TW201221131A - Compounds - Google Patents

Abstract

The present invention features compounds of formula (I): and salts thereof, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.

Description

201221131 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel compound suitable for use as an antiviral agent, in particular, a hepatitis C disease main (HCV) inhibitor, a pharmaceutical composition comprising the same, and The use of such compounds to treat or prevent viral infections such as HCV infection and diseases associated with such infections. [Prior Art] φ HCV infection is the main cause of human liver disease worldwide. In the United States, an estimated 4.5 million Americans are chronically infected with HCV. Although only 3% of acute infections are symptomatic, more than 85% of infected individuals develop chronic persistent infections. It has been estimated that the cost of treatment for HCV infection in the United States in 1997 was 546 million US dollars. It is estimated that more than 200 million people worldwide suffer from chronic infections. HCV infection causes 40%-60 of all chronic liver diseases. /. And 3% of all liver movements. In the United States, chronic HCV infection is the cause of all 30% of cirrhosis, end-stage liver disease, and liver cancer. The CDC estimates that the number of deaths due to HCV will increase to a minimum of 38,000 per year by 20 years. Due to the high variability of viral surface antigens, the presence of multiple viral genotypes, and proven immunospecificity, it is unlikely that successful vaccines will be developed in the near future. It has been widely used (X-interferon (alone or in combination with ribavirin) because it is approved for the treatment of chronic HCV infection. However, adverse side effects are usually associated with this treatment: flu-like symptoms, leukopenia (leukopenia) ), thrombocytopenia (thromb〇Cyt〇penia), interferon-induced depression, and ribavirin-induced anemia (Undsay, κ丄 (1997) Hepatology 26 (Supplement 1): 71s_77S)e compared to other 5 154007.doc 201221131 Infections caused by major HCV genotypes, this therapy is still less effective against infections caused by the diquat genotype HCV, which accounts for approximately 75% of all HCV infections in developed markets. However, only about 5% to 8% of patients respond to this treatment (by serum HCV RNA content and normalization of liver enzymes)' and in the treated patients, 50〇/〇-70% Recurrence within a few months after treatment discontinuation. Recently, with the introduction of pegylated interferon, both initial and sustained response rates have been substantially improved, and the combination of Peg_IFN and ribavirin constitutes the highest standard of therapy. However, in patients with genotype 1 and the second related to the side effects of combination therapy in impaired reaction provided for this improved disease management aspects of the opportunity, first in 1989 by molecular cloning identification (Choo, q_l et al. (1989)

Science 244:3 59-3 62), Hepatitis C virus (HCV) is currently widely accepted as a non-A, non-B hepatitis (NANBH) after transfusion (Kuo, G et al. (1989) Science 244:362-364 The most common pathogen. HCV is an enveloped virus containing a positive polarity single-stranded RNA molecule. Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide comprising about 3 amino acids of both structural and non-structural viral proteins. This larger polypeptide is then processed into individual structural and non-structural proteins by a combination of host-encoded proteases and viral-encoding proteases (Rice, C M. (1996) in BN Fields, DM·Knipe and PM Howley (ed.) Virology 2nd Edition 'pp. 931-960; Raven Press, NY). The NS5B protein of HCV (591 amino acids, 65 kDa) (Behrens, SE et al. (1996) EMBO J. 15: 12-22) encodes RNA-dependent RNA polymerase (RdRp) activity and is present in other rna viruses. Typical group in polymerase 154007.doc 201221131

yuan. The necessity of HCV NS5B RdRp activity for the production of infectious progeny virions has been officially demonstrated in chimpanzees (AA Kolykhalov et al. (2000) Journal of Virology, 74(4), pp. 2046-2051). Therefore, predictive inhibition of NS5B RdRp Activity (inhibition of RNA replication) can cure HCV infection. Based on the above, there is a significant need to identify synthetic or biological compounds having the ability to inhibit replication of both the 1 a g genotype and the 1 L genotype of HCV. SUMMARY OF THE INVENTION The present invention provides a benzofuran compound substituted with a boron-containing moiety at the 6th position, a pharmaceutical composition comprising the same, a synthetic method of the same, and a compound for treating and/or preventing a viral infection, such as yellow Viral infections, such as the use of HCV infection. [Embodiment] The present invention provides a compound of the formula (1):

(i) wherein: R1 is one or more substituents independently selected from the group consisting of halogen, Cw alkyl, alkoxy, -CN, -CF3 and OR1G, wherein R1G is optionally substituted by halogen Aryl; 154007.doc 201221131 1^ is hydrogen, thiol, (1!1.6 alkyl or 匸3-6 cycloalkyl) where (111.6 leucoyl or C3-6 cycloalkyl can be optionally substituted by hydroxy; Is (: 1.6 alkyl, (: 3.6 cycloalkyl or (: 1_6 alkoxy; R4 is -S(0)2R5, -C(0)0R5 or -C(0)NR6R7; R5 is c, _6 alkane Or a C3.6 cycloalkyl group; R6 is hydrogen; R7 is hydrogen or CN6 alkyl; X is a Cw alkyl group optionally substituted by Cw alkyl, hydroxy, amine or c3.6 cycloalkyl; R8 is (a) Heterocyclic (Het) optionally substituted with one or more substituents selected from the group consisting of Cw alkyl, hydroxy, halogen, alkoxycarbonyl, hydroxyalkyl, -CF3 and - OCF3; (b) 〇R9B(ORa)(〇Rb); or (c) N(R5)R9B(〇Ra)(〇Rb); R & Rb is hydrogen or Cl·6 alkyl, or as CN6 In the case of an alkyl group, Ra and Rb together with the oxygen atom to which they are attached form a 5- to 8-membered ring; R9 is an alkyl group substituted by C,·6 alkyl as appropriate. Or a pharmaceutically acceptable salt thereof. The term "alkyl" refers to a straight or branched hydrocarbon chain containing a specified number of carbon atoms. For example, Ci-alkyl means at least one and up to 6 carbons. A straight or branched alkyl group of an atom. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl. , #propyl, tert-butyl, and 1,1-dimercaptopropyl. 154007.doc 201221131 However, when a certain moiety is defined such that the alkyl carries a substituent, those skilled in the art will understand the alkyl group according to the context. The alkyl group may be included, for example, a methylene group (CH2), an ethylidene group (CH2CH2), and a propyl group (CH2CH2CH2). The term "alkylene group" means a straight or branched chain saturated hydrocarbon linking group. Examples include methylene (ch2), ethyl (CH2CH2) and propyl (CH2CH2CH2).

The term "alkoxy" refers to a straight or branched chain alkoxy group containing the specified number of carbon atoms. By way of example, Cl.6 alkoxy means a straight or branched alkoxy group containing at least up to at most one carbon atom. Examples of "alkoxy" as used herein include, but are not limited to, decyloxy, ethoxy, propoxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2. Amidino-4-yloxy, 2-mercaptopropen-2-oxy, pentyloxy and hexyloxy. The term "IS" or "Southern" refers to fluorine (gas, F), gas (chlorine, C1), desert (Mo, Br) or iodine (moth, atom. The term "hydroxy" refers to The term "cycloalkyl" refers to a saturated cyclic group containing from 3 to 6 carbon ring atoms (unless otherwise stated). Examples include cyclopropyl, cyclobutyl, cyclopentane. Base and cyclohexyl. The term "heterocyclic" refers to a 3 to 7 membered monocyclic heterocyclic ring or a 8 to 2 membered bicyclic ring system wherein any ring is saturated, partially saturated or unsaturated, if a single U is if Benzene fused or snail-fused, as appropriate. Each hybrid consists of one or more carbon atoms, and - a butterfly atom and - or more oxygen atoms, a shed atom, a g ® 〇 _ gas atom And - a nitrogen atom; or - a butterfly atom, or a Xi atom of the atom. The heterogeneous clothing can be attached to any carbon or N original I54007.doc 201221131 'There is a condition that the connection leads to a stable structure. When a ring system has a substituent, it is understood that the substituent may be attached to any atom in the ring, with the proviso that a stable chemical structure is produced. Is an oxaborolanyl, benzoxaborolyl, and dihyrobenzoxaborolyl. The present invention provides a compound of formula (I), wherein R1 is one or more substituents independently selected from the group consisting of halogen, Cu alkyl, alkoxy, -CN and -CF3; ^R2 is argon, hydroxy, Cw alkyl or C3-6 ring An alkyl group, wherein a Cl.6 alkyl group or a C3.6 cycloalkyl group may be optionally substituted with a hydroxy group; ... is 匚 "alkyl, C3-6 cycloalkyl or Cw alkoxy; R4 is -s(o)2r5, -c(o)or5 or -c(o)nr6r7 ; «5 is (:1.6 alkyl or (:3_6 cycloalkyl; R6 is hydrogen; R7 is hydrogen or Ci.6 alkyl; X is optionally Cw) An alkyl group, a hydroxyl group, an amine group or a (3-6 cycloalkyl substituted RuC!-6 alkylene group; R8 is (a) optionally substituted by one or more substituents independently selected from the group consisting of: Heterocyclic ring: Ci_6 alkyl and hydroxy; (b) 〇R9B(〇Ra)(〇Rb) ; ^ (c) N(R5)R9B(〇Ra)(〇Rb);

Ra&Rb is hydrogen; R9 is an alkylene group substituted by Ci.6 alkyl group as the case may be; 154007.doc

S 201221131 or a pharmaceutically acceptable salt thereof. The invention also provides a compound of formula (I), wherein: R1 is one or more substituents independently selected from the group consisting of: -, -CF3 and -R10, wherein r10 is optionally substituted by halogen R2 is a Ci.6 alkyl group optionally substituted by a hydroxyl group; r3 is a 〇3_6 cycloalkyl group; R4 is -s(o)2r5 φ 尺5 is (^.6 alkyl; x is optionally Ck alkane Substituted (: 丨_6 alkylene; R8 is (a) optionally substituted by one or more heterocyclic rings independently selected from the group consisting of Cw alkyl, hydroxy, halogen, alkane Oxyl group, hydroxyalkyl, -CF3 and -OCF3; or (b) 0R9B(0Ra)(0Rb);

Ra&Rb is hydrogen; • r9 is an alkylene group optionally substituted by a Cu alkyl group; or a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula (la)

Wherein: R is C1-6 alkyl, C3-6 cycloalkyl or Ci-6 alkoxy; 154007.doc -9- 201221131 r5 is c -6 alkyl or c3_6 cycloalkyl; X is optionally Cl. 6 alkyl, hydroxy, amine or c3 6 cycloalkyl substituted Cw alkyl; R8 is (a) optionally substituted by one or more substituents independently selected from the group consisting of Department: Cl6 alkyl, recorded, (d), aerobic acid group, hydroxyalkyl group, -CF3 and -〇Cf3; (b) 〇R9B(〇Ra)(〇Rb); or (c) N(R5)R9B( 〇Ra)(ORb); R and R are hydrogen or CN6 alkyl, or when 6 is alkyl, Ra&Rb together with the oxygen atom to which it is attached form a 5 to 8 membered ring; R9 is optionally C a 6 alkyl-substituted alkylene group; or a pharmaceutically acceptable salt thereof. The present invention provides a compound of the formula (la), wherein: R is (^.6 alkyl, (:3. 6 cycloalkyl or Cw alkoxy; R is Cw or 3.6 cyclyl; X is optionally) a C 1-6 alkylene group substituted by a Cw alkyl group, a hydroxyl group, an amine group or a c3-6 cycloalkyl group; R8 is (a) optionally substituted by one or more substituents independently selected from the group consisting of: Heterocyclic ring: CN6 alkyl and hydroxy; (b) 〇R9B(〇Ra)(〇Rb); or (c) N(R5)R9B(ORa)(〇Rb);

Ra&Rb is hydrogen; 154007.doc 201221131 R9 is an alkylene group substituted with a C 6 alkyl group as appropriate; or a pharmaceutically acceptable salt thereof. The present invention provides a compound of the formula (1) according to any of the above descriptions, wherein the rule 1 is one or two substituents selected from the group consisting of ruthenium. The invention provides a compound of formula (1) according to any of the above, wherein R2 is c1-6 alkyl. The present invention provides a compound of formula (I) or formula (la) according to any of the above descriptions, wherein R is a C3-6 ring hospital. The present invention provides a compound of formula (1) according to any of the above, wherein Μ is -s(o)2r5 〇 The invention provides a compound of formula (I) or formula (la) according to any of the above, wherein R8 is one or more The heterocyclic ring is independently selected from the group consisting of a substituent of the group consisting of: c -6 alkyl, a thiol, a halogen, an alkoxy group, a hydroxyalkyl group, -CF3 and -〇cf3. The present invention provides a compound of formula (I) or formula (la) according to any of the above descriptions, wherein R8 is a heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: Ci6 alkane Base and hydroxyl group. The present invention provides a compound of formula (I) or formula (la) according to any of the above descriptions, wherein the rule 8 is 〇R9B(〇Ra)(〇Rb). The present invention provides a compound of formula (1) or formula (Ia) according to any of the above, wherein R8 is N(R5)R9B(〇Ra)(〇Rb). The present invention provides a compound of formula (1) or formula (Ia) according to any of the above, wherein X is a fluorenyl group. The present invention also provides a compound selected from the group consisting of: 154007.doc •11 · 201221131 base))曱[({2-[{2-(4-fluorophenyl)·3_[(methylamino)carbonyl)] 5-[(1methylethoxy)-1-benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy]S-acid; & 5-cyclopropyl-2 -(4-fluorophenyl)_6_[[(1_hydroxy_13_dihydro-2, ι, oxaborane-6-yl)indolyl](sulfonyl)amino]_N _Methyl·ι = gasfuran-3-carboxamide; and 5-cyclopropyl-2-(4-fluorophenyl•hydroxy_13_dihydro-2, ι^heteroborolane- 4-yl) fluorenyl κ sulfonyl)amino]_N_indenyl, 1 = oxoanthran-3-amine; stupid 5_cyclopropyl_2_(4-fluorophenyl)_6- [[(ι·hydroxy_ι,3_dihydro-2, oxime, stupid] heterobora-5-yl) fluorenyl](nonylsulfonyl)amino]]N•methyl 1 Furan-3-carboxamide; and 2-(4-fluorophenyl)-6-[[(1-hydroxy-ι, 3-dihydro-2,1-stupidin, nucleus Ethyl: pentyl-4-yl)methyl](indolyl)amino]_ν·indenyl_5-[(ι·i-yloxy)-1-benzofuran-3-carboxamide ; 2-(4_fluorophenyl)-6·[[(卜经基{ 3-dihydro-2, benzophenanthene, heterocyclopentene-5-yl)methyl](anthracenyl)amino]-indole-indenyl-5-[(1-methyl-ethyl Oxy]-1-benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy- oxime, 2-oxo boron flavor _ 4-(yl)methyl](methyl hydrazino)amino]-indole-methyl-1-benzobenzoin _3_cartoamine. (+)-5-cyclopropyl-2-(4· Fluorophenyl)-6-[[(2-hydroxy-oxime, 2·oxysulphonic 4-yl)methyl](methylsulfonyl)amino]-indole-methyl-1-benzofuran_3 (-)-5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy_1,2_oxadole-4-yl) fluorenyl]( Further thiol)amino]-N-methyl-1-benzofuran·3_decylamine; 154007.doc -12· 201221131 « [({3-[{5-cyclopropyl-2-( 4-fluorophenyl)-3-[(indenyl)carbonyl]-i-benzofuran-6-yl}(methylsulfonyl)amino]propyl}oxy)methyl]-acid; 3-({2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1· benzopyran-6-yl} Amino]ethyloxy)propyl]hydroxyl [ [{2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl] -1- benzofuran-6-yl}(nonylsulfonyl)amine ]ethyl}oxy)methyl]ethanoic acid; {3-[{2-[{2-(4-fluorophenyl)·3·[(methylamino)carbonyl]-5-[(1·A Ethyl yl)oxy]-benzofuran-6-yl}(methylsulfonyl)amino]ethyl}(indenyl)amino]propyl hydrazide; 5-ethyl-2-(4 -fluorophenyl)-6-[[(2-yl-1,2-oxyxy-4-yl)methyl](nonylsulfonyl)amino]-indole/indenyl-1-benzene And furan-3-carboxamide; 2-(4-d-phenylphenyl)-6-[[(2-pyridyl-1,2-oxy ox-4-yl)methyl](methyl sulfhydryl) Amino]mercapto-5-(1-methylethyl)-1-benzofuran-3-amine; 2-(4-fluorophenyl)-6-[[(2-hydroxy-1, 2-oxomino-4-yl)methyl](methylsulfonyl)amino]-iV,5-dimethyl-1-benzofuran-3-carboxamide; Φ 5_cyclopropyl- 2-(4-Fluorophenyl)-6-(N-((2-hydroxy-1,2-oxoboroin-4-yl)methyl)indolyl]-nonylamino)-N-methylbenzo吱3_曱醢amine; 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-)-yl-1,2-oxo-ami-4-yl Ethyl)nonylsulfonylamino)-N-mercaptobenzofuran-3-indolylamine; 5-leafyl- 2-(4-carboyl)-6-[[(2· Base-1,2-oxygen shed 山山-5-yl) fluorenyl](anthracenyl)amine Alkyl] fluorenyl-1-bromo-2-pyran-3-amine; 5-cyclopropyl-2-(4-1phenyl)-6-[[2-(2-amino-1,2-) Oxygen-flavor-5-yl)ethyl](sulfonyl)amino]mercapto-1-benzopyran-3-nonanamine; [({(2))-3-[{5-哀 propyl-2-(4-fluorophenyl)-3-[(methylamino) benzyl]-1_ 154007.doc -13- 201221131 benzofuran-6-yl}(methylsulfonyl)amine ]]-2-methylpropyl}oxy)methyl]phosphonate; [({(2*S)-3-[{5-cyclopropyl-2-(4-fluorophenyl)_3_[ (Amidino) benzyl] small benzofuran-6-yl} (amino)amino]-2-mercaptopropyl}oxy)methyl]-acid; 5-cyclopropyl- 2-(4-Fluorophenyl)-6-(N-((2-carbo-l,2-oxygen ox-5-yl) fluorenyl) fluorenyl) anthranyl)-N-methylbenzene And biting _3_carbamamine; 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)_6-(N-((2-hydroxy-1,2-oxoboron-4) -yl)methyl)methyl-nonylamino)benzofuran_3_formamide; 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-) 1,2-oxoboropurin-4-yl) fluorenyl)ethylsulfonylamino)-N-methylbenzofuran-3-decylamine; 5-cyclopropyl-2-(4.fluorobenzene) Base)-6-[[(2-hydroxy-2,5-dihydro-1,2-oxygen) Boronheapto-4-yl)methyl](methylsulfonyl)amino]methyl-1-benzofuran-3-decylamine; 5-cyclopropyl-2-(4-fluoro Phenyl)-6-(N-((2-hydroxy-1,2-oxaborin-4-yl)indolyl)propan-2-ylsulfonylamino)-N-mercaptobenzofuran-3 - decylamine; 1^,5-dicyclopropyl-2-(4-phenylphenyl)-6-(1'11-((2-yl-1,2-oxy ox-4-yl) ) fluorenyl)methylsulfonylamino)benzofuran-3-decylamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1), 2-oxoboro-4-yl)methyl)methylsulfonylamino)benzofuran-3-carboxamide; 5-cyclopropyl-6-(N-((2-hydroxy-1,2) -oxyboroin-4-yl)methyl)methylsulfonylamino)-N-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-decylamine; -(4-Phenylphenyl)-5-cyclopropyl-6-(N-((2-hydroxy-1,2-oxoindole-4-yl)methyl)methylsulfonylamino)-N -methylbenzofuran-3-carboxamide; 201221131 5-cyclopropyl-2-(3-fluorophenyl)_6·(Ν-((2-hydroxy-1,2-oxo boron taste-4- Methyl)methylsulfonylamino)_N_mercaptobenzofuran_3_formamide; 5-cyclopropyl-2-(3-fluorophenyl)_6-(N-((l- Hydroxy-1,3-dihydrobenzene And [c][l,2]oxaborol-5-yl)methyl)decylsulfonylaminomethylbenzofuran-3-indolyl; 2-(4-phenylphenyl )_5_cyclopropyl_6_(#·((1-hydroxy-13-dihydrobenzo[CH7,2]oxaside heterocyclopenten-5-yl)indolyl)nonylsulfonylamino) -Ν-mercaptobenzophenanol -3 -carbamamine; 5-cyclopropyl-2-(3,4-difluorophenyl)-6-(Ν-((1-hydroxy-1, 3_Dihydro-p-[c][l,2]oxa-heterocyclopentene_5-yl)methyl)methylsulfonylamino-mercaptobenzoxanol-3 -cartoamine; 5-cyclopropyl-6-(Ν-((1-hydroxy-i}dihydro acyl[c][1,2]oxaborol-5-yl)methyl)indolylsulfonate Amino)-N-mercapto-2-(4-(trifluoromethyl)benyl)benzocarbonyl-3-carbamidamine; 5-cyclopropyl-2-(4-(4-fluoro) Phenoxy)phenyl)hydroxyindole,3•dihydrobenzo[c;][l,2]oxapteroyl-5-yl)methyl)indolylsulfonylamino)_N -Methylbenzopyrene _3_carbamamine; (±)-5-% propyl-2-(4-fluorophenyl)_6_[[(ι_hydroxy·3_曱基4,3二Nitrogen _ benzoxoxaborole _5-yl)methyl](methylsulfonyl)amino]-glycosyl-1-benzofuran-3-methyl Amine;

Stupid and furan-3-decylamine;

154007.doc -15- 201221131 Side-heterocyclopentene-5-yl)indolyl)methylsulfonylamino)_2·(4-fluorophenyl)-N-methylbenzf-m-am-3 Amine; 5-cyclopropyl-2-(4-fluorophenyl)_6·[{[(35«)_ hydroxy 3-indolyl-1}3_dihydro-2,1-benzoxazepine Boron heterocyclopentene-5-yl]methylsulfonyl)aminomethyl-benzo-3-indenyl-3-cartoamine; 5-cyclopropyl-2-(4-fluorophenyl) _6_[{[(3幻_卜hydroxy_3_曱yl_13-dihydro-2,1-benzoxoxaborole_5•yl)methyl hydrazine) ]_ fluorenyl-1-benzofuran_3_decylamine; 5·cyclopropyl-2-(4-fluorophenyl)_6_(iV-(1_(1•hydroxy-indole,3·dihydrobenzene) And [c][human 2]oxo-p-heterocyclopentene_5-yl)ethyl)methylsulfonylamino)-#·methylbenzofuran-3-formamide; 5-cyclopropyl -2-(4-(4-fluorophenoxy)phenyl)_6·(Ν·((2-hydroxy), 2 oxaborazo-4-yl)methyl)nonylsulfonylamino)_Ν _methylbenzofuran_3_decylamine; 5_cyclopropyl_6-(沁((6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][l,2]oxy) Heteroborolen-5-yl)fluorenyl)methylsulfonylamino)_2_(4-fluorophenylmethylbenzene And furan-3-carboxamide; 5_cyclopropyl-2-(4-fluorophenyl)-6-(iV-(2-(l-hydroxy-1,3-dihydrobenzo[C]U) , 2] oxaborole-5-yl)ethyl)methylsulfonylamino) 沁 沁 methyl benzo kefu-3 - an amine; 5-{[{5-cyclopropyl _2_(4-fluorophenyl)·3_[(methylamino)carbonyl]_丨_benzofuran-6-yl}(methylsulfonyl)amino]mercapto}-1-hydroxy-1,3 - dihydro-2,1-benzoxaborole-7·methyl decanoate; S cyclopropyl-2-(4-fluorophenyl)_6_[{[1_hydroxy_7_(hydroxyl)曱基)13·二154007.doc 55 -16 - 201221131 Hydrogen 2,1""Bist and oxaborole-5-yl]methyl}(methylsulfonyl)amine, N-decyl -1-benzofuran_3_carbamamine; 6 (#_((7-gas hydroxy·丨,3 dihydrobenzo[c][;,2]oxaborol-5)) Methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-(methyl) benzofuran-3-carboxamide;

5-cyclopropyl·2·(4-fluorophenyl)-6-[[(1-hydroxy-3,4-dihydro-l"-2,l-benzo-oxaborane-6-- Methyl](methylsulfonyl)amino]mercaptofuranfuran-3-indoleamine; 5_%propyl-^ethyl-6_[[(7-fluoro-1-hydroxy-1,3) -Dihydro-2,1-stupidoxy shed #ί展戊妇_5_基) 曱基](methyl-4-indenyl)amino]_2-(4-oxophenyl)]_benzofuran- 3-decylamine; 5·% propylfluorophenyl)-6-(ΛΓ-(2-(1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaboron) Alkenyl-3-yl)ethyl)methylsulfonylamino hydrazinyl hydrazin-3-ylamine; 5_ $propyl propyl-2-(4.fluorophenyl)-6-〇¥- ((1-Hydroxy-1,3-dihydrobenzo[c][l'2]oxalolecyclopentene_3_yl)methyl)methylsulfonylaminomethylbenzofuran -3- ketoamine; 5- 哀 propyl -2- (4- 笨 基)_6_(jv_((1_hydroxy·7_(trifluoromethyl}1,3_dihydrobenzo[c][ i,2]oxachocyclopentene_5_yl)indenyl)nonylsulfonylamino) 曱 曱 笨 呋 呋 呋 呋 呋 呋 呋 呋 呋 3 3 3 3 3 3 3 3 5 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 Fluoryl)-6-[{2-[(3*S)-l-trans-yl-1,3-dihydro-2,1-benzoxanium]-decene-3·yl]ethyl }( Amino group] good methyl group _ 1 - stupid and 0 phoran-3 - an amine; 5-cyclopropyl-2-(4-fluorophenyl)_6...(10) phantom] II atmosphere-2,1 _ 154007.doc •17- 201221131 Benzooxaborole 1-benzocypanol-3-carboxene, 3-yl]ethyl}(sulfonyl)amine Methyl hydrazide; benzyl 5-dipropyl-2-(4-indolyl)·6 [({1 hydroxy_7 [(trifluoromethyl)oxy]] U 虱·2'1 _Benoxa (4)cyclopentene-5-yl}methyl) (methyl sulfhydryl) amino] 4 methyl + stupid and acetyl 3-methyl decylamine; ) 6 · (Ν-(2· (7·• gas dihydrobenzo[[:][1,2]oxy_heterocyclic pentyl-3-yl)ethyl)methylsulfonylamino)_5_cyclopropyl_2_(4 benzene Methylbenzofuran-3-carboxamide; 5-cyclopropyl-6·[[(7-fluoro-1-hydroxy-1,3-dihydro-2,1-benzoxazole heterocycle) Pentene-5-yl)methyl](nonylsulfonyl)aminodibu 2_(4-fluorophenyl)-indole_benzotrile-3-cartoamine; 5-cyclopropyl-6·( #-(2-(7-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][l2]oxazacyclopenta-3-yl)ethyl)indolyl hydrazino) -2-(4-Denylphenyl)_n_methyl benzofuran-3-carboxamide; 6- [[2-(6-qi-1- Hydroxy-1,3-dihydro-2,1-benzooxaborolane-3-(yl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- Fluorophenyl•methyl-1-benzofuran-3-carboxamide; 6·[[2-(5-chloro-1-hydroxy-1,3-dihydro-2,1-benzoxylene boron) Heterocyclic pentylene-3-yl)ethyl](indolyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)·#• fluorenyl 1-benzofuran-3-methyl Indoleamine; 6-[[2-(4-chloro-1-alkyl-1,3-dihydro-2,1-benzoxaborolanyl)ethyl](methylsulfonyl) Amino]-5-cyclopropyl-2-(4-fluorophenylindolyl)benzofuran-3-indolylamine; 5-cyclopropyl-2-(4-fluorophenyl)-6- (#-(2-(1-hydroxy-3,4-dihydro-1Hbenzene 154007.doc -18- 201221131 and [c][l,2]oxaborohexen-3-yl)ethyl Methylsulfonylamino)-#-mercaptobenzofuran-3-carboxamide; 5-cyclopropyl-6-(Ν-(2-(4-fluoro-1-hydroxy-1,3-) Dihydrobenzo[c][i,2]oxaborol-3-yl)ethyl)methylsulfonylamino)-2-(4-fluorophenyl)-N-methylbenzene And furan-3 -decylamine; 5-cyclopropyl-6-(N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][i,2]oxa) Cyclopent-3-yl)ethyl)醯amino)-2-(4-phenylphenyl)_N_methyl benzofuran-3-indolylamine; 5-cyclopropyl-6-(N-(2-(6-fluoro-1-hydroxyl) -1,3-Dihydrobenzo[c][i,2]oxadolidene-3-yl)ethyl)methylsulfonylamino)-2-(4-fluorophenyl)· Ν _ 曱 benzobenzoindole-3--3-decalamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[(4R)-2-hydroxy-1, oxyborate _ 4_yl]methyl}(methylsulfonyl)amino] Ν 曱 · ^ benzobenzofuran _3_ mercaptoamine; and a pharmaceutically acceptable salt thereof. The present invention also provides a compound selected from the group consisting of underarms: 5-cyclopropyl-6-(Ν-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2 Oxaborolide-5-yl)fluorenyl)nonylsulfonylamino)-2-(4-fluorophenyl)·Ν_ψylbenzopyran-3-formamide;丨,3_Dihydrobenzo[c][7,2]oxaboron-5 (meth)yl)methyl)indolyl)-5-cyclopropyl-2-(4-fluorobenzene Base)_々_methylbenzopyran-3-cartotenamine; 5-cyclopropyl «4-fluorophenyl)_6_[{2_[(3iS>1_经基_13_二氢卜笨和Oxa-heterocyclic pentylene _3_yl]ethyl}(anthracene)amino]methyl ketone _ 154007.doc •19- 201221131 ^benzofuran-3-decylamine; 5-cyclopropyl -6-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaborol-3-yl)ethyl)- Alkylsulfonylamino)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide; and a pharmaceutically acceptable salt thereof. The present invention provides a group selected from the group consisting of Compound: (+)-5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2·hydroxy·1,2-oxaboron-4-yl) fluorenyl] Amidino)-indenyl-mercapto-1-benzofuran _3·carbamamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-(Ν-(2-(2-propionyl-1,2-oxoxy-4-yl)) Ethyl)methylcansamine)-fluorenyl-mercaptofuran-3-carboxamide; and pharmaceutically acceptable salts thereof. The present invention provides as [({2-[{5-cyclopropane") -yl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(nonylsulfonyl)amino]ethyloxy)methyl a compound of formula (I) or a pharmaceutically acceptable salt thereof. Certain compounds of formula (I) and (la) may exist in stereoisomeric forms (eg, they may contain one or more asymmetric carbon atoms) Individual stereoisomers (enantiomers and diastereomers) and mixtures of such stereoisomers are included within the scope of the invention. The invention also extends to compounds of formula (1) and formula (Ia) Configurational isomers and any geometric (cis and/or trans) isomers of such compounds. Racemic compounds can be separated or prepared using preparative HPLC and columns with a palmitic stationary phase. Methods known to those skilled in the art are resolved to produce individual enantiomers. The palmitic intermediate compound can be resolved and used to prepare the palm compound of the present invention. The diastereomeric mixture of the compound of formula (I) and formula (I a) can be known according to the literature 154007.doc •20· 201221131 A The method is isolated, for example, by preparative HPLC or by chromatographic purification. The racemic compound can be isolated using preparative ilPLC and a column having a palmitic solid phase or by methods known to those skilled in the art. Parsing to produce individual enantiomers. In addition, the palmitic intermediate compound can be resolved and used to prepare the antagonistic compounds of the present invention. It should be understood that the compounds of formula (I) and formula (Ia) are in addition to the forms shown in the formula.

