). LCMS (100% area) Rt = 4.53 min, (pos) [M + H] / z yield 388.4, detection 388.4.
[1334] Examples 49 (d) to 49 (x) can also be prepared in the same manner as in Example 49 (a) above.
[1335] Example 49 (d)
[1336]
[1337] Example 49 (e)
[1338]
[1339] Example 49 (f)
[1340]
[1341] Example 49 (g)
[1342]
[1343] Example 49 (h)
[1344]
[1345] Example 49 (i)
[1346]
[1347] Example 49 (j)
[1348]
[1349] Example 49 (k)
[1350]
[1351] Example 49 (1)
[1352]
[1353] Example 49 (m)
[1354]
[1355] Example 49 (n)
[1356]
[1357] Example 49 (o)
[1358]
[1359] Example 49 (p)
[1360]
[1361] Example 49 (q)
[1362]
[1363] Example 49 (r)
[1364]
[1365] Example 49 (s)
[1366]
[1367] Example 49 (t)
[1368]
[1369] Example 49 (u)
[1370]
[1371] Example 49 (v)
[1372]
[1373] Example 49 (w)
[1374]
[1375] Example 49 (x)
[1376]
[1377] Example 50: 6- [3- (5-Amino-2-fluorophenyl) carbamoyl-5-methyl- Yl) ethenyl] -1H-indazole &lt; / RTI &gt;
[1378]
[1379] Example 50 was prepared in the same manner as in Example 11, using the starting material prepared in the following manner. MS (ESI &lt; + &gt;) [M + H] / z yield 482, detection 482. Calculated: C, 67.35; H, 5.02; Detection: C, 66.70; H, 5.09; N, 19.95.
[1380] (i)
[1381]
[1382] Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid and HATU in place of benzoyl chloride in step (i) of Example 47. [ Methyl-2H-pyrazole-3-carboxylic acid (2-fluoro-5-nitro-phenyl) -amide. MS (ESI &lt; + &gt;) [M + H] / z yield 293, detected 293.
[1383]
[1384] Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (2-fluoro-5-nitro-phenyl) -amide was prepared in the same manner as in step (i) . MS (ESI &lt; + &gt;) [M + H] / z yield 263, detected 263.
[1385]
[1386] Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (5-amino-2-fluoro-phenyl) -amide was used instead of the starting material used in step (iii) 5-methyl-2-ethyl-2H-pyrazol-4-yl] -methanone was obtained in the same manner as in Example 48 (a) -3-E- [2- (pyridin-2-yl) ethenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole. MS (ESI &lt; + &gt;) [M + H] / z yield 612, detected 612.
[1387] Example 51: 6-pyrid-4-yl-3-E- (N- (pyrrol-1-yl) iminomethyl)
[1388]
[1389] (2-trimethylsilanyl-ethoxymethyl) -1H-indazole was reacted with 6-pyrid-4-yl-3- pyrid-4-yl-3-E- (N- (pyrrol-1-yl) iminomethyl) -1H-indazole in the same manner as in (a). _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.76 (s, 1H), 8.67 (d, 2H, J = 6.1 Hz), 8.53 (d, 1H, J = 8.4 Hz), 7.74 (s, 1H), 7.61 (d, 2H, J = 6.2 Hz), 7.54 (d, 1H, J = 8.5 Hz), 7.27-7.25 (m, 2H), 6.31-6.29 (m, 2H). MS (ES) [M + H] / z yield 288, Detection 288. Molecular weight calculation C (71.07), H (4.56), N (24.37). Detection: C (70.81), H (4.57), N (24.14).
[1390] The starting material was prepared as follows:
[1391]
[1392] 208 mg (0.59 mmol) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde, 145 mg (1.76 mmol) And 5.8 占 퐇 of acetic acid in 1 ml of ethanol was allowed to stand at 95 占 폚 for 16 hours. The solution was evaporated under reduced pressure and purified by silica gel chromatography to obtain the oil, 6-pyrid-4-yl-3-E- (N- (pyrrol-1-yl) iminomethyl) -1- (2-trimethylsilanyl -Ethoxymethyl) -1H-indazole (yield: 57%). _{^{1 H NMR (300MHz, CDCl 3}} ) · 9.08 (s, 1H), 8.71 (d, 2H, J = 6.1 Hz), 8.46 (d, 1H, J = 8.5 Hz), 8.34 (s, 1H), 7.85 ( 2H, J = 2.3 Hz), 7.80 (d, 1H, J = 8.5 Hz), 7.56 (t, 2H, J = 2.3 Hz), 6.25 1H), 5.74 (s, 2H), 3.64 (t, 2H, J = 7.9Hz), 0.86 (t, 2H, J = 7.9Hz), 0.00 (s, 9H).
[1393] Example 52 (a): 6- (7-azaindazol-4-yl) -3-E-styryl-1H-indazole
[1394]
[1395] In a similar manner to Example 27 (a), Sem-Example 52 (a) was transformed into Example 52 (a). ^{1 H NMR (300MHz, DMSO-} d 6) δ8.63 (d, 1H, J = 4.8 Hz), 8.41 (d, 1H, J = 8.5 Hz), 8.37 (s, 1H), 7.99 (s, 1H) , 7.76 (d, 2H, J = 7.3 Hz), 7.70 (d, 1H, J = 8.5 Hz), 7.60-7.85 (m, 6H). HRMS (FAB) [M + H] / z yield 338.1400, detection 338.1389. 1.1 Calculated C (60.21), H (3.51), N (15.13) analyzed with trifluoroacetic acid. Detection C (59.93), H (3.59), N (14.86).
[1396] The starting material was prepared as follows:
[1397]
[1398] Trimethylsilyl-ethoxymethyl) -6-trimethylstannyl) -1H-indazole, 1.0 g (1.90 mmol) of 1- (4-iodo-2- A solution of 0.56 g (1.90 mmol) of AspH _3, 116 mg (0.38 mmol) of AsPh ₃ and 87 mg (0.09 mmol) of Pd ₂ dba ₃ was dissolved at 110 ° C. And heated for 3 hours. The solution was diluted with 50 mL of ethyl acetate, washed with brine (2 x 10 mL), dried over MgSO ₄ and concentrated under reduced pressure. Purification by silica gel chromatography gave Example 52 (a) which was a white solid (412 g, 46%). _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.82 (d, 1H, J = 5.8 Hz), 8.52 (s, 1H), 8.29 (d, 1H, J = 8.2 Hz), 8.05 (s, 1H), 7.73 2H, J = 8.2 Hz), 0.92 (t, 2H, J = 8.2 Hz), -0.33 (s, 9H).
[1399]
[1400] To 10 ml of degassed dioxane were added 2.90 g (6.10 mmol) of 6-iodo-3-styryl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole, 2.00 g of hexamethylditin a solution prepared by dissolving (6.12 mmol) and _{Pd (PPh 3) 4 282mg (} 0.24mmol) was heated at 110 ℃ for 3 hours. The solution was diluted with 200 mL of ethyl acetate, washed with brine (2 x 20 mL), dried over MgSO ₄ , concentrated under reduced pressure and evaporated. The residue was purified by silica gel chromatography to obtain 3 g of 3-styryl-1- (2-trimethylsilanylethoxymethyl) -6-trimethylstannyl-1H-indazole as a yellow oil (yield: 96%). _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.02 (d, 1H, J = 7.4 Hz), 7.71 (s, 1H), 7.71-7.29 (m, 8H), 5.77 (s, 2H), 3.65 (t, 2H, J = 16.3 Hz), 0.95 (t, 2H, J = 16.4 Hz), 0.38 (s, 9H), -0.03 (s, 9H).
[1401]
[1402] A mixture of 820 mg (5.30 mmol) of 4-chloro-lH-pyrazolo [3,4-b] pyridine, 2.4 mg (16.0 mmol) of sodium iodide and 0.8 ml of acetyl chloride dissolved in 6 ml of acetonitrile was refluxed for 8 hours. 10% NaCO ₃ aqueous solution and 10% NaHSO ₃ aqueous solution were added to the mixture in that order, and the mixture was allowed to stand for 10 minutes. The mixture was diluted with 50 mL of ethyl acetate and the organics were washed with brine (2 x 10 mL), dried over MgSO ₄ , evaporated and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 650 mg (yield 42%) of 1- (4-iodo-pyrazolo [3,4-b] pyridin- 1-yl) -ethanone as a brown solid. _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.39 (d, 1H, J = 5.0 Hz), 8.04 (s, 1H), 7.76 (d, 1H, J = 5.0 Hz), 2.88 (s, 3H).
[1403]
[1404] (Dorn, H. et al., Prakt. Chem., 324, 557-8) were added to POCl ₃ at 0 ° C. 62 (1982)), 2.5 mg (0.01 mmol) of PCl ₅ was added. The solution was warmed to room temperature for 1 hour, then heated to 90 DEG C and left for 3 hours. The solution was concentrated under reduced pressure, and then 50 ml of ice and water were added. The resulting mixture was diluted with 100 mL of ethyl acetate and the organic layer was washed with 30 mL of a saturated aqueous sodium bicarbonate solution. The organic layer was dried over MgSO ₄ and evaporated under reduced pressure to obtain 820 mg (yield: 60%) of 4-chloro-lH-pyrazolo [3,4-b] pyridine as a yellow solid. _{^{1 H NMR (300MHz, CDCl 3}} ) δ8.57 (d, 1H, J = 5.2 Hz), 8.25 (s, 1H), 7.28 (d, 1H, J = 5.2 Hz).
[1405] Example 52 (b): 6- (7-azaindol-4-yl) -3E-styryl-lH-indazole
[1406]
[1407] Iodoindazole was changed to Example 52 (b) in the same manner as in Example 27 (a). ^{1 H NMR (300MHz, MeOH-} d 4) δ8.40 (d, 1H, J = 5.3 Hz), 8.53 (d, 1H, J = 8.6 Hz), 7.74-7.35 (m, 10H), 6.90 (s, 1H). HRMS (FAB) [M + H] / z yield 337.1448, detect 337.1457. Calculated C (77.31), H (4.90), N (16.39) analyzed with 0.3 H ₂ O. Detection C (77.51), H (4.88), N (16.27).
[1408] The starting material was prepared as follows:
[1409]
[1410] Chloro-lH-pyrrolo [2,3-b] pyridine (Clark, BA et al., J. Chem. Soc. Pl., 2270-74 (1974)) was reacted in the same manner as in Example 52 Iodo-1H-pyrrole [2,3-b] pyridine. ^{1 H NMR (300MHz, MeOH-} d 4) δ8.10 (m, 1H), 7.89 (d, 1H, J = 5.0 Hz), 7.58 (m, 1H), 7.50 (d, 1H, J = 5.0 Hz) , 6.26 (br s, 1 H).
[1411] Example 53 (a): 3- (lH-Benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-
[1412]
[1413] (0.7 mmol) of 4-aminophenol was added to a solution of 208 mg (0.7 mmol) of 3- (1H-benzoimidazol-2-yl) -1H- indazole-6-carboxylic acid in 6 ml of dry dimethylformamide And HATU (312 mg, 0.8 mmol) was added followed by 20 drops of triethylamine. The reaction was stirred at ambient temperature for one day. LC / MS showed the main component required for the product. The solvent was removed in vacuo and the residue was dissolved in water and ethyl acetate. The organic layer was separated and concentrated in vacuo. The residue was redissolved in 10 mL methanol and half of the solution was purified by HPLC over a gradient of 55% acetonitrile / water in 5% acetonitrile / water over 60 minutes with 0.1% trifluoroacetic acid in water to give a solid To obtain 20 mg of 3- (1H-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide. ¹ H NMR (methanol _{-d 4) δ6.87 (2H, d} , 8.8 Hz), 7.55 (2H, d, 8.7 Hz), 7.61 (2H, m), 7.55 (2H, d, 8.7 Hz), 7.87 ( 2H, br s), 8.00 (1H, d, 8.4 Hz), 8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1.
[1414] The starting material was prepared as follows:
[1415]
[1416] 2.0 g (12.42 mmol) of 1H-indole-6-carboxylic acid was dissolved in 100 ml of water and 8.56 g (124.2 mmol) of NaNO ₂ was added. To this suspension was added slowly 16 ml of 6N HCl via an addition funnel and the resulting slurry was stirred at room temperature for one day. The solid precipitate was filtered and washed with water (50 ml) to obtain 2.35 g (yield 100%) of 3-formyl-1H-indazole-6-carboxylic acid. _{^{1 H NMR (DMSO-d 6}} ) δ14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, d, J = 8.5 Hz), 8.20 (1H, d, J = 8.5 Hz), 7.90 (1H, d, J = 8.3 Hz). MS (APCI positive) 205 (methyl ester).
[1417]
[1418] Phenylenediamine (1.34 g, 12.42 mmol) and sulfur powder (1.1 eq, 13.66 mmol) were added to a solution of 2.35 g (12.42 mmol) of 3-formyl-1H-indazole- mmol). The mixture was refluxed for 6 hours, heated and then subjected to TLC and LC-MS. After cooling the reaction mixture, 50 ml of water was added and the mixture was collected by filtration to obtain 3.1 g (yield 90%) of 3- (1H-benzoimidazol-2-yl) -1H- indazole- . _{^{1 H NMR (DMSO-d 6}} ) δ14.01 (1H, s), 8.58 (1H, d, J = 8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, J = 8.7 Hz), 7.64 (2 H, m), 7.25 (2 H, m). MS (APCI positive) 279.
[1419] Example 53b: 3- (lH-Benzoimidazol-2-yl) -N-cyclopropyl-lH-indazole-6- carboxamide
[1420]
[1421] (0.719 mmol) of 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid was dissolved in 30 ml of DMF, and 98 mg (0.719 mmol) of cyclopropylamine, 273 mg mmol) and 0.1 ml (0.726 mmol) of triethylamine were added. The solution was stirred at ambient temperature for one day. The reaction was washed with aqueous solution and extracted with ethyl acetate (3x50ml). The organic layer was dried with MgSO _4, filtered and concentrated to give a black oil. (1H-benzoimidazol-2-yl) -N-cyclopropyl-1 H-indazole-6-carboxamide 0.130 via an analytical column chromatography (30-70% ethyl acetate / Petroleum ether) g (yield: 57%). _{^{1 H NMR (DMSO-d 6}} ) δ13.88 (1H, s), 8.63 (1H, m), 8.51 (1H, d, J = 8.5Hz), 8.09 (1H, s), 7.75 (1H, d, J = 8.7 Hz), 7.63 (2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m). MS (APCI Positive) 318.1.
[1422] Example 53 (c): 3- (lH-Benzoimidazol-2-yl) -N- (4-hydroxy-3-methylphenyl) -lH-indazole-
[1423]
[1424] Example 53 (c) was prepared in the same manner as in Example 53 (a) except that 3-methyl-4-aminophenol was used instead of 4-aminophenol. _{^{1 H NMR (DMSO-d 6}} ) δ8.59 (1H, d, J = 8.3 Hz), 8.25 (1H, s), 7.89 (1H, dd, J = 1.3, 8.5Hz), 7.68 (2H, br s ), 7.28 (2H, m), 7.14 (1H, d, J = 8.5Hz), 6.74 (1H, s), 6.68 (2H, dd, J = 3.0,8.3Hz). MS (APCI positive) 384.1.
[1425] Example 53 (d): 3- (lH-Benzoimidazol-2-yl) -N- (4-hydroxy-2,3- dimethylphenyl) -1H-indazole-
[1426]
[1427] Example 53 (d) was prepared in the same manner as in Example 53 (a) except that 2,3-dimethyl-4-aminophenol was used instead of 4-aminophenol. _{^{1 H NMR (DMSO-d 6}} ) δ9.93 (1H, s), 9.22 (1H, s), 8.56 (1H, d, J = 8.5Hz), 8.25 (1H, s), 7.90 (1H, d, D, J = 8.5 Hz), 7.73 (1H, br s), 7.53 (1H, br s), 7.23 8.5 Hz), 2.09 (6H, br s). MS (APCI positive) 398.4.
[1428] Example 53 (e): 3- (lH-Benzoimidazol-2-yl) -1H-indazole-6- carboxamide
[1429]
[1430] Example 53 (e) was repeated except that 1,1,1,3,3,3-hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane) was used instead of 4-aminophenol The title compound was prepared in the same manner as in Example 53 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.91 (1H, s), 13.04 (1H, s), 8.52 (1H, d, J = 8.3Hz), 8.20 (1H, br s), 8.15 (1H, s ), 7.81 (1H, d, J = 7.7Hz), 7.75 (1H, d, J = 6.6Hz), 7.51 (2H, m), 7.21 (2H, m). MS (APCI positive) 278.1.
[1431] Example 53 (f): 3- (lH-Benzoimidazol-2-yl) -N-benzyloxy-lH-indazole-
[1432]
[1433] Example 53 (f) was prepared in the same manner as in Example 53 (a), except that O-benzylhydroxyamine was used instead of 4-aminophenol. _{^{1 H NMR (DMSO-d 6}} ) δ13.94 (1H, s), 13.06 (1H, s), 11.97 (1H, s), 8.55 (1H, d, J = 8.8Hz), 8.02 (1H, s) , 7.78 (1H, d, J = 8.3 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.50 (3H, m) s). MS (APCI positive) 384.2.
[1434] Example 53 (g): 3- (lH-Benzoimidazol-2-yl) -N- (3-fluoro-4-hydroxyphenyl) -1H-indazole-
[1435]
[1436] Example 53 (g) was prepared in the same manner as in Example 53 (a) except that 3-fluoro-4-aminophenol was used instead of 4-aminophenol. _{^{1 H NMR (CH 3 OD)}} δ8.58 (1H, d, J = 8.5Hz), 8.20 (1H, s), 7.84 (1H, d, J = 8.7Hz), 7.68 (2H, br s), 7.63 (1H, dd, J = 2.4,13Hz), 7.29 (3H, m), 6.92 (1H, t, J = 9.2Hz). MS (APCI positive) 388.3.
[1437] Example 54 (a): 3- (5,6-Difluoro-1H-benzoimidazol-2-yl) -N- (4- hydroxyphenyl) -1H-indazole-
[1438]
[1439] In the same manner as in the synthesis of 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid in step (ii) of Example 53 (a) Hydroxyphenyl) -3-formyl-1H-indazole-6-carboxamide and 4,5-difluoro-1,2-phenylenediamine as a brown solid 3- (5,6- -1H-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide. _{^{1 H NMR (DMSO-d 6}} ) δ13.99 (1H, s), 13.27 (1H, s), 10.21 (1H, s), 9.25 (1H, s), 8.52 (1H, d, J = 8.7Hz) T, J = 9.8 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.47 (1H, t, J = 9.8 Hz), 6.75 (2H, d, J = 8.7 Hz). MS (APCI positive) 406.
[1440] The starting material is prepared as follows:
[1441] (i)
[1442]
[1443] 1.6 g (8.4 mmol) of 3-formyl-1H-indazole-6-carboxylic acid and 1.8 g (16.8 mmol) of 4-aminophenol were dissolved in 35 ml of dry dimethylformamide, 3.8 g (16.8 mmol) 1.4 ml (10.1 mmol) of triethylamine were added in turn. The reaction was stirred at room temperature and monitored by TLC and LC / MS. After 2 hours, the reaction was complete, the solvent was removed in vacuo and the product was purified by flash column chromatography using ethyl acetate: petroleum 1: 1 to yield N- (4-hydroxyphenyl) -3 -Formyl-1H-indazole-6-carboxamide was isolated. _{^{1 H NMR (DMSO-d 6}} ) δ6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (2H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz) , 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI positive) 282.1.
[1444] Example 54 (b): 3- (5,6-Dichloro-lH-benzoimidazol-2-yl) -N- (4- hydroxyphenyl) -lH-indazole-
[1445]
[1446] Example 54 (b) was prepared in the same manner as in Example 54 (a), except that 4,5-dichloro-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ14.08 (1H, s), 13.38 (1H, s), 10.22 (1H, s), 9.27 (1H, s), 8.52 (1H, d, J = 8.7Hz) (1H, s), 8.23 (1H, s), 8.02 (1H, s), 7.86 (1H, d, J = 8.7Hz) d, J = 8.7 Hz). MS (APCI positive) 438.
[1447] Example 54 (c): 3- (5-Methoxy-1H-benzoimidazol-2-yl) -N- (4- hydroxyphenyl) -lH-indazole-
[1448]
[1449] Example 54 (c) was prepared in the same manner as in Example 54 (a), except that 4-methoxy-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- . _{^{1 H NMR (DMSO-d 6}} ) δ13.76 (1H, s), 12.77 (1H, s), 10.13 (1H, s), 9.17 (1H, s), 8.45 (1H, d, J = 8.3Hz) (1H, s), 8.11 (1H, s), 7.75 (1H, d, J = 8.6Hz), 7.46 (2H, d, J = 8.7Hz), 7.32 , 6.77 (1H, m), 6067 (2H, d, J = 8.7 Hz), 3.72 (3H, s). MS (APCI positive) 400.
[1450] Example 54 (d): Synthesis of 3- [1 H-naphtho (2,3-d) imidazol-2-yl] -N- (4-hydroxyphenyl) Vox amide
[1451]
[1452] Example 54 (d) was prepared in the same manner as in Example 54 (a) except that 2,3-naphthalenenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. _{^{1 H NMR (DMSO-d 6}} ) δ14.11 (1H, s), 13.10 (1H, s), 10.24 (1H, s), 9.27 (1H, s), 8.64 (1H, d, J = 8.7Hz) D, J = 8.6 Hz), 7.56 (2H, d, J = 8.8 Hz, 1H), 8.28 (1H, s), 8.25 8.7 Hz), 7.38 (2H, b), 6.76 (2H, d, J = 8.7 Hz). MS (APCI positive) 420.
[1453] Example 54 (e): 3- [1 H-Naphtho (1,2-d) imidazol-2-yl] -N- (4- hydroxyphenyl)
[1454]
[1455] Example 54 (e) was prepared in the same manner as in Example 54 (a) except that 1,2-naphthalenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. _{^{1 H NMR (DMSO-d 6}} ) δ13.93 (1H, s), 13.38 (1H, s), 10.23 (1H, s), 9.27 (1H, s), 8.70 (2H, m), 8.22 (1H, (2H, d, J = 8.6Hz), 8.00 (1H, d, J = 8.0Hz), 7.87 Hz). MS (APCI positive) 420.
[1456] Example 54 (f): 3- (4,5-Dimethyl-1H-benzoimidazol-2-yl) -N- (4- hydroxyphenyl) -lH-indazole-
[1457]
[1458] Example 54 (f) was prepared in the same manner as in Example 54 (a), except that 3,4-dimethyl-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- &Lt; / RTI &gt; _{^{1 H NMR (DMSO-d 6}} ) δ13.77 (1H, d, tautomers (tautomers)), 12.70 (1H , d, tautomers), 10.11 (1H, s) , 9.16 (1H, s), 8.48 ( D, J = 8.3 Hz), 8.09 (1H, s), 7.73 (1H, d, J = 8.6 Hz), 7.47 Hz), 6.93 (1H, d, J = 8.3Hz), 6.65 (2H, d, J = 8.7Hz), 2.49 (3H, s), 2.24 (3H, s). MS (APCI positive) 398.4.
[1459] Example 54 (g): 3- (5-tert-Butyl-1H-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-
[1460]
[1461] Example 54 (g) was prepared in the same manner as in Example 54 (a) except that 4-tert-butyl-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- &Lt; / RTI &gt; ¹ H NMR (acetone _{-d 6) δ12.88 (1H, s} ), 9.47 (1H, s), 8.63 (1H, d, J = 8.7Hz), 8.18 (1H, s), 7.82 (1H, d, J = 8.3Hz), 7.57 (4H, m), 7.26 (1H, d, J = 8.4Hz), 6.74 (1H, d, J = 8.3Hz), 1.31 (9H, s). MS (APCI positive) 426.
[1462] Example 54 (h): 3- (5-Trifluoromethyl-1H-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-
[1463]
[1464] Example 54 (h) was prepared in the same manner as in Example 54 (a) except that 4-trifluoromethyl-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- Were prepared in the same manner. ¹ H NMR (methanol _{-d 4) δ6.86 (2H, d} , 8.9Hz), 7.54 (2H, d, 8.9Hz), 7.6 (1H, dd, 8.5Hz), 7.83 (1H, d, 8.3Hz) , 7.89 (1H, dd, 8.6 Hz), 8.04 (1H, br s), 8.25 (1H, s), 8.61 (1H, d, 8.6 Hz). MS (APCI positive) 438.1.
[1465] Example 54 (i): 3- (5-Fluoro-lH-benzoimidazol-2-yl) -N- (4- hydroxyphenyl) -lH-indazole-
[1466]
[1467] Example 54 (i) was prepared in the same manner as in Example 54 (a), except that 4-fluoro-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- . ¹ H NMR (acetone _{-d 6) δ13.40 (1H, b} ), 12.47 (1H, b), 9.74 (1H, s), 8.67 (1H, d, J = 8.6Hz), 8.66 (1H, s) , 8.29 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.67 (2H, J = 8.4 Hz), 7.64 (1H, J = 8.5 Hz), 6.83 (2H, d, J = 8.4 Hz). MS (APCI positive) 388.
[1468] Example 54 (j): 3- (5H- [1,3] dioxolo [4,5- f] benzoimidazol-6-yl) -N- (4-hydroxyphenyl) Indazole-6-carboxamide