It may exist in tautomeric forms, and such tautomeric forms are also included within the scope of the invention. It will also be appreciated that the compounds of the invention and mixtures thereof in the form of the alpha form are within the scope of the invention. The invention also provides a compound of formula (1) or formula (Ia) or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" means that the compound is suitable for use in medicine. The term "pharmaceutically acceptable" in relation to the use of ingredients which may be included in a pharmaceutical composition for administration to a patient means that the compound may be in association with any other ingredient present in the pharmaceutical composition. It is acceptable in the sense that it is harmless to its recipients. Salts of the compounds of formula (1) or formula (Ia) which are suitable for use in medicine are those in which the counter ions are pharmaceutically acceptable. However, a salt having a non-pharmaceutically acceptable counterion is useful in the present invention, for example, in the preparation of other compounds of the formula (1) or (la) and pharmaceutically acceptable salts thereof. For the use in medicine, the melon of formula (1) or formula (10) should be physiologically (i.e., pharmaceutically acceptable) acceptable. The compound of the present invention may be in the form of a free test thereof or a pharmaceutically acceptable compound, a pharmaceutically acceptable solvate or a pharmaceutically acceptable vinegar of the formula 154007.doc 21 201221131. Pharmaceutically acceptable salt complexes are also included in the present invention. The invention also encompasses pharmaceutically acceptable salts of the compounds of formula (I) and formula (la). As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits the lowest undesired toxic effects. For a review of suitable salts, see Berge et al, j. Pharm Sci, 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Such pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in the form of the free acid or free base with a suitable reagent or acid. The salt may be precipitated from the solution and collected by filtration or may be recovered by evaporation of the solvent. Thus, according to another aspect, the present invention provides a pharmaceutically acceptable salt of the compound of formula (1) or (4) and its examples. In certain embodiments, the compounds of formula (1) and formula (Ia) may contain an acidity. a functional group, thus being capable of forming a pharmaceutically acceptable test addition salt by treatment with a suitable test. The pharmaceutically acceptable test addition salt process can be carried out in a suitable solvent such as an organic solvent, as appropriate. A compound of formula (1) or formula (10) is reacted with a suitable base to produce a base addition salt which can be isolated, for example, by crystallization and filtration. Pharmaceutically acceptable base salts include ammonium salts (eg, or four (four)) a metal salt such as a metal or soil metal salt (such as a gas oxide, m-g); an organic amine such as a heart [also known as tromethamine or hydroxymethylaminomethane], ethanolamine, Diethylamine, triethanolamine, biliary test, isopropylamine, dicyclohexylamine or sense methyl s-glucosamine); cations 154007.doc -22- 201221131 s-amino acids (such as arginine, lysine Or histidine) or a base of insoluble salts (such as procaine) Or benzathine. In certain embodiments, the compound of formula (I) or formula (la) may contain a basic functional group and thus may be capable of forming a pharmaceutically acceptable acid by treatment with a suitable acid. Addition salts. Pharmaceutically acceptable acid addition salts may be prepared by a compound of formula (I) or formula (la) and a suitable strong mineral acid (such as hydrobromic acid, hydrochloric acid), as appropriate, in a suitable solvent such as an organic solvent. , sulfuric acid, wall acid, acid or peroxyacid) or suitable for strong organic acids (such as sulfonic acid [such as p-toluenesulfonic acid, benzenesulfonic acid, sulphuric acid, sulphuric acid, 2-ionyl ketone Acid, naphthoic acid (such as 2-naphthoic acid), acid (such as acetic acid, propionic acid, butyric acid, cis-succinic acid, benzoic acid, salicylic acid or succinic acid), anion Amino acids (such as glutamic acid or aspartic acid), transbasic acids (such as citric acid, lactic acid, tartaric acid or glycolic acid), fatty acids (such as caproic acid, caprylic acid, capric acid, oleic acid or stearic acid) Or an acid of an insoluble salt (such as a bishydroxy acid or a resin acid [e.g., polystyrene sulfonate])) is reacted to produce, for example, by Crystallized and filtered to form a salt which is separated. In one embodiment, the pharmaceutically acceptable acid addition salt of the compound of formula (I) or formula (Ia) is a salt of a strong acid such as hydrobromide or hydrochloric acid. Salt, hydroiodide, sulfate, nitrate, peroxy acid salt, phosphate, para-sulfonate, benzoate or methyl sulphate. Those skilled in the art should be aware of organic acid and / or an organic phthalate thereof may form an "ate" mis-addition salt, such as an organoborate mis-addition salt, in the presence of a suitable nucleophilic miscible reagent. Suitable nucleophilic mismatch reagents include, but are not limited to, An example of an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide) or an I compound "organic boronic acid mis-addition salt" and its preparation method will be known from 154007.doc -23 201221131. For example, one such suitable organic boronic acid mis-addition salt is an alkali metal trihydroxyorgano borate such as sodium trihydroxyorganoborate. For example, the sodium trihydroxyarylborate mis-addition salt and the sodium trihydroxyalkylborate mis-addition salt and the preparation method thereof are described in Cammidge, Α·Ν· et al.

Org. Lett·, 2006, 8, 4071-4074. Pharmaceutically acceptable "acid" mis-addition salts as described herein are also contemplated as being within the scope of the invention. The present invention provides a pharmaceutically acceptable salt for a compound of formula (I) or formula (la) 'including an acid salt' such as sodium, unloading, dancing, lock, Syrian, tetraburning and tris (hypoxic acid amine) a saponin and its analogues; or a monobasic or dibasic salt with a suitable acid such as an organic carboxylic acid such as acetic acid, lactic acid, tartaric acid, apple Acid, isethionic acid, lactobionic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzoic acid and p-toluenesulfonic acid and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and amine sulfonate Acids and their analogues. The present invention provides a pharmaceutically acceptable base addition salt of a compound of formula (I) or formula (la), which is a potent test, such as sodium, lysine, methyl glucosamine, potassium, choline, A salt of arginine (such as L_arginine) or magnesium. In another aspect, the salt is sodium, lysine, ammonium, N-methyl-D-glucosamine, guanidine, biliary or arginine (e.g., L_arginine) salt. Other non-pharmaceutically acceptable salts such as oxalate can be used, for example, in the separation of the compounds of formula (la) and are included within the scope of the invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (1) and formula (Ia). The salt of the compound of the formula (I) and the formula (la) can be, for example, in a solution state by subjecting the free acid calculated in the appropriate solvent to the free acid of the calculation of the free acid of the appropriate test (IV). The free acid and the appropriate acid of the compound of the formula (1) or the formula (la) are both in a solution state. Solvents suitable for dissolving the free acid compound of formula (1) or formula (Ia) include, for example, alcohols such as isopropanol; _, such as acetone; acetonitrile or methyl stupid. If you want to

The solvent may be included in the solvent, and the solvent used may include C-, methanol or water. The salt of the compound of the formula (1) or the formula (la) can be isolated as a solid from the solution obtained as above by a conventional means. For example, the amorphous salt can be obtained by precipitating from a liquid, spray drying a solution or cooling the bed, evaporating the solution to form a glass (g(iv), or vacuum drying oil, solidification from the free test and acid reaction. The melt is prepared. Salts of the compounds of formula (I) and formula (la) can be prepared by direct crystallization from a solvent in which the salt has limited solubility, or by wet milling of a non-crystalline salt or otherwise crystallizing the non-crystalline salt. For example, r can be used with an organic solvent such as acetonitrile, methyl ethyl ketone, 1-butanol, ethanol, propanol or tetragas or a mixture of such solvents. It can be evaporated by evaporation of some or all solvents or The improved yield of the salt is obtained by crystallization at elevated temperature followed by, for example, staged controlled cooling. Careful control of the precipitation temperature and inoculation (see (jing) can be used to improve the reproducibility of the production process and the particle size distribution and form of the product. The skilled artisan will appreciate that many organic compounds can form complexes with the organic compounds which react with them or from the solvent in which they are precipitated or crystallized. These complexes are referred to as "solvates".                                   。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The term "solvate" as used herein refers to a stoichiometrically variable error formed by a solute (in the present invention, a compound of formula (I) or formula (la)) and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, decyl alcohol, ethanol, and acetic acid. Optimally the solvent used is water and the solvate may also be referred to as A solvate suitable for use in medicines of the formula (1) and the formula (la) is a pharmaceutically acceptable solvate thereof. However, a solvate having a non-pharmaceutically acceptable solvent In the context of the present invention, for example, in the preparation of other compounds of the formula (I) and formula (la) and their pharmaceutically acceptable salts and solvates, they are used as intermediates. Furthermore, formula (I) or formula (la) Some crystalline forms of the compounds or salts and solvates thereof One or more polymorphic forms are present, and such crystalline forms are included in the present invention. Prodrugs of the compounds of Formula (I) and Formula (la) are included in the scope of the present invention. Those skilled in the art should understand Formula (1) or Formula Certain protected derivatives of (Ia) compounds, which may be prepared prior to the final stage of removal of the protecting group, may not themselves have pharmacological activity but in some cases may be administered orally or parenterally and thereafter in vivo. The inner s shots to form a pharmacologically active compound as defined in the first aspect. Thus such derivatives may be described as "prodrugs". All protected derivatives of the compounds defined in the first aspect and Prodrugs are included within the scope of the invention. Examples of suitable prodrugs of the compounds of the invention are described in Drugs of Today, Vol. 19, No. 9, 1983, pages 499_538 and 154007.doc • 26·201221131

Topics in Chemistry ’ Chapter 31, pages 3_6_316 and

Design of Prodrugs, H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures of which are hereby incorporated by reference). Those skilled in the art will further understand certain parts of the "partial group precursors" known to those skilled in the art (eg, Bundgaard in "Design of Prodrugs" (the disclosure of which is incorporated herein by reference) The intermediate) can be placed on such functional groups when suitable functional groups are present in the compounds of formula (1) and formula (Ia). Suitable prodrugs of the compounds of the invention include: esters, carbonates, half esters, phosphates, nitroesters, sulfates, hydrazines, guanamines, urethanes, azo compounds, phosphoniumamines, glycosides, ethers , acetal and ketal. The compounds of the present invention have been found to exhibit antiviral activity, in particular HCV inhibitory activity' and are therefore useful in the treatment or prevention of viral infections such as HCV infection or diseases associated with such infections. In vitro studies have been performed which demonstrate that the compounds described herein are useful as antiviral agents. The present invention provides a compound of the formula (1) or the formula (Ia) or a pharmaceutically acceptable salt thereof for use in medical therapy. The present invention provides the use of a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of viral infections such as HCV infection and/or diseases associated with such infections. . The present invention provides a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of viral infections such as HCV infection and/or diseases associated with such infections. The present invention provides a method of treating and/or preventing a viral infection such as HCV infection or a disease associated with such infection, which method comprises administering to a subject, such as a human, a therapeutically effective amount of formula (I) Or a compound of the formula (la) or a pharmaceutically acceptable salt thereof. It should be understood that reference to therapy or treatment herein may include, but is not limited to, preventing, delaying, preventing, and curing a disease. The present invention provides compounds and pharmaceutical compositions for the treatment and prevention of viral infections such as HCV infection and diseases associated with viral infections in living hosts. It is further understood that reference to treating or preventing HCV infection herein may include treating or preventing an HCV-related disease, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the context of the present invention, the terms used to describe the indications used herein are classified according to Merck Manual of Diagnosis and Therapy, 17th Edition and/or International Classification of Diseases 10th Edition (ICD-10). The various subtypes of the conditions mentioned herein are encompassed as part of the invention. The process for the preparation of the compounds of formula (I) forms a further aspect of the invention. Throughout this specification, the general formula is represented by Roman numerals (I) - (XXXVI). A method (A) for preparing a compound of formula II is included in the present invention.

The compound of formula (II) can be prepared by reacting a compound of formula (III) with a compound of formula (IV) wherein R2 represents hydrogen, Cw alkyl or C3-6 cycloalkyl, according to conventional guanamine forming chemistry. Similarly, 'R2 may represent a hydroxy group' as appropriate on the hydroxy group via 154007.doc •28·201221131, such as a suitable protecting group for benzyl.

(III)

For example, the reaction may suitably be from 0 to 5 (rc, eg. to > dish, in an even reagent, such as 2-(7-azabenzotriazole 1, 1, 3, 3 hexafluorophosphate) - Four 曱锞 (HATU) exists in the presence of -.

The protecting group, such as a phenylhydrazine group, can be removed via subsequent conversion and subsequent exposure to hydrogen and palladium on carbon. The compound of the formula (III) can be prepared by a compound of the formula (V) which hydrolyzes RX such as a mercapto group or an ethyl group by a C 1 -6 group.

(V) Suitable reaction conditions include at a suitable temperature, such as 〇 to 1 〇〇. (:, for example, 5 to 80 C or treated with an alkali metal hydroxide such as NaOH in a suitable solvent such as THF, ethanol or a mixture thereof under reflux. The compound of formula (V) can be alkylated or deuterated according to conventional methods. The condition is prepared by reacting a compound of the formula (VI) with a compound of the formula (VII) wherein R 4 represents _s(0) 2 R 5 and L 2 represents a leaving group such as a halogen such as a gas, COORx

R1 ^L2 (VII) For example, the compound of the formula (VI) can be suitably used in a suitable solvent such as DCM at a suitable temperature, such as 〇 to 5 〇 °c 'Example 154007.doc • 29· 201221131 such as 0 ° C In the case of DIPEA, for example, it reacts with CH3S02C1. As is known to those skilled in the art, conventional protecting groups can be used when required for this transformation. The compound of the formula (VI) can be obtained by a conventional reduction technique, for example, by suitably at 0 to 50 ° C, for example at room temperature, under normal pressure in the presence of a noble metal catalyst such as genomic/charcoal, in a suitable solvent, for example Preparation of a compound of formula (VIII) by catalytic hydrogenation in ethyl acetate (EtOAc):

A compound of the formula (VIII) wherein R3 represents a Cw alkoxy group (such as prop-2-oxy) can be synthesized from a compound of the formula (IX) by nitration with nitric acid (hno3) in a suitable solvent such as gas (chci3). Preparation: COOR"

The compound of formula (IX) can be prepared by suitably at a suitable temperature, such as reflux, in the presence of a catalyst such as ZnCl2, and in a suitable solvent such as methanol (MeOH), diethyl ether, ethanol (EtOH), THF or In the mixture, the compound of formula (X) and the compound of formula (XI) 154007.doc

•30· 0

0

S (XI) 201221131 reaction, then when appropriate, with L3 as a functional atom, such as bromine leaving group 'Y' means C!·6 alkyl or C3·6 ring system (χΗ) compound: Y— L3 (XII) reaction' and the reaction is suitably under a temperature range of, for example, a chamber to 10 0 C ', for example, 50 to 70 C, in a conventional Ο-methylation condition, for example, ν·methyl α A suitable reaction of, for example, Cs2C〇3 is carried out in the presence of a suitable solvent of belonidone (NMP) with, for example, an alkali metal carbonate. Meanwhile, γ and the ruthenium atom to which it is bonded form an R3 group selected from a Cw alkoxy group (such as a prop-2-oxy group), a C3.6 cycloalkyloxy group, a C2-6 alkenyloxy group or a hydroxyl group. According to another method (B), the compound of the formula (XIII) and L4 can be represented by a suitable activation group, such as a g-p-acid group, for example B(OH)2, by a conventional carbon-carbon bond coupling reaction method. Compound of formula (XIV): COORx

Optionally, in the presence of a suitable cofactor such as KF and NaBr, in the presence of a suitable catalyst such as hydrazine (triphenylphosphine) palladium (Pd(PPh3)4), in a suitable solvent such as toluene, and In such as 90 to 12 〇. (:, for example, a reaction under a suitable temperature range of reflux to prepare a compound of the formula (VIII) wherein R3 is a CM cycloalkyl group such as a cyclopropyl group. The compound of the formula (XIII) can be derived from the compound of the formula (XV): 154007.doc • 31 - 201221131 COORx

Suitable nucleophilic catalysts by suitable bases such as N,N-diisopropylethylamine (DIPEa), such as N-dimethylaminopyridine (DMAP), and suitable solvents such as dioxane (DCM) The reaction is carried out in the presence and at a suitable temperature range such as 丨5 to 30 ° C, for example 〇 to 10 ° C, with a trifluorosulfonate acidulant such as trifluoromethanesulfonic anhydride (Tf2 〇). The compound of the formula (XV) can be produced by a compound of the formula (VIII) which is suitably represented by R3 by a de-alkylation reaction. Suitable ether groups include, but are not limited to, the compound of formula (VIII) wherein the rule 3 is C!.6 alkoxy (such as prop-2-oxy). Suitable conditions for the oxime-dealkylation process include suitably from 3 to 3 Torr. (:, for example, from 1 Torr to 20 ° C, in a suitable solvent such as DCM, such as a suitable reagent for BC 13. According to another method (C), the compound of formula (I) or formula (la) can be The preparation is carried out by reacting an allyl or homoallyl leaving group of formula XVI or formula XVII (wherein X = CN8 alkyl) to produce XVIII or XIX. Conditions suitable for this coupling include conventional alkylation conditions. Wherein a base (such as potassium carbonate), a suitable solvent (such as MeCN), and a temperature (for example, 0-120. (: Wide P2 is suitable for an alcohol protecting group (for example, benzyl or tert-butyl dimethyl sulphur) The xvi type and XVII type allyl halides are known in the art or can be readily used to form allyl leaving groups (including mesylate, dentate, toluenesulfonic acid) Preparation of known methods such as esters, etc. I54007.doc -32· 201221131

The olefins XVIII and XIX are via a salt of the formula XXII (wherein Z may represent an aryl ring to produce catechol or a molecule related to the production of a related cyclic acid ester) in a suitable catalyst (for example Rh(CO) (PPh3) The hydroboration reaction is carried out in the presence of 2Cl) and then converted to the boron boron substrate XX by the removal of the protecting group of P2 using conditions known in the art, including H2 & Pd/C for the phenylhydrazine protecting group. XXI. When the reagent XXII includes a strong chelating ligand (such as pinacol or catechol), it is preferred to add a scavenger (such as a polymer supported type) in addition to an aqueous acid solution (for example, 6.0 N HCl) in the final conversion. Benzoic acid). According to another method (D), a compound of formula (I) or formula (la) can be prepared from a compound of formula XXIII. XXIII can be subjected to an alkylation reaction in a solvent such as DMF by a suitable alkylating agent such as 2-oxoethylphenyl decyl ether in the presence of, for example, potassium carbonate, followed by a reducing agent such as hydrogen It is prepared in the presence of a suitable catalyst such as palladium on activated carbon. Use includes a suitable alkylating agent (such as XXVI or allyl mercaptocarbonate), a base (including, for example, triethylamine or sodium hydride), a solvent (including DMF or THF), a catalyst (such as palladium acetate), and a temperature (0 to XXIII alkylation under conventional conditions of 120 ° C) produces decanoic acid XXIV. Those skilled in the art will recognize that Russell 154007.doc •33-201221131 uses an olefinic alkylating agent (such as allyl methyl carbonate as described above), followed by a suitable catalyst (eg Rh(CO)). Hydroboration with a boron source (e.g., XXII) in the presence of (PPh3)2Cl) will be necessary to produce a compound of formula XXIV. Similarly, treatment of XXIII with a suitable deuteration agent (e.g., decanesulfonium) in the presence of a test (e.g., triethylamine) and a solvent (e.g., dichlorohydrazine) can produce an activated mesylate which can be made from a suitable amine ( Substitution, for example, with methylallylamine, followed by hydroboration as described above to yield the compound of structure XXV.

According to another method (E), the compound of formula I can be alkylated by a compound of formula XXVII, formula XXVIII or formula XXIX (Y2 = proton or methyl) with a compound of formula II as known in the art and as described above. The reaction is prepared under conditions. Compounds of formula XXVII, formula XXVIII and formula XXIX are known in the art or can be readily prepared by known methods. The aryl bromide functional group can be converted to the corresponding oxime using a suitable catalyst such as palladium acetate, a base such as KOAc, a boron source such as bis(pinacolyl)diboron, and a solvent such as dioxane. Acid ester. Reduction of the ester functional group using a hydride source (e.g., DIBALH or LAH) produces a compound of formula XXX. Those skilled in the art will recognize that various regioisomers of XXVII, XXVIII and XXIX can be used to obtain unique positional isomers of XXX. For alkylation involving XXIX, those skilled in the art will recognize that removal of the protecting group (e.g., using 6.0 N HCl if P = MOM) will be replaced by the above reduction step. 154007.doc -34- 201221131

According to another method (F), the compound of formula I can be obtained by formulating a compound of formula XXX or formula XXXII (wherein L1 is a suitable leaving group) with a compound of formula II in the art and under the standard alkylation conditions described above. The reaction is prepared. Compounds of formula XXXI and formula XXXII are known in the art or can be readily prepared by known methods. Conversion of the aryl bromide functional group to the corresponding tanning acid can be achieved using a suitable catalyst (e.g., palladium acetate), a base (e.g., KOAc), a boron source (e.g., bis(pinacolyl) diboron), and a solvent (e.g., dioxane). ester. Removal of the ester functional group of XXXI using a source of a hydroxide (e.g., DIBALH or LAH) or removal of the protecting group P1 of XXXII using suitable conditions (e.g., 5.0 N HCl using Pt-MOM) can yield a compound of formula XXXIII. Those skilled in the art will recognize that various positional isomers of XXXI and XXXII can be used to obtain unique positional isomers of XXXIII, and that by using XXXI or XXXII, a point of attachment can be produced on an aryl or heteroaryl group, respectively. XXXIII.

According to another method (G), the compound of formula XXXIV can be treated with a suitable reducing agent (e.g., DIBALH) in a suitable solvent (e.g., DCM) to yield the corresponding alcohol. These alcohols are exposed to 154007.doc-35-201221131 in the presence of a phosphine (eg, triphenylphosphine) and a solvent (eg, THF), followed by a mildly extended (Mitsunobu) esterification with η to produce an activator (eg, DEAD) to produce XXXV. Treatment of XXXV with a suitable catalyst (eg, PdClJdppf) in the presence of a test (eg, acetic acid), a shed source (eg, a double-capacitor), and a solvent (eg, dioxane), followed by exposure to a strong acid (eg, 6.00) A cyclic ester of the general type XXXVI can be produced in N HC1).

The invention also extends to the novel intermediates disclosed herein for the preparation of the compounds of formula (1) and formula (Ia) or salts thereof. Further details regarding the preparation of compounds of formula (I) and formula (la) are found in the Examples section below. Those skilled in the art will appreciate that one or more sensitive groups may be necessary and/or required to protect a molecule or a suitable intermediate in the preparation of a compound of formula (1) and formula (Ia) and/or a salt thereof to prevent undesirable side effects. Protecting groups suitable for use in accordance with the present invention are well known to those skilled in the art and can be used in a conventional manner. See, for example, T.w. Greene and P.G.M. Wuts, "Protective groups in organic synthesis" (John Wiley & sons 1991) or P.J. Kocienski, "Protecting Groups" (Georg

Thieme Vedag 1994). Examples of suitable amine protecting groups include fluorenyl protecting groups (eg, formazan, trifluoroethenyl, ethenyl), aromatic amine phthalate protecting groups (eg, benzyloxycarbonyl (Cbz) and Substituted cbz), aliphatic urethane protecting group (eg 9-fluorenylmethoxycarbonyl (Fm〇c), third 154007.doc • 36 · 201221131 butoxycarbonyl (Boc), isopropyl Oxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl protecting groups (eg, benzyl, triphenylsulfonyl, chlorotrityl). The use of various intermediate compounds including, but not limited to, certain formula (??) compounds in the above-mentioned methods constitutes another aspect of the present invention. The present invention also encompasses a pharmaceutical group comprising a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable form-forming sputum

"Symbolic excipient" means a compound suitable for the preparation of a pharmaceutical composition such as a diluent or a carrier. The compounds of the present invention can be administered by conventional dosage forms prepared by combining the compounds of the present invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. Such procedures may involve mixing, granulating, and (d) or dissolving = as appropriate to obtain the desired formulation. Dosage forms and procedures may involve amorphous dispersions, / knife dispersions, hot melt extrusion (hQt meh, micron sizing or wet bead milling (nano milling) to reduce particle size, self-emulsifying systems, or Mismatch, for example, in combination with cyclodextrin. The pharmaceutical compositions of the invention may be formulated to achieve administration by any route and include those suitable for oral, topical, intravenous, intraperitoneal,::, intramuscular , pharmaceutical compositions in the form of transdermal or transmucosal administration 0 for oral administration of 'compounds can be formulated into any suitable agent: capsules, powders, granules, buccal bonds, creams or liquid preparations: mouth Or sterile solution or suspension, m-agent and concentrated drops. Tablets and capsules for oral administration can be presented in unit dosage form and 154007.doc -37- 201221131 can contain conventional excipients, such as a human machine For example, viscous alpha agents, such as syrup, gum arabic (caffeine cU), gelatin, sorbitol, yellow f ((10) (four) resistant) or polyethylene sputum bite; fillers, such as lactose, sugar, corn (four), Lin _, sorbitol or glycine; ingot slip Agents, such as magnesium stearate, talc, polyethylene glycol or cerium oxide; disintegrants such as potato starch; or acceptable,,,, etc., such as sodium lauryl sulfate. I. The method well known is to coat. When the composition is in the form of a capsule, any conventional encapsulation is suitable, such as a hard gelatin capsule shell or a soft gelatin capsule shell. When the composition is in the form of a soft gelatin shell capsule, it is generally considered Any pharmaceutical carrier for the preparation of a dispersion or suspension, such as an aqueous gel, cellulose, a sulphate or an oil, and which may be incorporated into a soft gelatin capsule shell. The oral liquid preparation may be, for example, aqueous or oily. In the form of a suspension, solution, emulsion, syrup or granule, or may be presented as a dry product for reconstitution with water or other suitable vehicle prior to use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbose Alcohol, methylcellulose, glucose syrup, gelatin, ethylcellulose, several f-based cellulose, sulphate, or ammoniated edible fat; emulsifiers, such as phospholipids, sorbitan Monooleic acid or gum arabic; non-aqueous vehicle (which may include edible oils), such as almond oil, oily vinegar, such as glycerin, propylene glycol or alcohol; preservatives such as methylparaben or p-hydroxybenzoic acid Propyl or sorbic acid: and, where necessary, conventional flavoring or coloring agents. A syrup formulation will usually consist of a compound or salt in a liquid carrier containing a flavoring or coloring agent (eg, ethanol, peanut oil, scented oil, glycerin or water) Composition of a suspension or solution. For example, intramuscular, intravenous, intraperitoneal, subcutaneous injection of I54007.doc •38-201221131 (parenteral administration), fluid unit dosage forms utilize compounds and sterile vehicles, such as water Prepared by brine solution, Hank's solution (Hank, ss〇hiti〇n) 4 Ringer's solution. The compound may be suspended or dissolved in the vehicle depending on the vehicle used and the concentration. In preparing the solution, the compound is dissolved in water for injection and sterilized and filtered, and then filled into a suitable vial or ampule and sealed. Furthermore, the compounds of the invention may be formulated in solid form and reconstituted or suspended immediately prior to use. Freeze-dried forms are also produced. The parenteral compositions comprise, by the compound or salt, a parenterally acceptable oil, such as polyethylene glycol, polyethylene, as appropriate. It consists of a solution or suspension in a sterile aqueous or non-aqueous carrier of (iv) steel, (iv) fat, peanuts>= or sesame oil. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be infiltrated is used in the formulation. Such penetrants are generally known in the art and include, for example, bile salts (bile _) and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to promote penetration. Administration via _ membrane can be achieved, for example, by nasal spray, rectal suppository or vaginal suppository. A typical suppository formulation is active when administered in this manner with a binder and/or a lubricating agent such as polyethyl hydrazine, g guar, cocoa butter or other low scented plant soil or fat or a synthetic analog thereof. Formula (1) or formula (10), or a pharmaceutically acceptable salt thereof. A typical inhalation composition is in the form of a solution, suspension or emulsion which can be administered in the form of a dry powder or in the form of an aerosol using conventional non-CFC propellants such as tetraethion or mum fluoropropane. ,, ' The present month's sputum can be presented as ointments, creams, gels, 154007.doc • 39- 201221131 ointments or lotions, ophthalmic softs and eye drops or ear drops, dip It is in the form of a dressing and an aerosol, and may contain suitable conventional additives such as preservatives, auxiliary: drug penetration solvents and ointments, and emollients in milk f. The formulation may also contain a compatible carrier such as a cream or ointment base and ethanol dioleate for use as a lotion. A formulation may be suitably formulated to produce a controlled/delayed release of the active compound. The amount of each compound to be administered can be considered by standard procedures such as compound (ICW potency, (EC^) efficacy and (compound) biological half-life, patient age, body and weight, and blood. The patient's disease or condition related factors are determined. For the test, the person is expected; g # yjr m 1< The importance of this temple and other factors is known to the general practitioner. The amount of administration also depends on the route of administration. And depending on the degree of σ bioavailability. For example, for compounds with lower oral bioavailability, relatively high doses will have to be administered. Oral administration is the preferred method of administration of the invention. Preferably, the combination The dosage form is a unit dosage form. For oral administration, for example, a tablet or a capsule can be administered. For nasal administration, a metered aerosol can be administered for transdermal administration, and a topical formulation or paste can be administered. And for transmucosal delivery, a transfluent patch can be administered. In each case, the administration allows the patient to administer a single dose. Each dosage unit for oral administration suitably contains 0.01 to 500 Γ^, and Good ~1 to 5G mg/kg A compound of the formula (1) or formula (ia) or a salt thereof as a dry acceptable salt is used as a free test. The daily dose for parenteral, nasal, oral inhalation, transmucosal or transdermal routes is suitably Containing a compound of formula (1) or formula (Ia), read 154007.doc 201221131 mg to 100 mg/Kg. The topical formulation suitably comprises from 0.01 to 5.0% of a compound of formula (1) or formula (Ia), as is known to those skilled in the art. It is obvious that the active ingredient can be administered daily for a period of 1 to 6-person, preferably 1 time, which is sufficient to exhibit the desired activity. The sub-dose can be 〇5 · 100 mg, 5 to 1000 mg or 50 to 5 per unit dosage form. Administration unit dosages of 〇〇mg, or 2〇 to 5〇〇mg, or 5〇 to 400mg of active ingredient. Those skilled in the art will recognize that the most optimal amount and spacing of individual doses of the compounds of the present invention will be The nature and extent of the treatment of the condition, the form, route and location of administration, and the particular mammal being treated are determined, and such optimal values can be determined by conventional techniques. Those skilled in the art will also be aware of the optimal course of treatment. , that is, the agent for continuously determining the number of days of the compound of the present invention given per day The amount can be determined by a person skilled in the art using a conventional treatment to determine the test procedure. The compound of formula (I) or formula (la) or a pharmaceutically acceptable salt thereof can also be used in combination with other therapeutic agents. In another aspect, the invention provides a combination of a compound of formula (1) or formula (la), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. The compounds of the invention may be combined with other therapeutic agents, such as immunization Therapies (such as interferons), therapeutic vaccines, anti-fibrotic agents, anti-inflammatory agents (such as corticosteroids or NS AIDs), bronchodilators (such as beta 2 adrenergic agonists and xanthine (such as tea) Alkali (the phylUne)), mucolytic agent, antimuscarinic agent, anti-leukotriene (antMeuk〇triene), cell adhesion inhibitor (such as ICAM antagonist), antioxidant (such as N_ acetamidine. 2:, cystine), cytokine agonist, cytokine antagonist, lung interface activity 154007.doc •41· 201221131 agents and / or anti-microbial and anti-viral agents (such as ribavirin and amantadine (amantidine )) combination cast versus. The compositions of the invention may also be used in combination with gene replacement therapy. The compounds of the invention may be administered in combination with other therapeutic antiviral agents selected from the list below: interferons, pegylated interferon' ribavirin, protease inhibitors (eg, fiilibuvir), polymerase inhibition Agents (eg, bpreCeprevir, telaprevi, or compounds disclosed in pcT/us 2010/046782), small interfering RNA compounds, antisense compounds, nucleotide analogs, Nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antiviral agents, and anti-infective compounds. For example, combination therapies may comprise a compound of formula (1) or formula (la) or Pharmaceutically acceptable salts and other antiviral agents, such as acyclovir (acycl〇vir), famciclovir, valgancicl〇vir and related compounds, ribavirin and related compounds, Amantadine and related compounds, various interferons such as interferon-α, interferon-β, interferon-丫 and their analogs, and alternative forms of interferon, such as PEGylated When a compound of formula (I) or formula (la) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent, the dose of each compound may be different from the dose when the compound is used alone. Those skilled in the art. Appropriate dosages will be readily apparent. It will be appreciated that the amount of the compound of the invention required for treatment will vary with the nature of the condition being treated and the age and condition of the patient and will ultimately be determined by the attending physician or veterinarian. It may conveniently be provided in the form of a pharmaceutical composition using 154007.doc -42.201221131 and thus comprising a carrier and/or an excipient as defined above. The combination and at least one pharmaceutically acceptable pharmaceutical composition constitutes Another state of the invention

When administered sequentially, the HCV inhibitor or the second therapeutic agent may be administered first, and when administered simultaneously, the combination may be administered in the same or different pharmaceutical compositions. When combined in the same formulation, it will be understood that the two compounds must be stable and compatible with each other and with the other components of the modulating agent. When separately formulated, the two compounds are conveniently provided in any suitable formulation in the manner known in the art for use in such compounds. The following non-limiting examples illustrate the invention. EXAMPLES Those skilled in the art should be aware that when solvents are used in the reaction, anhydrous solvents are required. When appropriate, it is further desirable to carry out the reaction under an inert atmosphere, for example under nitrogen or argon. Abbreviation DMSO Dimethyl sulfoxide HATU Hexafluorophosphate 0_(7-azabenzotriazole small base Ν, Ν, Ν', Ν·- four gas paper ISCO CompanionTM available from Presearch and by Teledyne Isco

An automatic flash chromatography equipment manufactured by Inc. that has the function of dissolving by UV absorption 154007.doc • 43 - 201221131 analysis. THF —... tetrahydrofuran intermediate 1 2-(4-fluorophenyl)_5-radyl·j Benzobite _3_ formic acid methyl vinegar

Dry the glassware and use the anhydrous zinc hydride (25 g, 183 rhyme. 〇, then heat to the hunger within the anhydrous sterol (60 mL) under nitrogen atmosphere. Add in single serving Ethyl 4-fluorophenylhydrazinacetate (39.6 g '202 mm〇1)' followed by dropwise addition of a solution of p-benzoquinone (19.83 g, 183 mmol) in anhydrous ethyl acetate (5 mL) over 4 hours This is carried out simultaneously with the distillation of the diethyl ether from the reaction mixture, so the volume of the reactants remains approximately constant (the bath temperature of 140 C maintains the internal temperature initially at the bottom, then gradually increases to a maximum of 115 C). After 25 hours, more sterol (20 mL) was added to facilitate stirring. After the complete addition of phenylhydrazine, the reaction mixture was heated under 〇〇t (internal) for a few hours. The reaction mixture was cooled to warm and partitioned. Between water (5 〇〇 mL) and ethyl acetate (8 〇〇 mL). Insoluble solids were removed from the two-phase solution by filtration and the organic layer was then separated, dried (NaJO4), filtered and evaporated in vacuo The brown residue is in warm dioxane (about 225 mL) The slurry was allowed to stand in the refrigerator for 18 hours. The resulting solid was filtered from a deep standard solution and washed with a small volume of dioxins, followed by drying under vacuum to give 2-(4-fluorophenyl)-5- Hydroxyl 1-benzofuran-3-carboxylic acid decyl ester. LCMS (m/z, ES + ) = 285 (M-1). Intermediate 2 154007.doc •44· 201221131 2-(4-fluorophenyl) -5-[(1-methylethyl)oxydim·benzofuran_3_carboxylic acid methyl ester

The methyl 2-(4-fluorophenyl)-5-hydroxy-indole-benzofuran-3-carboxylate (18.86 g, 65.9 mmol) and isopropyl bromide (24.74 mL·, were stirred at 60 ° C under nitrogen. 264 mmol) and a mixture of carbonic acid (42.9 g, 132 mmol) in anhydrous N-mercapto-2-0 ratio of ruthenone (191 mL) for 2 hr. The resulting thick suspension was cooled to room temperature and then a 7% aqueous ammonia solution (2 mL) was added with rapid stirring. The mixture was extracted with heptane (700 mL) and then the aqueous phase was separated. Ethyl acetate (ca. 100 mL) was added to the organic phase and the resulting mixture was shaken and then dried and evaporated to give a fading oil which crystallised upon standing overnight. This material is recrystallized from hot methanol and the solids are collected by the reaction, washed with methanol and finally dried under vacuum to give <RTI ID=0.0>> A vinegar. Lcms • ES>329 (M+1). "The first recrystallized mother liquor is subjected to a second crystallization to produce another-batch 2. (4-fluorophenyl)·5_[(1-methylethyl)oxy]small benzofuran-3-decanoate Ester. Intermediate 3 _1- benzofuran _3_ 2-(4-fluorophenyl)-5-[(1-mercaptoethyl)oxy]6-nitromethyl ester iPrO o2n

F 154007.doc -45· 201221131 2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]_丨_benzofuran-3-decanoate A at -15 °C A solution of 70% nitric acid (11 mL, 172 mmol) in EtOAc (EtOAc) (EtOAc) After stirring at 0 °C for 1 hour, the reaction mixture was washed with water (50 mL The solid was triturated with methyl tert-butyl ether (25 mL) and the obtained pale yellow powder was filtered, washed with heptane and dried under vacuum to give 2-(4-fluorophenyl)-5-[(1) -Methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylic acid oxime ester LCMS (m/z, ES+) = 764 (2M+NH4)+. Intermediate 4 6-Amino-2-(4-fluorophenyl)-5-[(l-methylethyl)oxydimethane benzofuran_3_carboxylic acid methyl ester

Stirring 2-(4-fluorophenyl)-5-[(l-fluorenylethyl)oxy group with 1% palladium on carbon (11 丨 mg, 0.105 mmol) under hydrogen atmosphere at 21 °C A solution of 6-nitro-1-benzopyran-3-decanoic acid methyl vinegar (391 mg, 1.047 mmol) in ethyl acetate (15 mL) for 16 h. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. This was redissolved in a small volume and re-evaporated to give 6-amino-2-(4-fluorophenyl)-5-[(1-indolyl)oxy]-1-benzofuran- 3-decanoic acid ester. LCMS (w/z, ES+)=344 (M+l) 〇154007.doc • 46- 201221131 Intermediate 5 6-[Bis(methylsulfonyl)amino]-2-(4-fluorophenyl)- 5-[(1-methylethyl)oxy] 1-benzofuran-3-carboxylic acid decyl ester

To a solution of 6-amino-2-(4-sulfanyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylic acid methyl ester (1.49 g, under nitrogen at 0C) 4.34 mm 〇 1) Diisopropylethylamine (1.895 mL, 10.85 mmol) and sulfonium sulfonate (0 744 mL, 9 55 mmol) were added sequentially to a stirred mixture of anhydrous dioxane (25 mL). The reaction mixture was stirred for 1 hour and warmed to room temperature, washed with water and evaporated under vacuum to give 6-[bis(sulphonyl)aminosyl-2-(4-fluorophenyl)-5-[(1-pyrene) Ethylethyl)oxy]-1-benzo[alpha] is called _3_ citrate vinegar. lcmS (m/z, ES+)=517 (Μ+ΝΗ4)+. Intermediate 6 2-(4-Fluorophenyl)-5-[(1-indolylethyl)oxy]·6-[(methyl aryl)amino] benzofuran-3-carboxylic acid

Heating 6-[bis(indenyl)amino group in a mixture of methanol (20 mL), tetrahydrofuran (20.00 mL) and 2 Μ sodium hydroxide (20 mL, 40.0 mmol) at 80 ° 2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzopyran-3-carboxylate (2.199 g, 4.40 mmol) 16 h. Partially steamed under vacuum;::<· Solvent and the reaction mixture was partitioned between dilute HC1 aqueous solution and dioxane 154007.doc • 47· 201221131. The organic phase is separated by a hydrophobic transition tube and evaporated to dryness to give 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-[(sulfonyl)amine Kebu ^ stupid and furan-3-carboxylic acid. LCMS (m/z, ES+) = 406 (M- Η) 〇 Intermediate 7 2-(4-fluorophenyl)-N-methyl·5-[(1-methylethyl)oxy]-6 -[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide CONHMe

F Stirring 2-(4-fluorophenyl)_5 with diisopropylethylamine (1.639 mL, 9.39 mmol) in anhydrous N,N-dimethylamine (20 mL) at 21 °C -[(l-methylethyl)oxy]-6-[(anthracenyl)amino]-1-benzopyrene _3_carboxylic acid (1.738 g ' 4.27 mmol) » Add HATU (1.946 g) ' 5.12 mmol) and after 10 min, 2 M methylamine in THF (10.66 mL, 21.33 mmol). The reaction mixture was stirred for 18 hours and then evaporated under vacuum. The residue is distributed between the two gas chambers and the water. The organic phase is separated, passed through a hydrophobic filter tube and evaporated under vacuum. The residue was purified by autoflash chromatography on <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; The appropriate fractions are combined and evaporated under vacuum to give 2_(4-fluorophenyl)-#-methyl·5-[(1-indolyl)oxy]_6_[(methylsulfonyl)amino]- 1-benzofuran-3-carboxamide. LCMS (m/z, ES+) = 421 (Μ + Η). Intermediate 9 2-(4-propenyl)-5-ylamino-6-nitro-1-benzonaphindyl _3_carboxylic acid methyl vinegar 154007.doc •48· 201221131

Using a syringe pump at -15 ° C for 3 〇 to 2_(4-decyl)-5-[(1-methylethyl)oxy]_6_shixyl-i-benzo . Add 1 Μ boron trichloride in dioxane solution (23.85 mL, a solution of 南南·3· decyl decanoate (5.237 g, 14.03 mmol) in anhydrous dichloromethane (7 〇 mL). 23.85 mmol). The dark brown red reaction mixture was poured into ice (about 25 〇 mL). The ice was thawed and the mixture was extracted with dioxane (about 450 mL). The organic phase was separated by a hydrophobic filter tube and evaporated under vacuum to give &lt;RTI ID=0.0&gt;&gt;&gt;&gt; lHNMR(d6-DMSO): δ 10.97 (1Η, br. s), 8.34 (1H, s), 8.07 (2H, dd), 7.67 (1H, s), 7.43 (2H, t), 3·86 (3H , s). Intermediate 10 2·(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}·ι_benzofuran-3-carboxylic acid methyl ester

2-(4-fluorophenyl)·5-hydroxy-6-nitro-1-benzofuran-3-carboxylic acid decyl ester (4.915 g, 14.84 mmol) and 4-(diamine-amine) under nitrogen Pyridine (0.181 g' 1.484 mmol) was added to an ice-cooled stirred mixture in anhydrous methylene chloride (nmL), and then triethylamine (3 〇mL, 22.26 mmol) and trifluoromethane anhydride (3.76 mL, 22.26). Mm). After 50 minutes, the reaction still in the 〇C ice bath was quenched by the addition of water. The reaction mixture was divided into 154007.doc •49· 201221131 and was mixed with a gas and water and separated organic matter. The aqueous phase was extracted with more dioxins and the combined organics were sequentially treated with 2 M HCl and water. The organics are dried by a hydrophobic filter tube and evaporated to give 2 (4·fluorophenyl)_6_nitro-5·{[(trifluoromethyl)sulfonyl]oxyindole_benzofuran_3_ Ethyl formate. LCMS (w/z, ES.) = 481 (Μ + ΝΗ 4) +. Intermediate 11 5-Cyclopropyl-2-(4-fluorophenyl)-6-nitro-indole_benzofuran_3_carboxylic acid methyl ester

Stir 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl] with a mixture of methyl (90 mL) and water (2.25 mL) under nitrogen Methyl bromide (7.i2 g, 15.37 mmol), cyclopropyl acid (2.19 g, 25·5 mmol) 'KCl (3·26 g, 561 mm〇) 1) sodium bromide (1.75 g, 17.01 mm 〇l) and hydrazine (triphenylphosphine) palladium (〇) (〇85 g, 〇 736 mmol) and heated at 10 °C for 18 hours. The reaction mixture was cooled. Diluted with ethyl acetate and washed with water. The organic phase was separated, dried and dried with EtOAc EtOAc EtOAc EtOAc. The gradient of ethyl ester in cyclohexane was eluted by ruthenium. The fractions containing the product were evaporated under vacuum to give 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran. 3-carboxylic acid decyl ester. lCMS (w/z, ES+) = 728 (2M+NH4) + intermediate 12 6-amino-5-cyclopropyl-2-(4-fluorophenyl)_1_benzo Furan_3_carboxylic acid methyl ester 154007.doc •50 201221131

Stirring 5·cyclopropyl_2_(4•fluorobenzene) containing 2 M Hcl(1h^) under a hydrogen atmosphere at 10 ° C / palladium / carbon (〇 951 g, 〇 894 mmol) at 21 ° C a solution of 6-nitro-1-benzofuran_3_carboxylic acid decyl ester (3 175^, 8 94 in ethyl acetate (250 mL). The reaction mixture was filtered over celite and filtrate Evaporation under vacuum to give a dark green solid. This was dissolved in dichloromethane, washed with sodium bicarbonate, separated by a hydrophobic frit, then evaporated to dryness and purified by IS CO Companion automated flash chromatography. The gradient of 0-30% ethyl acetate in cyclohexane was eluted by ruthenium. The appropriate fractions were combined and evaporated under vacuum to give 6-amino-5-cyclopropyl-2-(4-fluorophenyl) Ethyl benzofuran-3-carboxylate. LCMS (m/z, ES+) = 326 (M+H). Intermediate 13 6·[bis(methylsulfonyl)amino]-5-cyclopropyl-2 -(4-fluorophenyl)-1-benzofuran-3-carboxylate

Cooling 6-Amino-5-cyclopropyl-2-(4-phenyl)-1-benzopyran-3-carboxylate (1.96 g, 6-02 mmol) and triethylamine (2.52 mL, 18.07) Methyl acetate in anhydrous dioxane (40 mL) was taken to EtOAc (EtOAc). The reaction was stirred at 0 ° C (ice bath) for 2 hours. TLC (1:1 ethyl acetate / cyclohexane) showed no enthalpy η04 anode 154007.doc 51 · 201221131 The starting material remained in the reaction mixture. Water (100 mL) was added and the organics were extracted 3 times with di-methane. Drying with a hydrophobic frit and evaporation to dryness to give 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2- Methyl (4-fluorophenyl)-1-benzofuran-3-carboxylate. LCMS 〇/z, ES+) = 482 (M+H). Intermediate 14 5-Cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran·3-carboxylic acid

[Bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylic acid methyl ester (2.88 g, 5.98 mmol) in ethanol (50 The suspension in mL) and water (25 mL) was treated with hydrazine deoxidation (6.7 μg '12 〇 mmol) and heated under reflux for 1 hour (the suspension was dissolved after heating). The reaction was concentrated under vacuum. Water (100 mL) was added and the solution was acidified with 2M EtOAc (50 mL). The resulting precipitate was filtered, washed with 0.5 M EtOAc and then dissolved in methanol. This &gt; trough solution is evaporated to dryness and azeotroped twice with toluene to give 5-cyclopropyl·2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]_!•benzofuranic acid . lCMS (w/2, ES+)=390 (M+H). Intermediate 15 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amine benzofuran-3-carboxamide

154007.doc -52- 201221131 Stirring 5_cyclopropyl·2_(4·Fluorophenyl)·6_[( 续 酿 胺 ] 小) benzofuran·3_ carboxylic acid (2.52 g, 6.47 _o1) at room temperature ), hATU (2.95 g, grade 1) and triethylamine (1 984 machine, i4 24 surface 〇 1) in anhydrous dichloromethane (_ mL), 丨 hour, followed by methylamine (i6i8 32.4 mmo丨) Treatment. The solution was stirred at room temperature under nitrogen for # hour, during which time a sag was formed. The reaction was diluted with two gas (burning) and sodium carbonate solution (200 mL) and (iv) 1 () minutes. The layers were separated and the aqueous layer was extracted with another gas (15 mL). The combined organics were dried with brine (dry) using a hydrophobic frit and evaporated to dryness to give an off white solid. The crude product was slurried in dichloromethane and applied to the top of a pre-filled silica gel cartridge (Bi〇tage SNAP, 1 〇〇g), followed by dissolution using an isc〇companion automated flash chromatography apparatus with ethyl acetate/ring It has been burned and dissolved. Some products which were dissolved but less in mass in the range of 4〇_6〇% acetic acid acetate were recovered from the column. The column was rinsed with 1% methanol/diqi methane, but some of the white solid remained on top of the ceria cartridge. The dissolved product, the methanol/dioxane rinsed solution and the residual white solid from the top of the column were combined in a single flask and evaporated to dryness. This material was dissolved in hot methanol-chloroform (10% v/v) (still some insoluble solids) and loose tannin was added. The mixture was evaporated and the resulting solid was dried and loaded on top of a 2x1 〇〇g Biotage SNAP pre-filled ruthenium tube column that was not pre-equilibrated in the starting solvent and purified using ISCO Companion automated flash chromatography with 0-10% methanol/ Dioxane is dissolved. The fractions containing the product are combined and evaporated to give 5-cyclopropyl-2-(4-fluorophenyl)_#-methyl-6-[(sulfonyl)amino]- 1- benzofuran-3 - guanamine. LCMS (m/z, ES+) = 403 (M+H). 154007.doc •53-201221131 EXAMPLES Example 1 [({2-[{2·(4-Fluorophenyl)-3-[(methylamino))]_5·[(1-methylethyl)oxy 1-benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy)methyl]decanoic acid

Stage 1: 2-(4-Fluorophenyl)-indole-methyl-5-[(1-methylethyl)oxy]-6-((), {2-[(benzyl) Ethyl]ethyl decyl benzofuran _3_indanamine 2-(4-fluorophenyl)-N-methyl-5-[(l-fluorenylethyl)oxy]-6 -[(Methanesulfonyl)amino]-1-benzofuran-3-decylamine (350 mg, 0.832 mmol) dissolved in acetonitrile (16 mL) with potassium carbonate (230 mg, 1.665 mmol) Treatment: Add phenylhydrazino 2 - dimethylethyl _ (0.145 mL, 0.916 mmol) and according to 2·(4-fluorophenyl)-#-fluorenyl-5-[(1-methylethyl)oxy The procedure described for the 6-[(methylsulfonyl)(2-propen-1-yl)amino]-1-benzofuran-3-amine was heated at 65 C under nitrogen for 24 hours. The mixture was diluted with water and extracted with trichloromethane. The mixture was separated and washed with brine, washed with brine and dried over sodium sulfate &lt;&apos;&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& The gradient of ethyl acetate in hexane was eluted with ruthenium. The appropriate fractions were combined and evaporated to give 2-(4-fluorophenyl)-N-methyl- 154007.doc •54·201221131 5- [(l-A Base ethyl Oxy]-6-((oxasulfonyl){2-[(phenylhydrazino)oxy]ethyl}amino)-1-benzofuran-3-carboxamide. LCMS (m/z, ES+)=555 (M+H). 掩 Ί 2·(4_fluorophenyl)·6-[(2_hydroxyethyl)(methyl hydrazino)amino]_N_methylmethylethyl Oxy]-1-benzofuran-3-carboxamide 2-(4-fluorophenyl)-N-methyl-5-[(l-fluorenylethyl)oxy] under normal pressure - 6-((oxasulfonyl) {2-[(benzyl)oxy)ethyl}amine] benzofuran-3_carbamidamine (340 mg, 0.613 mmol) and 100 mg 10% A mixture of palladium on carbon (Degussa type) in decyl alcohol (5 mL) was placed in a Buchi hydrogenator for 2 hours, filtered through celite and the filtrate evaporated in vacuo using Isco Companion. The crude product was purified by chromatography, eluting with EtOAc EtOAc (EtOAc) (Methanesulfonyl)amino]-N-mercapto-methylethyl)oxy]-benzofuran-3-amine. LCMS (w/z, ES+) = 465 (M+H). Masking 3 ·. [({2-[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(l-methylethyl)oxy]-1- Benzofuran-6-yl}(methylsulfonyl)amino]ethyl}oxy) decyl]decanoic acid to 2-(4.fluorophenyl)_6.[(2-hydroxyethyl)( Indolesulfonyl)amino]-N-indolyl-5-[(1-indolylethyl)oxy]-1-benzofuran-3-carboxamide (100 mg, 0.215 mmol) and potassium carbonate (89 mg, 0.646 mmol) of 2-(bromodecyl)-4,4,5,5-tetramethyl-13,2-dioxaboron (101 mg, added to a mixture of anhydrous acetonitrile (1 mL) 0.458 mmol). The reaction was heated at 85 &lt;0&gt;C for 18 hours&apos; diluted with di-methane, filtered and concentrated. The crude product was purified by flash chromatography using Isco Companion 154007.doc -55 - 201221131, eluting with 0-1 〇% methanol in dioxane over a mixture of oxime and evaporation of the appropriate fractions. Further purification was achieved by reverse phase chromatography to give [({2-[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(l-decylethyl)) Oxy]_ι_benzofuran-6-yl}(indolyl)amino]ethyl}oxy)methyl]g-acid. *H NMR (sterol-d4) δ 7.83-7.97 (m, 2 Η), 7.50-7.58 (m, 1 Η), 7.20-7.28 (m, 3 Η), 4.79 (dt, 7=12.1, 6.0 Hz , 1 Η), 3.82 (br. s., 2 H), 3.47 (t, J=5.6 Hz, 2 H), 3.27 (br. s., 2 H), 3.00-3.10 (m, 3 H), 2.93 (s, 3 H), 1·32-1·49 (m, 6 H), no 3 exchangeable protons. LCMS (m/z, ES+) = 523 (Μ-H). Example 2 5-Cyclopropyl-2-(4-fluorophenyl•hydroxy-13-dihydro-21-benzoxoxaborole-6-yl)methyl](methylsulfonyl)amine Keb N_methylbenzopyran·3-cartoamine

Step 1: 2-Bromo-4-{[{5-cyclopropyl_2_(4-fluorophenyl)·3_[(methylamino)indolyl]-1-indolofuran-6-ylsulfonate醯-)Amino]methyl}benzoic acid vinegar vinegar heated at 70C 5-cyclopropyl 2 - (4-fluorophenyl) Ν 曱 曱 _ 6_[(methylsulfonyl) amine group]-1 · Benzofuran-3-decylamine (52 mg, 0.130 _〇1), 2-/odor 4 (/ skaki) benzoic acid oxime ester (4 ton, 〇mm〇1, 3B 154007.doc 201221131

Scientific Corporation) and a mixture of potassium carbonate (18 mg, 〇 13〇 〇 1) in acetonitrile (8 mL) for 4 hours. The suspension was concentrated under reduced pressure, brine was added and aqueous layer was evaporated. The combined organics were washed with brine, dried over sodium sulfate, filtered and purified by silica gel chromatography eluting eluting Phenyl)_6-[[(1-trans-l-1,3-dihydro-2,1-benzaooxaborole-6-yl)indolyl](aminophenyl)amino] -N-Methyl-1-benzoxofan-3-carbamidamine (59 mg, 72%). 4 NMR (CDCI3): S 7.81 (m, 2 Η), 7.67 (m, 1 Η), 7.55 (m, 1 Η), 7.25-7.12 (m, 5 Η), 5.80 (m, 1 Η), 4.91 (m, 1 Η), 4.74 (m, 1 Η), 3.88 (2, 3 Η), 3.02-2.94 (m, 6 Η), 2.13 (m, 1 Η), 1.03-0.83 (m, 3 Η) , LC ( ( ( ( ( ( ( ( f ^ ^ j ^ ^ j.]. Benzophthyl-6-yl}(A continued fluorenyl)amino]methyl}_2-(4Ί5_tetramethyl-1,3,2-dioxaboron咮-2-yl)benzoic acid 曱 将 2- 2- 2- 2- 4-[{5-cyclopropyl-2-(4-phenylphenyl)-3-[(methylamino) thiol]_1_ benzene °夫D南-6-yl}(甲石黄基)Amino]mercapto}benzoic acid methyl vinegar (23 mg, 0.03 7 mmol), dicyclohexylphosphinobiphenyl (1 mg, 3.65 μπιοί) And a mixture of palladium acetate (0.4 mg, 1.8 μηιοί) dissolved in dioxane (3 mL), added pinacol borane (1 mL) and triethylamine (0.02 mL, O.lio mm〇i) and mixture The mixture was immersed in a 100 ° C oil bath. The reaction was heated for 2 h, concentrated under reduced pressure and purified by reverse phase HPLC to yield 4-{[{5-cyclopropyl-2-(4) as a white solid. -fluorophenyl)-3-[(decylamino)carbonyl]-1-benzone _6_基}(曱sulfonyl)amino]methyl}-2-(4,4,5,5-tetradecyl-1,3,2_dioxaboroxide·2_ 154007.doc - 57· 201221131 phenyl benzoate (11 mg ' 45%). 4 NMR (CDC13): δ 7.83 (m, 3 Η), 7.32-7.13 (m, 6 Η), 5,73 (m, 1 Η), 5.02 (m, 1 Η), 4.73 (m, 1 Η), 3.87 (m, 3 Η), 3.03-2.96 9 (m, 6 Η), 2.19 (m, 1 Η), 1.34 (s, 12 Η), 1.03-0.83 (m, 3 Η), 0.53 (m, 1 Η); LCMS (m/z, ES+) = 677 (M+l) Step 3: 5-cyclopropyl-2-( 4-fluorophenyl)-6-[[(i-pyridyl-i-dihydro-2,i_benzoxoxaborole-6-yl)methyl](methylphenyl)amino] Mercapto-i-benzofuran-3-carboxamide 4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl; benzofuran- 6-yl}(indolyl)amino]mercaptopurine_2·(4,4,5,5-tetramethyldioxos-2-yl)benzoic acid methyl ester (11 mg, hydrazine 1 6 mmol) was dissolved in THF (2 mL) and cooled to 0 °C. A solution of hydrogenated aluminum (〇〇3 mL, 1 Μ in THF) was added and the mixture was stirred for 30 minutes, then poured into ice water and diluted with ethyl acetate and &lt;RTI ID=0.0&gt; Mix for 3 minutes. The aqueous layer was extracted with EtOAc. Purification by reverse phase HPLC gave 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1,3-dihydro-2,1-benzene) as a white solid. Oxazepine heterocyclopentene-6-yl)methyl](methylsulfonyl)amino]-N-mercapto-1-benzofuran-3-decylamine (5 mg, 57%). NMR (CDC13): δ 7.81 (m, 2 Η), 7.56 (s, 1 Η), 7.38 (m, 1 Η), 7.25-7.13 (m, 5 Η), 5.75 (m,1 H), 5.03 ( m 3 H), 4.79 (m, 3 H), 3.01 (s, 1 H), 2.96 (m, 3 H), 2.19 (m, 1 H), 1.02 (m, 1 H), 0.87 (m, 1) H), 0.49 (m, 1 H); LCMS (w/z, ES+) = 549 (M+l). No exchangeable protons were observed. 154007.doc -58 - 201221131 Example 3 5-Cyclopropyl-2-(4-fluorophenyl)_6_[[(1.a-based 13 diaza--21 benzoxahydrocyclopent-4-yl) )methyl](methylsulfonyl)amino]_N_methylbenzofuran-3-cartoamine

Similar to about 5·cyclopropyl 2 -(4-fluorophenyl)_6·[[(1_hydroxy",3_dihydro-2,1-benzoxoxaborole_6_ Methyl](methylsulfonyl)amino]_ Ν-methyl-1- benzofuran·3-formamide in the manner described above from 5-cyclopropyl-2-(4-fluorobenzene ))-Ν·曱基_6_[(sulfonyl)amino]-benzofuran_3_decylamine (18 mg '〇·〇45 mmol) and 3-(bromomethyl)_2_ Methyl iodobenzoate (17 mg, 0.048 mmol; V/MC. 2005, deduct (7), 615) was prepared in 3 steps in 5-cyclopropyl-2_ as a white solid after purification by reverse phase HPLC. (4-fluorophenyl)-6-[[(1-hydroxy-1,3-dihydro-2,1-benzooxaborolan-4-yl)methyl](methylsulfonyl) Amino]-N-methyl-1-benzofuran-3-cartoamine. lHNMR (CDCl3): δ7·80 (m, 2H), 7.61 (m, lH), 7·23- 7.12 (m , 6 H), 5.78 (m, 1 H), 4.96-4.77 (m, 4 H), 3.01 (s, 3 H), 2.94 (m, 3 H), 2.04 (m, 1 H), 0.92 (m) , 1 H), 0.82 (m, 1H), 0.63 (m, 1 H), 0.22 (m, 1 H) ; LCMS (m/z, ES+) = 549 (M+1). No exchangeable protons were observed. Example 4 154007.doc 59· 201221131 5_Cyclopropyl-2-(4- Phenyl)-6-[[(l-mono-l-1,3-dihydro-2, i-benzobenzoborole-5-yl)methyl](methylsulfonyl)amino 】-Ν·Methyl-j-benzobenzoin-3-carboxamide

Similar to about 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(ι_基基_丨3-di-argon-2,1-benzoquinone oxylcyclopentane- 6-yl)methyl](methyl aryl)amines thereof]_N-mercapto-1-benzofuran-3-decylamine in the manner described above from 5-cyclopropyl-2--(4- Fluorophenyl)-N-methyl-6-[(oxasulfonyl)amino]benzaldehyde benzopyrazine_3_carbamamine (124 mg '0.308 mmol) and 5-(bromoindolyl)-2 -Iodobenzoic acid methyl vinegar (109 mg '0.308 mmol ' /OC, 1990, 55(7), page 2064) was prepared in 3 steps in 5_cyclopropyl-2-(5) as a white solid after purification by reverse phase HPLC. 4-fluorophenyl)-6-[[(1-hydroxy-1,3_dihydro-2, penta-5-yl)indolyl](indolyl)amino]_ν·decyldihydro- 2,1-Bist and oxaborolane. 4 NMR (CDC13): δ 7.79 (m, 2 7.23-7.11 (m, 6 Η), 5.73 (m, 1 Η), 5.05 -1- benzofuran _3_曱 (m, 1 H), 2.99 (s, 3 H), 2.95 (m, 3 H), (m, 1 H), 0.86 (m, 2 H), 〇 49 (% i ES+) = 549 (M+l). No exchange is observed. Protons (m, 2 H), 0.49 (m, i no exchangeable protons were observed. 79 (m, 2 H), 7.61 (m, 1 H), H), 5.05-4.94 (m, 4 h), 4.74 m,3 H), 2.16 (m,ih), 0.99 1 H) ; LCMS (m/z, Example 5 2-(4-fluorophenyl)-6-[[(1-hydroxy-1)&gt;稀(_4_yl)methyl](methanesulfonyl)amino]_Ν Dihydro-2,1-benzoxoxaborole]-Ν-methyl_5-[(ι·methyl Ethyl)oxy 154007.doc 201221131 base]-1-benzofuran-3-carboxamide

Similar to about 5-cyclopropyl-2_(4-fluorophenyl)_6_[[(1_hydroxy-1,3·dihydro-2,1·benzooxaborole-6-yl) (曱)](methylsulfonyl)amino]_ Ν-fluorenyl-1-benzofuran_3_decylamine in the manner described by 2·(4-fluorophenyl)·Ν·methyl Benzyl)oxy]_6 [(methylsulfonyl)amino] benzobenzoin-3-carboxamide (148 mg, 0.352 mmol) and 2-(bromomethyl)-6-mothene formate Methyl vinegar (125 mg, 0.352 mmol, five μγ· «/. Med· CAew., 2005, 4吖7; 'p. 615) was prepared in 3 steps in a white solid after purification by reverse phase HPLC. (4-fluorophenyl)-6-[[(1-hydroxy-1,3-dihydro-2,1-benzooxaborole-4-yl)methyl](methylsulfonyl) Amino]-N-methyl-5-[(1·methylethyl)oxy]_1_benzofuran_3_decylamine. 1HNMRd6-DMSO: δ 9.16 (s, 1 Η), 8.41 (m, 1 Η), 7.87 (m, 2 Η), 7.56 (m, 1 Η), 7.41 (s, 1 Η), 7.34 (m, 2 Η), 7.22 (m, 2 Η), 7.06 (s, 1 Η), 5.09-4.74 (m, 4 Η), 3.13 (s, 3 Η), 2.79 (m, 3 Η), 1.34 (br s, 6 Η) ; LCMS (m/z, ES+)=567 (Μ+1). No exchangeable protons were observed. Example 6 2-(4-Fluorophenyl)-6-indole [(1-hydroxy-indole, 3-dihydro-2,1-benzoxoxaborole-5-yl)methyl] ( Methanesulfonyl)Amino]_Ν_Methyl_5-[(1-methylethyl)oxy 154007.doc • 61 - 201221131 】-1-Benzoacetate-3-cartoamine iPrO CONHMe MeSO .