[1469]
[1470] Example 54 (j) was prepared in the same manner as in Example 54 (a) except 4,5-methylenedioxy-1,2-phenylenediamine was used in place of 4,5-difluoro-1,2- . &Lt; / RTI &gt; ¹ H NMR (methanol _{-d 6) δ6.85 (2H, d} , 8.9Hz), 7.15 (2H, s), 7.54 (2H, d, 8.9Hz), 7.86 (1H, dd, 8.6Hz), 8.23 ( 1H, s), 8.55 (1H, dd, 8.5 Hz). MS (APCI pos) 414.1.
[1471] Example 54 (k): 3- (5,6-Dimethoxy-1H-benzoimidazol-2-yl) -N- (4- hydroxyphenyl) -lH-indazole-
[1472]
[1473] Example 54 (k) was prepared in the same manner as in Example 54 (a) except that 4,5-dimethoxy-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- Were prepared in the same manner. ¹ H NMR (methanol _{-d 6) δ3.98 (6H, s} ), 6.85 (2H, d, 8.78Hz), 7.29 (2H, br s), 7.54 (2H, d, 8.73Hz), 7.86 (1H, d, 8.57 Hz), 8.24 (1H, s), 8.57 (1H, d, 8.58 Hz). MS (APCI pos) 430.1
[1474] Example 54 (1): 3- (5-Chloro-1 H-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-
[1475]
[1476] Example 54 (1) was prepared in the same manner as in Example 54 (a), except that 4-chloro-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2- . ¹ H NMR (methanol _{-d 4) δ8.62 (1H, d} , J = 8.6Hz), 8.30 (1H, s), 7.90 (1H, dd, J1 = 8.6Hz, J2 = 1.3Hz), 7.69 (b , 2H), 7.56 (2H, d, J = 6.89 Hz), 7.33 (1H, dd, J1 = 8.59, J2 = 1.97 Hz), 6.88 (2H, MS (APCI pos) 404.1.
[1477] Example 55: 3-1H-Benzoimidazol-2-yl-6-pyridin-4-yl-
[1478]
[1479] Example 55 was modified to Example 55 in the same manner as in Example 27 (a). _{^{1 H NMR (300MHz, CDCl 3}} + MeOH-d 4 + DMSO-d 6) δ8.71-8.64 (m, 3H), 8.03 (s, 1H), 7.86 (dd, 2H, J = 4.7, 1.6Hz) , 7.77-7.72 (m, 3H), 7.32 (dd, 2H, J = 6.0, 3.1 Hz). HRMS (FAB) [M + H] / z yield 312.1244, detect 312.1253. Calculating analysis in _{1.40 H 2 O C (67.80)} , H (4.73), N (20.81). Detection C (68.06), H (4.45), N (20.68).
[1480] The starting material was prepared as follows:
[1481]
[1482] (2.0 mmol) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde, 10 g 0.26 g (2.4 mmol) and 77 mg (2.4 mmol) of sulfur were dissolved and heated in a 90 DEG C oil bath for one day. To the resulting mixture was added 200 ml of brine and extracted with EtOAc (3 x 60 ml). The resulting organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to give 6-pyridin-4-yl-l- (2-trimethylsilanylethoxymethyl) -3- [1- (2-trimethylsilanylethoxy) Methyl) -1H-benzoimidazol-2-yl] -1H-indazole (yield: 65%). _{^{1 H NMR (CDCl 3) δ8.82}} (d, 1H, J = 8.5Hz), 8.73 (d, 1H, J = 5.8Hz), 7.94-7.89 (m, 2H), 7.87 (s, 1H), 7.69 2H, J = 8.3Hz), 0.67 (t, 2H, J = 8.2Hz), 7.67-7.62 (m, 4H), 7.40-7.34 -0.03 (s, 9H), -0.13 (s, 9H).
[1483] Example 56: Synthesis of 6- [3- (propyn-3-ylcarbamoyl) benzoyl] -3-E- [2- (pyridin- 2- yl) ethenyl]
[1484]
[1485] To a solution of 1.5 mg of DMF was added 55.4 mg (0.15 mmol) of 2- {1- [3 - ((E) -2-pyridin-2-yl- (7-azabenzotriazol-1-yl) -n, n, N-dimethylformamide was dissolved by dissolving 15.4 μl (0.225 mmol) of propargylamine and 41.8 62.7 mg (0.165 mmol) of n ', n'-tetramethyluronium hexafluoro-phosphate was added. The mixture was stirred for 1 hour, then concentrated in a high vacuum and purified by preparative C18 reverse phase column chromatography. The product 40 mg was purified by " chromatotron " radiochromatography eluting with 25% CH ₃ CN / CH ₂ Cl ₂ to give 16.5 mg (27% yield) of product as a white solid. _{^{1 H NMR (DMSO-d 6}} ) δ13.30 (s, 1H), 8.58 (d, J = 5.00Hz, 1H), 8.05 (d, J = 8.29Hz, 1H), 7.92 (d, J = 16.2Hz 2H), 6.89 (d, J = 8.3 Hz, 1H), 7.79 (m, 3H) 8.48 Hz, 1 H). Anal. Calcd. For C ₂₅ H ₁₈ N ₄ O ₂ .0.5 H ₂ O: C, 72.27; H, 4.61; N, 13.49. Detection: C, 72.39; H, 4.62; N, 13.69.
[1486] (i)
[1487]
[1488] Yl] -methanoyl} -benzoic acid: 2- {1- [3- (3-Fluoro- Yl) -methanoyl} -benzoic acid (4.02 mg, 0.805 mmol) was added to a solution of (4-chloro-pyridin- ) (Prepared as described below), 215 μL (3.22 mmol) of ethylenediamine and 1M TBAF were dissolved in 6.44 mL (6.44 mmol) of THF and stirred in a 90 ° C. oil bath for 4 hours. The crude reaction mixture was cooled to 386 L (6.44 mmol) of acetic acid, diluted with 100 mL of ethyl acetate, extracted with 1 M sodium bicarbonate solution (2x20 mL), brine (5x20 mL), dried over magnesium sulfate and filtered And concentrated to a 3 mL volume. The crude product was purified by preparative C18 reverse phase column chromatography to give 2- {1- [3- ((E) -2-pyridin-2-yl-vinyl) -1H-indazol- Methanoyl} -benzoic acid (yield: 71%). _{^{1 H NMR (DMSO-d 6}} ) δ13.50 (bs, 1H), 8.68 (d, J = 5.27Hz, 1H), 8.29 (d, J = 8.86Hz, 1H), 8.13-7.90 (m, 4H) , 7.81-7.43 (m, 7H).
[1489]
[1490] 2- {1- [3 - ((E) -2-Pyridin-2-yl-vinyl) -l- (2- trimethylsilanyl- ethoxymethyl) -lH- indazol- } -Benzoic acid: 477 mg (1.0 mmol) of 6-iodoindazole was dissolved in 10 ml of THF at -100 ° C. and 440 μl (1.10 mmol) of 2.5 M n-butyllithium dissolved in hexane was added dropwise at the temperature Was stirred for 5 minutes and then 222 mg (1.5 mmol) of phthalic anhydride dissolved in 10 ml of THF was added. The resulting mixture was slowly warmed to room temperature to remove THF, diluted with ethyl acetate, extracted with 1N citric acid, extracted with brine, dried over magnesium sulfate and concentrated to an oil. The oil was triturated with methylene chloride and diethyl ether to give 2- {1- [3 - ((E) -2-pyridin-2-yl-vinyl) -l- (2-trimethylsilanylethoxy) Methyl) -1 H-indazol-6-yl] -methanoyl} -benzoic acid (yield: 81%). _{^{1 H NMR (DMSO-d 6}} ) δ8.67 (d, J = 5.09 Hz, 1H), 8.31 (d, J = 8.85 Hz, 1H), 8.08-7.55 (m, 4H), 7.50-7.37 (m, 2H), 5.81 (s, 2H), 3.53 (t, J = 8.10 Hz, 2H), 0.78 (d, J = 8.15 Hz, 2H), -0.12 (s, 9H).
[1491] Example 57: Synthesis of 6- [3 - ((1,3-dimethyl-1H-pyrazol-5-yl) carboxamido) phenoxy] -3- E- E- [2- (pyridin- / RTI &gt; &lt; RTI ID = 0.0 &gt;
[1492]
[1493] Example 57 was prepared in the same manner as in Example 58. ^{1 H NMR (300MHz, DMSO-} d 6) δ13.15 (s, 1H), 10.17 (s, 1H), 8.60 (d, 1H, J = 4.2 Hz), 8.22 (d, 1H, J = 8.7 Hz) , 7.94 (d, IH, J = 16.4Hz), 7.84-7.79 (m, IH), 7.68-7.50 1H), 7.06 (s, 1H), 7.00 (dd, 1H, J = 8.8, 1.9 Hz), 6.87 (dd, 1H, J = 8.0, 1.9 Hz) , 2.17 (s, 3 H); ESIMS m / z 451 [M + H] &lt; ⁺ &gt;. Analysis for C ₂₆ H ₂₂ N ₆ O ₂ x 0.5 H ₂ O x 0.4 hexane (494.0 g / mol): C, 69.05; H, 5.84; N, 17.01. Detection: C, 68.78; H, 5.55; N, 17.05.
[1494] Example 58: 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) phenoxy] 2-yl) ethenyl] -1H-indazole
[1495]
[1496] To a solution of 7.5 ml of tetrabutylammonium fluoride (dissolved in THF at a concentration of 1.0 M, 7.5 mmol, 15.0 eq) and 0.33 ml (5.0 mmol, 10 eq) of 1,2-diaminoethane was added 2-ethyl- Methyl-2H- pyrazole-3-carboxylic acid [2-methyl-5- (1- (2- trimethylsilanylethoxymethyl) -3 - {(E) -2- [ 360 mg (0.5 mmol, 1.0 eq) of 1,4-di (tert-butyldimethylsilanyl-ethoxymethyl) -1H-imidazol- In 5 ml of oxalic acid was added, and the mixture was heated at 90 占 폚 for 18 hours. Concentration under reduced pressure at the end of the reaction and the orange oil product was diluted with 50 mL of ethyl acetate. The organic layer was washed vigorously with saturated sodium bicarbonate (5x50ml), brine, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil (287mg). The crude product was purified by radioactive chromatography on silica gel using 0.1% ammonium hydroxide ( _Rf 0.1) and 5% methanol-chloroform as the eluent to give 2-ethyl-5-methyl-2H-pyrazole as a pale yellow solid Yl) -vinyl] -1H-indazol-6-yloxy} -2-methyl-phenyl) -1H-indazol- ) -Amide (yield 61%): HPLC R _t = 11.8 min .; TLC R _f = 0.8 (0.1% ammonium hydroxide and 10% methanol-chloroform); ^{1 H NMR (300MHz, DMSO-} d 6) δ13.03 (s, 1H), 12.30 (br s, 1H), 9.78 (s, 1H), 8.00 (d, 1H, J = 8.6 Hz), 7.54 (d 1H, J = 16.8 Hz), 7.32 (d, 1H, J = 8.5 Hz), 7.27 (d, 1H, J = 16.9 Hz), 7.13-7.12 (m, 3H), 7.00-6.94 , 6.78 (s, 1H), 4.39 (q, 2H, J = 7.1 Hz), 2.23 (s, 3H), 2.19 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz). Analysis for C ₂₆ H ₂₅ N ₇ O ₂ x 0.5 H ₂ O x 0.4 hexane (511.0 g / mol): C, 66.75; H, 6.23; N, 19.19. Detection: C, 66.95; H, 6.25; N, 18.83.
[1497] The starting material is prepared as follows:
[1498] (i) Preparation of 1- (2-trimethylsilanylethoxymethyl) -1H-indazole
[1499]
[1500] 2.0 g (29.4 mmol, 1.0 eq) of 1H-imidazole was dissolved in 70 ml of THF, and 1.5 g of sodium hydroxide (dissolved in 60% mennal oil, 38.2 mmol, 1.3 eq) was dissolved in 30 ml of THF at 0 deg. . After stopping the gas evolution, the mixture was warmed to room temperature for 45 minutes and then cooled to 0 占 폚. 5.4 ml (30.2 mmol, 1.0 eq) of [2- (trimethylsilanyl) ethoxy] methyl chloride was added to the mixture and the mixture was warmed to room temperature for one day. The reaction was cooled with saturated sodium bicarbonate, THF was removed under reduced pressure and the beige slurry product was extracted with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated to give 6.9 g of a yellow oil. The oil was purified by flash chromatography on silica gel eluting with 2% methanol-chloroform to give 4.7 g (yield 81%) of 1- (2-trimethylsilanylethoxymethyl) -1H- imidazole as a pale yellow oil. ); HPLC R _t = 0.3 min (5% methanol-chloroform); ^{1 H NMR (300MHz, DMSO-} d 6) δ7.77 (s, 1H), 7.26 (d, 1H, J = 1.2 Hz), 6.93 (s, 1H), 5.32 (s, 2H), 3.45 (t, 2H, J = 8.0 Hz), 0.83 (t, 2H, J = 8.0 Hz), -0.05 (s, 9H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) 137.9, 128.8, 119.6, 74.8, 65.1, 17.1, -1.4.
[1501] (ii) Preparation of [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -methanol
[1502]
[1503] 3.0 g (15.4 mmol, 1.0 eq) of 1- (2-trimethylsilanylethoxymethyl) -1H-imidazole was dissolved in 150 mL of THF and cooled to -78 째 C. nBuLi (1.6 M hexane as a solvent, 16.9 mmol, 1.1 eq) was added and the temperature was raised to -40 캜 over 15 minutes. The pale yellow solution was stirred at -40 &lt; 0 &gt; C for 30 min and the anion was then cooled to 1.3 ml (16.9 mmol, 1.1 eq) of DMF. The reaction mixture was warmed to room temperature for one day and then cooled with water. The solvent was removed and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried with brine and magnesium sulfate, and then filtered and concentrated to obtain a crude product (3.5 g, TLC R _f = 0.5 (5% methanol-chloroform)). An aldehyde proton was obtained from the proton NMR spectrum at 9.73 ppm. The crude product was dissolved in 15 ml of methanol, cooled to 0 캜 and treated with 1.2 g (30.8 mmol, 2.0 eq) of sodium borohydride. The reaction mixture was allowed to warm to room temperature for one day. The solvent was removed and the crude product was diluted with chloroform, washed with water, dried with brine and magnesium sulfate, filtered and concentrated to give 3.6 g of a clear oil. The oil was purified by flash chromatography on silica gel using 0.1% ammonium hydroxide and 3-6% methanol-chloroform as the eluent to give [1- (2-trimethylsilanylethoxymethyl) -lH (41% 2-step): TLC _Rf = 0.4 (8% methanol-chloroform); ^{1 H NMR (300MHz, DMSO-} d 6) δ7.22 (d, 1H, J = 1.1 Hz), 6.81 (d, 1H, J = 1.0 Hz), 5.36 (s, 2H), 5.31 (br, t, 2H, J = 8.0 Hz), 4.0 (d, 2H, J = 4.8 Hz), 3.48 ); ^{13 C NMR (75MHz, DMSO-} d 6) δ148.9, 127.8, 122.5, 75.5, 66.5, 56.9, 18.5, 0.0.
[1504] (iii) 2-Chloromethyl-l- (2-trimethylsilanylethoxymethyl) -lH-imidazole hydrochloride
[1505]
[1506] 0.87 ml (12.0 mmol, 3.0 eq) of thionyl chloride was dissolved in 8 ml of chloroform, and the solution was cooled to 0 캜. To the chloroform was added [1- (2-trimethylsilanylethoxymethyl) Azol-2-yl] -methanol (4.0 mmol, 1.0 eq) dissolved therein was treated. The clear solution was stirred at 0 &lt; 0 &gt; C for 30 minutes and then at room temperature for 2 hours. The solvent was removed and the product was slurried and then concentrated in chloroform, toluene and cyclohexane to give 1.1 g of 2-chloromethyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole hydrochloride as a beige solid (yield: 97%) was ^{obtained: 1 H NMR (300MHz, DMSO} -d 6) δ7.85 (d, 1H, J = 1.9 Hz), 7.70 (d, 1H, J = 1.9 Hz), 5.62 (s, 2H ), 5.14 (s, 2H), 3.57 (t, 2H, J = 8.3 Hz), 0.90 (t, 2H, J = 8.3 Hz), -0.02 (s, 9H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) 142.1, 123.2, 120.2, 76.5, 66.8, 31.7, 17.3, -1.4.
[1507] (iv) Preparation of 3-amino-4-methyl-phenol
[1508]
[1509] Black solid (95%); HPLC R _t = 4.4 min .; ^{1 H NMR (300MHz, DMSO-} d 6) δ8.61 (s, 1H), 6.64 (d, 1H, J = 8.1 Hz), 6.05 (d, 1H, J = 2.4 Hz), 5.88 (dd, 1H, J = 8.0, 2.4 Hz), 4.64 (br s, 2H), 1.92 (s, 3H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) 156.1, 147.2, 130.2, 111.7, 103.3, 101.1, 16.6.
[1510] (v) Preparation of 3- (benzhydrylidene-amino) -4-methyl-phenol
[1511]
[1512] Yellow solid (49%); mp 106-108 [deg.] C; HPLC R _t = 15.3 min ,; TLC R _f = 0.2 (10% ethyl acetate-cyclohexane); ^{1 H NMR (300MHz, DMSO-} d 6) δ8.91 (s, 1H), 7.67-7.56 (m, 2H), 7.53-7.43 (m, 3H), 7.35-7.31 (m, 3H), 7.13-7.10 (m, 2H), 6.82 (d, 1H, J = 8.3 Hz), 6.22 (dd, 1H, J = 8.1, 2.5 Hz), 5.88 ; ^{13 CNMR (75MHz, DMSO-d} 6) δ166.4, 155.2, 150.6, 138.9, 136.0, 130.8, 130.2, 128.7, 128.4, 128.2, 128.0, 117.3, 109.9, 106.2, 17.0.
[1513] (vi) Synthesis of benzhydrylidene- {2-methyl-5- [3 - ((E) -styryl) -1- (2-trimethylsilanyl- ethoxymethyl) -1H-indazol- ] -Phenyl} -amine &lt; / RTI &gt;
[1514]
[1515] To a round bottom flask was added 5.5 g (26.0 mmol, 2.0 eq) of potassium phosphate, 3.9 g (13.6 mmol, 1.1 eq) of 3- (benzhydrylidene- E) -styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole and 13 ml of o-xylene. After the gas was removed from the slurry and purified by argon, 916 mg (1.1 mmol, 8 mol%) of tris (dibenzylideneacetone) dipalladium (0) and 656 mg of biphenyl-2-yl-di-tert- (2.2 mmol, 16 mol%) was treated. The flask was immersed in a oil bath and stirred at 100 DEG C for 18 hours. The black slurry was cooled to room temperature, filtered through celite and concentrated. The black oil was dissolved in chloroform, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give a black oil (12.1 g). The crude product was purified by flash chromatography on silica gel using 10-15% ether-cyclohexane as the eluent to give the yellowish benzhydrylidene- {2-methyl-5- [3 - (( 1.4 g (yield 16%) of the title compound was obtained as a colorless oil: HPLC R _{t &lt;} RTI ID = 0.0 _&gt; 24.3 _{&lt; /} RTI & min .; TLC R _f = 0.5 (20% ether-cyclohexane); ^{1 H NMR (300MHz, DMSO-} d 6) δ8.10 (d, 1H, J = 8.8 Hz), 7.75-7.66 (m, 4H), 7.53-7.31 (m, 11H), 7.14-7.08 (m, 4H 1H), 6.62 (dd, 1H, J = 8.8,2.0 Hz), 6.55 (dd, 1H, J = 8.2, 2.5 Hz), 6.20 (t, 2H, J = 7.8 Hz), 2.12 (s, 3H), 0.78 (t, 2H, J = 7.7 Hz), -0.14 (s, 9H).
[1516] (vii) Preparation of 2-methyl-5- [3 - ((E) -styryl) -1- (2-trimethylsilanyl- ethoxymethyl) -1H-indazol-6-yloxy] -phenylamine
[1517]
[1518] Yellow oil (80%); HPLC R _t = 21.0 min .; TLC R _f = 0.4 (10% ethyl acetate-cyclohexane); ^{1 H NMR (300MHz, DMSO-} d 6) δ8.18 (d, 1H, J = 8.8 Hz), 7.74-7.71 (m, 2H), 7.52 (s, 2H), 7.43-7.38 (m, 2H), 1H, J = 2.0 Hz), 7.33-7.28 (m, 1H), 7.20 (d, 8.0, 2.5 Hz), 5.66 (s, 2H), 5.01 (br s, 2H), 3.52 (t, 2H, J = 8.0 Hz), 2.03 ), -0.11 (s, 9H).
[1519] (viii) 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid {2-methyl-5- [3 - ((E) -styryl) Ethoxymethyl) -1H-indazol-6-yloxy] -phenyl} -amide
[1520]
[1521] White foam (85%); HPLC R _t = 21.5min .; TLC R _f = 0.2 (20% ethyl acetate-cyclohexane); ^{1 H NMR (300MHz, DMSO-} d 6) δ9.75 (s, 1H), 8.24 (d, 1H, J = 8.8 Hz), 7.74-7.72 (m, 2H), 7.53 (s, 2H), 7.43- 1H), 7.38 (m, 2H), 7.34-7.28 (m, 3H), 7.12 (d, 1H, J = 2.6 Hz), 7.00 (dd, 2H, J = 7.9 Hz), 2.22 (s, 3H), 4.40 (s, 2H) , 2.19 (s, 3H), 1.27 (t, 3H, J = 7.1 Hz), 0.78 (t, 2H, J = 7.9 Hz), -0.15 (s, 9H).
[1522] (ix) 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid {5- [3-formyl- 1- (2-trimethylsilanylethoxymethyl) -Yloxy] -2-methyl-phenyl} -amide &lt; / RTI &gt;
[1523]
[1524] To a solution of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid {2-methyl-5- [3 - ((E) - To a mixture of 774 mg (1.28 mmol, 1.0 eq) of a mixture of osmium tetra (trimethylsilanyloxymethyl) 7 mg (0.03 mmol, 0.02 eq) of oxide was treated. The solution was stirred for 5 minutes and then 822 mg (3.84 mmol, 3.0 eq) of sodium periodate was added. The resulting dark brown slurry was stirred at room temperature for one day, 100 ml of 15% Na ₂ S ₂ O _{3 was} added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to give 902 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel using 10-50% ethyl acetate-cyclohexane as the eluent to give 2-ethyl-5-methyl-2H-pyrazol- 590 mg (yield: 86%) of the carboxylic acid {5- [3-formyl-1- (2-trimethylsilanylethoxymethyl) -1 H- indazol- ) was obtained: HPLC R _t = 18.9min .; TLC R = _f 0.2 (40% ethyl acetate-cyclohexane); ^{1 H NMR (300MHz, DMSO-} d 6) δ10.16 (s, 1H), 9.75 (s, 1H), 8.14 (d, 1H, J = 8.8 Hz), 7.48 (d, 1H, J = 1.8 Hz) 2H), 7.32 (d, 1H, J = 8.5 Hz), 7.16-7.13 (m, 2H), 6.93 (S, 3H), 1.27 (t, 3H, J = 7.2 Hz), 4.39 (q, 2H, J = 7.1 Hz), 3.55 (t, 2H, J = 7.8 Hz) 0.79 (t, 2H, J = 7.8 Hz), -0.15 (s, 9H).
[1525] (x) 2- ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [2-methyl-5- (1- (2- trimethylsilanyl- ethoxymethyl) Preparation of 2- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -vinyl} -1H- indazol- 6-yloxy) -phenyl] -amide
[1526]
[1527] A solution of 344 mg (1.22 mmol, 2.0 eq) of 2-chloromethyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-hydrochloride dissolved in 20 mL of chloroform was treated with saturated sodium bicarbonate The base was removed. The organic layer was dried with brine and magnesium sulfate, filtered and concentrated to give 301 mg (yield 100%) of a yellow oil. The oil was dissolved in 12 ml of acetonitrile and treated with 304 mg (1.16 mmol, 1.9 eq) of triphenylphosphine and heated to 70 ° C for 18 hours. Removal of the solvent and addition of crude 1- (2-trimethylsilanylethoxymethyl) -2 - [(triphenyl- ⁵ -phosphanyl) -methyl] -1H-imidazole chloride in 12 mL of THF After cooling to -78 deg. C, 1.2 ml of potassium tert-butoxide (dissolved in THF at a concentration of 1.0 M, 1.22 mmol, 2.0 eq) was treated. After 15 min, a solution of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid {5- [3-formyl- 1- (2-trimethylsilanylethoxymethyl Ylide) was added to a solution of 325 mg (0.61 mmol, 1.0 eq) of (2-methyl-1H-indazol-6-yloxy] -2-methyl-phenyl} The bright yellow solution was warmed to room temperature overnight, cooled with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude product as a yellow oil (1.0 g). The crude product was purified by radioactive chromatography on silica gel using 0-5% methanol-chloroform as the eluent and left standing for one day to obtain 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [ (2-trimethylsilanylethoxymethyl) -3 - {(E) -2- [1- (2-trimethylsilanylethoxymethyl) - IH- imidazol- 2-yl] -vinyl} -1H-indazol-6-yloxy) -phenyl] -amide (yield: 88%). HPLC R _t = 20.6 min .; TLC R _f = 0.4 (4% methanol-dichloromethane); ^{1 H NMR (300MHz, DMSO-} d 6) δ9.75 (s, 1H), 8.14 (d, 1H, J = 8.8 Hz), 7.64 (d, 1H, J = 16.2 Hz), 7.42 (d, 1H, 1H, J = 16.3 Hz), 7.39-7.35 (m, 3H), 7.30 (d, 1H, J = 8.5 Hz), 7.12 2H, J = 8.8, 1.9 Hz), 6.78 (s, 1H), 5.70 (s, 2H, J = 7.9 Hz), 2.22 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J = 7.1 Hz), 0.84 ), -0.11 (s, 9H), -0.15 (s, 9H).
[1528] Example 59 (a): 6- [3 - ((1-Ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -Yl) ethenyl] -1H-indazole &lt; / RTI &gt; hydrochloride