Similar to about 5·cyclopropyl-2-(4-fluorophenylhydroxy-u-dihydro-2,1-benzooxaborole-6-yl)indolyl] Amino]-N-methyl-1-benzofurancarboxamide in the manner described by 2-(4-fluorophenyl)-indolemethyl-5-[(1-methylethyl)oxy Base]-6·[(oxasulfonyl)amino] benzobenzopyran-3-carboxamide (96lmg, 2.29mm(^5_mf&amp;)_24 formic acid Ml. 1〇g ' 3.09 mm〇l 2-(4-Fluorophenyl)_6_[[(1•hydroxy_DU'1-benzoxazepine) is obtained as a white solid after purification by reverse phase muscle C in three steps. Methyl](anthracenyl)amino]-N-mercapto-5-[(1-methyl- 7-glycol, 匕w ί Αethyl)oxy]- 1- benzofuran-3- Guanamine. NMR (CDC13): δ 7 , 3; δ 7.70 (raj 2 Η), 7.57 (m, 2 H), 7.37 (s, 1 H), 7.27-7.11 (m, 5 c , H), 5.69 (m, 1 H), 5.09-4.50 (m 5 H), 3.02 (s, 3 H), 2.91 ^ 〕

(10), 3 H), 1.45 (m, 6 H); LCMS (m/z, ES+) = 567 (M+l) 〇 Example 7 5-cyclopropyl-2-(4-fluorophenyl)_6 ru, 1 J 6-[[(2_hydroxy-1,2-oxaboron-4-yl)methyl](methanesulfonyl)amino]-N-methyl,, +„ 】 Tl-1-benzene Furan-3-carboxamide

MeSO

I54007.doc 201221131 Step 1: 3-Chloro-2-(chloroindolyl)propane-i-ene was added dropwise to a solution of sulfite gas (290 g, 119 mmol) in DCM (200 mL). A mixture of mercaptopropane-1,3-diol (88 g, im〇1), anhydrous pyridine (150 mL) and anhydrous DCM (10 mL). The reaction mixture was heated to reflux with stirring for 3 hours and then allowed to stand overnight. The mixture was cooled to room temperature and poured into ice. The solution was neutralized with solid sodium hydrogencarbonate and then extracted with diethyl ether (3.times..sup.6 L), and then the ether extract was washed with dilute sulfuric acid. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 32%). Step 2: ((2-(Chloromethyl) allyloxy) indenyl)benzene was added to a dry flask to add DME (240 mL), sodium nitrite (4.12 g, 120 mmol), and then benzene was added dropwise. Methanol (12.4 mL, 120 mmol). After the complete addition, the mixture was heated to reflux for 1 hour, and the mixture was cooled to 0 ° C in an ice water bath and added 3·gas-2-(gasmethyl)prop-1-ene (12.7 mL' in 1 part. 120 mmol). The mixture was heated to reflux for 19 hours to cool to room temperature and poured into saturated aqueous sodium bicarbonate (250 mL). The aqueous layer was extracted with diethyl ether (4×200 mL). The combined organic layers were dried <RTI ID=0.0>(</RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> (10.7 g, 45.5%) ° LCMS (m/z, ES+) = 219 (M+l) Step 3: ({[2-(bromomethyl)-2-propen-1-yl]oxy} yl) To the drying flask, (2- gas decylallyloxymethyl)benzene (8.70 g, 44.4 mmol), quaternary ammonium chloride 336 (Aliquat 336) (1 mL, 2.22 154007.doc • 63) · 201221131 mmol), anhydrous THF (22.6 mL) and anhydrous LiBr (7.72 g, 88.78 mmol). The reaction mixture was stirred in a 60 ° C oil bath for 2 hours and then cooled to ambient temperature. The mixture was filtered using Florisil and washed with sulphur. The volatile component was removed in vacuo to give (m.m.)-2-propyi-1 -yl]oxy}methyl)benzene (6, 53 g, 6 %) as a colorless oil. MS {m/z, ES+)=223 (M+l) Step 4: 5-cyclopropyl-2-(4-fluorophenyl)_N_indolylsulfonyl) (2_{[(phenylmethyl)) Oxy] fluorenyl}-2-propen-1-yl)amino]dihydro·1 benzo-yano-3-branched amine maintains 5_cyclopropyl_2_ under stirring at 8 (TC) 4-fluorophenylindenyl-6-[(decylsulfonyl)amino]-benzofuran_3_formamide (1 4〇〇g, 3 48 mmol), ({[2-(bromo) a suspension of 2,2,1,1,1,1,5,5,5,5,5,5,5,5 The mixture was concentrated under reduced pressure and diluted with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 5_cyclopropyl-2-(4-fluorophenyl)_N•methyl_6_[(oxasulfonyl)(2 {[(phenylhydrazo)oxy]methyl}-2-propene_ι·yl Amino] small benzofuran_3_formamide (丨g, 3.02 mmo, 87% yield). LCMS (w/z, ES+) = 563 (M+1). Step 5: 5-cyclopropyl Base_2·(4-fluorophenyl)N f-based _6_((methylsulfonyl)-[(benzyl)oxy]-2-[(4,4,5,5- Tetramethyl-1,3,2-dioxaboran-2-yl)f-yl]propyl}amino)-5,6-dihydro-benzofuran_3_decylamine 5-mercaptopropyl 2 (4-fluoro-based)_N-methyl-6-[(methyl sulfhydryl) (2·{[(phenylmethyl)oxy)fluorenyl}_2-propenyl)amino]_b a solution of benzofuran imine 154007.doc 201221131 (1.58 g, 2.81 mmol) and Rh(CO)Cl(PPh3)2 (〇.194 g, 0.281 mmol) in tetrahydrofuran (30 mL) with HBPIN (2.426) The mixture was treated with EtOAc (3 mL). -cyclopropyl-2-(4-fluorophenylmethyl-6-((methylsulfonyl){3-[(benzyl)oxy].2-[(4,4,5,5- Tetramethylhydrazone_1,3,2-dioxaboron-2-yl)methyl]propyl}amino)_1_benzofuran_3_decylamine (1.63 g, 2.360 mmol ' 84% yield LCMS 〇/z, ES+)=691 (M+1) Step 6: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1ί2_oxyboron) _4_ 基)Methyl](A)-amino]-indole-methyl-1-benzoxam-carbamoylamine at 50 psi (psi): under gas Maintain 5_cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-((methylsulfonyl){3-[(phenylhydrazino)oxybu 2_[(4, 4,5,5-tetradecyl-1,3,2-dioxan-2-yl)indolyl]propyl}amino)-1-benzofuran-3-carboxamide (1.25 g' A suspension of 1.810 mmol) and 10% Pd/C (Degusset type '750 mg) in tetrahydrofuran (5 mL) for 16 hours. The mixture was purged with nitrogen, filtered through celite, and the celite was washed with additional THF and chloroform. The filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran and treated with &lt;RTI ID=0.0&gt;&gt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&gt; The suspension was stirred for 2 hours, filtered, and concentrated under reduced pressure to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-i) - Oxygen oxime _4_yl)methyl](methylsulfonyl)amino]-N-mercapto-1-benzofuranylcarbamide (973 mg, 1.945 mmol, quantitative yield). 1h NMR (CDC13): 154007.doc -65- 201221131 δ 7.83 (m, 2 Η), 7.44 (m, 1 Η), 7.26-7.14 (m, 3 Η), 5.71 (m, 1 Η), 4.30- 4.06 (m, 2 Η), 3.90-3.62 (m, 3 Η), 2.96 (m, 3 Η), 2.58-2.27 (m, 2 Η), 1.23 (m, 2 Η), 1.15-1.06 (m, 3 Η), 0.95-0.67 (m, 3 Η); LCMS (m/z, ES+) = 501 (Μ +1). No exchangeable protons were observed. Examples 8 and 9 (+) and (-)-5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1,2-oxobutyr-4-yl)-) Base] (methanesulfonic acid) amine group]-N-methyl-1-brown and biting _3·armamamine

(士)-5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-amino-1,2-oxoindole-4-yl) fluorenyl] Amino]mercaptobenzofuran-3-indoleamine was resolved into individual enantiomers by dissolving in 1:1 chloroform:nonanol and using supercritical fluid chromatography (25% Me0H/ C02, 140 bar (bar), 10 ml/min, ChiralPak 1C 10χ250 mm, 254 nM) were separated to produce 241 mg and 298 mg earlier and later dissolved diastereomers. Isomer: 4 NMR (chloroform-d) δ: 7.78-7.95 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.20 (m, 2H), 5.75 (br. s., 1H), 4.32 (br. s., 1H), 4.05-4.21 (m, 1H), 3.54-4.00 (m, 3H), 2.91-3.14 (m, 6H), 2.17-2.68 (m, 2H), 1.03-1.25 (m, 3H), 0.66-1.02 (m, 3H)» LCMS (7w/z, ES+) = 501 (M+l). Late dissolving enantiomer: NMR (gas-d) 154007.doc -66· 201221131 d: 7.78-7.95 (m, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.13-7.24 (m, 2H), 5.76 (d, J=3.7 Hz, 1H), 4.36 (br. s., 1H), 4.04-4.22 (m, 1H), 3.56- 4.01 (m, 3H), 2.87-3.13 (m, 6H), 2.21-2.66 (m, 2H), 1.05-1.25 (m, 3H), 0.63-1.05 (m, 3H). LCMS (w/z, ES+) = 501 (M+l). Example 10 [({3-丨{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]benzofuran-6-yl}(methyl aryl)amine Propyl}oxy)methyl]decanoic acid

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-royl-6-((methioninyl)[(benzyl)oxy]propyl}amino)-1- Stupid. Potassium 3-carbamine potassium carbonate (0.209 g, 1.5 mmol) and benzyl 3-bromopropyl ether (0.198 mL, 1.1 mm 〇G added to 5-cyclopropyl·2·(4-fluorobenzene) )λγ-曱基·6_[(oxasulfonyl)amino]-1-benzofuran-3-indoleamine (2〇1 mg, ο” mmol) in acetonitrile (5.5 mL total volume) In a suspension, the mixture was heated under reflux for 2.5 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL). The organic layers were combined, dried over sulphuric acid, filtered and evaporated. The crude product was purified by column chromatography to give 5-cyclopropyl-2-(4-fluorophenylindenyl-6-((methylphenyl)) (3·[(benzoyl)) as a colorless oil. Oxy]propyl}amino)-1-indolofuran-3-indoleamine (334 mg, quantitative yield 154007.doc •67·201221131 rate). LCMS (m/z, ES+)=551 (Μ +l) Step 2. 5-Cyclopropyl-2-(4-fluorophenyl)-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-#-methyl-1- Benzofuran-3-carboxamide added 10% palladium on carbon (0.12 g) to 5-cyclopropyl-2-(4-fluorophenyl)-carbocyclyl-6-((methylsulfonyl){ 3-[(phenylhydrazino)oxy]propyl}amino)) 丨 benzofuran _3_ a mixture of decylamine (270 mg, 0.49 mmol) in ethyl acetate (24.4 mL). The mixture was shaken on a Parr shaker under a hydrogen atmosphere of 0.4 MPa for 25 hours. The mixture was rinsed with ethyl acetate and methanol. Filtration of the diatomaceous earth. The broth was concentrated under reduced pressure and the crude product was purified by column chromatography to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[ 3-hydroxypropyl)(anthracenyl)amino]-iV-mercapto-1 -benzofuran-3-carbamide. The oil was dissolved in ethyl acetate and wet-milled via petroleum ether. To give a white solid (丨25 mg, 55.% yield). LCMS (tw/z, ES+) = 461 (M+1). Step 3: [({3-[{5·cyclopropyl-2 -(4-fluorophenyl)-3-[(decylamino)carbonyl]_ι·benzofuran-6-yl}(methylsulfonyl)amino]propyl)oxy)methyl]-tanning Maintenance of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(3-hydroxypropyl)(aminophenyl)amino]-N-methyl-1-benzofuran at 80 C _3-Proline (100 mg, 0.217 mmol), 2-(bromomethyl)·4,4,5,5-tetramethyl-1,3,2-dioxaboron (120 mg '0.543 mmol) And carbonic acid clock (90 mg, 0.651 mmol) at Carbonitrile (5 mL) in the solution for 6 hours. The mixture was cooled, diluted with chlorohydrazine and filtered through celite. The filtrate was concentrated under reduced pressure, purified by column chromatography, and purified by reverse phase HPLC to yield [[{{[[5-- 5-[ Phenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]propyl}oxy)methyl]oxime 154007.doc 201221131 acid ( 38 mg, 0.073 mmol, 33.8% yield). 1H NMR (gas-d) δ: 7.79-7.95 (m, 2H), 7.51 (s, 1H), 7.31 (s, 1H), 7.11-7.25 (m, 2H), 5.68-5.89 (m, 1H), 5.00 (br. s., 1H), 3.71-3.97 (m, 2H), 3.42-3.62 (m, 2H), 3.21 (s, 2H), 3.02 (s, 3H), 3.00 (d5 J=5.1 Hz, 3H), 2.21-2.40 (m, 1H), 1.73-1.90 (m, 2H), 1.64 (br. s., 1H), 1.03-1.16 (m, 2H), 0.88-1.01 (m, 1H), 0.72 (dd, 1H). LCMS (m/2, ES+) = 519 (M+l). Example 11 [3-({2-[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl)-1-benzofuran-6-yl}) Sulfhydryl)amino]ethyl}oxy)propyl]decanoic acid

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl)[2-(2-propen-1-yloxy)ethyl] Amino-benzofuran 3-carbamide maintains 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)amine at room temperature ]]-N·decyl·1_benzofuran_3-carboxamide (228 mg, 〇·511 mmol, PCT International Application 2004, WO 2004041201), BINAP (63.6 mg, 0.102 mmol), Pd2 (dba) 3 (46.8 mg, 0.051 mol) and a solution of thiol anti-smectone (0.087 mL, 0.766 mmol) in tetrahydrofuran (5 mL) for 16 h. The mixture was mixed with diatomaceous earth, quenched with sterol 'concentrated under reduced pressure' and purified by column chromatography to give 5-cyclopropyl-2- as a white 154007.doc-69-201221131 foam. (4-fluorophenyl)-N-fluorenyl-6·{(methylsulfonyl)[2-(2-propen-1-yloxy)ethyl]aminobenz benzofuran_3 decylamine (168 mg, 0.345 mmol, 67.6% yield). Step 2: 5-Cyclopropyl-2-(4-fluorophenylμΝ_methyl_6_[(methylsulfonyl{[3-(4,4,5,5-tetramethyl-1,3, 2-dioxaboron-2-yl)propyl]oxy}ethyl)amino]-1-benzo-flavone-3-carboxamide 5-cyclopropyl-2-(4-fluorobenzene ))-Ν-methyl-6-{(methylsulfonyl)[2-(2-propen-1-yloxy)ethyl]amino}-1_benzofuran·3·bristamine 127 mg, 0.261 mmol) and Rh(CO)Cl(PPh3)2 (18.01 mg, 0.026 mmol) in tetrahydronamine (8 mL) were treated dropwise with HBPIN (0.783 mL, 0.783 mmol) and The mixture was maintained for 6 hours with stirring. The mixture was concentrated on diatomaceous earth and purified by column chromatography to give 5-cyclopropyl-2-(4-fluorophenyl hydrazine-methyl-6-{(methylsulfonyl) [2_(propoxy)ethyl]amino}_丨_benzofuran_3-carbamamine contaminated 5_cyclopropyl_2_(4-fluorophenyl)N_indenyl_6_[( (2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)propyl]oxy}ethyl)amine 1-benzofuran_3·decylamine (142 mg, 0.162 mmol, 62.0% yield) (approximately 2: i). Step 3: [3-({2-[{5-cyclopropyl) -2-(4-fluorophenyl)-3-[(methylamino)carbonyl]_ 1-benzopyrene -6-yl}(indolyl)amino]ethyl methoxy)propyl] decanoic acid maintained 5-cyclopropyl-2-(4-fluorophenyl)-N-fluorenyl group ·6·[(oxasulfonyl) (2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)propyl]oxy } Ethyl)amino]bromofuran-3-carboxamide (140 mg, 0.137 mmol), polymer-supported phenylglycolic acid (10 〇 mg, 2.73 mmol) and 1.0 N HCl (aqueous solution) ( 2.73 mL, 2.73 mmol) suspension in tetrahydrofuran (15 mL) 154007.doc -70·201221131 16 hr. The mixture was filtered over Celite, concentrated under reduced pressure and purified by column chromatography (MeOH) Purification to obtain [3-({2-[{5-cyclopropyl-2-(4-fluorophenyl)_3_[(decylamino)carbonylbenzofuran) in the form of a white bubble. 6-yl}(methylsulfonyl)amino]ethyl}oxy)propyl]carboxylic acid (22 mg '0_041 mmo, 30% yield). NMR (gas imitation - £1) 3:7.82- 7.97 (m, 2H), 7.51 (s, 1H), 7.32 (s, 1H), 7.13-7.24 (m, 1H), 5.70-5.87 (m, 1H), 3.99-4.21 (m, 1H), 3.75-3.89 (m, 1H), 3.41-3.65 (m, 5H), 3.11 (s, 3H), 3.00 (d, J = 4.9 Hz, 3H), 2.23-2.42 (m, 1H) , 1.63-1.80 (m, 2H), 1.19-1.34 (m, 1H), 1.03-1.16 (m, 2H), 0.64-0.99 (m, 3H), (2 exchangeable protons are not obvious). LCMS (w/z, ES+) = 533 (M+l). Example 12 [({2-[{5·cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl)benzofuran-6-yl}(methylsulfonyl)amino group Ethyl}oxy)methyl]-acid

Maintenance of 5-cyclopropyl·2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(indolyl)amino]-indolyl-1-benzofuran under reflux _3_decylamine (150 mg, 0.336 mmol) and 2-(glymethyl)_4,4,5,5-tetradecyl-1,3,2-dioxaboron (186 mg, 0.840 mmol) A suspension of potassium carbonate (139 mg ' 1.008 mmol) in acetonitrile (5 mL) was applied for 24h. The mixture was cooled, concentrated with dichloromethane (EtOAc) EtOAc (EtOAc) The residue was diluted by trituration, and the residue was purified by EtOAc. EtOAc (EtOAc: EtOAc) And furan-6-yl}(methylsulfonyl)amino]ethyl}oxy)indolyl]Sp-acid (65 mg, 〇·129 mm〇1, 38 4〇/〇 yield). 4 NMR (chloroform-d) δ: 7.78-7.95 (m, 2H), 7.60 (s, 1H), 7.34 (s, 1H), 7.11-7.24 (m, 2H), 5.79 (br. s., 1H) , 3.07-3.79 (m, 6H), 2.92-3.05 (m, 6H), 2.20-2.39 (m, 1H), 1.02-1.18 (m, 2H), 0.87-1.00 (m, 1H), 0.60-0.84 ( m, 1H) (2 exchangeable protons are not obvious). LCMS (m/z, ES+) = 5 〇 5 (M+l). Example 13 {3-[{2-丨{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]_5_[(1-methylethyl)oxy]-1-benzofuran -6-yl}(methylsulfonyl)amino]ethyl}(methyl)amino]propyl}-acid

Step 1: 2-[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1-benzoate methanesulfonate Furan-6-yl}(methylsulfonyl)amino] acetoacetate treated with MsC1 (0.092 mL, 1.175 mmol) at 0 ° C 2-(4-d-phenylphenyl)-6-[(2-hydroxyethyl) (methanesulfonyl)amino]-N-methyl-5-[(l-mercaptoethyl)oxy]-benzofuran-3-carboxamide (312 mg, 0.672 mmol) and 154007.doc • 72- 201221131 DIPEA (0.352 mL, 2.015 mmol) in dichlorohydrazine (DCM) (1 mL) and maintained at (TC) for 2 hours under stirring. The solution was poured to saturated hydrogen carbonate. The organic layer was separated, dried over sodium sulfate, filtered and evaporated tolulululululululululululululululu (4-fluorophenyl)·3_[(methylamino m&amp;]_5[(1_methylethyl)oxy]-1_benzofuran_6_yl}(sulfonyl)amino]B Ester (294 mg '0.542 mmol '81% yield). [CMS (m/z, ES+) = 543 (M+1) ° Step 2 · 2_(4_Phenyl)-N-methylmethyl Ethyl]oxy]_6_[{2_ [methyl(2-propen-1-yl)amino]ethyl Amidino)benzotrile-3-carbamide maintains methanesulfonic acid 2_[{2-(4-fluorophenyl)-3-[(amine) in a sealed pressure flask at 80 C with stirring Carbonyl]•,[(i-ethylethyl)oxy]-benzoxan-6-yl}(indolyl)amino]ethyl ester (284 mg, 〇523 mmol), potassium carbonate (217 Mg, 1.570 mm〇i) and decylallylamine (1·〇〇3 mL, 10.47 mmol) in a suspension of hydrazine, hydrazine-dimethylhydrazine (5 mL) for 48 hours (added at 24 hours) Additional methylallylamine (1〇〇3 m]L, 1〇47 mmol)). The solution was cooled, poured into ethyl acetate and washed sequentially with LiCl (aq) and saturated sodium sulfate (aq). The organic layer was dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Ethyl]oxy]-6-[{2-[indolyl(2-propen-1-yl)amino]ethyl}(methylsulfonyl)amino]-1-benzofuran-3-indole Amine (132 mg, 0.255 mmol, 49% yield). LCMS (m/z, ES+) = 518 (M+1). 154007.doc ·73· 201221131 Step 3: {3-[{2-[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl) )oxy]-1-benzofuran-6-yl}(methylsulfonyl)amino]ethyl}(methyl)amino]propyl} propyl acid with 1 Μ HBPIN in THF (0.638 mL, Treatment of 2-(4-fluorophenyl)-N-indenyl 5-((l-decylethyl)oxy]-6-[{2-[methyl(2-propen-1-yl) with 0.638 mmol) Amino]ethyl}(methylsulfonyl)amino]-1-benzofuran·3_decylamine (110 mg, 0.213 mmol) and Rh(CO)Cl(PPh3)2 (7.33 mg, 10.63) A solution of the solution in tetrahydrofuran (5 mL) was maintained at room temperature for 15 hours with stirring. The mixture was concentrated under reduced pressure and purified by reverse phase hplc to yield a mixture of acid and acid. The residue was dissolved in THF (5 mL) and 5.0 N EtOAc (EtOAc) Polymer-supported benzene-acid (3.9 mmol/g '400 mg) was added and the suspension was maintained under rapid stirring for 24 hours. The mixture was filtered through celite, and the solid was washed with acetonitrile/water, and the filtrate was concentrated under reduced pressure and again by reverse phase hplc to give a white bubble-like shape of 3-3-[{2-[{2-(4) - gas base) _3_[(methylamino) benzyl]-5-[(l-methylethyl)oxy]_ι_benzofuran _6_yl fluorenyl) (Methyl)amino]propyl}-acid (6 mg, 1 〇 65 μϊη〇ι, 5% yield). NMR (methanol-d4) δ: 7.82-7.96 (m, 2 Η), 7.62 (s, 1 Η), 7.11-7.34 (m, 3H), 4.13 (br. s., 1H), 3.80 (br. s.5 1H), 3.05 (s, 3H), 2.98 (br. s., 2H), 2.94 (s, 3H), 2.78 (br. s., 3H), 2.60 (br. ss 4H), 1.55-1.69 (m , 2H), 1.45 (d, 6H), 0.74 (m, 2H). LCMS (w/2, ES+) = 564 (M+l). Example 14 5-Ethyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1,2-oxaboron-4-yl)methyl] (A 154007.doc -74· 201221131 Sulfhydryl)amino]methyl-1-benzofuran-3-formamide

Step 1. 5-Ethyl-2-(4-fluorophenyl)-fluorenyl-fluorenyl-6-[(methyl aryl) (2-{[(indolyl)oxy]fluorenyl}-2 -propion-1-yl)amino]·ι_ 吱曱 and decanoic acid added potassium carbonate (642 mg, 4.65 mmol) and ({[2-(bromoindolyl)-2-propan-1-yl) ]oxy}indenyl)benzene (825 mg, 3.44 mmol) to 5-ethyl-2-(4-fluorophenyl)-iV-methyl-6-[(methylsulfonyl)amino]_ι_ Benzofuran-3-decylamine (600 mg, 1.54 mmol, PCT International Application 2004, WO 2004041201) was suspended in acetonitrile (7.5 mL). The mixture was maintained overnight under reflux, cooled, diluted with water and extracted with di-methane. The organic layer was combined, dried over magnesium sulfate, filtered, evaporated, evaporated, m. 1,1-oxoboromid-4-yl)indenyl](indolyl)amino]-iv-indenyl-1-benzofuran-3-indoleamine (180 mg, 21%) Yield). LCMS (w/z, ES)=551 (M+1) 〇 Step 2: 5-ethyl-2-(4-fluorophenyl)-N-methyl-6-((methylsulfonyl){3 -[(phenylf-yl)oxy]-2-[(4,4,5,5-tetramethyl-l,3,2-dioxaboron-2-yl)methyl]propyl}amino )-1-Benzo-indole-3-amine to 5-ethyl-2·(4-fluorophenyl)-6-[[(2-hydroxy-1,2-oxobenol-4-yl) )methyl](nonylsulfonyl)amino]mercapto-1-benzofuran_3_decylamine (330 154007.doc •75· 201221131 mg), [Ir(COD)Cl)]2 (40 A mixture of mg) and DPPE (47 mg) was suspended in THF (18 mL). The mixture was cooled to 〇 ° C under nitrogen and HBPIN ( 767 mg) was added. The mixture was stirred at room temperature for 48 hours. The solution was filtered through celite and the filtrate was diluted with ethyl acetate and water and stirred for 5 min. The organic layer was washed with brine and dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure and purified by preparative HPLC to yield 5-ethyl-2-(4-fluorophenyl)-iV -Methyl-6-((indolyl){3-[(benzyl)oxy]-2-[(4,4,5,5-tetradecyl-1,3,2-dioxo) Boron-2-yl)methyl]propyl}amino)_1_benzopyrene_3_carbamamine (220 mg, 54% yield). LCMS (m/z, ES+) = 679 (M+1). Step 3: 5-Ethyl-2-(4-fluorophenyl)-6-[[(2-pyridyl-1,2-oxo-n-yl-4-yl)indolyl](nonylsulfonyl)amine 5-ethyl-2-(4-fluoroquinoline) was mixed with Pd/C (140 mg) under argon at 0.4 MPa under argon at 0.4 MPa. Methyl-6-((oxasulfonyl){3·[(phenylhydrazino)oxy]_2_[(4,4,5,5-tetradecyl-1,3,2-dioxaboronium) a solution of -2-yl)methyl]propyl decylamino) benzoxofan-3-carboxamine (220 mg, 0.32 mmol) in ethyl acetate for 48 hours. The filtrate was evaporated under reduced pressure to give a white solid which was purified by preparative HPLC to give &lt;RTI ID=0.0&gt;&gt; Oxygen-flavor-4·yl)methyl](methyl mercapto)amino]^-methyl-1-benzofuran-3-cartoamine (6 mg, 38% yield). 4 NMR (300 MHz, MeOD) δ: 7.96 (m, 2H), 7.72 (m, 2H), 7.27 (m, 2H), 3.71 (m, 4H), 2.98 (m, 3H), 2.94 (m,

5H), 2.05 (m, 1H), 1.34 (m, 3H), 0.98 (m, 2H). LCMS (w/z, ES+) = 495 (M+l). The two exchangeable protons are not obvious. 154007.doc -76- 201221131 Example 15 2-(4-Fluorophenyl)-6-[[(2-hydroxy-1,2-oxoboryl-4-yl)methyl](methyl-indenyl)amine ]]-N-methyl- 5-(1-methylethyl)·1-benzo-cough taste

Step 1: 2-(4-Fluorophenyl)-5-(1-methylvinyl)shisylbenzopyrene °N-3-carboxylic acid ethyl acetate 2-(4-fluorophenyl)-6-nitro -5-{[(Trifluoromethyl)sulfonyl]oxybenzoate ethyl benzofuran-3-carboxylate (2.27 g ' 4.77 mmol), KF (0.910 g, 24 mmol), NaBr (0.488 g ' A solution of 9.54 mm〇l), i_propenyl acid (0.613 g, 7.1 mmol) and Pd(PPh3) 4 (274 mg, 0.24 mmol) was dissolved in toluene and water (24 mL). The flask was purged with nitrogen and refluxed under nitrogen for 25 h. The mixture was cooled to room temperature, diluted with ethyl acetate and brine and brine. The organic layer was dried with sodium sulfate, filtered and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj _6_Nitrobenzofuran_3_carboxylic acid ethyl ester (1.5 g, 85% yield). [CMS 〇/z, ES+) = 370 (M+1). Step 2: 6-Amino-2-(4-fluorophenyl)-5-(1-methylethyl)-indole-benzofuran-3-carboxylate at room temperature under hydrogen atmosphere with pd/c(3)75 g) A solution of 2 (4-fluorophenyl) 5-(1-methylvinyl)-6-6-nitro-indole benzofuran-ethyl acetate (1.5 g) in ethyl acetate was stirred for 12 hr. The mixture was filtered through celite and the mash was evaporated under reduced pressure. The obtained solid was washed with diethyl ether to give 6-amino-2-(4-fluorophenyl)_5_(1·methylethyl hydrazinobenzofuran-3) as a pale yellow 154007.doc • 77-201221131 color solid. - ethyl formate (1.1 g, 79 〇 / 〇 yield). lcms (w / z, es +) = 342 (M + 1) ° Step 3.2 - (4 · fluorophenyl • methyl ethyl) _ 6 to A Sulfhydryl)amino]_benzophenan-3-carboxylic acid with methanesulfonate (0.6 mL, Π.3 111111〇1) to 6-amino-2_(4-fluorophenyl)-5_( Ethyl 1-nonylethyl hydrazide - benzofuran _3_carboxylate (1"g, 爻22 mmol) in a cold solution of di-methane (ice/water bath). Mixture with DIPEA (1_3 mL) After treatment with 8.1 mmol), the mixture was stirred for 1 hour with warming to room temperature. The mixture was diluted with water and extracted with di-methane. The organic layers were combined, dried over magnesium sulfate and evaporated to give a yellow solid. Potassium hydroxide (4 56 g, 8 〇mm〇1) and water were added to the acetaldehyde, and the mixture was maintained under reflux for 5 hours and then concentrated under reduced pressure. The remaining solid was dissolved in water and the solution was neutralized with 丨N. Until a precipitate forms. The solid passes through the vacuum Collected by filtration to give 2-(4-fluorophenyl)-5-(1-methylethyl)-6-[(methylsulfonyl)aminobenzofuran_3_decanoic acid (1.25 g, 80) as a white solid. % yield). [CMS (m/z, ES+) = 392 (Μ +1). Step 4: 2-(4-fluorophenyl Ν Ν _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Methylsulfonyl)amino]-1-benzobenzoin-3-carboxamide was treated with triethylamine (0.98 mL), HATU (1.46 g) and decylamine (0.8 mL of 2 hydrazine solution) 2-( 4-fluorophenyl-mercaptoethyl)_6_[(methylsulfonyl)amino]1-benzo-fus--3-carboxylic acid (ι·25 g '3.2 mmol) in DMF and in a solution The solution was stirred under a gas atmosphere for 5 hours, and the mixture was concentrated under reduced pressure and the obtained oil was dissolved in methylene methane and 2 〇M HCl (aqueous solution). Organic I54007.doc 201221131 layer was separated by knife and magnesium sulfate Drying, filtration, concentrating under reduced pressure, and purifying by EtOAc EtOAc (EtOAc) [(Methanesulfonyl)amino benzofuran _3· mercaptoamine (0.98 g, 76% yield). LCMS 〇/z, ES+) = 405 (M+1). Step 5: 2-(4-Fluorophenyl)_N_methyl·5_(1_methylethyl)_6_[(7-sulfonylphenylphenyl)oxy]indolyl}_2-propenyl)amino ]ι benzophenone-3-carboxamide• Add potassium carbonate (5 16 mg, 3.74 mmol) and ({[2-(bromomethyl)-2-propen-1-yl)oxy} fluorenyl) Benzene (663 mg, 2.76 mmol) to 2-(4-fluorophenyl)-#-methyl-5-0 methylethyl[(methylsulfonyl)amine benzyl bromide-3-carboxamidine A suspension of the amine (5 mg, i_24 mmol) in acetonitrile (6 mL). The mixture was maintained overnight under reflux with stirring, cooled, diluted with water and extracted with a dichlorohydrazine. The organic layer was combined, dried with EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH _Methylethyl)_6_[(甲计醯• 基)(2_{[(Benzyl)oxy)methyl}-2-propen-1-yl)amino]benzophenan-3-yl Indoleamine (620 mg, 89% yield pLCMS (w/z, ES+) = 565 (M+1) ° Step 6: 2-(4-fluorophenyl)-6·[[(2-amino-1) , 2-oxo boron _4·yl)methyl](methyl decyl)amino]mercapto-5-(1-methylethyl benzo oxazolamide is cooled in a nitrogen atmosphere 2 (4·fluorophenyl)-#-fluorenyl·5-(ι_methylethyl)_6-[(methylsulfonyl)(2-{[(phenylmethyl)oxy]methyl}· 2-propenyl-amino)amino]·1·benzofuran-3-carboxamide (620 mg), [Ir(COD)Cl]2 (74 mg), 154007.doc -79- 201221131 dppe (87 Mixture of mg) and THF (25 mL). Add hydrazine (1·40 g) and the mixture was stirred at ambient temperature for 48 hours. The mixture was filtered over celite and the filtrate was partitioned between ethyl acetate and water. And stirred for 5 minutes. The organic layer was washed with water and brine, separated, and sodium sulfate was added. Drying, filtration, EtOAc (EtOAc m.) Ethyl acetate (1 〇 mL) was mixed with Pd/C (100 mg) for 48 hours under 0.4 MPa of hydrogen. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure and purified by preparative Hpl. To give 2-(4-fluorophenyl)-6-[[(2-hydroxy-1,2-oxoboran-4-yl)indolyl](methylsulfonyl)amino) as a white solid Methyl-5-(1-mercaptoethyl)-1_benzophenan-3-carboxamide (7 mg, 5 〇 / 〇 yield) NMR (300 MHz, MeOD) δ 7.93 (m, 2Η), 7.70 (m} 2H), 7.27 (m, 2H), 3.69 (m&gt; 4H), 3.06 (m, 3H), 2.98 (m, 3H), 2.04 (m, 2H), 1.30 (m, 6H) ), 0.93 (m, 2H). [CMS (m/z, ES+) = 503 (M+l). 2 exchangeable protons are not obvious. Example 16 2_(4-Phenylphenyl)-6-[[( 2-hydroxy-1,2-oxoborom-4-yl)methyl](methylsulfonyl)amine-based N,S-dimethyl·ι_benzofuran_3·formamide