[1529]
[1530] Example 41 (a) 4.57 g (9.59 mmol) was dissolved in 96 ml of methanol and light was blocked with aluminum foil. 20 ml of methanol was added to the second flask, and 684 占 퐇 (1.00 equiv) of acetyl chloride was treated for 5 minutes. The acid solution was washed several times with methanol ( 20 mL) and added to the first mixture. The volatiles were removed under reduced pressure and the residue was triturated with 1: 1 ethyl acetate-hexane, filtered and dried to give a yellow powder (4.82 g, 98%). 1.0 H ₂ O, C (61.85), H (5.07), N (15.46). Detection: C (61.15), H (5.15), N (15.38).
[1531] Example 59 (b): Synthesis of 6- [3 - ((1,3-dimethyl-1H-pyrazol-5-yl) carboxamido) benzoyl] ) Ethenyl] -1H-indazole &lt; / RTI &gt; hydrochloride
[1532]
[1533] Example 59 (b) was prepared in the same manner as in Example 59 (a) except that Example 41 (p) was used instead of Example 41 (a). HPLC: 3.92 min (100% area); ^{1 H NMR (DMSO) δ10.45 (} s, 1H), 8.85 (d, 1H, J = 4.8 Hz), 8.49 (d, 1H, J = 8.7 Hz), 8.38-8.30 (m, 4H), 8.21 ( 1H, J = 7.5, 2.1 Hz), 8.01 (s, 1H), 7.90-7.79 (m, 2H), 7.72-7.64 , &Lt; / RTI &gt; 2.33 (s, 3H). Analysis for C ₂₇ H ₂₀ N ₄ O ₂ S 1.3 H ₂ O, 0.2 EtOAc: C, 62.15; H, 5.18; N, 15.64. Detection: C, 61.81; H, 5.01; N, 15.64.
[1534] Example 59 (c): 6- [N- (5- ((1-Ethyl-3-methyl-1H-pyrazol- Amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole hydrochloride
[1535]
[1536] Example 59 (c) was prepared in the same manner as in Example 59 (a) except that Example 48 (a) was used instead of Example 41 (a). Analysis calculated: C, 63.21; H, 5.12; N, 18.43; Cl, 6.66. Detection: C, 60.86; H, 5.38; N, 17.28; Cl, 6.52.
[1537] Example 59 (d): 6- [N-3 - ((1,3-Dimethyl-1H-pyrazol-5-yl) carboxamido) -4-fluoro-phenyl) - [2- (pyridin-2-yl) ethenyl] -1H-indazole hydrochloride
[1538]
[1539] Example 59 (d) was prepared in the same manner as in Example 59 (a) except that Example 41 (a) was used instead of Example 41 (a). ^{1 H NMR (300MHz, DMSO-} d 6) δ13.2 (b, 1H), 9.97 (s, 1H), 8.75 (d, 1H, J = 5.44 Hz), 8.51 (bs, 1H), 8.35 (m, 1H), 7.41 (dd, 1H), 8.20 (d, 1H, J = 16.59 Hz), 8.06 1H, J = 6.65 Hz, J = 2.67 Hz), 7.24 (t, 1H, J = 9.54 Hz), 7.12 , 4.0 (s, 3H), 3.84 (bs, IH), 2.20 (s, 3H).
[1540] Example 59 (e): 6- [3 - ((l-Ethyl-3-dimethyl-lH-pyrazol-5- yl) carboxamido) phenoxy] 2-yl) ethenyl] -1H-indazole hydrochloride
[1541]
[1542] Example 59 (e) was prepared in a similar manner to Example 59 (a), except that Example 31 (d) was used instead of Example 41 (a). _{^{1 H NMR (DMSO-d 6}} ) δ13.53 (s, 1H), 10.23 (s, 1H), 8.78 (d, 1H, J = 5.5 Hz), 8.30 (m, 4H), 7.80 (m, 2H) , 7.59 (d, IH, J = 7.7 Hz), 7.55 (s, IH), 7.41 , 6.81 (s, 1H), 4.38 (q, 2H, J = 7.0Hz), 3.75 (bs, 1H), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.0Hz). Analysis for C ₂₇ H ₂₅ ClN ₆ O ₂ .1.7 H ₂ O, 0.1 EtOAc: C, 60.89; H, 5.45; N, 15.55. Detection: C, 60.88; H, 5.51; N, 15.27.
[1543] Example 59 (f): 6- [2- (Methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2- yl) ethenyl] -1H-indazole hydrochloride
[1544]
[1545] Example 59 (b) was prepared in the same manner as in Example 59 (a) except that Example 33 (a) was used instead of Example 41 (a). 2.0 H ₂ O: C, 57.58; H, 5.05; N, 12.21; Cl, 6.99. Detection: C, 57.24; H, 5.048; N, 11.91; Cl, 6.63.
[1546] The compounds prepared in the above examples were tested for their activity by the following methods.
[1547] Biological test; Enzyme assay (enzyme assay)
[1548] Cell proliferation by VEFG, FGF and other growth factors is stimulated by the tyrosine kinase autophosphorylation of each growth factor receptor. Therefore, the function of protein-kinase inhibitors, which interfere with the growth of cells induced by these growth factors, is directly related to the function of inhibiting receptor autophosphorylation. The protein kinase inhibitory activity of the compound was determined as follows.
[1549] VEGF-R2 Recombinant Protein for Quantification : This recombinant protein is intended to measure the activity of a test compound that inhibits tyrosine kinase activity. The recombinant protein (VEGF-R2 50) of the cytoplasmic domain of human VEGF-R2 deficient in the middle 50 residues of the 68 residues of the kinase insert domain was expressed in the baculovirus / embryonic cell system. VEGF-R2 50 consists of residues 806-939 and 990-1171 among the 1356 residues corresponding to the standard length of VEGF-R2 and has a point mutation (E990V) in the canine insert domain corresponding to wild-type VEGF-R2 . The autophosphorylation reaction of the purified recombinant protein was carried out by adding 3 mM ATP and 40 mM MgCl ₂ to 100 mM HEPES and incubating 4 μM of the enriched enzyme at pH 7.5, 5% glycerol and 5 mM DTT in the presence of 3 mM ATP and 40 mM MgCl ₂ at 4 ° C. And cultured for 2 hours. After the autophosphorylation reaction, it was found that this recombinant protein had catalytic activity equivalent to that of the kinase domain recombinant protein that underwent wild-type autophosphorylation (see Parast et al., Biochemistry, 37 , 16788-16801 (1998)).
[1550] FGF-R1 Recombinant Proteins for Quantification : The intracellular kinase domain of human FGF-R1 is described in Mohammadi et al., Mol. Cell. Biol., 16, 977-989 (1996), starting from the endogenous methionine 456 residue to glutamate 766 using the baculovirus vector expression system. In addition, three amino acids (L457V, C488A, C584S) were substituted for the recombinant protein.
[1551] LCK recombinant protein : LCK tyrosine kinase was expressed in inserted cells starting from 233 amino acid residues and lacking the N-terminus to 509 residues of the protein terminus. That is, P233M and C224D, the N-terminal of two amino acids, were substituted.
[1552] CHK-1 Recombinant Protein for Quantification : The His-Marked Standard Length Human CHK-1 (FL-CHK-1) at the C-terminus was expressed using the baculo / insertion cell system. This recombinant protein has 6 histidine residues (6x His-tag) at the C-terminus of the human CHK-1 476 amino acid. The recombinant protein was purified by a conventional chromatography technique.
[1553] Recombinant protein for quantification of CDK2 / Cyclin A for quantitation : CDK2 was prepared from the infected cells infected with the baculovirus expression vector (Rosenblatt et al., J. Mol. Biol. 230, 1317-1319 (1993) ). &Lt; / RTI &gt; Cyclin A was purified from Escherichia coli expressing standard length recombinant Cyclin A. A truncated form of cyclin A recombinant protein was prepared through limited proteolysis and purified by the method described in the prior art (Jeffrey et al., Nature, 376, 313-320 (July 27, 1995)).
[1554] CDK4 / cyclin D recombinant protein for quantification : The fusion protein of human CDK4 and cyclin D3 or the CDK and cyclin D1 complex and the fusion protein of human CDK4 and glutathione-S-transferase (GST-CDK4) coincide with baculovirus expression vectors Lt; RTI ID = 0.0 &gt; biochemical &lt; / RTI &gt; chromatography technique.
[1555] Recombinant protein for FAK quantitation for quantification : The catalytic domain of human FAK (FAKcd409) was expressed using the baculovirus vector expression system. The 280 amino acid domain was composed of residues ranging from methionine 409 to glutamate 689. P410T in which one amino acid is substituted is associated with the known sequence identification number L13616 (Whithey, GS et al., DNA Ceoo Biol 9, 823-830, 1993). Proteins were purified using conventional chromatographic techniques.
[1556] Recombinant protein for TIE-2 (TEK) quantification : The TIE-2 tyrosine kinase domain was expressed in cells of N-terminal deficient insects ranging from 774 residues to 1124 residues of protein amino acids. This recombinant protein was also expressed in the R774M mutation, which initiates translation of the methionine residue.
[1557] VEGF-R2 quantitation
[1558] Coupled spectrophotometric (FLVK-P) quantitation
[1559] The process of producing ADP in ATP accompanied by phosphorylation was linked to the oxidation of NADH using a system with phosphoenolpyruvate (PEP), pyruvate kinase (PK) and lactate dehydrogenase (LDH). The oxidation of NADH resulted in a decrease in absorbance using a Beckman DU650 spectrophotometer at ₃₄₀ nm (e ₃₄₀ = 6.22 cm ^-1 mM ^-1 ). The quantification conditions for the phosphorylation of VEGF-R2Δ50 indicated by FLVK-P in the table below are as follows. 1 mM MPEP; 250 [mu] M NADH; LDH / ml 50 units; PK / ml 20 units; 5 mM DTT; 5.1mM poly (E ₄ Y _1); 1 mM ATP, and 25 mM HCl in 25 mM MgCl ₂ , pH 7.5. Quantitative conditions for the removal of phosphoric acid from VEGF-R2Δ50 are as follows. 1 mM PEP; 250 [mu] M NADH; LDH / ml 50 units; PK / ml 20 units; 5 mM DTT; 20 mM poly (E ₄ Y ₁ ); 3mM ATP; A mixture of 60 mM MgCl ₂ and 2 mM MnCl ₂ in 200 mM HEPES, pH 7.5. Quantification was started at 5 nM of enzyme and 40 nM of enzyme. The K _i value was determined by measuring the enzyme activity through the change in the concentration of the test compound. The data were quantified using enzyme kinetics and Kaleidagraph software.
[1560] ELISA quantitation
[1561] Biotinylated gastrin peptide (1-17) was used as a substrate to form phosphogastrin. Biotinylated phosphogastrin was fixed using streptavidin coated with 96-well microtiter plates obtained from anti-phosphotyrosine antibody conjugated with wasabi peroxidase. The activity of this horseradish peroxidase was investigated using 2,2'-azino-di- [3-ethylbenzazatriazoline sulfonate (6)] diammonium salts (ABTs). The composition of a typical quantitative solution is a mixture of ₂ μM of biotinylated gastrin peptide, 5 mM of DTT, 20 μM of ATP, 26 mM of MgCl ₂ and ₂ mM of MnCl _{2 in} 200 μM of herpes, pH 7.5. Quantitation was initiated at 0.8 nM phosphorylated VEGF-R2 50. Horseradish peroxidase activity was quantitated with 10 mM ABTS. Horseradish peroxidase reaction was inhibited by addition of acid (H ₂ SO ₄ ) and showed an absorbance at 405 nm. The K _i value was determined by measuring the enzyme activity through the change in the concentration of the test compound. The data were analyzed using enzyme kinetics and Caledagraph software.
[1562] FGF-R Quantification
[1563] Spectrophotometer quantification was performed using the above VEGF-R2 except for the change in concentration: FGF-R = 50 nM, ATP = 2 mM, poly (E4Y1) = 15 mM.
[1564] LCK quantitation
[1565] Quantification of the spectrophotometer was carried out using the VEGF-R2 described above except for the change in concentration: LCK = 60 nM, MgCl ₂ = 0 mM, poly (E4Y1) = 20 mM.
[1566] Quantification of CHK-1
[1567] The production of ADP in ATP, a process of phosphorylation in synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK), is catalyzed by the activity of pyruvate kinase and lactate dehydrogenase through the oxidation of NADH using PEP . The oxidation of NADH appeared to be a decrease in absorbance at 340 nm (ε340 = 6.22 cm ^-1 mM ^-1 ) using an HP8452 spectrophotometer. A typical reaction solution was 4 mM PEP; 0.15 mM NADH; LDH / ml 2850 units; PK / ml 16 units; 3 mM DTT; 0.125 mM Syntide-2; In _{50mM TRIS 25mM MgCl 2;; 0.15mM} ATP pH 7.5; And 400 mM NaCl. Quantitation began at 10 nM FL-CHK-1. The K _i value was determined by measuring the enzyme activity through the change in the concentration of the test compound. The data were quantified using enzyme kinetics and Caledagraph software.
[1568] CDK2 / cyclin A and CDK4 / cyclin D quantitation
[1569] Cyclin-dependent kinase activity was measured by enzyme-catalyzed quantification of the time-dependent binding of radioactive phosphoric acid from [ ³² P] in the recombinant segments of the retinoblastroma protein. Unless otherwise stated herpes 10mM (N- [2- hydroxyethyl] piperazine pajin -N '- [2- ethanesulfonic acid]) (pH 7.4), 10mM MgCl 2, 25μM adenosine triphosphate (ATP), 1mg / Ml of ovalbumin, 5 μg / ml leupeptin, 1 mM dithiothreitol, 10 mM β-glycerophosphate, 0.1 mM sodium vanadate, 1 mM sodium fluoride, 2.5 mM ethylene glycol-bis (total amount of 50 μM) containing N, N, N ', N'-tetraacetic acid (EGTA), 2% (v / v) dimethyl sulfoxide and 0.03-0.2 μCi [ ³² P] ATP 96-well plate. The substrate (0.3-0.5 μg) contains the recombinant retinoblastoma protein segment (Rb) (residues 386-928 of the native retino-blastoma protein, a native 106-bp fragment of six histidine residues facilitating purification, kDa &lt; / RTI &gt; protein with a major portion of the phosphorylation site found). The reaction was terminated by adding 250 mM of ethylenediaminetetraacetic acid (EDTA) after 20 minutes, starting from incubating CDK2 (150 nM CDK2 / cyclin A complex) or CDK4 (50 nM CDK4 / cyclin D3 complex) at 30 ° C. The 96-wells were then filtered several times through nitrocellulose membranes to obtain phosphorylated substrates, and the unbound radioactive material was removed by repeated washing with 0.85% phosphoric acid. The radioactive material was quantitated by passing through a nitrocellulose membrane dried in a phosphorimager. Certain K _i values were determined by enzyme activity quantification in the presence of other compound concentrations based on the baseline natural activity values measured in the absence of enzyme. Kinetic parameters (kcat, Km for ATP) were measured for each enzyme under conventional quantitation conditions, which were determined by the initial ratio of ATP concentration. This data is suitable as an equation for competitive inhibition using Callaid graph (Synergy software) or as an equation for the inhibition effect caused by competitive tight coupling using software kinetic (KineTic, BioKin, Ltd.). The K _i readings of the known inhibitory substances CDK4 and CDK2 were consistent with the known IC ₅₀ . The specific activity of CDK4 is the same as standard length cyclin D3 or truncated cyclin D3, which are two complexes produced with very similar K _i values for the selected inhibitor.
[1570] FAK quantitation
[1571] FAK HTS used fluorescence polarization quantification produced by the LJL biological system. The kinase reaction composition is 100 mM HEPES pH 7.5, 10 mM MgCl ₂ , 1 mM DTT, 1 mM ATP, and 1 mg / ml poly Glu-Tyr (4: 1). The reaction was initiated by the addition of 5 nM FAKcd409, and EDTA was added and terminated by the addition of fluoride labeled peptides and anti-phosphotyrosine antibodies provided in the LJL vital system. In this result inhibition was interpreted as an analyzer (LJL) detector.
[1572] TIE-2 spectrophotometric determination quantitative
[1573] The kinase catalysis that produces ADP in ATP carried out by transferring phosphoric acid in any copolymer poly (Glu ₄ Tyr) catalyzes the oxidation of NADH through the activity of pyruvate kinase (PK) and membrane dehydrogenase (LDH) Process. NADH transformed to NAD ⁺ was observed to reduce the absorbance at 340 nm (ε = 6.22 cm ^-1 mM ^-1 ) using a Beckman DU650 spectrophotometer. Generally, the reaction solution consists of 1 mM phosphoenolpyruvate, 0.24 mM ATP, 15 units / ml PK, 15 units / ml LDH in 100 mM of the herpesvirus at pH 7.5. Quantitation was initiated by the addition of 4-12 nM phosphorylated Tie-2 (aa 775-1122). Inhibition (%) was measured in triplicate at the 1 [mu] M level of the inhibitor.
[1574] TIE-2 delphia quantitation
[1575] The production of phosphotyrosine was monitored using the biotinylated p34cdc2 (aa6-20 = KVEKIGEGTYGVV YK) peptide as a substrate. The biotinylated peptides were fixed using a 96 well plate incubator coated with neurotavidin ( ^TM ), and then measured by conjugating the anti-phosphotyrosine-antibody (PY20) with an europium N1 chelate. Generally, the quantitative solution consists of 1 μM biotinylated p34cdc2 peptide, 150 μM ATP, 5 mM MgCl ₂ , 1 mM DTT, 0.01% BSZ, 5% glycerol, 2% DMSO, 25 mM HEPES pH 7.5. The 50 nM TIE-2 intracellular domain was placed in a neutroavidin incubator to start quantification. The kinase reaction is terminated with 50 nM EDTA. After the incubator was washed, the europium antibody was added. The incubator was measured with a standard europium time-resolved setting (ex 340 nm, em 615 nm, delay 400 μsec, window 400 μsec). The inhibition (%) was calculated by subtracting both the control group and the test group from the wells in which the EDTA was added before addition of the enzyme, and plotting the wells in the incubator to which DMSO was added for the DMSO compound.
[1576] HUVEC proliferation quantification
[1577] This quantification determines the efficacy of a test mixture that inhibits growth factor-promoting proliferation of human Umbilical Vein Endothelial Cells (hereinafter "HUVEC"). HUVEC cells (3-4 culture, Clonetics Corp.) were dissolved in a T75 flask containing EGM2 culture medium (Clonetics Corp.). Fresh EGM2 medium was added to the flask after 24 hours. After 4 to 5 days, the cells were cultured in different culture media (F12K medium supplemented with 10% fetal bovine serum (FBS), 60 μg / ml endothelial cell growth supplement (ECGS) and 0.1 mg / ml heparin) . Exponentially growing HUVEC cells were used in subsequent experiments. 100,000 to 12,000 HUVEC cells cultured in the above culture medium were inoculated into 100 占 퐇 of a rich 96-well dish. Cells were adhered in this medium for 24 hours. The medium was removed by aspiration and 105 [mu] l starvation media (F12K + 1% FBS) was added to each well. After 24 hours, only the starvation medium or the vehicle containing 15 μl of the assay reagent dissolved in 1% DMSO was added to each well and the final DMSO concentration was 0.1%. One hour later, KIA medium supplemented with 30 μl of VEGF (30 ng / ml) was added to all the wells except for the control to adjust the final VEGF concentration to 6 ng / ml. After 72 hours, the cells were exposed to MTT (Promega) for 4 hours to quantitate cell proliferation by MTT dye reduction. Pigment reduction was measured with a 96-well spectrophotometer plate reader at an absorbance of 595 lambda after termination by adding a termination solution (manufactured by Promega).
[1578] IC ₅₀ values were measured by A ⁵⁹⁵ curve-fitting reactions at various concentrations of the assay reagent; Seven concentrations, generally separated by 0.5 log, were used as triplet wells for each concentration. One or two concentrations (concentration for one well) was used to detect the compound library plate, and the inhibition (%) was measured by the following equation.
[1579] (%) = (Control group - test group) / (control group - starvation)
[1580] Control group = A ⁵⁹⁵ without treatment of the black reagent with VEGF
[1581] Test group = A ⁵⁹⁵ treated with a black reagent to VEGF
[1582] Starvation = untreated A ^{595 with} both VEGF and assay reagents
[1583] Quantification of cancer cell proliferation (MV522)
[1584] The protocol for determining cell proliferation of cancer cells is similar to that used in HUVEC cells. Two thousand lung cancer cells (obtained from the MV522 line, an American tissue culture collection) were cultured in RPMI1640 growth medium supplemented with 2mM glutamine and 10% FBS. Cells were allowed to attach for one day before addition of the assay reagents and / or vehicle. Cultured cell proliferation was measured by MTT redox quantitation after 72 hours exposure to the assay reagent. Because MV522 cells were not cultured in starvation media, the total length of HEVEC cells was 4 for 4 days.
[1585] Mouse PK Quantification
[1586] Pharmacokinetics (pharmacokinetics) of mice (for example, absorption or release of the body) were analyzed by the following experiment. As the test compound, a 30:70 (PEG 400: acidified H ₂ O) carrier solution or suspension, or 0.5% CMC suspension was used. The compounds were administered into variable oral (po) and abdominal cavities in two separate groups (n = 4) of B6 female mice. Blood samples were obtained via orbital bleeding at the following time points: 0h (pre-dose), 0.5h, 1.0h, 2.0h, and 4.0h and 7.0h. Each sample was centrifuged at 2500 rpm for 5 minutes to obtain a plasma. The test compound was extracted by the plasma organic protein precipitation method. 50 μl of the plasma generated at each bleeding time was reacted with 1.0 ml of acetonitrile, vortexed for 2 minutes, and then spun at 4000 rpm for 15 minutes to precipitate the protein and extracted with the test compound. The acetonitrile supernatant (the extract contained in the test compound) was then placed in a new test tube and evaporated on a hot plate (25 ° C) in the presence of N ₂ gas steam. Dry test To each test tube containing the compound extract, 125 μl of mobile phase (60:40, 0.025M NH ₄ H ₂ PO ₄ + 2.5 ml / l TEA: acetonitrile) was added. The test compound was centrifuged at 4000 rpm for 5 minutes and resuspended in the mobile phase. Each sample was placed in an HPLC vial for test compound analysis with a UV detection Hewlett Packard 1100 series HPLC. 95 [mu] l of each sample was applied to a Phenomenex-Prodigy reversed-phase C-18, 150 x 3.2 mm column and gradient eluted in 45-50% acetonitrile for 5 minutes. The test compound plasma concentration (占 퐂 / ml) was measured in comparison with a standard curve (peak area for concentration (占 퐂 / ml)) obtained from the concentration of the test compound extracted from the plasma sample in the same manner as previously described. Three groups (n = 4) of quality control (0.25 占 퐂 / ml, 1.5 占 퐂 / ml and 7.5 占 퐂 / ml) ensured analytical concentrations according to the standard curves and unknown curves. The standard curve was R2> 0.99 and quality control was all within 10% of the expected value. Quantified test group samples were visualized using Kalidagraph software and their pharmacokinetic parameters were measured with WINNONIN software. Example 1 (a) showed the following results: 0.69 (mouse pK, AUC, ip, ug-h / ml); 0.33 (mouse pK, AUC, po, 占 퐂-h / ml).
[1587] Human liver microsomes (HLM) quantitation
[1588] The metabolism of compounds in human liver microsomes was measured by the following quantitative LC-MS analysis procedure. First, the human liver microspheres (HLM) were thawed and diluted to 5 mg / ml in a cold 100 mM potassium phosphate (KPO ₄ ) buffer solution. An appropriate amount of potassium phosphate buffer, NADH-regeneration solution (containing B-NADP, glucose-6-phosphate, glucose-6-phosphate dehydrogenase and MgCl ₂ ) and HLM were placed in a 13 x 100 mm glass tube, Lt; 0 &gt; C for 10 minutes. Test group compounds (final 5 [mu] M) were added to each tube for the initial reaction, mixed with gentle vortexing, and incubated at 37 [deg.] C. At t = 0, 2 hours, a 250 μl sample was removed from each culture tube to separate into 12 × 75 glass tubes containing 0.05 μM reserpine and 1 ml of ice-cold acetonitrile. Samples were centrifuged at 4000 rpm for 20 minutes to precipitate proteins and salts (Beckman allegra 6KR, S / N ALK98D06, # 634). The supernatant was transferred to a new 12x75 glass tube and concentrated by a Speed-Vac centrifugal vacuum concentrator. Samples were reconstituted in 200 [mu] l 0.1 formic acid / acetonitrile (90/10) and vortexed vigorously for dissolution. The samples were separated into polypropylene microcentrifuge tubes and centrifuged at 14000 xg for 10 minutes (Fisher Micro 14, S / N M0017580). Samples of each test group compound identified by repeating (# 1-3) at each time point (0 and 2 hours) were combined with a single HPLC vial (total 6 samples) insert for LC-MS analysis as follows.
[1589] The combined compound samples were run on a Hewlett-Packard HP1100 diode array HPLC and a Quattro II triple quadruple mass spectrophotometer operating in negative electrospray SIR mode (to specifically probe the molecular ion of each sample compound) Lt; RTI ID = 0.0 &gt; LC-MS &lt; / RTI &gt; Peaks of each test group compound were recorded at each time point. For each compound, the peak area at each time point (n = 3) was an average, in which case the peak area at 2 hours was the average peak area at time point 0 to obtain test group compound residuals remaining at 2 hours It was divided.
[1590] The test results of the compounds using the above various quantities are shown in Table 1 below. In the following Table 1, "% @ " represents the percent inhibition at a given concentration, and " * " values indicate Ki (nM) or inhibition (%) at compound concentrations of 50 nM, ). &Quot; NT " indicates no inhibitory action.
[1591] [Table 1]
[1592]
[1593]
[1594]
[1595]
[1596]
[1597]
[1598] [Table 2]
[1599]
[1600]
[1601] * Values are Ki (μM) or inhibition (%) at a compound concentration of 1 μM, unless otherwise noted. NI indicates no inhibitory action.
[1602] [Table 3]
[1603]
[1604]
[1605]
[1606] * Values are Ki (μM) or inhibition (%) at a compound concentration of 1 μM, unless otherwise noted. NI is the case without inhibition.
[1607] Library Example 1
[1608]
[1609] Three library building blocks (hereinafter referred to as "amine templates"), 6- (3-aminophenoxy) -3-E-styryl-1H-indazole 3-Estyryl-1H-indazole (Y = NH), and 6- (3-aminobenzoyl) Were prepared in Example 7, Example 18 and Example 46, respectively. Solutions of 1 M acid, amine template, o- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate and triethylamine in anhydrous DMF . 105 [mu] l (0.0105 mmol) of another kind of acid was added to each tube in an array of 8x11 culture tubes (10 x 75 mm). N, N ', N', N'-tetramethyluronium tetrafluoroborate was added to the solution after adding 100 μl (0.01 mmol) of an amine solution and 105 μl (0.0105 mmol) (0.0105 mmol) of tetra-methyluronium hexafluorophosphate solution was added thereto, followed by stirring at 50 ° C for 3 hours in a heating block. The reaction mixture was placed in a 96-well incubator with a liquid handler in an amount of 1 ml. Remove the solvent by using a speed Bark ^TM (SpeedVac ^TM) apparatus and the crude product re-dissolved in DMSO to give a final theoretical concentration to 10mM.
[1610] The compounds shown in the table were tested for inhibiting the proliferation of HUVEC at a low concentration of 10 nM and the results are shown in Table A below and were calculated as follows:
[1611] Inhibition (%) = (control-treated group) / (control group-starvation) x100
[1612] In this test condition, when the inhibitory action was 50% or less, no inhibitory action was considered.
[1613] [Table A]
[1614]
[1615]
[1616]
[1617]
[1618]
[1619]
[1620] Library Example 2
[1621] (a) when Y is S in formula (I)
[1622]
[1623] (Y = S) was synthesized in the same manner as in the above Example (1), except that 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3- E- E- 35 (a). A solution of the amine 261 (1.5μmol) and Et ₃ N 0.1393㎕ (1.0μmol) in DMF 15㎕ was partitioned 96-0 incubator. The amine was used the hydrochloride salt, the free base of Et ₃ N 0.4179㎕ (3.0μmol) was added to the glass. A solution of 0.5395 mg (1.0 μmol) of pentafluorophenyl ester in 30 μl of DMF was added to each well, followed by stirring at room temperature for 24 hours. Concentrating the crude product as a Speed Bark ^TM (SpeedVac ^TM) apparatus, and then diluted with DMSO to give a final concentration of 10mM.
[1624] (b) when Y is NH in formula (I)
[1625]
[1626] A solution of the amine 263 (2.0μmol) and Et ₃ N 0.4181㎕ (3.0μmol) in DMF 20㎕ was partitioned 96-0 incubator. The amine was used the hydrochloride salt, the free base of Et ₃ N 0.5575㎕ (4.0μmol) was added to the glass. The following solutions were treated in each well: 0.447 mg (0.75 mmol) of 6- [2-carboxyphenyl-amino] -3-E- [2- (pyridin- 2- yl) ethenyl] was dissolved in DMF (20 mu l), and a solution prepared by dissolving 0.570 mg (1.5 mu mol) of HATU in 10 mu l of DMF was added thereto, followed by stirring at room temperature for 72 hours. Concentrating the crude product as a Speed Bark ^TM (SpeedVac ^TM) apparatus, and then diluted with DMSO to give a final concentration of 10mM.
[1627] The compounds shown in Table B were found to inhibit HUVEC proliferation at low concentrations of 0.5 and 2 at Y = S and the results are shown in Table A below and are calculated as follows:
[1628] Inhibition (%) = (control-treated group) / (control group-starvation) x100
[1629] In this test condition, when the inhibitory action was 50% or less, no inhibitory action was considered.
[1630] [Table B]
[1631]
[1632]
[1633]
[1634]
[1635]
[1636]
[1637]
[1638]
[1639]
[1640]
[1641]
[1642]
[1643]
[1644] Library Example 3
[1645]
[1646] The 0.1M solutions of amine, triethylamine and 4-dimethylaminopyridine were each dissolved in anhydrous DMF and placed in a glovebox. -3-E [2- (pyridin-2-yl) ethenyl] -1H-indazole, tetrabutylammonium salt, and tetrabutylammonium salt prepared in Example 33 (g) - (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate in a glovebox. To each tube in an array of 8x11 culture tubes (10 x 75 mm) in a glove box was added 100 μl (0.01 mmol) of another type of amine solution and tetrabutylammonium 2- {3- (E) -2- (0.01 mmol) of a triethylamine solution, 100 占 퐇 (0.01 mmol) of a 4-dimethylaminopyridine solution, and o- (0.01 mmol) of a solution of (7-azabenzotriazol-1-yl) -N, N, N ', N'- tetra-methyluronium hexafluorophosphate was added. The solution was stirred in a 50 &lt; 0 &gt; C heating block for 3 hours. The reaction mixture was placed in a 96-well incubator with a liquid handler in an amount of 1 ml. Remove the solvent by using a speed Bark ^TM (SpeedVac ^TM) apparatus and the crude product re-dissolved in DMSO to give a final theoretical concentration to 10mM.
[1647] The compounds shown in the table were found to inhibit HUVEC proliferation at a low concentration of 0.5 nM. The results are shown in Table C below and were calculated as follows:
[1648] Inhibition (%) = (control-treated group) / (control group-starvation) x100
[1649] In this test condition, when the inhibitory action was 50% or less, no inhibitory action was considered.
[1650] [Table C]
[1651]
[1652]
[1653]
[1654]
[1655]
[1656]
[1657]
[1658]
[1659]
[1660]
[1661]
[1662]
[1663]
[1664]
[1665]
[1666]
[1667]
[1668]
[1669]
[1670]
[1671]
[1672]
[1673]
[1674]
[1675]
[1676]
[1677] [Table 4]
[1678]
[1679]
[1680]
[1681]
[1682] [Table 5]
[1683]
[1684]
[1685]
[1686]
[1687] * Tested at a concentration of 10 μM.
[1688] The values in bold are the results of the spectrophotometer quantification, and the only values are the DELFIA quantification values.
[1689] Changes in inhibitor concentration in mouse plasma after intraperitoneal and oral administration
[1690] Inhibitor was dissolved in one of the 30% or 60% water-soluble polypropylene glycol solution or 0.5% carboxymethylcellulose carrier in a molar equivalent of HCl dissolved in water. For a dose of 5 or 10 ml / kg, the final concentration was usually 5 mg / ml. For female mice from Taconic (Germantown, NY), the amount of the functional compound is usually 50 or 25 mg / kg body weight. Blood collection was performed by ocular hemorrhage through a puncture in the heart at a final time point of 0.5 or 1.4 hours within 7 hours. Blood was centrifuged to collect the plasma and then fed to -80 ° C until analysis. Samples were prepared by internal standard and sodium hydroxide analysis. After vortexing, ethyl acetate was added and mixed at ambient temperature for 15-20 minutes. After centrifugation, the resulting organic layer was evaporated and reconstituted with acetonitrile and buffer. The sample was then analyzed by HPLC or LC-MS.
[1691] Compound levels were determined on the basis of a standard curve of the known compound plasma concentration of the plasma. Compound concentrations were plotted over time and the concentration curves (AUC ng * hr / ml), optimal concentration (Cmax ng / ml), minimum concentration (Cmin or ng / ml over 7 hours) -life) (T1 / 2hr).
[1692] [Table 6]
[1693]
[1694]
[1695]
[1696] In vivo quantification of retinal vascular growth in newborn rats
[1697] Growth of the retinal vessels of the rat occurs between days 1 and 14 of birth, and this process depends on the activity of VEGF (J. Stone, et al., J. Neurosci., 15, 4738 (1995)). First, it is necessary to demonstrate that VEGF acts as a survival factor acting on the retinal blood vessels during early vascular growth (Alon, et al., Nat. Med., 1, 1024 (1995)). To investigate the efficacy of specific compounds that inhibit the activity of VEGF in vivo, the compounds were formulated into 50% polyethylene glycols with an average molecular weight of 400 Daltons, 50% solution with 300 mM sucrose in deionized water, Zero. In general, 2 μl of the drug solution was added to the vitreous of the eyes of the littermates that were 8 days old or 9 days old. Six days after injecting the drug solution into the vitreous, the pups were sacrificed and the retina was incised freely from the tissue of the remaining eye. The retina was isolated and stained with endothelial cell specific staining (Lutty and McLeod, Arch. Ophthalmol., 110, 267 (1992)). The retina was placed on a glass slide flat surface and examined to confirm the extension of the angiogenesis. Effective compounds inhibited the growth of the retinal vasculature and induced degeneration of all but the largest blood vessels in the retina. The results of vascular degradation were used in vivo to assess the potential efficacy associated with compound retinal vascular growth. Vascular degeneration is categorized into three stages in one stage. One stage is degenerated to about 25% or less, the second stage is about 25-75% degenerated, and the third stage is almost all degenerated (about 75% or more).
[1698] To further measure the degree of degeneration, ADPase-stained images were captured with a digital camera attached to the flat surface of the retina by microscopic analysis. The image of the retina was represented by image analysis software (Image Pro Plus 4.0, Media Cybertics, Silver Spring, MD). The software measures and displays the percentage of retinal areas containing stained blood vessels. This value for the experimental eye was used to compare the contralateral eye with the vehicle in the same animal. Compared with the vehicle-injected eyeballs shown in the sample as " percent degenerated ", it was shown that the area of the blood vessels decreased in the eye that received the compound. Degeneration percentages are the average of 5-8 animal groups.
[1699] Percent degeneration values of 65-70% were typically measured in samples close to total degeneration observed through a microscope. This is due to folds due to the delivery agent used for drug infusion and dye deposits in the wrinkles of the retina. The image analysis software shows that these wrinkles contain these dye deposits. They did not attempt to eliminate these wrinkles because they were deformed from eye to eye. Percent degradation values are thus reported as a result of measurements that are preserved in the correct ranking compounds for which the absolute potential is not underestimated.
[1700] Retinopathy In vivo quantification of retinal vascular growth in premature neonatal rat models
[1701] A second model of VEGF-dependent retinal neovascularization was used to assess the activity of the compounds according to the present invention. (N = 16) in this model (Penn et al., Invest. Ophthalmol. Vis. Sci., 36, 2063 And released. The rats were exposed for 24 hours at 50% oxygen concentration and for 24 hours at 10% oxygen concentration. The mice were repeatedly subjected to the cycle of feeding the hypoxic and hypoxic oxygen alternately after removing air (P14) from the room seven times. The compounds were administered via intravitreal injection in the removed room air, and the rats were sacrificed after 6 days. The retina was isolated, stained and analyzed using the above growth model. The effects were classified into stages described as growth models.
[1702] [Table 7]
[1703]
[1704]
[1705]
[1706]
[1707] Recombinant protein of phosphorylase kinase for quantification
[1708] A subunit (gamma subunit) of the cleaved catalyst of phospholylase kinase (amino acids 1-298) was expressed in E. coli and isolated from the inclusion body. The phosphorylase kinase was then refolded and stored in glycerol at -20 ° C.
[1709] Quantification of phosphorylase kinase
[1710] The subunit of the purified catalyst in a quantitative manner undergoes a phosphorylation reaction with phosphorylase b using ATP labeled with a radioactive isotope. Simply phosphorylase kinase b 1.5mg / ㎖ incubated in the phosphorylase kinase kinase, 50mM herpes (Hepes) and pH7.4, 37 ℃ of 10nM dissolved in 10mM MgCl _2. The reaction was started at 25 캜 or 37 캜 for 15 minutes, starting from the addition of 100 M of ATP. The reaction was terminated and the protein was added with TCA to give a precipitate with a final concentration of 10%. The precipitated proteins were separated on a 96-Millipore MADP NOB filter plate. The filter plate was extensively washed and dried at 20% TCA. Scintillation fluid was then added to the plate and the contained radioisotope was calculated as a Wallac microbeta counter. The inhibition (%) of phospholylase b phosphorylation in ATP in the presence of 10 μM of compound is shown in Table 8 below.
[1711] [Table 8]
[1712]
[1713] Exemplary compounds above may be represented by pharmaceutical formulations by the following common formulation examples.
[1714] Formulation Example 1: Parenteral Composition &lt; RTI ID = 0.0 &gt;
[1715] To prepare a safe parenteral pharmaceutical formulation to be dosed by injection, 100 mg of a water-soluble salt of the compound of formula I above was dissolved in DMSO and mixed with 0.9% sterile saline. The mixture was prepared in the form of a capacity determining unit which can be safely injected by injection.
[1716] Formulation Example 2: Oral formulation
[1717] To provide a pharmaceutical formulation for oral administration, 100 mg of the compound of formula I is mixed with 750 mg of lactose. The mixture was prepared in the form of an oral dosage unit such as a hard gelatin capsule to be safe for oral administration.
[1718] Formulation Example 3: intraocular formulation
[1719] Continuous dosing for administration to eyes To provide a pharmaceutical formulation, an isotonic solution of hyaluronic acid (1.5% concentration) dissolved in phosphate buffer, pH 7.4 neutral to the compound of general formula I, is suspended in the form of a 1% suspension Respectively.
[1720] The above detailed description is intended to illustrate and explain the invention in essence and to show the invention and the preferred embodiment specifically. Through routine experimentation, one of ordinary skill in the art would recognize that obvious variations and modifications are within the spirit of the invention. Accordingly, the present invention is not limited to the claims and their equivalents or those described above.