Step 1: 2~(4-Fluorophenyl)-5-methyl-6-nitro-1-benzofuran-3-carboxylic acid 154007.doc 201221131 Ethyl acetate vaccination 2-(4-fluorophenyl)-6 -Nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylic acid ethyl ester (2.86 g, 6 mmol), KF (1.15 g, 30 mmol), A solution of NaBr (614 mg, 12 mmol), thioglycolic acid (538 mg, 9 mmol) and Pd (PPh3) 4 (345 mg '0.3 mmol) in terpene (30 mL) for 3 min and then purified with nitrogen . The mixture was refluxed under nitrogen for 24 hours, cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried with sodium sulfate, filtered, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl 3-carboxylate (2.2 g, quantitative yield). [CMS 〇/z, ES+) = 344 (M+1). Step 2: 6-Amino-2-(4-fluorophenyl)-5-methyl-1_benzofuran·3·carboxylic acid ethyl acetate 2-(4-fluorobenzene) at room temperature under hydrogen atmosphere a solution of p-alladium/carbon in ethyl acetate (100 g, 6.4 mmol) in ethyl acetate (100 mL) Stir together overnight. The mixture was filtered through celite and the filtrate evaporated in vacuo. The resulting brown solid was triturated with MeOH (MeOH) to afford ethyl 6-amino-2-(4-fluorophenyl)-5-methyl-m-benzopyranyl-3-yl-formate as a solid N (1.07 g, 53 〇/〇 yield). LCMS (w/2, es+) = 314 (M+l) 〇 Step 3: 2-(4-Fluorophenyl)-5-methyl-6-[(methylsulfonyl)amino]benzophenan -3 - Formic acid added decane sulfonium chloride (0.573 mL, 11.7 Amino-2_(4_ succinyl)·5-fluorenyl-benzofuran-3- decanoic acid ethyl ester (1 〇 5 g, 3.4 154007 .doc -81 - 201221131 Job 01) in a chilled solution in di-methane. Then, DIPEA (1.46 mL) was added and the reaction was allowed to warm to room temperature, and the reaction was maintained at this temperature for 1 hour while stirring. The mixture was diluted with water and extracted with EtOAc EtOAc EtOAc EtOAc EtOAc. Potassium hydroxide (4 7 g, 56 claws...) was added to water (15 mL). The resulting solution was heated to reflux for 5 hours, and then concentrated. The solid was dissolved in water and the solution was passed.丨N hc1m was added dropwise to acidify. A white precipitate was formed which was collected by vacuum filtration to give a white solid (2·(fluorophenyl)-5-mercapto-6-[(methylsulfonyl)amino group. ]_布benzofuran_3 formic acid (0.9 04 g, 92% yield). LCMS (m/z, ES+) = 364 (M+1). Step 4: 2-(4-fluorophenyl)-N,5 dimethyl[(methylsulfonium) Amino]-benzoyl-vaginin-3-cartoamine treatment of 2-(4-fluorophenyl)-5-methyl-6_ [(sulfonyl) with HATU (1.64 g, 4.3 mmol) Amino]-1-benzofuran_3_carboxylic acid (〇9〇4 g, 2 5 mm〇i) in DMF (3.6 mL) and diethylamine (ii mL) and at room temperature It was maintained for 1 hour with stirring. A solution of decylamine (9 mL, 2 M solution) was added and the mixture was stirred under nitrogen for 12 hours. The reaction mixture was evaporated in vacuo to give an oily liquid, which was dissolved in dichloromethane and HCl ( The organic layer was separated, dried over MgSO4, filtered and evaporatedEtOAc Dimethyl _6_[(oxasulfonyl)amino] 丨 benzofuran-3- decylamine (0.52 g, 56% yield). LCMS (m/z, ES+) = 377 (M+ 1)° 154007.doc 201221131 Step 5: 2-(4-Fluorophenyl)-N,5-dimethyl_6_[(methylsulfonyl)(2_{[()methyl)oxy]methyl }-2-propene-1 Addition of potassium carbonate (570 mg, 2.4 mmol) and ({〇(bromoindolyl)-2-propenyl)oxy}•methyl)benzene (570) Mg, 2.4 mmol) to 2-(4-fluorophenyl)_ #,5-dimercapto-6-[(methylsulfonyl)amino]-1-benzofuran-3-decylamine (4〇 〇mg, 1.06 mmol) in acetonitrile (5_5 mL). The mixture was heated to reflux and maintained overnight with stirring. The reaction was cooled, diluted with water and extracted with dioxane. The organic layer was combined, dried over magnesium sulfate, and evaporated tolululululululululululululululululululululu _Dimethyl_6_[(oxasulfonyl)(2_{[(phenylhydrazo)oxy)methyl}-2-propenyl-1-yl)amino]-i_benzofuran_3_A Indoleamine (435 mg, 76% yield). lcmS (m/z, ES+) = 537 (M+1). Step 6: 2-(4-Fluorophenyl)-6.[[(2-hydroxy-12-oxaboron-4-yl)methyl](methylsulfonyl)amino], 5-dimethyl · ι_benzofurancarbamide cooled 2-(4-fluorophenyl)-#,5-dimethyl-6-[(oxasulfonyl phenyl fluorenyl)oxy]methyl under nitrogen atmosphere }-2-propen-1-yl)amino]-1-benzofuran-3-carboxamide (435 mg ' 0.8 mmol), [Ir(COD)Cl] 2 (55 mg) and dppe (64 mg a solution in anhydrous tetrahydrofuran to hydrazine. Then, it is treated with HBPIN (l.〇4 g). Molecular sieves were added and the mixture was stirred at ambient temperature for 18 hours. The mixture was filtered through celite and the filtrate was partitioned between ethyl acetate and water and stirred for 5 min. The organic phase was washed with water and brine and EtOAc EtOAc m. The oil was dissolved in ethyl acetate and stirred with palladium/carbon (110 mg) under hexanes &lt;EMI&gt; The mixture was filtered over celite and the filtrate was evaporated in vacuo to give white crystals crystals crystals -1,2-oxo-decyl-4-yl)methyl](A)-amino]-#,5-dimethyl-1-benzo-Funnan-3-cartoamine (5 〇mg, 32% yield). NMR (300 MHz, MeOD) δ: 7.96 (m, 2H) 7.36 (m, 2H), 7.26 (m, 2H), 3.69 (m, 4H), 3.05 (m, 3H), 2.98 (m, 3H), 2.53 (m, 3H), 2.05 (m, 1H), 0.93 (m, 2H). LCMS (m/z, ES+) = 495 (M+l). The two exchangeable protons are not obvious. Example 17 5-Cyclopropyl·2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaboronyl)methyl)methylsulfonylamino)-N -methylbenzofuran-3-carboxamide

Step 1 : 4-(Benzyloxy) butyl can be treated with PCC (17.94 g, 83.2 mmol) at 0 C for 4-(stupyloxy)-but-1-drink (10 g '55_5 mmol) in anhydrous DCM ( The solution in 50 mL) was mixed for 45 minutes. The mixture was allowed to warm to 25 and allowed to mix for 3 hours. The suspension was filtered through celite, concentrated, and purified by column chromatography to afford 4-(benzophenoxy)butyraldehyde (9.5 g, 96% yield). Step 2: 4-(Benzyloxy)-2-methylene butyl to 4-(benzomethoxy)butyl (9·5 g, 53 3 mm〇1) K H2O (40 mL) under nitrogen Dimethylamine (3 6 ι, 27 6 154007.doc • 84-201221131 mmol), AcOH (3.4 mL '55.3 mmol) and aqueous formaldehyde (36%) (4.31 mL, 5 5.3 mmol) were added to the solution. Heat to reflux for 1 hour. The reaction mixture was poured into EtOAc / EtOAc (EtOAc (EtOAc) The combined organic layers were washed sequentially with 1N NaHC EtOAc EtOAc (EtOAc)EtOAc. The crude product was used without further purification. Step 3: 4-(Benzyloxy)-2-methylenebutan-1-ol was cooled under N2 to give 4-(benzomethoxy)-2-indolylbutyric acid (9 g, 47.4 mmol) The solution in MeOH (150 mL) was taken to EtOAc. 〇, NaBH4 (2.7 g, 71 mmol) was added and the solution was stirred overnight. The reaction mixture was evaporated and poured with EtOAc EtOAc m. The organic extract was washed with h.sub.2 and brine, dried and concentrated. The crude product was purified by column chromatography to yield 4-(phenyl phenoxy)-2-ylidene-butan-l-ol (1.8 g, 178 〇 / 〇 yield, two steps). Step 4: ((3-(Bromofluorenyl)but-3-enyloxy)methyl)is 4-(benzyloxy)-2-indenylbutanol. . g, 9.3 mm 〇丨) PPh3 (4.85 g, 18.6 mmol) and NBS (3.30 g, 18.6 mmol) were added to a solution of DCM (100 mL) and the solution was stirred for 5 min. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with DCM (3.times. The organic extract was dried over anhydrous NkSO4 and concentrated. The crude product was purified by column chromatography to yield ((3-(bromomethyl)buty- 3 - alkenyloxy) decyl)benzene (145 s, 61% yield). Step 5: 6-(N-(4-(Benzyloxy)-2-methylenebutyl)methylsulfonylamino)_ 5-cyclopropyl-2-(4-fluorophenylmethyl) Benzofurancarbamide 154007.doc 85- 201221131 Treatment of 5-cyclopropyl-2 with ((3-(bromomethyl)but-3-enyloxy)methyl)benzene (419 mg; 1.65 mmol) -(4-fluorophenyl)-N-methyl-6-(methyl-hydroxylamino)benzofuran-3-carbamide (300 mg, · 0.745 mmol) and carbonic acid (309 mg; 2.24 mmol) The suspension was taken up in anhydrous acetonitrile (10 mL) and the mixture was stirred at reflux under nitrogen for 6 h. The reaction was cooled, then diluted with water (30 mL) and dioxane Extracted 3 times. The combined organic solution was dried over anhydrous Na.sub.2.sub.4 and evaporated. The crude product was purified by column chromatography (solvent: 0-50% ethyl acetate · (4-(Benzyloxy)-2-indenyl butyl) fluorenyl hydrazino) _5_cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran- 3-decylamine, 400 mg, 93% yield. LCMS (w/z, ES+) = 599 (M+Na) Step 6: 6-(N-(4-(benzyloxy)-2-( (4,4,5,5-tetramethyl-1,3,2-dioxo column -2-yl)methyl)butyl)nonylsulfonylamino)_5_cyclopropyl-2-((fluoropropionylmethylbenzofuran-3-carboxamide) carbonyl chloride double under nitrogen atmosphere (triphenylphosphine) ruthenium (1) (48, 0.069 mmol) and 6-(N-(4-(benzyloxy)-2_ylidenebutyl)methylsulfonylamino)-5-cyclopropane Base-2-(4-fluorophenyl)heptinylbenzofuran_3·carbamamine (400 mg, 0.694 mmol) was dissolved in THF 〇〇 mL). Add the pinacol borane (1.01 mL, 6.94 mmol) and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the crude material was purified by column chromatography (solvent: 〇········· Methoxy) 2_((4,4,5 5 -tetramethyl-1,3,2-dioxaboromid-2-yl)methyl)butyl)nonylsulfonylamino)·% Cyclopropyl Benzyl-2-(4-fluorophenyl)-indole-methyl benzofuran·3-formamide (11 g, 225 ratio) 154007.doc • 86 - 201221131 Step 7: 5-cyclopropyl-2 -(4-Phenylphenyl)-6-(N-((2-hydroxy-1,2-oxoborogen)-methyl)methylsulfonylamino)-N-mercaptobenzofuran -3-carboxamide will be 6·(Ν-(4-(phenylhydroxy)-2-((4,4,5,5-four Base-1,3,2-dioxaboran-2-yl)indenyl)butyl)nonylsulfonylamino)_5_cyclopropyl_2_(4-fluorophenyl)_N-methylbenzene The furan_3_formamide (395 mg, 0.685 mmol) was dissolved in THF (10 mL). 395 mg of Pd/C (10%) was added and stirred at room temperature for 6 hours under H2 (60 min/c). Filter and concentrate the mixture. The crude product was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-l, 2-oxaboronium-4-yl)indole Base) mercaptosulfonylamino)-N-mercaptobenzofuran-3. formamide. (65 rng, 22.6% yield). 1HNMR (300 MHz, CDC13) 5=7.89-7.83 (m, 2H), 7.48 (s, 1H), 7.28-7.16 (m, 3H), 5.75 (s, 1H), 4.4-4.11 (m, 1H), 3.92-3.82 (m, 1H), 3.74-3.52 (m, 2H), 3.00-2.98 (m, 6H), 2.41-2.27 (mj ih), 2.03-1.36 (m, 4H), 1.13-0.96 (m, 3H), 0.77-0.50 (mj 2H); LCMS (m/z) ES+=515 (M+l) « 1 exchangeable proton is not obvious. Example 18 5-Cyclopropyl-2-(4-fluorophenyl)_6_(n-(2_(2-hydroxy)itoxyboryl)ethyl)methyl-branched amine)_N-methylbenzofuran _3·carbamamine

Step 1: ((2-Mercaptopropoxy)methyl)benzene 154007.doc -87- 201221131 Add 2-methylprop-2-en-1-ol (7.5) at 0 °C under N2 atmosphere g, l 〇 4 mmol) to a solution of NaH (3.93 g' 114.4 mmol) in anhydrous THF (50 mL) and stirring the mixture at this temperature for 30 minutes, then benzyl bromide (12.4 mL, 104 mmol) of anhydrous THF (50 mL) was stirred for 5 hours. The reaction was quenched with H.sub.2 (50 mL). The mixture was extracted with EA (3×200 mL). EtOAc (EtOAc m. Yield). Step 2: 3-(Benzyloxymethyl)butan-ol-ol at -78 ° C in the presence of MS 4A to 3·(benzomethoxyindolyl)but-3-enol ( 16.87 g, 104 mmol), a solution of paraformaldehyde (3.1 g, 104 mmol) and anhydrous dichloromethane (240 mL) was added with di-n-butyl aluminide (115.6 mL of a 0.9 hexane solution). The reaction temperature was gradually increased to room temperature, and the mixture was stirred for 10 hours. Next, a saturated aqueous solution of sodium sulfate and hydrazine were added to the reaction mixture. After 12 hours, anhydrous sodium sulfate was added to the mixture. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes / EtOAc: 2:1) to yield 3-(phenyl hydrazinyl)but-3-en-1-ol (2.3 g, 11.5%). ' Step 3 : ((4-Bromo-2-methylenebutoxy)methyl)benzene to 3-(benzomethoxymethyl)but-3-en-1-ol (2.2 g, ii, 4 Pph3 (3 6 g, 13 68 on call and CBW 6.8 g '20.52 mmol) was added to the solution in mmol)s DCM (200 mL) and stirred for 5 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium bicarbonate (3×100 ml). The organic layer was separated, dried over anhydrous NaJCU and concentrated. The crude product was purified by column chromatography to give 154007.doc

S-88-201221131 ((4-bromo-2-indenylbutoxy)indolyl)benzene (1.7 g, 58% yield). Step 4: 6-(N-(3-(Benzyloxymethyl)but-3-enyl)nonylsulfonylamino)· 5-cyclopropyl-2-(4-phenylphenyl)- Treatment of 5-cyclopropyl-2- with N-mercaptobenzopyrene-3-carboxamide with ((4-bromo-2-indenylbutoxy)methyl)benzene (349 mg; 1.37 mmol) (4-Fluorophenyl)-N-methyl-6-(fluorenyl sulphate) benzoxfkon-3--3-decylamine (250 mg; 0.622 mmol) and carbonic acid unloading (257 mg; 1 - 87 mmol) of a suspension in anhydrous acetonitrile (10 mL) and the mixture was stirred under nitrogen for 6 hours under reflux. The reaction was allowed to cool, then diluted with water (3 mL) and extracted three times with dioxane (1 mL). The combined organic solutions were dried over anhydrous NajO4 and evaporated. The crude product was purified by column chromatography (solvent: 0-50%, ethyl acetate in petroleum) to yield (benzyloxymethyl) Cyclopropyl is phenyl)-N-methylbenzofuran-3-carboxamide {25\mg, Ί0% insult). Step 5: 6-(N-(4-(Benzyloxy)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborole_2_))) Butyl) decylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl y:N-methylbenzofuran-3-decylamine will be chlorinated under nitrogen atmosphere Alkyl bis(triphenylphosphine) money (I) (3〇, 0.0435 mmol) and 6-(N-(3-(benzophenoxymethyl)butyl-3-enyl) decylsulfonylamino -5-cyclopropyl-2-(4-fluorophenyl)·Ν-mercaptobenzofuran_3_曱醯^ (251 mg, 0.435 mmol) was dissolved in THF (10 mL). Which borane borane (0.635 mL, 4.35 mmol) was stirred and the mixture was stirred for 5 hr. The solvent was removed in </ br> and the crude product was purified by column chromatography (solvent: 〇_5 〇%, ethyl acetate in petroleum) To produce 6_(Ν·(4_(benzyloxy)_3_((4,4,5 ' ' 5 154007.doc •89- 201221131 methyl-1,3,2-dioxaboroin-2-yl) Methyl)butyl)nonylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-n-methylbenzofuran-3-carboxamide (215 mg, 70% yield) Step 6: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxy-l, 2-oxo boron. East-4-yl)ethyl) hydrazine Sulfonamide)-N-methylbenzofuran-3-decylamine containing 6-(N-(4-(benzyloxy)_3-((4,4,5,5-tetramethyl-) 1,3,2-dioxaboronic-2-yl)indenyl)butyl)nonylsulfonylamino)_5_cyclopropyl_2_(4-fluorophenyl)_N-mercaptobenzopyrene Ammonium-3-mannamidine (215 mg, 0.305 mmol) in hydrazine (1 mL) was treated with Pd/C (100/.' 215 mg) and stirred at room temperature under h2 (60 psi) 6 hours. The crude product was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxy-1,2-oxyxy)- 4-yl)ethyl)methyl </ br> </ br> 7.98 (m, 2H), 7.74 (s, lH), 7.29-7.34 (m, 2H), 7.22 (s, 1H), 4.04 (m, 1H), 3.77-3.85 (m, 2H), 3.56 (m, 1H), 3.15 (s, 3H), 3.01 (s, 3H), 2.48 (m, 1H), 2.28 (m, 1H)S 1.36-1.67 (m, 2H), 0.97-1.14 (m, 4H), 0.73 -0.57 (m, 2H). LCMS (m/z, ES+) = 515 (M+l). The two exchangeable protons are not obvious. Example 19 5-Cyclopropyl-2-(4-fluorophenyl)-6-indole [(2-hydroxy-1,2-oxo I)-5-yl)methyl] (methanesulfonic acid) Amino]-N-methyl_ι_benzofuran_3_formamide 154007.doc 201221131 HNI〆

Step 1: Add hydroxymethyl (tributyl) tin to a stirred solution of diisopropylamine (08 〇 mi, 575 mmol) in thf (25 ml) at 0 ° C (3.50 m b 5.5 mmo b 1_57 Μ In hexane). At 0. (The solution was stirred for 30 minutes, then (tributyl)tin hydride (1.33 nU' 5.0 mmol) was added dropwise and the resulting mixture was stirred for a further 2 minutes. Adding polyfurfural (0·210 g, 7·) 〇mm〇1) e The reaction mixture was then warmed to room temperature, stirred for another 3 hours, and poured into Et 2 〇 / H 2 。. The organic phase was separated, the aqueous layer was extracted once with EhO, and the combined organics were taken with η 2 〇 (5) (ml) and brine (5 ml) washed and dried (NazSCU) * solvent was removed and subjected to flash chromatography to give hydroxymethyl(tributyl)tin (1.324 g, 82 〇 / 〇 yield). Step 2: Iodine To a stirred solution of PPh3 (1.27 g, 4.86 mmol) in THF (10 ml), N-iodobutanediamine (1.〇〇g, 4 86) was added dropwise. THF (10 ml) of <RTI ID=0.0>m </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> THF (10 ml) with methyl (tributyl) tin (1.05 g, 3.25 mmol). The reaction mixture was poured into pentane / H.sub.2, and the organics were separated, dried (Na.sub.2.sub.4) and concentrated. EtOAc EtOAc Step 3: Suspension of (Z)-4-(benzyloxy)but-2-en-uol to NaH (5.44 g, 113.6 mmol) in C) MF (100 ml) 154007.doc - (Z)-Butyl-2-di-1,4-diol (10 g, 136.1 mmol) in DMF (50 ml) was added. Add bromomethyl-benzene (29 g, 170.4 mmol) in EtOAc (EtOAc) (EtOAc) 500 ml x 3) extraction. The organic layers were combined, dried (Na.sub.2.sub.4). Yield). Step 4: Suspension of (Z)-((4-(benzyloxy)but-2-enyloxy)methyl)tributyl tin pit to NaH (22.8 mg '0.95 mmc^) MTHF (3 ml) (Z)-4-(N-methoxy)but-2-en-1-ol (164 mg, 0.95 mmol) in THF (2 mL). After HMPA (449 mg, 1·〇4 mmol) was added at 0 ° C, the mixture was stirred at room temperature for 12 hours and quenched with water (5 〇 mi), and extracted with Et 2 〇 (50 ml×3). The organic layers were combined, dried (Na 2 S 〇 4) and concentrated. Flash chromatography gave (Z)-((4-(phenyloxy)butan-2-yloxy)methyl)tributyltin (*, 116 mg, 20% yield). Step 5: 2-(Benzyloxymethyl)butane-, alkene--alcohol slowly added n-BuLi (3.5 ml, 5.59 mmol) to (Z)-((4-(benzene) under a gas atmosphere at 78C a solution of decyloxy)but-2-enyloxy)indenyl)tributylstannane (2 2 g, 4.7 mmol) in THF (100 ml). (1 〇〇 ml) quenched. The layers were separated and extracted with EhCKlOO mlx3). The organic layer was combined and washed with water (5 mL mi.sub.3), dried (Na.sub.4) and concentrated. Flash chromatography gave 2_(benzyloxymethyl)buten-1-ol (1.1 g, 95% yield). Step 6: ((2-(Bromomethyl)butyl-3-(alkenyloxy)) phenyl) 154007.doc 201221131 To a mixture of PPh3 (1. 〇7 g, 4.09 mmol) in THF (30 ml) N-Bromopyrrolidine (5 88 mg, 3.44 mmol) in THF (3 mL) was added dropwise. The solution was stirred for 10 minutes and 2_(phenylhydroxyfluorenyl)but-3-en-1-ol (330 mg ' 1.72 mmol) was added. Additional THF (30 ml) was added and the mixture was stirred further for 2 hr. The reaction mixture was poured into Et.sub.2 /H.sub.2 (100.sub.1). Flash chromatography gave (2-(bromomethyl)but-3-enyloxy)methyl)benzene (196 mg, 45% yield). Step 7: 6-(bf-(2-(Benzyloxymethyl)butyryl)methanesulfonylamino-5-cyclopropyl-2-(4-fluorophenyl)-indole-methyl Addition of 5-cyclopropyl-2-(4-fluorophenyl)-#-methyl-6-[(methylsulfonyl)amino]-1-benzofuran to benzofuran-3-carboxamide 3-carbamide (166 mg; 1.2 mmol) to dry DMF (10 mL) with (2-(bromomethyl)but-3-yloxy)methyl)benzene (100 mg; 0.400 mmol) The reaction was stirred under nitrogen for a period of 48 h under nitrogen. The reaction was cooled and diluted with water (1 mL) and extracted three times with dioxane (total 150 mL). Na2s 〇 4M was dried and evaporated. The crude product was purified by column chromatography to yield 6-(N-(2-(benzyloxymethyl)but-3-enyl) decylsulfonylamine ring Propyl 2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (45 mg, 20% yield). LCMS (m/z, ES+) = 577 (M+H ) Step 8 ··· 6-(N-(2-(Benzyloxyf-bub-4_(4455-tetramethyl-I,3,2·dioxaboron-2-yl)butyl)methylsulfonate)醯Amino)_5_cyclopropyl_2-(4-fluorophenyl)-N-mercaptobenzophene oxime-3-indole amine in nitrogen atmosphere Circulating carbonyl bis(triphenylphosphine) ruthenium (〗 〖) (7 mg, 0.01 154007.doc •93-201221131 mmol) and 6-(N-(2-(phenyloxymethyl))- 3-Lessyl) fluorenylamino) 5-cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran_3_formamide (45 mg, 0.08 mmol) dissolved In THF (10 mL), HBPIN (102 mg, 0 80 mmol) was added and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the crude material was purified by column chromatography to yield crude 6-(N-( 2-(Benzyloxyindenyl)_4_(4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)butyl)methylsulfonylamino)_ 5-Cyclopropyl-2-(4-phenylphenyl)-N-mercaptobenzotrile-3 - an amine, which was used in the next step without further purification. Step 9: 5- Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxoboroindole-5-yl)indolyl)methyl arylaminomethylbenzo A-fused amine can be crude 6-(N-(2-(benzyloxyindenyl)-4-(4,4,5,5-tetradecyl-l,3,2-dioxole -2-yl)butyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran_3_decylamine (from the above procedure) Dissolve thfqo mL) and treated with 195 mg Pd / C (10%) and stirred under H2 (60 lbs / square inch) at room temperature for 6 hours. The mixture was filtered and concentrated. The crude product was purified by HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-1,2·oxy-l-p--5-yl) fluorenyl [(sulfonyl)amino]methyl-1-benzofuran_3_carbamamine. (9 mg, 22.6% yield). LCMS (w/z, ES+) = 515 (M+l). Hl-NMR (300 MHz, CD3OD) d 7.96 (t, J = 5.1 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 8.7 Hz, 1H), 7.17 (d, j=5.4 Hz, 2H), 3.79-3.37 (m, 5H), 3.09 (s, 3H), 2.51 (m, 1H), 1.74 (m, 1H), 1.31-0.90 (m, 7H), 0.71 (m , 2H). No exchangeable protons were observed. Example 20 154007.doc •94-201221131 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[2-(2-hydroxy-1,2-oxaborami-5-yl)ethyl) 】 (曱 醯 )) amino group] methyl-1- 咦 咦 _ _3_ 甲

Step 1: 3-Addition of n-BuLi (41 nd, 1 〇 3 mm 〇l) to diisopropylamine (10.4 g '103 mmol) in THF at 〇 °C. In a solution of 500 ml), stir for 15 minutes 'cooled to -78 ° C, and slowly added distilled Et 〇Ac (10.2 g, 116 mmol). Continue to stir the b], time. Acrolein (5 g, 89 mmol) was added and stirring was maintained for 30 min then quenched with water (2 mL). The layers were separated and the mixture was extracted with EtOAc (400 mL). Combined organic layer

NaJO4 was dried <RTI ID=0.0></RTI> to EtOAc (EtOAc) Step 2: 3-(Tert-butyldiheptyldecyloxy)penta- 4-acid ethyl acetate at room temperature to ethyl 3-hydroxypentate-4-ate (100 mg, 〇 69 mm 〇 1) Imidazole (95 2 mg '1 38 was added to the solution in THF (10 ml). TBSC1 (156 mg, 1.04 mmol) was added and stirring was maintained for 2 hours. The mixture was quenched with water (10 ml). The mixture was extracted with EtOAc (3 mL). 8 mg, 74% yield) 154007.doc •95· 201221131 Step 3: 3-(Tertiary dimethyl dimethyl decyloxy) pentane-“ene”• alcohol is given wrestling under A suspension of Lv (17.1 mg, 0.45 mmol) in anhydrous DCM (10 ml) was added dropwise ethyl 3-(t-butyldimethyl-methyl-decyloxy)pentanoate (1 〇〇) The reaction mixture was refluxed for 3 h and quenched with water (1 mL).

Extracted with EtOAc (15 ml &lt;3). The organic layer was washed with water (3 〇mi), dried over Na.sub.ss.ss.ssssssssssssssssssssssssssss En-1-ol (85 mg, 96% yield). #锧4 .· {[1-(2-Bromoethyl)-2-propen-1-yl]oxy} (1, bisdidecylethyl) dimethyl slag burned under vigorous stirring Partially cooled to ice bath 3_(t-butyl-methylpyroxy)pent-4-en-1-ol (85 mg), triphenylphosphine (3〇6 mg, 1.17) Add a mixture of mmol) and anhydrous methylene chloride (1 Torr) / odoro-di-imine (138 mg '0·78 mmol). Stirring was continued for 3 hours at room temperature, followed by the addition of hexane (50 ml) to the flask, and the mixture was purified by gelatin chromatography to yield {[1-(2-bromoethyl)-2-propan-1- (yl)oxy}(1,1-didecylethyl)dimethyl decane (5 〇 mg, 40% yield). Step 5: 6-(Ν-(3·(Tertiary butyldimethylmethylalkyloxy)pent-4-enyl)methylsulfonylamino)-5-cyclopropyl-2-(4- Fluorophenyl)-fluorene-methylbenzofuran-3-carboxamide added 5-cyclopropyl·2-(4-fluorophenyl)-#-mercapto-6-[(oxasulfonyl)amine Base]_ 1_ benzofuran-3-carboxamide (360 mg; 0.9 mmol) and potassium carbonate (370 mg; 2.7 mmol) in anhydrous DMF (15 mL) with {[1_(2_bromoethyl) _ 2_Propyl-1·yl]oxy}(1,1-dimethylethyl)dimethyl decane (25 〇 mg; 201221131 0.9 mmol). The reaction was stirred at 6 (r.sub.2) under nitrogen. The reaction was cooled, then diluted with water (1 mL) and extracted with dichloromethane (to a total of 2 mL). Anhydrous Na2S〇4 was dried and evaporated. The crude product was purified by column chromatography to yield 6-(n-(3 (t-butyl decyl decyl decyloxy) pent-4-enyl)methylsulfonamide _5-cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran-3-amine (281 mg, 52% yield). LCMS (m/z, ES+) = 601 (M) +H) • Step 6: 6-(N-(3-(t-butyldi-f-decyloxy)5_(4 4,5 5 - tetramethyl-H2-dioxaboryl) fluorenyl)曱 sulfonylamino)_5 cyclopropyl-2-(4-fluorophenyl fluorenyl benzofuranamine carbonyl bis(triphenylphosphine) 铑^ under nitrogen atmosphere (34, 0.05 Ment) and 6-(N_(3_(t-butyldimethylmethylalkyloxy)pentanyl)methanesulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl) - Ν-methylbenzofuran-3- decylamine (281 mg, 0.47 mmol) was dissolved in THF (20 mL). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The solvent is removed and the crude product is purified by column chromatography to give 6-(3 - (2 - butyl dimethyl decyloxy) - 5 - (4, 4, 5, 5 - tetramethyl-H 2 · Dioxaborom-2-yl)pentyl)methylsulfonylamino)_5_cyclopropyl_2_(4-fluorophenyl)- hydrazine-methylbenzobenzopyran-3-carboxamide (170 Mg, 50% yield). Step 7: 5-cyclopropyl-2-(4-fluorophenyl)·6_(Ν_(2_(2_hydroxy-12-oxo-5-yl)ethyl) Sulfonamide methylbenzofuran_3_decylamine 6-(Ν-(3_(t-butyldimethylmethylalkyloxy)_5·(4,4,5,5_tetra -1,3,2-dioxaboromid-2-yl)pentyl)methylsulfonylamino)_5_cyclopropyl_2_(4-phenylene)-indole-methylbenzofuran 3-decylamine (17 〇 mg, 〇.23 154007.doc •97·201221131) 'Extensively dissolved in absolute ethanol (15 ml) and added ppts (58, 〇·23 mm〇l) in 1 part. The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed in vacuo and the residue was taken in ethyl acetate. The organic solvent was washed with saturated brine, washed with water, and then dried over MgSO. Crude product by HPLC To produce 5-cyclopropyl-2-(4-1phenyl)-6-[[2-(2-yl-1,2-oxo boron-5-yl)ethyl](sulfonyl) Amino]-iV~mercapto-1-benzoin-3-ylamine (20 mg, 17% yield). LCMS 〇/z, ES+) = 515 (M+l). H1-NMR (300 MHz, CD3OD) d 8.46 (s, 1H), 7.99-7.94 (dd, J=2.1 Hz, 2H), 7.74 (d, J=4.2 Hz, 1H), 7.32-7.27 (dd, J =2.1 Hz, 2H), 7.22 (d, J=3.3 Hz, 1H), 4.13 (m, 1H), 4.11-3.83 (m, 2H), 3.16 (s, 3H), 3.04 (s, 3H), 2.47 (m, 1H), 2.08 (m, 1H), 1.78-1.50 (m, 4H), 1.03-0.71 (m, 5H). No exchangeable protons were observed. Example 21 [({(2R)-3-[{5-Cyclopropyl-2-(4-fluorophenyl)-3_[(methylamino)carbonyl]_1_benzofuran-6-yl}) Sulfhydryl)amino]-2-methylpropyl}oxy)methyl]noic acid