权利要求:
Claims (17)
[1" claim-type="Currently amended] A compound represented by the following general formula (I):

Wherein R ¹ is a substituted or unsubstituted aryl, heteroaryl or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from the group consisting of substituted or unsubstituted alkyl, , Heterocycloalkyl, aryl, or heteroaryl; And
R ² is a substituted or unsubstituted aryl, heteroaryl or XY wherein Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , alkylidene, C ₁ -C ₈ alkyl), X is optionally substituted Ar (where Ar is aryl), heteroaryl, NH- (alkyl), NH- (cycloalkyl), NH- (heterocycloalkyl) NH (aryl), NH (heteroaryl), NH- (alkoxy) or NH- (dialkylamide);
Or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[2" claim-type="Currently amended] A compound represented by the following general formula I (a):

Wherein R ¹ is a substituted or unsubstituted aryl, heteroaryl or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from the group consisting of substituted or unsubstituted alkyl, , Heterocycloalkyl, aryl, or heteroaryl; And
R ² is a substituted or unsubstituted aryl or Y-Ar, where Y is _{O, S, C = CH 2} , C = O, S = O, SO 2, CH 2, CHCH 2, NH or N- (C ₁ -C ₈ alkyl), Ar is optionally substituted aryl;
Or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[3" claim-type="Currently amended] A compound represented by the following formula II:

Wherein R ¹ is a substituted or unsubstituted aryl, heteroaryl or a group of the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is optionally substituted alkyl, cycloalkyl, heterocyclo Alkyl, aryl, or heteroaryl;
R ⁴ and R ⁷ are each independently selected from the group consisting of hydrogen, OH, halo, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkenyl, aryloxy, thioaryl ), CH ₂ -OH, CH ₂ -O- (C ₁ -C ₈ alkyl), CH ₂ -O-aryl, CH ₂ -S- (C ₁ -C ₈ alkyl) or CH ₂ -S-aryl;
R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, OH, halo, Z-alkyl, Z-aryl or Z-CH ₂ CH═CH ₂ wherein Z is O, S, NH, or CH ₂ , Alkyl and Z-arylalkyl moieties and aryl moieties are each optionally substituted;
Or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[4" claim-type="Currently amended] The method of claim 3,
Wherein R ¹ is a substituted or unsubstituted bicyclic heteroaryl, or CH = CH-R ³ , wherein R ³ is optionally substituted aryl or heteroaryl;
R ⁴ and R ⁷ are each independently hydrogen or C ₁ -C ₈ alkyl; And
Wherein R ⁵ and R ⁶ are each independently halo, Z-alkyl, or Z-CH ₂ CH = CH ₂ , wherein Z is O or S, and alkyl is optionally substituted;
A pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[5" claim-type="Currently amended] A compound represented by the following general formula (III):