Step 1: 5·Cyclopropyl (4) fluorophenyl) Ν 甲基 methyl winter {(methylsulfonic acid) [(2R)-2-methyl winter (tetrazo 2 Η ° 喃 基 methoxy) propyl Amino}-i-154007.doc -98- 201221131 Benzyl-fusin-3-branched amine maintains 5-cyclopropyl-2-(4-fluorophenyl) in a microwave reactor at 50 °C )-#-Methyl-6-[(甲醯醯基)amino]-1-benzopyrano_3_ 曱 胺 (1〇mg, 〇.〇25 mmol), 2-{[(25&gt ; 3-bromo-2-methylpropyl]oxy}tetrahydro-2//-pyran (Orgam'c 2005, 7(13) pp. 2599-2602) (18 mg, 0.075 mmol), TBAI ( A solution of 9 mg, 0.025 mmol) and potassium butoxide (3 mg, 0.0275 mmol) in tetrahydrofuranium) was stirred for 1 min at 100 ° C in a microwave reactor for a total of 3 min. The tetrahydrofuran was removed under reduced pressure and the mixture was diluted with water and dichloromethane. The organic layer was dried over sodium sulfate and purified by column chromatography to give &lt;RTI ID=0.0&gt;>&&&&&&&&&&&&&&&&&&& _2. Mercapto-3-3-(tetrahydro-2/f-pyran-2-yloxy)propyl]amino}_ι_benzofuran-3-amine (4 mg, 32% yield). Step 2: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2κ)_3-hydroxy-2-methylpropyl](indolyl)amino]methyl-i -benzofuran_3_formamide treated with 4_0 N HC1 (1 mL) 5·cyclopropyl_2_(4_fluorophenyl)·decyl·6-{(methylsulfonyl)[(2 ;?)-2-methyl-3-(tetrahydro-2//-piperidin-2-yloxy)propanyl]amino} 1 Benf 〇南_3_carbamamine (8〇mg , 〇·ΐ 4 mmol) in tetrahydrofuran and maintained at room temperature for 24 hours under search. The mixture was diluted with EtOAc and the organic layer was washed with brine, dried and dried over sodium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography to give &lt;RTI ID=0.0&gt;&gt; ]methyl-i_benzofuran_3_decylamine. Step 3 '[({(2R)-3-[{5_cyclopropyl·2_(4·Phenyl)3 [(methylamino) 154007.doc •99- 201221131)]-1-benzo Furanyl Η f sulfonyl)amino 2, p-propyl propyl) oxy) fluorenyl] octanoic acid maintains 5-cyclopropyl-2-(4- |L phenyl)-6 at 8 ° C -[[(2R)-3-hydroxy-2-methylpropyl](methylsulfonyl)amino]-N-methyl-1-benzofuran_3·decylamine (39 mg, 〇· 〇82 mmol), 2-(bromomethyl)-4,4,5,5-tetradecyl-1,3,2-dioxane (45.4 mg, 0.205 mm〇l) and potassium carbonate (34_1 mg) , 0.247 mmol) in acetonitrile (5 mL) for 12 h. The mixture was diluted with dioxane, filtered through celite, concentrated, and purified by reverse phase HPlc to yield [({(2R)_3_[{5•cyclopropyl_2_(4_) Fluorophenyl)_3_[(methylamino)carbonyl]-1-benzofuran-6-yl}(indolyl)amino]_2-methylpropyl}oxy)methyl]carboxylic acid (18) Mg, 0.034 mmol, 41.1% yield). NMR (methanol-d4) δ: 7.91 (dd, J = 8.9, 5.4 Hz, 2H), 7.72 (d, J = 13.7 Hz, 1H), 7.24 (t, J = 8.7 Hz, 2H), 7.12 (s, 1H), 3.76-3.92 (m, 1H), 3.60 (dd, J=13.7, 7.2 Hz, 1H), 3.15 (d, J=12.7 Hz, 1H), 3.06 (d, J=1.6 Hz, 3H), 2.93 (s, 3H), 2.41-2.56 (m, 4H), 1.78-1.95 (m, 1H), 0.84-1.14 (m, 6H), 0.59-0.74 (m, 1H). LCMS (m/z, ES+) = 533 (M+H) </RTI> </RTI> <RTIgt; Amino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]-2-methylpropyl}oxy)methyl]decanoic acid

154007.doc -100- 201221131 Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-{(methylsulfonyl U(2S)-2-methyl 3- (Tetrahydro-2Η-piperidin-2-yloxy)propyl]amino}-1-benzofuran-3-carboxamide was maintained at 100 ° C in a microwave reactor to maintain 5-cyclopropyl- 2-(4-Fluorophenyl)-iV-indolyl-6-[(曱醯)amino]-1-benzopyran-3-carbamide (230 mg, 0.5 7 mmol), 2 -{[(2i?)-3-bromo-2-mercaptopropyl]oxy}tetrahydro- guar (Tetrahedron Letters. 1986, 27(28) p. 3311) (403 mg ' 1.711 mmol), Potassium tributoxide (71 mg, 0.63 mmol) and TBAI (210 mg '0.57 mmol) in tetrahydrofuran (5 mL) for 40 minutes. Add chlorinated solution (aqueous solution) and use two gas in aqueous layer. Extraction by simmering. The organic layer was separated, dried <RTI ID=0.0> -methyl-6-{(methylphosphonium)[(25)-2-methyl-3-(tetrahydro-2//-pyran-2-yloxy)propyl]amino}- 1-benzofuran-3-indoleamine (150 mg, 67% yield). Step 2. 5-cyclopropyl-2-(4-fluorophenyl) -6-[[(2S)-3-carbyl-2-methylpropyl](Amidyl)amino]-N-mercapto-1-benzoindole-3-indole amine 4 _〇N HC1 (0.4 mL) treatment of 5·cyclopropyl-2-(4-fluorophenyl-indolyl-6-{(methylsulfonyl)[(23)-2-methyl-3-(four a solution of hydrogen-2//-piperidin-2-yloxy)propyl]amino}-1-benzopyran-3-cartoamine (200 mg '0.36 mmol) in tetrahydrofuran (2 mL) And the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added and the organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated 5-cyclopropyl-2-(4-(phenyl)-6-[[(2iS)-3-yl]-2-indolyl][methanesulfonyl)amine group as a white solid Methyl 丨 丨 benzofuran oxime 154007.doc -101 - 201221131 (97 mg, 57 ° / yield) Step 3 : [({(2S)-3-[{5-cyclopropyl- 2-(4-Fluorophenyl)-3-[(indolyl)methyl]-1-benzofuranyl}(indolyl)amino]-2-mercaptopropyl}oxy) A酉 酉 酉 acid maintains 5-cyclopropyl-phenyl)-6-[[(2S)-3-yl-2-ylmethyl)] Methyl-1-benzene Beta-amylamine (43.1 mg, 0.091 mmol), 2-(bromomethyl)-4,4,5,5-tetramethyl-ι,3,2· diboron (50.2 mg, 0.227 mmol And a solution of potassium carbonate (38 mg, 0.247 mmol) in acetonitrile (5 mL) for 12 h. The mixture was diluted with methylene chloride. filtered over EtOAc (EtOAc)EtOAc. 4-fluorophenyl)-3_[(methylamino)carboyl]-1-benzoxanf-6-yl}(anthracene)amino]_2_mercaptopropyl}oxy) Methyl]-acid (16 111 §, 0_〇3〇111111〇1, 33.1% yield). !H NMR (sterol-d4) δ: 7.91 (dd, J=8.9, 5.4 Ηζ, 2Η), 7.72 (d, J-13.7 Hz, 1H), 7.24 (t, J=8.7 Hz, 2H), 7.12 (s, 1H), 3.76-3.92 (m, 1H), 3.60 (dd, J=13.7, 7.2 Hz, 1H), 3.15 (d, J=12.7 Hz, 1H), 3.06 (d, J=1.6 Hz, 3H), 2.93 (s, 3H), 2.41-2.56 (m, 4H), 1.78-1.95 (m, 1H), 0.84-1.14 (m, 6H), 0.59-0.74 (m, 1H). LCMS (m/z, ES+) = 533 (M+H) Example 23 5-cyclopropyl-2-(4-fluorophenyl)-6·(Ν-((2-amino-1, 2-oxy) Rotten _5_yl)methyl)methyl-branched amino)-N-methylbenzo-bite _3_carbamamine 154007.doc -102 201221131

Step 1: ((1-Bromobuten-2-yloxy)methyl)benzene in 1N2 atmosphere to 1-bromobut-3-en-2-ol (50 mg, 0.33 mmol) in 1 Et2 To the solution was added 2,2,2-trisethoxyacetamilide (336 mg, 1.33 mmol) i2 mL Et2 hydrazine, and then in hydrazine. 2 mL of Et20 containing trifluorosilane (50 mg, hydrazine, 33 mmol) was added under the sputum. The mixture was stirred overnight at rt. EtOAc (3 mL) EtOAc (EtOAc m. . The residue was purified by column chromatography (solvent eluted with EtOAc) to afford ((l-bromobut-3-en-2-yloxy) decyl)benzene (59 mg, 74% yield). Step 2: 6-(N-(2-(Benzyloxy)butan-3 alkenyl)methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-N- 5-benzopropyl-2-(4-fluorobenzene) treated with ((1-bromobut-3-en-2-yloxy)methyl)benzene (24 mg, 0.1 mmol) -N-methyl-6-(methylsulfonylamino)benzofuran-3-carboxamide (20 mg, 〇.〇 5 mmol) and potassium carbonate (21 mg, 015 mmol) in 2 mL The suspension in anhydrous DMF was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with EtOAc EtOAc (EtOAc) The combined organic layers were dried without AA.sub.2.sub.4 and evaporated. The residue was purified by column chromatography (solvent eluting with EtOAc EtOAc) to afford 6-(N-(2-(benzyloxy)buty-3-enyl)methyl 154. 103· 201221131 sulfonylamino)-5-cyclopropyl_2_(4-fluorophenyl)_N-mercaptobenzofuran_3_formamide (16 mg '56% yield). LCMS (m/z, ES+)=563 (Μ+ι)+ Step 3: 6-((2-(Benzyloxy)_4_(4,4,55-tetramethyl-132 dioxane mil-2 -yl)butyl)(hydrosulfonyl)amino)_5_cyclopropyl_2-(4fluorophenyl)_n-mercaptobenzofuran-3-carboxamide A gasified carbonyl bis (nitrogen) Triphenylphosphine) ruthenium (I) (5 〇 mg, 0.073 mmol) and 6-(N-(2-(benzyloxy)butan-3 alkenyl)methylsulfonylamino)-5-cyclo Propyl-2-(4-fluorophenyl)-indole_methylbenzofuran_3_decylamine (41 mg, 0.73 mmol) was dissolved in THF (15 mL). The pinacolborane (467 mg, 3.65 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc EtOAc 5,5•Tetramethyl-1,3,2-dioxaboromid-2-yl)butyl)(hydrosulfonyl)amino)_5_cyclopropyl-2-(4-fluorophenyl) -N-methylbenzofuran·3·carbamamine (4〇7 mg, 81% yield). Step 4: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxoboroindole)-yl)methyl)nonylsulfonylamino )-·Ν-mercaptobenzofuran-3-carboxamide 6-((2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2) -dioxaboron-2-yl)butyl)(hydrosulfonyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)-indole_methyl

Bentofunan-3-carbamide (407 mg, 0.59 mmol) was dissolved in 1 mL of THF' and then 407 mg Pd/C (10%) was added and h2 (6 mins) at room temperature / 吋 吋) stir for 6 hours. Filtration and concentration of the mixture was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(indole-((2)-yl-1,2-oxo boron -5-yl)methyl)methylsulfonylamino)-indole-methylbenzoate. South _ 154007.doc -104- 201221131 3-Proline (115 mg, 39% yield). lHNMR (3 00 MHz, CD3OD-d4) δ=7.97-7.91 (m, 2H), 7·75·7·34 (d, 1H), 7.30-7.23 (m, 3H), 4.27 (m, 1H), 3.99-3.60 (m,3H),3 45 (m,3H),3.12 (m,3H),2.97(s,3H),2.54-2.36 (m,ih),1.96 (m,1H),1.61 (m , 1H), 1.10 (m, 1H), 1.07-0 65 (m, m). [CMS (m/z) ES+=501 (M+l) Example 24 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-i, 2-oxo boron) Mimi-4-yl)methyl)methyl-branched amino)-N-isopropylbenzo-f-flavor_3_formamide

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-isopropyl-6-(methylglycosyl)benzofuran-3-carboxamide • At ambient temperature Stir 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonylamino)benzofuran-3-indole (1.0 g, 2.568 mmol) in 15 mL of dry DMF and add DIPEA (0.730 g, 5.650 mmol) and HATU (1.171 g ' 3.082 mmol). After stirring for 15 minutes, propan-2-amine (0.608 g, 10.272 mmol) was added. The reaction mixture was further stirred for 2 h and diluted with EtOAc (30 mL) The organic layer was separated and aqueous layer was extracted with EtOAc (30 mL &lt; The combined organic layers were washed with EtOAcq. The residue was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to yield 5-cyclopropyl-2·154007.doc-105-201221131 (4-fluorophenyl)-N- Isopropyl-6-(mercaptosulfonylamino)benzofuran_3_decylamine (0.75 mg, 68° yield). Step 2: 6·(Ν-(2-(benzyloxymethyl)allyl)methylsulfonylamino)-5-cyclopropyl-2-(4-oxophenyl)-indole-isopropyl Benzo. husband. Treatment of 5-cyclopropyl-2-(4-fluorophenyl)-N-iso with (2-(bromoindolyl)-propyloxy)methyl)benzene (921 mg, 3.836 mmol) Propyl-6-(mercaptosulfonylamino)benzofuran-3-indoleamine (750 mg ' 1.744 mmol), KI (29 mg, 0.174 mmol) and K2C03 (723 mg ' 5.232 mmol) in anhydrous The suspension in DMF (10 mL) was heated to reflux under nitrogen for half an hour. The reaction mixture was cooled with EtOAc EtOAc m. The combined organic layers were dried over anhydrous Na.sub.s. The residue was purified by column chromatography (solvent eluting with EtOAc EtOAc: EtOAc) to afford 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonamide _5_cyclopropyl-2-(4-fluorophenyl)-N-isopropylbenzofuran-3-amine (580 mg, 56% yield). LCMS (m/z, ES+) = 591 (M+l) + Step 3: 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-) 1,3,2-dioxobicin-2-yl)methyl)propyl)decylsulfonylaminocyclopropyl-2-(4-indolyl)isopropylbenzofuran in a nitrogen atmosphere Gasification of carbonyl bis(triphenylphosphine) ruthenium (][) (68 mg, 0.0983 mmol) and 6-(N-(2-(benzyloxyindenyl)allyl) decylsulfonamide 5-)cyclopropyl-2-(4-fluorophenyl)-N-isopropylbenzofuran_3_decylamine (580 mg, 0.983 mmol) was dissolved in THF (10 mL). Pinacol borane (629 mg ' 4.91 mmol) and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (with 〇 5 〇 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 I I I I 54 54 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 Purification of oil to produce 6-(N-(3-(stupyloxy)_2-((4,4,5,5-tetradecyl-1,3,2-dioxo odor_2) _ base) fluorenyl) propyl) decylsulfonylamino) _5_cyclopropyl · 2-(4- phenyl)_N-isopropylbenzofuran _3_ decylamine (957 called, i36 〇/〇 yield). Step 4. 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaboron-4-yl)-) base) 5-sulfonium isopropyl benzobenzopyranamine 6-(Ν-(3-(phenylhydroxy)_2-((4,4,5,5-tetramethyl-13,2_2) Oxyborax ♦ imido) mercapto) propyl) mercaptosulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)·N-isopropylbenzofuran_3_decylamine (957 〇983 mm〇l, crude) Dissolved in 1'&gt;^(1〇11^), and added 957 11^?~(:(10%) and at room temperature at H2 (60 lbs/square) The mixture was stirred for 6 hours. The mixture was filtered and concentrated. The residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Stir for 4 hours, filter, and concentrate in vacuo. The residue was purified by preparative HPLc to yield 5-% propyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1), 2_oxoboron-4-yl) ® mercapto)methylsulfonylamino)·Ν-isopropylbenzofuran-3-decylamine (137 mg, 26% yield). 111 Lan 11 ( 300 顾冗,〇〇3〇〇-(14)5=7.92-7.86 (m, 2H), 7.47-7.45 (d5 1H), 7.33 (m, 1H), 7.28-7.17 (m, 2H), 5.57- 5.54 (d, 2H), 4.42-4.31 (m, 1H), 4.18-4.08 (m, 1H), 3.94-3.90 (m.lH), 3.82-3.62 (m, 3H ), 3.00 (m, 1H), 2.52-2.30 (m, 2H), 1.27-0.69 (m, liH). LCMS (m/z) ES+ = 529 (M + 1) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 5-cyclopropyl-2·(4-fluorophenyl)_6_(Ν·((2_hydroxyoxyboron-4-yl)methyl 154007. Doc -107· 201221131 基)Methylsulfonylamino)-Ν·(2·hydroxyethyl)benzofuran-3-decylamine

Step 1: N-(2-(Benzyloxy)ethyl)-5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonylamino) benzofuran-3- The guanamine was mixed with DIPEA (0.730 g, 5.650 mmol) and HATU (1.71 g, 3.082 mmol) in anhydrous DMF (15 mL) at ambient temperature to mix 5-cyclopropyl-2-(4-fluorobenzene). )--6-(fluorenyl-based guanamine) benzo- ke _3_carboxylic acid (1 〇g, 2_568 mmol) 〇 After stirring for 15 minutes, add benzyloxymethylamine (1.552 mg, 10.272) Methyl) 15 mL THF. The reaction mixture was again stirred for 2 h and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and aqueous was extracted with EtOAc EtOAc. The combined organic layers were washed with brine (3 mL) dried &lt The residue was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to give s-(2·(benzyloxy)ethyl)-5-cyclopropyl-2-(4- Fluorophenyl)-6-(methylsulfonylamino)benzofuran-3-carboximine (1.4 g, crude, 104% yield). Step 2: Ν-(2·(Benzyloxy)ethyl)-6-(Ν-(2·(benzyloxymethyl))propyl)methylsulfonylamino)-5-cyclopropane Keto-2-(4-fluorophenyl) benzofuran_3_formamide. Treatment of N-(2-(benzyloxy)ethyl)-5-cyclopropyl_2_(4 with (2-(bromomethyl)allyloxy)methyl)benzene (1.416 g, 6.215 mmol) -Fluorophenyl)_6·(曱基154007.doc 201221131 醢 醢 )) benzo benzo-3-amine (1.4 g, crude, 2.681 mmol), KI (45 mg, 0.268 mmol) and K2C03 ( A suspension of 1.11 g, 8.043 mmol) in dry DMF (10 mL). The reaction was cooled, diluted with EtOAc EtOAc (EtOAc &lt The combined organic layers were dried over anhydrous NaJCU and evaporated. The residue was purified by column chromatography (solvent eluting with EtOAc EtOAc EtOAc) to afford N-(2-(phenylmethoxy)ethyl)-6- φ (N_(2)曱oxymethyl)allyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)benzopyran-3 - anthraquinone (1.3 g, 710/〇) Yield). LCMS (m/z, ES+) = 683 (M+l) + Step 3: 6-(]^-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl) -1,3,2-dioxaboran-2-yl)methyl)propyl)methylsulfonylamino)_N_(2_(benzyloxy)ethyl)-5-cyclopropyl-2- (4-Phenylphenyl)benzoindolocarbamide gasified carbonyl bis(triphenylphosphine) ruthenium (1) (132 mg, 0.191 mmol) and N-(2-(benzyloxy) under nitrogen atmosphere Ethyl)ethyl)_6_(ν_(2·(benzyloxymethyl)allyl)methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)benzofuran- 3-Protonamine (1.3 g ' 1.91 mmol) was dissolved in THF (10 mL). The pinacol borane (1.22, 9.56 mmol) was added and the mixture was stirred for 3 hours. The solvent was removed in vacuo and the crude product was purified by column chromatography (solvent eluted with petroleum containing EtOAc EtOAc) to yield 6 _(3 _(benzyloxy) ,5,5_tetramethyl-1,3,2-dioxaboronic acid 2-1-yl)methyl)propyl)decylsulfonylamino)·Ν_(2·(phenylhydroxy)ethyl) _5·cyclopropyl-2-(4-fluorophenyl)benzofuran_3 formamide (1.9 g, 127% yield). Step 4. 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2- mercapto-1,2-oxaboron- 154007.doc -109- 201221131 4-base) Sulfhydryl)methylsulfonylaminoethyl)benzofuran-3-carboxamide 6-(N-(3-(phenylmethoxy)...seven^-tetradecyl-^^dioxygen Indole-2-yl)methyl)propyl)methyl hydrazinyl)_n_(2-(phenyloxy)ethene) 5-cyclopropyl-2-(4-fluorophenyl)benzofuran 3-Mergamine (9 g, crude, 1.91 mmol) was dissolved in THF (10 mL). Add epoch/activated carbon (! 9 g, loading) and stir at room temperature for 6 hours at H2 (60 psi). Filter and concentrate the mixture. The residue was taken up in EtOAc (10 mL)EtOAcEtOAcEtOAc. The suspension was stirred for 4 hours, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborin-4-yl). Methylsulfonylamino)-indole-(2-hydroxyethyl)benzoquinone-3-indolylamine (50 mg, 5% yield). NMR (300 MHz CD3OD-^) 6 = 8.04-7.99 (m, 2H), 7.75-7.71 (d, 1H), 7.3〇- 7.24 (m,3H), 3.81-3.55 (m,8H),3.10 (s , 3H), 2.50 (m, 2H), 1.11-0.73 (m, 6H) 〇LCMS (m/z) ES+=531 (M+1) Example 26 5-cyclopropyl-2·(4-fluorophenyl) - 6-(N-((2-hydroxy-1,2-oxaborimidin-4-yl)methyl)-2-methylpropylsulfonylamino)-N-methylbenzofuran-3 -Procarbamide

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-6-(2-methyl-N-(methylsulfonyl)propylsulfonylamino)benzofuran-3-carboxylic acid Vinegar•110· 154007.doc 201221131 6-Amino-5-cyclopropyl-2-(4-fluorophenyl) benzofuran-3-anthracene ethyl ester under 乂15C under 乂15C i 2 g, 3 54 mm 〇i) Add τεα (1.32 mL, 8.8 mmol) to a bath of anhydrous dcm (22 mL), followed by dropwise addition of propane-2-merine (1 94 g) , 12. 4 mmol). The solution was warmed to room temperature and allowed to stand for 1 hour. The reaction mixture was diluted with water (15 mL) The organic layers were combined, dried over MgS(R) 4, dried, and evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&& Propylsulfonylamino)benzofuran_3_carboxylic acid ethyl ester 〇53 g, 75%). Step 2: 5-cyclopropyl-2-(4-fluorophenyl)_6_(2_f-propylsulfonylamino)benzopyran-3-indole acid was added with potassium hydroxide under nitrogen rolling (2.97 g, 53 Methyl) to 5-cyclopropyl-fluorene-fluorophenyl)-6-(2-indolyl-N-(decylsulfonyl)propylsulfonylamino)benzofuran-3-furoate ( I_5 g, 3.54 mmol) in a solution of ethyl acetate (2 mL) and water (1 mL). The reaction was heated to reflux and stirred for 1 hour and then dried in a vacuum. The remaining solid was dissolved in water and the solution was acidified with 1 N HCl until a precipitate formed. The solid was filtered and dissolved in Et EtOAc (3 mL), dried and concentrated to give &lt;RTI ID=0.0&gt; ) Benzoin-3-carboxylic acid (white solid, 1.45 g, 95%). Step 3. 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(2-methylpropylguanidino)benzofuran-3-carboxamide at 21 C 5-Cyclopropyl-2-(4-fluorophenyl)-6-(2-methylpropyl hydrazinyl)benzofuran-3-decanoic acid (1.45 g ' 3.36 mmol) with DIPEA ( 956 mg, 7.39 mmol) and HATU (1.54 g, 4·〇3 mmol) were dissolved in 154007.doc 111 201221131 water DMF (30 mL). After stirring for 15 minutes, the title of the knife &lt;stupid was added THF (6.72 mL, 13.44 mmol) containing 2 methyleneamine. Mi sits ν * a ) and mixes the trough for 2 hours and evaporates to dryness. The residue was dissolved in ethyl acetate. The mixture was washed sequentially with saturated sodium bicarbonate and 2M HCl (40 mL). The organics were dried using anhydrous MgSO.sub.4, filtered and evaporated. The residue was purified by column chromatography (EtOAc/EtOAc = EtOAc) to yield Mercaptopropylsulfonylamino)benzofuran_3_formamide (0.65 mg, 44%). Step 4: 6-(N-(2-(Benzyloxyindenyl)allylprop-2-methylpropyl sulfenyl)-5-cyclopropyl-2-(4-fluorophenyl) Treatment of 5-cyclopropyl-2-(4) with mercaptobenzofuran_3_decylamine with (2-(&gt;odoromethyl)allyloxy)methyl)benzene (700 mg, 2.92 mmol) -fluorophenyl)_N-methyl-6-(2-methylpropylsulfonamide) benzofuran-3-formamide (0.65 g, 1.46 mmol), KI (12 mg, 0.07 mmol) And a suspension of Κ2〇Ο3 (0·6 g' 4.38 mmol) in anhydrous DMF (10 mL) and the mixture was stirred at room temperature under nitrogen for 2 min. The reaction was diluted with water (3 mL) Extracted with EtOAc (3 mL &lt; 5 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub. N-(2-(phenylhydroxycarbonyl)allyl)-2-mercaptopropylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-fluorenyl Benzofuran-3-decylamine (510 mg, 60%) Step 5: 6-(Ν-(3·(Benzyloxy)-2-((4,4,5,5-tetramethyl) -1,3,2-dioxaborom-2-yl)methyl)propyl)-2-methylpropylsulfonylamino)-5-cyclopropyl-2-(4-fluoro Phenylmethyl benzofuran

154007.doc -112· S 201221131 Chlorocarbonyl bis(triphenylphosphine) ruthenium (I) (58 mg, 0.08 mmol) and 6-(N-(2-(indoleoxycarbonyl) group under nitrogen atmosphere Allyl)2methylpropylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-decyl benzofuran_3_decylamine (500 mg, 0.83 mmol) ) Dissolved in THF (2 mL). The pinacol borane (1.06 g, 8.3 mmol) was added and the mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (solvent: 〇_5 〇%, ethyl acetate in petroleum) to yield 6-(N-(3-(benzophenoxy)_2_ ((4,4,5,5四曱•yl_1,3,2-dioxaboron-2-yl) fluorenyl)propyl)·2-methylpropylsulfonylamino)_ 5- Cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran-3-amine (crude, 780 mg, quantitative yield %). Step 6: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N_((2-hydroxy·12-oxobenzo-4-yl)methyl)-2-mercaptopropylsulfonamide Methyl)benzofuran_3•carbamamine 6-(Ν·(3·(benzyloxy)·2·((4,4,5,5-tetramethyl-hl bisphosphonium bromide) -2-yl)methyl)propyl)-2-methylpropylsulfonylamino)_5_cyclopropyl_2_(4_

• Fluorophenyl is methylbenzofuran, _3_formamide mg, ι·〇6 _〇1) is dissolved in THF (25 mL). 3 〇〇 mg Pd/c (l 〇〇 / 0) was added and stirred at room temperature (50 psig) for 16 hours. Filter and concentrate the mixture. The residue was taken up in EtOAc (EtOAc (EtOAc)EtOAc. The residue was redissolved in THF (25 mL) and EtOAc (EtOAc) (EtOAc) The crude product was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(Ν-((2-hydroxy-154007.doc •113-201221131 1'2-oxo boron) M.sup.4)yl)methyl)_2-methylpropylsulfonylamino)_N_methyl benzofuran-3-carboxamide (95 mg, 16%). LCMS (m/z) ES+ =542 9 (M+1). NMR (300 MHz, CD3OD) δ=7.96-7.91 (m,2H) 7.74-7.69 (m, 1H), 7.30-7.24 (m, 2H), 7.14 (m, 1H) } 4.l〇. 3.61 (m,4H), 3.19-3.14 (m,2H), 2.97 (S,3H),2.52-2.43 (m,old), 2.36-2.19 (m,2H),1.16-1.13 (m,8H),1.〇〇_〇·82 (m? 2H), 0.76-0.68 (m, 2H) Example 27 5-cyclopropyl_N·ethyl_2_(4-fluorophenyl)_6_ (N_((2_hydroxy_12_ oxyborate _ 4_yl)methyl)methylsulfonylamino)benzofuran_3_ formazan

Step 1: 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(nonylsulfonylamino)benzofuran-3-carboxamide at ambient temperature in anhydrous DMF (15 mL) was stirred with 5·cyclopropyl-2-(4-fluorophenyl)-6-(indolylsulfonylamino)benzofuran-3-carboxylic acid (1.0 g, 2.568 mmol) and DIPEA ( 0.730 g, 5.650 mmol) and HATU (1.71 g, 3.082 mmol). After stirring for 15 minutes, 15 mL of THF containing ethylamine (463 mg ' 10.272 mmol) was added. The reaction mixture was stirred at room temperature for 2 hr and diluted with EtOAc (30 mL) The organic layer was separated and aqueous was extracted with EtOAc EtOAc. The combined organic layers were washed with brine (30 mL) dried over anhydrous Na.sub. The residue was purified by column chromatography (solvent eluting with EtOAc EtOAc EtOAc EtOAc) Phytosulfonylamino)benzofuran-3-decylamine (720 mg, 67% yield). Step 2: 6-(N-(2-(Benzyloxymethyl)allyl)indolylsulfonylamino)-5-cyclopropyl-N-ethyl-2-(4-fluorophenyl) Benzofuran-3-indolylamine (2-(bromoindolyl)propoxy)indolyl)benzene (1.49 g, 6.215 mmol) was treated with 5-cyclopropyl-N-ethyl-2-( 4-fluorophenyl)-6-(methylsulfonylamino)benzoxan-3--3-carboxamide (720 mg, crude, 2.825 mmol), KI (47 mg, 0.2825 mmol) and K2C03 ( 1.17 g, 8.475 mmol) of a suspension in dry DMF (10 mL) and warmed to reflux under nitrogen for half an hour. The reaction mixture was cooled with EtOAc EtOAc m. The combined organic layers were dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to yield 6-(N-(2-(benzophenoxymethyl)allyl) decylsulfonamide ))·5_ Cyclopropyl-indole-ethyl-2-(4-fluorophenyl)benzofuran-3-decylamine (786 mg, 79% yield) LCMS (m/z, ES+) 577 (M+l)+ Step 3: 6-(N-(3-(Benzyloxy)-2-((4,4,5,5-tetramethyl-i,3,2-dioxaboron) Mimi-2-yl)methyl)propyl)methylsulfonylamino)·5-cyclopropylethyl-hydrazine-fluorophenyl)benzofuran-3-decylamine chlorinated under nitrogen atmosphere Carbonyl bis(triphenylphosphine) ruthenium (1) (95 mg, 0.136 mmol) and 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonylamino)-5- Cyclopropyl-N-ethyl-2-(4-fluorophenyl)benzofuran_3-carbamide (786 mg, 1.364 mmol) was dissolved in THF (10 mL). The pinacol borane (873 mg, 6.82 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was removed in the air at 154007.doc -115· 201221131 and the crude product was purified by column chromatography (dissolved with petroleum containing 0-50 〇/〇 ethyl acetate) to give 6-(N-(3-(phenyl) Oxy)-2-((4,4,5,5-tetramethyl-1,3,2-dioxos-2-yl)indolyl)propyl)methylsulfonylamino)_5_ Cyclopropyl-N-ethyl 2 -(4-fluorophenyl)benzofuran-3-decylamine (942 mg, 980% yield). Step 4: 5-Cyclopropylethyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxoborate-4-yl)methyl)decylsulfonate醯Amino)benzofurancarbamide will be ό-(Ν-(3-(phenylhydroxy)_2-((4,4,5,5-tetramethyl-1,3,2-dioxaboron) Ole-2-yl)hydrazino)propyl)nonylsulfonylaminocyclopropyl-indole-ethyl-2-(4-d-phenyl)benzofuran-3-decylamine (942 mg, 1.337 mmol) Dissolved in THF (10 mL). Add 942 mg of Pd/C (10%) and stir at room temperature under H2 (60 psig) for 6 hours. Filter and concentrate the mixture. Dissolve the residue in THF (10 mL) and treated with 5 N HCl (1_4 mL) and &lt;RTI ID=0.0&gt;&gt; Purification by HPLC to give 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborin-4-yl)) Methylsulfonylamino)benzofuran_3_decylamine (341 mg, 50% yield). 4 NMR (300 MHz, CD3OD-Mountain) δ=7.96-7.93 (m, 2H), 7.75 -7.70 (d, 1H), 7.30-7.14 (m, 3H), 3.89-3.64 (m, 4H), 3.51-3.37 (m, 2H), 3.10 (s, 3H), 2.49 (m, 1H), 2.45 (s, 1H), 1.28-1.23 (m, 3H), 1.47-00.69 (m, 6H). LCMS (m/z) ES+=515(M+1) Example 28 5·cyclopropyl-2-( 4-fluorophenyl)_6-(N-((2-hydroxy-1,2-oxaboron-4-yl)-methyl 154007.doc •116·201221131) Ethyl-ethylamine-N-A Benzo-indolyl -3-3-cartoamine