Wherein R ¹ is a substituted or unsubstituted aryl or heteroaryl, or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is selected from substituted or unsubstituted alkyl, cycloalkyl , Heterocycloalkyl, aryl, or heteroaryl;
Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N- (C ₁ -C ₈ alkyl);
R ⁸ is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl or aryloxyl;
R ¹⁰ is independently selected from hydrogen, halogen, and lower alkyl;
Or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[6" claim-type="Currently amended] 6. The method of claim 5,
Wherein R ¹ is a non-substituted non-cyclic heteroaryl, or CH = CH-R ^3, where R ³ is aryl or heteroaryl which is unsubstituted or substituted; wherein Y is O, S, C = CH ₂ , C = O, NH or N- (C ₁ -C ₈ alkyl); Wherein R ⁸ is substituted or unsubstituted aryl, heteroaryl, alkyl and alkenyl, and R ¹⁰ is hydrogen or halogen.
A pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[7" claim-type="Currently amended] A compound represented by the following general formula III (a):

Wherein R ¹ is a substituted or unsubstituted aryl or heteroaryl, or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is optionally substituted alkyl, cycloalkyl, Heterocycloalkyl, aryl, or heteroaryl;
Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N- (C ₁ -C ₈ alkyl);
R ⁸ is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl or aryloxyl;
Or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[8" claim-type="Currently amended] 8. The method of claim 7,
Wherein R ¹ is substituted or unsubstituted bicyclic heteroaryl, or CH = CH-R ³ wherein R ³ is substituted or unsubstituted aryl or heteroaryl;
Y is O, S, C = CH ₂ , C = O, NH or N- (C ₁ -C ₈ alkyl); And
Wherein R &lt; ⁸ &gt; is optionally substituted aryl or heteroaryl
A pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[9" claim-type="Currently amended] 8. The method of claim 7,
Wherein R ¹ is CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl group;
Y is O or S; And
Wherein R &lt; ⁸ &gt; is optionally substituted aryl or heteroaryl
A pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[10" claim-type="Currently amended] A compound represented by the following general formula IV:

Wherein R ¹ is a substituted or unsubstituted aryl or heteroaryl, or a group represented by the formula CH = CH-R ³ or CH = NR ³ wherein R ³ is optionally substituted alkyl, cycloalkyl, Heterocycloalkyl, aryl or heteroaryl;
Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N- (C ₁ -C ₈ alkyl);
R ⁹ is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxyl, cycloalkoxyl, NH- (C ₁ -C ₈ alkyl), NH- (Heteroaryl), N = CH- (alkyl), NH (C = O) R ¹¹ , or NH ₂ , wherein R ¹¹ is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, &Lt; / RTI &gt;heteroaryl; And
R ¹⁰ is independently selected from hydrogen, halogen, hydroxy, lower alkyl;
Or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[11" claim-type="Currently amended] 11. The method of claim 10,
R ¹ is a group represented by the formula CH = CH-R ³ , wherein R ³ is substituted or unsubstituted aryl or heteroaryl;
Y is S or NH, and
R &lt; ⁹ &gt; is optionally substituted alkyl, alkoxy or NH- (heteroaryl)
A pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.
[12" claim-type="Currently amended] A pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof.



[13" claim-type="Currently amended] (a) a therapeutically effective amount of a compound according to claim 1, a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof; And
(b) a pharmaceutically acceptable carrier, diluent, or vehicle.
[14" claim-type="Currently amended] Comprising administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in claim 1, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof, wherein the activity of the protein kinase RTI ID = 0.0 &gt; a &lt; / RTI &gt;
[15" claim-type="Currently amended] 15. The method of claim 14, wherein the disease of the mammal is associated with tumor growth, cell proliferation, or angiogenesis.
[16" claim-type="Currently amended] The activity of a protein kinase receptor comprising contacting the effective amount of a compound as defined in claim 1, a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof, with a kinase receptor, How to control.
[17" claim-type="Currently amended] 17. The method of claim 16, wherein the protein kinase receptor is a VEGF receptor.

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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:
1999-07-02|Priority to US14213099P

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1999-07-02|Priority to US60/142,130

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2000-06-30|Application filed by 개리 이. 프라이드만, 아구론 파마슈티컬스, 인크.

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2002-04-13|Publication of KR20020027379A

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2006-01-16|Application granted

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2006-01-16|Publication of KR100529639B1

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2017-09-18|First worldwide family litigation filed

优先权:

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申请号 | 申请日 | 专利标题

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US14213099P| true| 1999-07-02|1999-07-02|

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US60/142,130|1999-07-02|