Step 1: 5-cyclopropyl-6-(N-(ethylsulfonyl)ethylsulfonylamino)-2-(4-indolyl)benzopyridin-3-carboxylate To a solution of 6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (1.2 g, 3.5 mmol) in anhydrous DCM ΤΕΑ (1.3 1 mL, 8.8 mmol) was added to the solution in 15 mL), and then B-brewed chlorine (1·57 g, 12-2 mmol) was added dropwise. The mixing solution was allowed to warm to room temperature for one hour. The reaction mixture was diluted with water (1 mL) and extracted with DCM (3×20 mL). The organic layers were combined, dried over MgSO4, filtered and evaporated in vacuo to yield 1. <RTIgt; Fluorophenyl)benzofuran-3-ethyl decanoate (crude, 101%). Step 2: 5-cyclopropyl-6-(ethylsulfonylamino)-2-(4-fluorophenyl)benzotrile-3-carboxylic acid was added with potassium hydroxide under II gas (2.48 g' 44.2 Methyl) to 5-cyclopropyl-indole-(indolyl-(ethylsulfonyl)ethylsulfonylamino)-2-(4-fluorophenyl)benzofuran-3-ethyl decanoate (1.85 g, 3.54 mmol) in a solution of ethanol (11 mL) and water (5.5 mL). The reaction mixture was heated to reflux and stirred for 1 hour then concentrated in vacuo. The remaining solid was dissolved in water, and the solution was acidified with 1 N HCl until a precipitate formed. The solid was filtered and washed with 1 〇〇 mL of mixed solvent 154007.doc • 117·201221131 (Et2〇/PE=l:l). To give 5-cyclopropyl-6-(ethylsulfonylamino)-2-(4-fluorophenyl)benzofuran-3-indoleic acid (1.22 g, 87%) as a white solid. Step 3: 5-cyclopropyl-6-(ethylsulfonylamino)-2-(4-fluorophenyl)-N-f-benzobenzopyran-3-carboxamide at 5 C will be 5- Cyclopropyl-6-(ethyl decylamino)-2-(4-fluorophenyl)benzofuran-3-carboxylic acid (1.22 g, 3.1 mmol) with DIPEA (875 mg, 6.7 mmol) and HATU ( 1.41 g, 3.7 mmol) - dissolved in anhydrous n,N-dimethylformamide (34 mL). After stirring for 15 minutes, 2 amine-containing THF (6.15 mL ' 12.3 mmol) was added. The solution was stirred for 2 hours and evaporated. The residue was taken up in ethyl acetate (30 mL)EtOAc. The organics were dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssss 2-(4-Fluorophenyl)-N-mercaptobenzofuran-3-carboxamide (0.89 g, 69%). Step 4: 6-(N-(2-(Benzyloxymethyl)allyl)ethylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-N-nonylbenzene And furancarboxamide was treated with ((2-(bromomethyl)allyloxy)methyl)benzene) 3 g, 4.28 mmol) of 5-cyclopropyl-6-(ethylsulfonylamino-fluoro Phenyl)-N-methylbenzofuran-3-carboxamide (0.89 g ' 2.14 mmol), KI (18 mg, 0.11 mmol) and K2CO3 (0.89 g ' 6.42 mmol) in anhydrous DMF (15 mL) The suspension was stirred at room temperature under nitrogen for half an hour. The mixture was diluted with water <RTI ID=0.0>(</RTI> <RTIgt; The combined organic layers were dried over anhydrous NaACU and evaporated. The crude product was purified by column chromatography 154007.doc -118· 201221131 (EA:PE = 1:2) to give 6-((-((phenylphenoxymethyl)allyl)ethylsulfonium) Amino)-5-cyclopropyl-2-(4-fluorophenyl)-indole-methylbenzofuran-3-indoleamine (820 mg, 66%). Step 5: 6-(1^-(3-(Benzyloxy)_2-((4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)) Propyl)ethylsulfonylamino-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzo-f-oxan-3-cartoamine gasified carbonyl under nitrogen Bis(triphenylphosphine)ruthenium (1) (96 mg, 0.14 mmol) and 6-(N-(2-(benzyloxyindenyl)allyl)ethylsulfonylamino)-5-cyclo Propyl-2-(4.fluorophenyl)-N-mercaptobenzofuran_3_formamide (8 mg [ 1.39 mmol) was dissolved in anhydrous THF (20 mL). Alkane (1.78 mg, 13.9 mmol) and the mixture was stirred for 3 hr. The solvent was removed in vacuo and the crude material was purified by column chromatography (solvent: EtOAc EtOAc (N-(3-(Benzyloxy)-2-((4,4,5,5-tetradecyl-1,3,2-dioxaboran-2-yl)methyl)propyl) Ethylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran·3·carbamamine (crude, 165 g, 168%) 〇Step 6 : 5 -cyclopropyl-2-(4-fluorophenyl)-6-(N_((2-hydroxy_1&gt;2_oxaboron-4-yl)methyl)ethylsulfonylaminomethyl stupid Furan Methionine 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)) Methyl)propyl)ethylsulfonylamino)_5_cyclopropyl_2_(4•fluorophenyl 曱N曱 basic and η 喃 _ _3_ 曱 胺 amine (1.65 mg, 2.34 mmol, crude) dissolved In THF (30 mL), 660 mg of Pd/C (10%) was added and stirred at room temperature for 2 hours (50 psi). The mixture was filtered and concentrated. 30 mL) with 5 N HC1 (3.27 mL) and PS-benxinpeng 154007.doc •119· 201221131

Acid (4.49 g, 11.7 mmol) was treated. The suspension was stirred for 2 hours, filtered and concentrated under reduced pressure. The residue was redissolved in THF (3 mL) and treated with &lt;RTI ID=0.0&gt;&gt; The suspension was stirred for 2 hours, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 5·cyclopropyl-2_(4-fluorophenyl)·6·(Ν·((2•hydroxy-1,2-oxaboron-4-yl)methyl Ethylsulfonylamino)-indole-methylbenzofurancarbamide (105 mg, 9%). LCMS (m/z) ES+ = 514.9 (Μ +1). Η NMR (300 MHz, CD3OD) δ=7.97-7.95 (m, 2Η), 7.73-7 69 (m, 1Η), 7.31-7.25 (m, 2Η), 7.15-7.14 (m,1Η), 4.10-3.57 (m, 4H), 3.34-3.26 (m, 2H), 2.98 (S, 3H), 2.55-2.42 (m, 1H), 2.40-2.22 (m, 1H), 1.44-1.39 (m, 3H), 1.12 -1.10 (m, 2H), 0.99-0.94 (m, 2H), 0.78-0.69 (m, 2H). Example 29 5-Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-amino-2,5-dihydro-1,2-oxa-p-cyclopentenyl-4) Methyl](methylsulfonyl)amino]-N-methyl-1_benzofuran·3-carboxamide

Step 1: (2Z)-3-Bromo-2-({[(methyloxy)methyl)oxy}methyl)-2-propan-1-ol) with DIBALH (32.5 mL) at 〇 °C , 32.5 mmol) treatment (2Ε)-3-bromo- 154007.doc •120· 201221131 2- ({[(indolyloxy)indolyl]oxy}methyl)-2-propenoic acid y

Organic C/zewiWr;/, 2007, 72, page 6143) (ι 37 S 1 5.41 mmol) in tetrahydrofuran (80 mL) and maintained with stirring for 3 hours. The solution was added by adding 10 ° /. The aqueous solution of Rochelle's brine was quenched and then further diluted with ethyl acetate. The mixture was maintained under rapid stirring for 5 hours, and then the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to residue to yield (2Z)-3-br. [(Methyloxy)-methyl]oxy}indenyl)-2-propen-1-ol (98 mg, 4.64 mmo, 86% yield). 4 NMR (gas-d) δ: 6.41 (s, 1H), 4.69 (s, 2H), 4.37 (s, 2 Η), 4.23 (s, 2 Η), 3.42 (s, 3 Η). Step 2: 6-[[(2Z)-3-bromo-2-({[(methyloxy)methyl)oxy}methyl)2-propen-1-yl](methylsulfonyl)amino Cyclopropyl-2_(4•fluorophenyl)_N_methyl-benzoxan-N-methyl-ternamine maintains 5-cyclopropyl-2-(4-fluorophenyl)-N under stirring _Methyl_6_[(methylsulfonyl)amino]-1-benzofuran_3_formamide (8〇〇mg, 1988 • mm〇1), (2Z)-3_bromo-2- ({[(Methyloxy)methyl)oxy}methyl)-2-propen-1-ol (839 mg, 3.98 mmol) and triphenylphosphine (1173 mg, 4.47 mmol) in tetrahydrofuran The suspension in (25 mL) was treated dropwise with DIAD (0.773 mL, 3.98 mmol). The mixture was warmed to room temperature, stirred for 5 hours 'and mixed with Shishizao soil>. All volatile components were removed under reduced pressure and the residue was purified by column chromatography to yield 6-[[ (2Z)_ 3-bromo-2-({[(methyloxy)methyl)oxy}methyl)_2-propenyl]-yl](methylsulfonyl)amino]-5-cyclopropane 2-(4-Fluorophenyl)-indolyl-l-benzofuran-3-carboxamide (800 mg ' 1.343 mmo, 67.6% yield). LCMS (w/z, 154007.doc -121 · 201221131 ES+)=597 (M+H) Step 3 · 5-Cyclopropyl-2-(4-fluorophenyl)6 [2-hydroxy-2 5 2 Hydrogen _12_ oxa shed heterocycloalkenyl-4-yl)methyl](methylsulfonyl)amino]_N_methyl-1-benzofuran-3-carboxamide at 5 ° C Mixing T to maintain 6-[[(2Z)-3-involved-2·({[(methyloxy)indolyl)oxy}indolyl)-2-propenyl](methylsulfonyl)amine ]_5_cyclopropyl_2_(4-fluorophenyl)-N-indenyl-i-benzofuran_3 formamide (75 mg, 1.259 mmol), potassium acetate (494 mg, 5·04 mm) 〇1), bis(pinacolyl)dicarboxylate (800 mg' 3.15 _〇1) and Pdcl2(dppf)_CH2Cl2 adduct (1〇3 mg '0.126 mmol) in 1,4-dioxane (15 The solution in mL) was 16 hours. The mixture was cooled to room temperature and 5.0 N HCl (aq) (12 mL) was added and stirring was continued for 3 hr. The solution was filtered through a pad of EtOAc (EtOAc) EtOAc (EtOAc) Cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy-2,5-dihydro-1,2-oxaborolan-4-yl)methyl] (Methanesulfonyl)amino]-N-methyl-indole_benzofuran-3-cartoamine (92 mg, 0.185 mmol, 14.66 〇 / 〇 yield), followed by lyophilization. 1H NMR (methanol-d4) δ: 7.91 (dd, J = 8.5, 5.4 Hz, 2H), 7.68 (s, 1H), 7.24 (t, J = 8.7 Hz, 2H), 7.11 (s, 1H), 5.62 (s, !H), 4.51-4.69 (m, 4H), 3.12 (s, 3H), 2.93 (s, 3H), 2.36 (t, J=8-2 Hz, 1H), 1.07 (br. s. , 2H), 0.91 (br. s., 1H)} 0.64 (br. s', called LCMS (m/z, ES+)=499 (M+H) Example 30 5_Cyclopropyl-2-(4 -fluorophenyl)-6-(N-((2-hydroxy-1,2.oxaboron-4-yl)-methyl 154007.doc • 122·

S 201221131 Amidino)propan-2-ylsulfonylamino)·Ν_methylbenzofuran_3 A

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-6-(indolyl-(isopropylsulfonyl)propan-2-yl-hydroxylamino)benzindole, formic acid formate 6-Aminocyclopropyl-2-(4-fluorophenyl) benzofuran-3-furoate ethyl ester (12 g, 3·5 mm〇1) K anhydrous at -15 ° C under &amp; atmosphere Triethylamine (13 mL, 8.8 mmol) was added to a solution of dioxane (15 mL). The solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with water (10 mL) and EtOAc. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt; Ethyl benzofuran-3-furoate (1.3 g, 67 〇/〇). Step 2: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(1-methylethylsulfonylamino)benzofuran-3-decanoic acid was added to the hydroxide under nitrogen (1.51 g,27 mmol) to 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(isopropylsulfonyl)propan-2-ylsulfonylamino)benzofuran-3 - a solution of ethyl decanoate (i.oo g, is mmol) in ethanol (14 mL) and water (7 mL). The reaction was heated to reflux and stirred for 1 h then concentrated in vacuo. The remaining solid was dissolved in water, and the solution was acidified with 1 N HCl (20 mL·) until a precipitate formed. The solid was filtered and dissolved in 154007.doc •123· 201221131

EtOAc (200 ml), dried and concentrated to give 5-cyclopropyl-2-(4-phenyl)-6-(1-mercaptoethylsulfonylamino)benzofuran-3-indole (white solid, 0.6 g, 80%). Step 3: 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(1-methylethylsulfonylamino)benzofuran-3-carboxamide at 21 C 5-3⁄4 propyl-2-(4-(phenyl)-6-(1-methylethyl-bromoamino)benzofuran-3-furic acid (0.6 g, 1.44 mmol) with DIPEA ( 0.55 ml, 3·17 mmol) and HATU (0.65 g' 1.73 mmol) - dissolved in anhydrous N,N-didecylguanamine (15 mL), stirred for 15 minutes, and then added with 2 Μ methylamine THF (2.88 mL, 5.76 mmol). The solution was stirred for 2 hours and evaporated to dryness. The residue was dissolved in ethyl acetate and washed sequentially with saturated sodium hydrogen carbonate and &lt The organic layer was separated and dried <RTI ID=0.0>: </ RTI> </ RTI> <RTIgt; The residue was purified using column chromatography (EtOAc / EtOAc = EtOAc) toield Methylethylsulfonylamino)benzofurazin-3-decylamine (260 mg, 42%). Step 4: 6-(N-(2-(Benzyloxyindenyl)allyl)propan-2-ylsulfonylamino)-5-cyclopropyl-2·(4-Iphenylmethyl) Treatment of 5-cyclopropyl-2-(4- with benzofuran-3-cartoamine with (2-(&gt;odoromethyl)allyloxy)methyl)benzene (298 mg, 1.2 mmol) Fluorophenyl)·Ν-methyl-6-(1-methylethylsulfonylamino)benzofuran-3-indoleamine (0.26 g, 0.6 mmol), KI (5 mg, 0_03 mmol) and K2C 〇3 (0.248 g ' 1.8 mmol) in EtOAc (3 mL EtOAc) (EtOAc) Extraction. Combined 154007.doc • 124· 201221131 The organic layer was dried over anhydrous Na^CU and evaporated. The crude product was purified by column chromatography (EAzPEM: 2) to yield 6-(N_(2_(()) Allyl) allyl) propan-2-ylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)_N_methyl benzoate-3-mercaptoamine (320 mg , 90%). Step 5 ·· 6-(Ν-(3·(benzyloxy)-2-((4,4,5,5-tetraf-yl-1&gt;3,2_ diboron- 2·yl)mercapto)propyl)propan-2-ylsulfonylamino)_5_cyclopropyl_2_(4_gasphenyl -N-methylbenzofuran-3.carbamamine gasification of several groups of bis(triphenylphosphine) money (1) (34 mg, 0.05 mmol) and 6-(N-( 2-(Benzyloxyindenyl)allyl)propanylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)·Ν·methylbenzofuran_3- Methotrexate (320 mg, 0.5 mmol) was dissolved in THF (10 mL). EtOAc ( EtOAc, EtOAc, EtOAc (EtOAc) Column chromatography (solvent: 〇_5〇%, ethyl acetate in petroleum) was purified to give 6-(N-(3-(benzophenoxy)_2_((4,4,5,5_tetraindole) Base_1,3,2-dioxos-2-yl)methyl)propyl)propan-2-yl guanylamino)_5•cyclopropyl-2-(4-fluorophenyl)-N -methylbenzofuran-3-3-decylamine (330 mg, 85% yield) Step 6: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-((2- Hydroxy-1,2-oxobenzoate 4-yl)methyl)propan-2-yl-branched amino-methylbenzo-a-saling winter-sweet amine 6-(N-(3-(benzoquinone) )-((4,4,5,5-tetramethyl-1,3,2-dioxomid-2-yl)indolyl)propyl)propan-2-ylsulfonylamino)_5 _Cyclopropyl-2-(4-fluorophenyl) -N-Methylbenzopyran-3-ylamine (330 mg, 0.46 mmol) was dissolved in THF (15 mL), 130 mg Pd/C (10%) was added at room temperature at H2 ( Stir for 16 hours at 50 psi. Filter and concentrate the mixture. The residue was dissolved in THF (15 mL) and treated with &lt;RTI ID=0.0&gt;&gt;&gt; The suspension was stirred for 2 hours, filtered and concentrated under reduced pressure. The residue was redissolved in THF (15 mL) eluting with &lt;RTI ID=0.0&gt;&gt; The suspension was stirred for 2 hours, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaboronium). Base) propan-2-ylsulfonylamino)-N-methyl benzofuran-3-indoleamine (9 mg, 370 / yield). LCMS (m/z) ES+ = 528.9 (M+1). iH NMR (3〇〇MHz, CD30D) δ = 7.84-7.79 (m, 2H), 7.58-7.54 (d, j = 12 Hz, 1H), 7.18-7.12 (m, 2H), 6.99 (s, lH) , 3·9ι-3.50 (Μ, 4H), 3.48-3.39 (m, 1H), 2.84 (S, 3H), 2.37-2·29 (m} 1H), 2.21-2.06 (m, 1H), 1.37- 1.25 (m, 6H), 1.02-0.82 (m, 4H), 0.74_0.56 (m, 2H). Example 31 N,5-Dicyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxoboromid-4-yl)methyl)methyl Sulfonamide)benzofuran-3-carboxamide

Step 1: N,5-Dicyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonylamino)benzox ψmm at ambient temperature in anhydrous DMF (15 mL) with DIPEA (730 mg, 154007.doc 201221131 5.650 mmol) and HATU (1.71 g, 3.082 mmol) - stirring 5-cyclopropyl-2-(4-fluorophenyl)-6-(nonylsulfonylamino)benzene And furan-3-decanoic acid (1.0 g, 2.568 mmol). After stirring for 15 minutes, 15 mL of THF containing cyclopropylamine (587 mg, 10.272 mmol) was added. The reaction mixture was stirred for 2 h and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and aqueous was extracted with EtOAc (3 EtOAc) &lt; The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to give N,5-dicyclopropyl-2-(4-1phenyl)-6- Acrylamino)benzoindole-3_ decylamine (1.4 g, crude, 119% yield). Step 2: (Bestylmethyl) allyl)methylsulfonylamino) Ν,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxamide . Treatment of N,5-dicyclopropyl-2-(4-fluorophenyl)-6-(A) with ((2-(indiyl)-propyloxy)methyl)benzene (1.49 g, 6.215 mmol) Phytosulfonyl)benzofuran-3-indolylamine (1.4 g, crude, 2.825 mmol), KI (47 mg, 0.2825 mmol) and K2C03 (1.17 g, 8.475 mmol) in anhydrous DMF (10 mL) The suspension was heated to reflux under nitrogen for 30 minutes. The reaction was cooled with water (15 mL) and EtOAc (30 mL & The combined organic layers were dried over anhydrous EtOAc EtOAc (EtOAc). The residue was purified by column chromatography (solvent eluting with EtOAc EtOAc EtOAc) to yield 6-(N-(2-(benzyloxy decyl) allyl)methylsulfonamide N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran_3-formamide (726 mg, 440% yield). LCMS (m/z, ES+) = 589 ( M+l)+ Step 3 ·· 6-(Ν·(3-(Benzyloxy)_2-((4,4,5,5•tetramethyl·1&gt;3,2_dioxo 154007.doc - 127- 201221131 m-missyl)methyl)propyl)methylsulfonamide-based 5-dicyclopropylphenyl)benzoate. Nan-3-indene amine gasified carbonyl double under nitrogen atmosphere Triphenylphosphine) ruthenium (I) (85 mg, 0.123 mmol) and 6-(N-(2-(benzyloxymethyl)allyl)methylsulfonylamino)-N,5-di Cyclopropyl 2-(4-fluorophenyl)benzofuran_3-formamide (726 mg, 1.23 mmol) was dissolved in THF (10 mL) EtOAc. &lt;RTI ID=0.0&gt; The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the crude material was purified by column chromatography (solvent eluting with EtOAc EtOAc EtOAc EtOAc) Methoxy)_2_((4 4 5 5_tetramethyl-1,3,2-di Boron-flavored 2·yl)mercapto)propyl)methylsulfonylamino)_N,5-dicyclopropyl-2-(4-fluorophenyl)benzofuran_3_formamide (863 mg, 98% yield) Step-Step 4 · N,5-Cyclopropyl propyl-2-(4-fluorophenyl)-6-(N-((2-yl)-yl-1,2-oxo-4- ))methyl)methylsulfonamide) benzofuran _3_carbamamine ό-(Ν-(3-(benzyloxy)_2·((4,4,5,5-tetramethyl) -1,3,2-dioxaboronic acid 2-1-yl)methyl)propyl)nonylsulfonylamino)-N,5-dicyclopropyl-2-(4-fluorophenyl)benzene And furan-3-carboxamide (863 mg, 1.205 mmol) was dissolved in THF (10 mL). 942 mg Pd/C (10%) was added at room temperature under H2 (60 psi) After stirring for 6 hours, the mixture was filtered and concentrated. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give N,5-dicyclopropyl-2-(4-fluorophenyl)·6-(Ν·((2-hydroxy-1) , 2-oxoborom-4-yl)indolyl)hydrazinosulfonylamino)benzofuran-3-decylamine (113 mg, 21% yield 154007 .doc -128· 201221131 rate). 4 NMR (300 MHz, CD3OD-c^) δ = 7·95 (m, 2H), 7.74 (d, 1H), 7.31 (t, 2H), 7.12 (s, 1H), 3.81 (m, 2H), 3.68 (m, 1H), 2.99 (s, 3H), 2.95 (m, 1H), 2.50 (m, 1H), 2.38 (m, 1H), 1.11 (m, 3H), 0.91 (m, 4H), 0_74 (m, 4H). LCMS (m/z) ES+ = 527 (M + 1) Example 32 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1, 2-oxo) 4-yl)methyl)methylsulfonylamino)benzofuran-3-carboxamide

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonylamino)benzoguanamine is dialed in anhydrous DMF (15 mL) at ambient temperature Mix 5-cyclopropyl-2-(4-fluorophenyl)-6-(methylsulfonylamino)benzofuran-3-carboxylic acid (600 mg, 1.542 mmol) and add DIPEA (439 mg, 3.392 mmol) And HATU (704 mg ' 1.85 mmol). After stirring for 15 minutes, 15 mL of THF containing ammonia (104 mg ' 6.169 mmol) was added. The reaction mixture was further stirred for 2 h and diluted with EtOAc (30 mL) The organic layer was separated and aqueous was extracted with EtOAc EtOAc. The combined organic layers were dried with EtOAc EtOAc EtOAc. The residue 5-cyclopropyl-2-(4-fluorophenyl(methylsulfonylamino)benzofuran-3-carboxamide (1. g, crude) was used for next purification without further purification Step 154007.doc •129-201221131 Step 2: 6-(N-(2-(Benzyloxymethyl)allyl)indolylsulfonylamino)_5_cyclopropyl-2-(4-fluoro Phenyl)benzonafuran-3-indolyl. Treatment of 5-cyclopropyl-2- with ((2-(bromomethyl)allyloxy)methyl)benzene (815 mg, 3.392 mmol) (4-Fluorophenyl)-6-(indolylsulfonylamino)benzofuran_3·Nacine (1.0 g 'crude, 1.542 mmol), KI (256 mg, 1.542 mmol) and K2C03 (639 mg) , 4.626 mmol), EtOAc (30 mL EtOAc). The organic layer was dried over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub. Allyl)methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carbamide (574 mg , 67% yield) LCMS (m/z, ES+) = 571 (M+l) + Step 3: 6-(1^-(3-(benzyloxy)-2-((4,4, 5,5-tetramethyl-1,3,2-dioxaboran-2-yl)indolyl)propyl)decylsulfonylaminocyclopropyl-2-(4-fluorophenyl)benzo Σv-am-3-ylamine vaporized carbonyl bis(triphenylphosphine) ruthenium (1) (72 mg, 0.1 mmol) and 6-(N-(2-(benzophenoxy) Allyl)methylsulfonylamino)_5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxamide (570 mg, 1.04 mmol) dissolved in THF (10 mL The pinacol borane (666 mg, 5.2 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (with 0-50% ethyl acetate Purification of the ester petroleum to produce 6-(N-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl) 1,3,2-dioxaboron- 2-yl)methyl)propyl)decylsulfonylamino)-5-cyclopropyl- 154007.doc •130 201221131 2-(4-fluorobenzyl)benzo-folly-3-anthracene (906 mg, 128% yield) Step 4 · 5-cyclopropyl-2-(4-fluorophenyl)_6_(N-((2-hydroxy-1,2-oxo boron -4- 4-) Methyl)methyl Treatment of 6-(Ν(3-(benzophenoxy)_2-((4,4,5,5-tetraindole) with 906 mg Pd/C (10%) Base-1,3,2-dioxaboron-2-yl)methyl)propyl)decylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran A solution of 3-carbamide (906 mg, crude, 1.04 mmol) in THF (10 mL). Filter and concentrate the mixture. The residue was dissolved in THF (10 mL) and was taken &lt;RTI ID=0.0&gt;&gt; The suspension was stirred for 4 hours, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxaborimidin-4-yl)indole Base sulfonylamino)benzofuran-3-carboxamide (201 mg, 400/ yield)"*H NMR (300 MHz, CD3OD-^) 5=8.05 (m, 2H), 7.75 (d, 1H), 7.31 (q, 3H), 7.12 (s, 1H), 3.82( m, 4H), 3.10 (s, 3H), 2.50 (m, 2H), 1.12 (m, 3H), 0.96 ( m, 2H), 0.73 (m, 1H). LCMS (m/z) ES+ = 487 (M + 1) Example 33 5-cyclopropyl-6-(N-((2-hydroxy)1,2 oxaboron-4-yl)methyl)methyl Sulfonamide)-indole-methyl-2-(4.(trifluoromethyl)phenyl)benzofuran-3-carboxamide

154007.doc -131 - 201221131 Step 1: 3-(4-(Trifluoromethyl)phenyl)-3_oxoxypropionic acid ethyl acetate to 4-(difluoromethyl)benzoic acid (30.0 g, 0.58 Mol) A solution of DCM (250 mL) was added with ethylene dioxane (Μ mL, 0.23 7 mol) followed by DMF (0-5 mL). The reaction mixture was refluxed for 2 hours. The resulting clear yellow solution was concentrated in vacuo. An acid gasification in the form of a yellow liquid is obtained. Add TEA (55 mL) to a solution of monoethyl malonate (34 g, 0.2 mol) in MeCN (500 mL) and cool in ice-salt bath to add MgCh (23 g, 0.242 mol) And the resulting mixture was stirred at the temperature for 3 hours. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After complete reaction (monitored by TLC), the mixture was cooled in an ice bath and the intermediate was treated with &lt The mixture was stirred in an ice bath for 1-5 h and then transferred to a sep. funnel and extracted with EA (3×200 mL). The combined organic layers were washed with EtOAc EtOAc (EtOAc m. Ethyl 3-oxopropionate (42 g, 1% 2%). It was used for further purification without purification. Step 2: Ethyl 2-(4-(trifluoromethyl)phenyl)-5-hydroxyindolofuran-3-carboxylate was stirred in absolute ethanol (45 mL) (22.9 g, 〇.169 m 〇 1), and then heated to 95 C &gt; c (reflux) using a drying glassware under a nitrogen atmosphere. Ethyl 4-(trifluoromethyl) benzhydrylacetate (4 i 2 g, 〇·158 mol) was added in a single portion, followed by dropwise addition of alum (18.4 g, 〇171 mol) over 2 hours. A solution of anhydrous MTBE (500 mL). This is accompanied by the distillation of the puddle while the distillation of the reaction mixture is carried out, so that the volume of the reactants remains approximately strange. 154007.doc -132· 201221131 Maintain a bath temperature of l45_155〇C and within /75 degrees of 75_95 °C during most additions. At the middle of the addition, more absolute ethanol (45 mL) was added as the reaction mixture thickened and some of the inherent (〇rganic) volume of ethanol was suspected to be lost via distillation. After the addition is complete, continue heating for 3 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) andEtOAc. The insoluble solids were removed by filtration of the two phase solution and the organic layers were separated, washed with more water, dried and evaporated in vacuo. The residual brown color solid was slurried in warm dichloromethane and the mixture was cooled to room temperature and was further cooled overnight by refrigering. The tan solid was filtered from a dark brown solution and washed with a small volume of DCM and dried in vacuo to yield ethyl 2-(4-(difluoromethyl)) &amp; 6 g, 30%). Step 3: 2-(4-(Trifluoromethyl)phenyl)-5-isopropoxybenzofuran_3_carboxylic acid ethyl acetate 2-(4-(trifluoromethyl)phenyl)-5-hydroxyl Benzofuran _3_ decanoic acid ethyl ester • (14·94 g, 0'047 mol) dissolved in NMP (155). Add isopropyl bromide (13.8 mL), carbonate planer (30.7 g, 〇〇94) M〇i). The reaction mixture was stirred in an oil bath at 60 ° C for 20 hours and then cooled to ambient temperature. The reaction mixture was treated with a 5% ammonium solution and stirred for 15 minutes. The mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated tolulululululululululululu g, 94%) Step 4: 5-Isopropoxy-6-nitro-2(4•(trifluoromethyl)phenyl)benzoate _-3-carboxylic acid ethyl vinegar 154007.doc •133 - 201221131 Ethyl 5-isopropoxy-2-(4-(trifluoromethyl)phenyl)benzofuran_3·carboxylate 4 (17.6 g, 0.045 mol) was dissolved in air (41 mL) The resulting solution was cooled in an ice bath. Nitric acid (29 5 mL) was also dissolved in gas (41 mL). Cooling in an ice bath. Add the acid solution to a solution of ethyl 2-(4-(trifluoromethyl)phenyl)-5-isopropoxybenzofuran-3-decanoate over 1 hour, and then The reaction mixture was stirred for 15 h at EtOAc then EtOAc (EtOAc)EtOAc. Purification by column chromatography (PE/EA = 5/1) to give 5-isopropoxy- 6-nitro-2(4-(difluoromethyl)benzyl)benzofurancarboxylic acid as a brown solid.乙g(5.2 g, 26'50/〇) Step 5: 5-Hydroxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran·3_ decanoic acid Ethyl 5-isopropoxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran_3_carboxylate (6 g, 2.28 mmol) was dissolved in anhydrous DCM (50 mL) And cooling in an ice bath under a nitrogen atmosphere. Add boron trioxide (4 2 mL, 6.86 mmol) over 30 min. After complete reaction, the reaction mixture was quenched by pouring onto an ice/water mixture. Wash into ice/water with D (:Ma. Mix with DCM (3x5) 0 ml), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give &lt;RTIgt;5-hydroxy-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran 3-ethyl decanoate (3 8 g, 280 / 〇) 〇 Step 6: 6-nitro-2-(4-(trifluoromethyl)phenyl)_5_(trifluoromethanesulfonyloxy) And furan-3-carboxylic acid ethyl vinegar 154007.doc -134·

S 201221131 to 5-carbyl-6-nitro-2_(4•(trimethyl)phenyl)benzoate ethyl 3-(3-ethyl)carboxylate (3.8 g, 9.6 mmol) in anhydrous DCM (6 mL) In the mixture, add DMAP (0.117 g, 0.96 mmol) and anhydrous TEA (1.9 g, 192)

Mol). The resulting mixture was cooled in an ice bath under nitrogen then trifluoromethanesulfonic anhydride (4.06, 14.4 mmol). The reaction mixture was stirred at 〇 °c under nitrogen for 30 min then quenched with water (1 mL) and extracted with (3×100 mL). The combined organic layers were washed with water (3×2 mL), EtOAc (EtOAc) Methyl 2-(4-(trifluoromethyl)phenyl)-5-(trifluoromethanesulfonyloxy)benzofuran-3-carboxylate (5.7 g '105%). This material was purified without further purification Use: Step 7: 5-Cyclopropyl-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran_3_carboxylic acid ethyl acetate 6-nitro-2-(4- (Trifluoromethyl)phenyl)_5_(trifluorosulfonyloxy) benzobenzofuran-3-carboxylate (5.7 g, 10.8 mmol), KF (2.0 g, 35.6 mmol), NaBr (ll g, 10.6 mmol), cyclopropyl-folic acid (1.4 g, 16.2 mmol) and Pd(Ph3P) 4 (0.62 g, 0.09 mmol) were dissolved in a mixture of toluene (80 mL) and water (1.45 mL). The flask was stirred for about 3 minutes, then was taken up with EtOAc (3 mL). Washed with brine (3x1 L) and dried over anhydrous sodium sulfate Filtration, concentrating under reduced pressure and purification by column chromatography (PE/EA = 2:1) to give 5-cyclopropyl-6-nitro- I54007.doc. 135. 201221131 2 - (4-(Trifluoromethyl)phenyl)benzofuran.3-ethyl decanoate (3.5 g, 78%). Step 8: 6-Amino-5-cyclopropyl-2-(4 -(Trifluoromethyl)phenyl)benzoaphthyl-3-ethyl formate to 5-cyclopropyl-6-nitro-2-(4-(trifluoromethyl)phenyl)benzofuran _3 ethyl citrate (3_5 g' 8.3 mmol) in ethyl acetate (200 mL) was added 10% palladium / activated carbon (1.0 g), 1 N HCl (0.95 mL), and at room temperature Stirring under 0.4 MPa of hydrogen for 4 hours. The reaction mixture was subjected to a mixture of celite and the filtrate was evaporated in vacuo to give 6-amino-5-cyclopropyl 2 (4-(-) Benzyl-fusan-3-decanoic acid ethyl ethane (crude, 3.5 g, 95%). Step 9: 5-cyclopropyl-6-(N-(methylsulfonyl)methylsulfonylamino)_2_ (4_(Trifluoromethyl)phenyl)benzofuran·3-formic acid ethyl acetate to 6-amino-5-cyclopropyltrifluoromethyl)phenyl)benzoate at -i5C under &amp; atmosphere Methyl furan-3-furoate (3.2 g, 8.2 mmol) Anhydrous TEA (2.07 g, 20.5 mm 〇1) was added to a solution of anhydrous methane (5 mL) and then methane sulfonium (3.27 g, 28.7 mmol) was added dropwise. The mixture was also warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (5 mL EtOAc)EtOAc. The organic layers were combined, dried <RTI ID=0.0></RTI> &amp; Cool the residue to 0 〇 and pull 1 I ± for 1 hour. The solid was filtered, washed with EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjj 4-(TriHmethyl)phenyl)benzofuran-3-carboxylic acid ethyl acetate (4.7 g '105〇/〇) 〇Step 10. 5~Cyclopropyl_6•(methylsulfonylamino)_2_ (4_(Trifluoromethyl)benzene 154007.doc 201221131 】) 笨 吱 吱 曱-3-曱 acid Add potassium hydroxide (5.6 g, 1 〇〇 6 mmol) to 5-cyclopropyl _ 6- under nitrogen (N-(Methanesulfonyl)nonylsulfonylamino)_2_(4(trifluoromethyl)phenyl)benzoxofan-3-carboxylic acid ethyl ester in ethanol (6 mL) and water (30) In the solution in mL). The reaction was refluxed for 1 hour and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCl until a precipitate formed. The solid was filtered and then dried in air to give 5-cyclopropyl-6 (mercaptosulfonyl)-[2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylic acid (3.1) g, 82%). This material was used without further purification. Step 11: 5-cyclopropyl-N.methyl_6·(fluorenylsulfonylamino)·2_(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide at 21C Anhydrous 5-cyclopropyl-6-(methylsulfonylamino) 2 -(4-(trifluoromethyl)phenyl)benzofuran-3-decanoic acid (3.1 g, 7.06 mm〇1) DIPEA (2.2 g, 14.0 mmol) and HATU (3.1 g, 8.4 mmol) were added to DMF (30 mL). After stirring for 15 min, THF (13_6 mL, 27.2 mmol) ). The mixture was stirred for additional 2 hours, then water (60 mL) was added. The mixture was extracted with EA (3xl 〇〇 mL) and saturated

Washed with NaHC03 (100 ml), 2 M HCl (1 mL), water (1 mL) and brine (100 ml), dried over Na.sub.2.sub.4, concentrated and purified by column chromatography to yield white. Solid 5-cyclopropyl-N-indenyl_6·(decylsulfonylamino)-2-(4-(difluoroindolyl)phenyl)benzofuran_3_decylamine 7 , 88%). Step U. 6-(N-(2·(Benzyloxymethyl)allyl)methylsulfonamide 5% Cyclopropylmethyl-2-(4-(trifluoromethyl)phenyl Benzofuran winter formazan 154007.doc •137· 201221131 to 5-cyclopropyl-N-mercapto-6-(indolylsulfonylamino)-2-(4-(trifluoro) under nitrogen Potassium carbonate (2〇g, 145 mm〇1), KI (81) was added to a solution of decyl)phenyl)benzofuran_3·decylamine (2.2 g, 4.86 mmol) in anhydrous DMF (20 mL) Mg, 0.49 mmol) and ((2-(bromomethyl)allyloxy)methyl)) (1·76 g ' 7.29 mmol). The reaction mixture was stirred at room temperature for 2 hr then water (60 mL) Diluted, extracted with EtOAc (3×1 mL), washed with water (1 mL) and brine (1 mL), dried and concentrated in vacuo to give crude product. =1: 2) Purification to give 6-(N-(2-(benzyloxymethyl)allyl)indolyl)-5-cyclopropyl-N- as a color solid. Methyl-2-(4-(trifluoromethyl)phenyl)benzofuran_3_formamide (1.5 g, 52%) » Step\3',6-(1^-(3-(benzene)曱oxy)-2-((4,4,5,5-tetra-indenyl-1,3,2 -dioxaborom-2-yl)methyl)propyl)methylsulfonylamino)_5_cyclopropylmethyl-2-(4-(trifluoromethyl)phenyl) benzofuran·3 ·Metformin vaporizes carbonyl bis(triphenylphosphine) ruthenium (I) (192 mg, 0.26 mmol) and 6-(N-(2-(benzophenoxy) allyl under nitrogen atmosphere ) mercaptosulfonylamino)-5-cyclopropyl-N-mercapto-2-(4-(trifluoromethyl)phenyl)benzofuran_3-formamide (1.5 g, 2.6 mmol) Dissolved in THF (50 mL). Add the pinacol boron (3.3 g '26 mmol) and mix the mixture for 24 hours. The solvent was removed in vacuo and the crude was purified by column chromatography (solvent: 0-50 Purification to give 6-(N-(3-(benzyloxy))-2-((4,4,5,5-tetramethyl-1) as a yellow solid. 3,2-dioxaboron-2-yl)methyl)propyl)methylsulfonylamino)-5-cyclopropyl-N-methyl-2-(4-(trifluoromethyl)benzene Benzofuran·3_decylamine (1.4 g, 79%). 154007.doc •138· 201221131 Step U: 5_cyclopropyl·6_(Ν·((2_hydroxy'2_oxyboron 4 Methyl)methylsulfonylamino)-indole-l-yl-2(4-(trifluoromethyl)phenyl)benzo Furan_3_carbamamine will be ό-(Ν-(3-(benzyloxy)·2_((4,4,5,5·tetramethyldioxaborin-2-yl)methyl)propane Methylsulfonylamino)_5_cyclopropyl_N_methyl_2_(4_(monofluoromethyl)phenyl)benzofuran_3-cartoamine (ι·4 g, 2. 〇mm〇i) was dissolved in THF (30 mL) and added 1.38 g Pd/C (10 〇/o). The mixture was stirred under hydrogen (40 psig) for 16 hours at room temperature. Filter and concentrate the mixture. The residue was taken up in EtOAc (30 mL)EtOAcEtOAcEtOAc. The suspension was stirred for 2 hours, then dried and concentrated in vacuo. The residue was redissolved in THf (3 mL) and treated with &lt;RTI ID=0.0&gt;&gt; The suspension was stirred for 2 hours then filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 5-cyclopropyl-6-(N-((2-hydroxy-1,2-oxo!醯 ) ) ) ) ) ( ( ( ( ( ( 〇 〇 〇 〇 〇 〇 〇 〇 LCMS (m / z) ES + = 550.8 ( M+1). 4 NMR (300 MHz, CD3OD) 6=7.94-7.91 (m, 2H), 7.69-7.60 (m, 3H), 7.02 (s, 1H), 3.95-3.40 (m, 4H), 2.97 (s, 3H) , 2.85 (S, 3H), 2.39- 2.28 (m, 1H), 2.24-2.02 (m, 1H), 1.05-0.50 (m, 6H) Example 34 2·(4·Phenylphenyl)-5·Cyclopropane -6-(N-((2-hydroxy-1,2-oxaboron-4-yl)methyl)methylsulfonylamino)-N-methylbenzofuran_3_formamide 154007 .doc -139- 201221131

Step 1: 3-(4-Phenylphenyl)-3-oxo-propionic acid ethyl acetoacetate To a solution of 4- benzoic acid (30.0 g, 0.192 mol) in DCM (250 mL) (25 mL, 0.288 mol) 'The DMF (0.5 mL) was then added dropwise. The reaction mixture was refluxed for 2 hours. The resulting clear yellow solution was concentrated in vacuo. An acid gasification in the form of a yellow liquid is obtained. Add TEA (67 mL) to a solution of malonate monoethyl acetate (41 g, 0.241 mol) in MeCN (537 mL) and cool in ice-salt bath. Add MgCl2 (27.4 g, 0.288 mol) And the resulting mixture was stirred at the temperature for 3 hours. The acid sulphate prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After complete reaction, the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2 N HCl (600 mL). The mixture was stirred in an ice-bath for 1.5 h then transferred to a sep. funnel and extracted with EA (3×200 mL). The combined organic layers were washed with saturated sodium bicarbonate (45 mL), brine (250 mL), dried over anhydrous sodium sulfate, and evaporated and evaporated Ethyl 3-oxopropionate (48.6 g '11% yield) which was used for further purification without purification. Step 2: 2-(4-Phenylphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl acetate was stirred in absolute ethanol (45 mL) with zinc chloride (28.3 g, 0.207 mol). JDI was heated to 95 °c (reflux) under a nitrogen atmosphere. 4-Chlorobenzylidene ethyl acetate (44 g, 0.194 154007.doc -140 - 201221131 mol) was added in a single portion, followed by dropwise addition of phenylhydrazine (22.6 g, 0·21 mol) over anhydrous over 2 hours. Solution in MTBE (50 mL). This is accompanied by the simultaneous distillation of the MTBE from the reaction mixture, so the reactant volume remains approximately constant. The bath temperature of 145-155 ° C and 75-95 were maintained during most of the additions. (: Internal temperature. At the middle of the addition, more absolute ethanol (45 mL) was added as the reaction mixture thickened and some of the original volume of ethanol was suspected to be lost via distillation. After the complete addition, the heating was continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (1 mL) and EtOAc (250 mL). The insoluble solid was removed by filtration of the two-phase solution and the organic layer was then separated and washed with more water. Evaporation under vacuum. Residual brown solids were taken up in warm methylene methane and the mixture was cooled to room temperature and further cooled by freezing overnight. The tan solid was filtered from a dark brown solution and washed with a small volume of DCM and under vacuum Dry to produce benzofuran (27 g, 43. Step 3: 2-(4-chlorophenyl)-5-isopropoxybenzofuran_3_carboxylic acid ethyl acetate to 2-(4-phenylphenyl) Add isopropyl bromide (15 mL) to NMP (160 mL) of ethyl benzofuran-3-carboxylate (26 g, 0.051 mol), followed by addition of carbonic acid (33 g, 〇.1〇) 1 molp reaction mixture was mixed in 6 (Γ: oil bath for 20 hours and then cooled to ambient temperature. The mixture is treated with a 5% solution and (iv) 15 min. This mixture is then diluted with water and extracted with EtOAc. The organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 2 ( 4- chlorophenyl) _5_Isopropoxybenzofuran-% ethyl formate (15 g, 820 / 〇) » Step 4: 2-(4-Chlorophenyl)-5-isopropoxy winter nitrobenzophene. South winter formate vinegar 154007.doc •141 · 201221131 Ethyl 2-(4-phenylphenyl)-5-isopropoxybenzofuran·3•carboxylate 4 (3〇g, 0.084 mol) dissolved in gas In the imitation (75 mL) and the obtained solution was cooled in an ice bath. Nitric acid (55 mL) was dissolved in chloroform (75 mL) and cooled in an ice bath. The acid solution was added dropwise to the compound 2_(4) over a period of 1 hour. _ gas phenyl) 5- isopropyloxybenzofuran-3- decanoic acid ethyl ester, and the reaction mixture was stirred for 1.5 hours under hydrazine. The reaction mixture was then diluted with water (6 〇 mL) and the layers were separated. The organic layer was dried over anhydrous sodium sulfate (EtOAc m. Ethyl 2-(4-phenylphenyl)-5-isopropoxy-6-nitrobenzofuran-3-furoate (11 g, 32.4%). Step 5: 2-(4- Gas phenyl)-5-hydroxynitrobenzofuran-3·acetic acid ethyl acetoacetate 2-(4-oxaphenyl)-5-isopropoxy-6-nitrobenzofuran-3-acid Ethyl ester (11 g, 27.2 mmol) was dissolved in anhydrous DCM (150 mL). Trifibrate boron (41 mL, 41.0 mmol) was added over 20 minutes. After complete reaction, the mixture was quenched by pouring into an ice/water mixture. The reaction mixture was poured into ice/water mixed with DCM. The mixture was extracted with DCM, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 2·(4- phenylphenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid Ester (10.2 g, 84%). Step 6: (4-Chlorophenyl)-6-nitro-5-(trifluoromethanesulfonyloxy)benzoquinone-3-carboxylic acid ethyl acetonate in an ice bath to 2-(heart) Chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid ethyl ester (10.2 g, 22.9 mmol) and DMAP (0.289 g, 2.3 mmol) in anhydrous dcm (300 mL) and anhydrous TEA ( In the solution of 4.8 mL) 154007.doc s • 142- 201221131 Add the chaotic acid-burning acid (5.62 mL, 34 mmol). The reaction mixture was stirred with EtOAc (3 mL EtOAc (EtOAc) (2x300 mL), EtOAc (EtOAc) (EtOAc) Ethyl sulfonyloxy)benzofuran_3_decanoate (10 g, 80%) was used without further purification. Step 7: 2-(4-chlorophenyl)-5-cyclopropane Ethyl 6-nitrobenzofurancarboxylate 2-(4-phenylphenyl)-6-nitro-5-(trifluorosulfonyloxy)benzofuran-3-carboxylate ( 10 g, 18 mmol), KF (4.64 g, 79.9 mmol), NaBr (2.48 g, 24 mmol), cyclopropyl acid (3.2 g, 37 mm〇1) and Pd(Ph3P)4 (1.33 g, 1.15) A mixture of mmol) was dissolved in toluene (13 mL) and water (2.8 mL). The reaction flask was evacuated for about 3 minutes, then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hours and then cooled to ambient. Dilute with EtOAc (150 mL), water (3×200 mL;), brine (2 00 mL) Washing strips were dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified by column chromatography ( petroleum ether / ethyl acetate = 3 0/1 to 10/1). Yellow solid (7 9 g, 99%) Step 8: 6-Amino-2-(4-phenylphenyl)-5-cyclopropylbenzofuran_3_carboxylic acid ethyl acetate to 2-(4- gas Add 1% palladium / active to a solution of ethyl phenyl)-5-cyclopropyl-6-nitrobenzofuran_3_decanoate (8 g, 18.2 mmol) in ethyl acetate (450 mL) Carbon (1.83 g), 1 N HCl solution (2.5 mL), and mixed for § hr at room temperature under 〇·4 J54007.doc -143· 201221131 MPa hydrogen. The reaction mixture was filtered through Shixiazao and mashed. Evaporation under vacuum to give the title compound as a brown solid (7.4 g, 99%): Step 9: 2-(4-chlorophenyl)-5-cyclopropyl·6-(Ν-(甲) Ethyl)methylamino benzofuran-3-carboxylic acid ethyl acetate to 6-amino-2-(4-phenylphenyl)-5-cyclopropyl at &lt; -15 ° C under & atmosphere An anhydrous TEA (6.73 mL, 45.15 mmol) was added to a solution of ketone-3-carboxylic acid B (7.4 g, 18.06 mmol) in anhydrous succinium (170 mL) and then added dropwise曱 醯 醯 ( 4 (4 9i mL, 63.2 mmol). The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100 mL) andEtOAc. The organic layers were combined, dried over Na.sub.4, filtered and evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt; Ethylamino)benzofuran-3-carboxylic acid ethyl ester (9·2 g, 99%). This material was used without further purification. Step 10: 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonylamino)benzo-3-pyran-3-carboxylic acid was added under nitrogen. Potassium hydroxide (15.1 g, 270 mmol) to 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonylamino)benzofuran A solution of ethyl-3-acetate in ethanol (64 mL) and water (32 mL). The reaction was refluxed for 1 hour' and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCl (250 mL) until a precipitate formed. The solid was filtered and dried to give 5-cyclopropyl-2-(4- phenylphenyl)-6-(methylsulfonylamino)benzofuran-3-carboxylic acid (8-7 g, 111%). This 154007.doc •144- 201221131 The material was used without further purification. Step 11: 5-cyclopropyl_2_(4-hydrophenyl)N-methyl-6 (methylsulfonylamino) benzofuran-3-mercaptoamine at 5C to 5-cyclopropyl Add DIPEA (3 3) to a solution of _2_(4_ phenyl)-6_(nonylsulfonylamino)benzofuran-3·carboxylic acid (5 g, H. 52 mmol) in dry DMF (30 mL) g, 25 34 mm 〇 1), HATU (5 15 g, 13.5 mmol). After 15 minutes, 2 mmol of methylamine in THF (23.04 mL ' 46.08 mmol) was added dropwise and the mixture was stirred for a further 2 hr then water (60 ml). The mixture was extracted with ea (3) &lt;&lt;&gt;&gt;&lt;&gt;&gt;&lt;&gt;&gt;&lt;&gt;&gt; -6-(Methylsulfonylamino)benzofuran_3.carbamamine (4.7 g, 97%). Step 12: 6-(N-(2-(Benzylmethoxynonyl)allyl) decylsulfonylamino (4-chlorophenyl)-5-cyclopropylmethylbenzofuran_3_ Potassiumamine was added with potassium carbonate (1 g, 717 mm〇l), KI (〇397 0 g, 2.39 mmol) and (2-bromodecylallyloxyindenyl)benzene (115 g, 478) under a nitrogen atmosphere. Methyl) to 5-cyclopropyl-2-(4-phenylphenyl)_N_indolyl-6-(methylsulfonylamino) benzofuran-3-carboxamide (1 g, 2.39 mmol) in anhydrous In a solution of DMF (10 mL), the reaction mixture was stirred at room temperature for 3 hrs, then diluted with water (30 mL) and dried over EtOAc. Column chromatography (first EA / PE = 丨: 丨〇, then EA / PE = 1: 2) was purified to give 6_(N_(2_(phenylhydrazinyl) allyl) oxime as a brown solid. Phytosulfonyl)-2-(4-phenylphenyl)-5.cyclopropyl-N-methylbenzopyran-3-cartoamine (0.97 g, 70%). 154007.doc • 145· 201221131 Step 13 : 6-(N-(3-(Benzyloxy)_2_((4,4,5)5_tetramethyl_132_dioxaboroin-2-yl)methyl)propyl) Methylsulfonamide)_2_(4 gas phenylcyclopropane Base-~Ν-methylbenzofuran-3-carboxamide to gasify carbonyl bis(triphenylphosphine) 锗mg, 0.167 mmol) and 6-(N-(2-(benzyloxy)) under nitrogen atmosphere Allyl)methylsulfonylamino)-2-(4-chlorobenzyl)-5-cyclopropyl-N-methylbenzopyran·3_decylamine (9 70 mg ' 1.67 mmol) was dissolved in THF (12 mL). Pinacolborane (1.07 g, 8.35 mmol) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the crude residue was purified by column chromatography (e.g. EA/pE = 1:5, then EA/PE = 1:2) to yield 6-(N-(3-(phenyloxy) Base)·2-((4,4,5,5_tetradecyl-1,3,2-dioxos-2-yl)indenyl)propyl)methyl-hydrocarbylamino)_2_(4_chloro Phenyl)-5-cyclopropyl-indole-methylbenzofuranium amide (1 g, 55%). Step 14: 2-(4-Chlorophenyl)-5-cyclopropyl·6-(Ν-((2-hydroxy-1,2-oxoboro-4-yl)methyl)methylsulfonamide Methyl benzopyrene can be 6-(Ν-(3-(benzyloxy)-2-((4,4,5,5-tetramethyl-1,3,2-dioxo) Boron-2-yl)methyl)propyl)decylsulfonylamino)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-A Indoleamine (1 g, ι·41 mmol) was dissolved in THF (15 mL). 300 mg of activated palladium/carbon (10%) was added and stirred at room temperature under hydrogen (4 lbs/ft). Hour "Filtered and concentrated mixture. The residue was dissolved in THF (15 mL) eluting with 5 N EtOAc (1. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Hydroxy-1,2-oxaboron-4-yl)indolyl)methylsulfonylamino)-N-methylbenzofuran-3-carboxamide 154007.doc •146 201221131 (130 mg,18% Yield) 1H NMR (300 MHz, CD3OD) δ=7·90· 7.87 (d, 2H), 7.75-7.71 (d, 1H), 7.55-7.52 (m , 2H), 7.14 (s, 1H), 3.85-3.63 (m, 4H), 3.09 (s, 3H), 2.97 (s, 3H), 2.46 (m, 1H), 2.24 (m, 1H), 1.10 ( m, 2H), 0.95-0.88 (m, 2H), 0.70 (m, 2H). LCMS (m/z) ES+= 516_8 (M+1) Example 35 5 · cyclopropyl-2-(3-fluorobenzene) -6-(N-((2-hydroxy-1,2-oxoboran-4-yl)indolyl)methylsulfonylamino)-N-methylbenzofuran-3-carboxamide

Step 1 : Add 3-ethyl 3-(3-fluorophenyl)-3-oxopropionate to a mixture of 4-fluoro benzoic acid (3 〇. 〇g, 0.214 mol) in DCM (150 mL) Dioxane (28 mL, 0.33 mol) was then added dropwise to DMF (0.5 mL). The reaction mixture was then heated to reflux with stirring for 2 hours. The resulting clear yellow solution was concentrated in vacuo. An acid gasification in the form of a yellow liquid is obtained. Cooling the mixture of monoethyl malonate potassium salt (45.6 g, 0.268 mol) and TEA (75 mL) in MeCN (600 mL) in an ice-salt bath, adding MgCl2 (30.6 g, 0.322 mol) and The resulting mixture was stirred at this temperature for 3 hours. Adding the acid hydride prepared above, and mixing the reaction

154007.doc -147· 201221131 Bucket and extract with EA (3x200 mL). The combined organic layers were washed with saturated sodium bicarbonate (500 mL), brine (250 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-(3-fluorophenyl)-3- side. Crude propyl acetoacetate (48.4 g, quantitative). It was used in the next step without purification. Step 2: 2-(3·Fluorophenyl)-5-carbylbenzo. Furug-3-carboxylic acid ethyl acetate The zinc oxide (3 1 g, 0.229 mol) was stirred in absolute ethanol (45 mL), and then heated to 95 ° C (reflux) under a nitrogen atmosphere using a drying glass. Ethyl 3-fluorobenzylideneacetate (45 g, 0.214 mol) was added in a single portion, and then a solution of phenylhydrazine (25 g, 0.231 mol) in anhydrous MTBE (500 mL) was added dropwise over 2 hr. This is accompanied by simultaneous distillation of the MTBE from the reaction mixture, so the reactant volume remains approximately constant. During most of the addition, a bath temperature of 145-155 ° C and an internal temperature of 75-95 T were maintained. Over the course of the addition, more absolute ethanol (45 mL) was added as the reaction mixture thickened and some of the original volume of ethanol was suspected to be lost via distillation. After the addition was complete, heating was continued for 30 minutes. The reaction mixture was cooled to rt and partitioned between EtOAc (EtOAc) The insoluble solids were removed by filtration of the biphasic/trol solution and the organic layer was then separated, washed with more water, dried and evaporated in vacuo. The residual brown solid was slurried in warm dioxane and the mixture was cooled to room temperature and further cooled overnight by freezing. The tan solid was filtered from a dark brown solution and washed with a small volume of 1) (: 1 ) and dried under hexanes to give benzene. (14.6 g, 22, 8%). Step 3 ·· 2-(3 -Fluorophenyl)-5-isopropoxybenzofuran-3f acid ethyl acetate to ethyl 2-(3-fluorophenyl)-5-hydroxybenzofuran·3_decanoate (i4 6 g, 0.049 mol) Isopropyl (i42 154007.doc •148· 201221131 mL) was added to the solution in NMP (160 mL), followed by the addition of carbonic acid (32 g, 〇〇98 m〇1). The reaction mixture was at 6 The mixture was stirred for 20 hours and then cooled to ambient temperature. The reaction mixture was taken with 5% EtOAc EtOAc EtOAc. Filtration and concentration in vacuo to give ethyl 2-(3-fluorophenyl)-5-isopropoxy benzohydanto-3-decanoate (14.8 g, 890 / 〇). -(3-Fluorophenyl)-5-isopropoxy-6_nitrobenzofurancarboxylic acid φ B 2-(3-Fluorophenyl)-5-isopropoxybenzofuran_3· Ethyl citrate 4 (14 8 g, 43.3 mol) was dissolved in chloroform (4 〇 mL) in an ice bath The resulting solution was cooled. Nitric acid (28.5 mL) was also dissolved in air (40 mL) and cooled in an ice bath. The acid solution was added to 2_(3_fluorophenyl)-5-isopropoxybenzene over 1 hour. The reaction mixture was stirred for 1.5 hours under hydrazine. The reaction mixture was diluted with water (60 mL) and the organic layer was separated and dried over anhydrous sodium sulfate. Concentrate in vacuo to give a brown oil which was purified by column chromatography (PE/EA=5/1) to give 2-(3·fluorophenyl)-5. Propyloxy-6-nitrobenzofuran-3-furoate ethyl ester (4.2 g, 25%) Step 5: 2-(3-Fluorophenyl)-5-hydroxy-6-nitrobenzofuran Ethyl 2-(3-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran_3_carboxylate (4.2 g' 10.9 mmol) was dissolved in anhydrous DCM (50) Addition of tri-carbitride boron (16.3 mL, 16.3 mmol) over a period of about 20 minutes in mL) and under nitrogen atmosphere. After complete reaction, the reaction mixture was quenched by pouring into ice/water mixture. The reaction mixture is poured into a mixture with DCM / 154007.doc • 149-201221131 In water, the mixture was extracted with DCM, and the combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-(3·fluorophenyl)-5-hydroxy-6- Ethyl nitrobenzopyran-3-carboxylate (4.3 g, 11 5%). It was used in the next step without purification. Step 6. 2-(3-1Phenyl)-6-desyl-5-(Santon-methyl phenyloxy)benzobenzoin-3-carboxylic acid ethylacetate to 2-(3-fluorophenyl) Add anhydrous DCM (160 mL) and anhydrous hydrazine (2) to a mixture of -5-hydroxy-6-nitrobenzofuran-3-furic acid ethyl ester (4.2 g'11 mmol) and DMAP (0.139 g, 1.1 mmol) · 3 mL). The resulting mixture was cooled in an ice-bath under a nitrogen atmosphere, and then trifluorohexane succinic acid (2.7 mL, 16 mmol). The reaction mixture was stirred with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with EtOAc EtOAc EtOAc m. Crude fluorophenyl)-6-nitro-5-(trifluoromethanesulfonyloxy)benzofuran·3·carboxylate (5.8 g, quantitative). It was used without further purification. Step 7: 2-(3-Fluorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylic acid ethyl acetate to 2-(3-carbophenyl)-6-nitro-5 (Three gas, succinyloxy) benzof, -3-, -3- (5.8 g, 12.2 mmol), KF (2.47 g, 42.6 mmol), NaBr (1.33 g, 13 mmol), cyclopropyl To a mixture of gp-acid (1.7 g, 20 mmol) and Pd(Ph3P)4 (〇.7 g, 50 mmol) was added toluene (66 mL) and water (1. 5 mL). The reaction flask was evacuated for 3 minutes and then filled with nitrogen. Reaction 154007.doc • 150- 201221131 The mixture was refluxed under nitrogen for 2 hrs and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography (EtOAc (EtOAc) elute ° South-3 - ethyl decanoate (3.2 g, 71%). Step 8: Ethyl 6-amino-2-(3-fluorophenyl)-5-cyclopropylbenzofuran-3carboxylate to 2-(3-fluorophenyl)-5-cyclopropylnitrobenzofuran ·3·ethyl formate (3.2 g ' 8.67 mm〇i) was added 10% palladium/activated carbon (0.73 g), i N HC1 solution (1 mL) to a solution of ethyl acetate (1 mL). And stirring for 8 hours at 0.4 MPa of hydrogen at room temperature. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. Step 9. 5-cyclopropyl·2-(3-phenyl)·6·(Ν_(methylsulfonylmethyl)methylglycosylamino)benzofurancarboxylic acid ethyl acetate at -15C, In the atmosphere of Ν2, 6_Amino·2_(3_ιphenyl)·5_cyclopropylbenzopyranyl_3_decanoic acid B. (2 94 §, 8.673 匪 in anhydrous di-methane (6〇) Add anhydrous hydrazine (3.23 πα' 2168 丽〇1) to the solution in mL), then add methane sulfonium chloride (2.36 rainbow, 30 356 ♦ ♦ lin solution to room temperature and (4) 2 hours. The reaction mixture with water (30 (mL) diluted and extracted with DCM (3x6 〇 machine). The organic layers were combined, passed through Na2S 〇4, _ and evaporated in true η to yield % Cyclopropane "· (3-Denylphenyl)·6-(Ν· (曱 酿 甲基 甲基 甲基 甲基 甲基 甲基 ) 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 Step 10: 5-cyclopropyl-2_(3-fluorophenyl)6(f-sulfonylamino)benzoate. Southern-3-carboxylic acid was added with potassium hydroxide (7.3 g, 130 mmol) under nitrogen. To 5-cyclopropyl-2-(3-fluorophenyl)-6-(N-(methylsulfonylmethyl)methyl The guanidino)benzofuran-3-carboxylate (4.3 g, 8.68 mmol) was dissolved in a solution of ethanol (31 mL) and water (15.5 mL). The reaction was refluxed for a few hours and then concentrated. The solid was dissolved in water and the solution was acidified with EtOAc (EtOAc) (EtOAc). Step 11: 5-Cyclopropyl-2-(3-fluorophenyl-methyl(flatylsulfonylamino)benzofuran-3-indolylamine in anhydrous N,N-difluorene at 2 1 C Mix 5-cyclopropyl-2-(3-fluorophenyl)·6·(methylsulfonylamino)benzofuran_3-carboxylic acid (3.38 g ' 8.68 mmol) in carbamide (15 mL) ' Then add mDIPEa (2.47 g, 19" mm 〇 1) and HATU (3.98 g ' 10.414 mmol). After stirring for 15 minutes, add 2 Μ methylamine in THF (17.3 mL, 34.7 mmol). The mixture was mixed for 2 hours, then water (30 ml) was added. The mixture was washed with EA (3×50 mL), washed with water (2×1 〇〇mL), dried and concentrated to give 5-cyclopropyl-2 as a brown solid. -(3-fluorophenyl)-N-methyl· 6-(Methyl-nonylamino)benzofuran-3-carboxamide (2.8 g, 80%). Step 12: 6-(N-(2-(Benzyloxyindenyl)allyl)methylsulfonylamino)_2_(3-1phenyl)-5-cyclopropylindenylbenzo. Methylamine 154007.doc • 152· 201221131 Add potassium carbonate (0.82 g, 5 97 mm〇l), KI (〇33 g, 1.99 mmol) and (2-bromodecylallyloxyfluorene) under nitrogen. Benzene (〇96 g &gt; 3.98 mmol) to 5·cyclopropyl-2-(3-fluorophenyl)_N_methyl_6_(methylsulfonylamino)benzofuran-3-carboxamidine A solution of the amine (〇·8 g, 1.99 mmol) in anhydrous DMF (10 mL). The reaction mixture was stirred at room temperature for 5 hours, diluted with water (3 mL) and filtered. The residue was dissolved in EtOAc, dried and concentrated in vacuo to give crude. It was purified by column chromatography (first # EA / PE = 1:10, followed by ΕΑ / ΡΕ = 1 · 2) to give 6-(Ν-(2-(benzoquinone)) as a brown solid. Allyl)methylsulfonylamino)_2_(3-fluorophenyl)-5-cyclopropyl-indole-methylbenzofuran_3-carbamamine (〇8 g, γι%). Step 13 ··· 6-(Ν-(3-(Benzyloxyoxaborimidin-2-yl)methyl)propyl)methyl hydrazinyl)_2_(3_fluorophenyl)_5_cyclopropane Gasification of carbonyl bis(triphenylphosphine) ruthenium (98 j mg, 0.142 mmol) and 6-(N-(2-(phenylene)) under nitrogen atmosphere Oxymethyl)allyl)mercaptosulfonamide•yl)-2-(3-fluorophenyl)-5-cyclopropyl-N-methyl benzopyran- 3·cartoamine (8 〇〇mg, 1.42 mmol) was dissolved in THF (12 mL). Pinacolborane (0.91 g, 7.1 mmol) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the crude residue was purified by column chromatography (e.g. EA/PE = 1:5 followed by ΕΑ / ΡΕ = 1 · 2) to yield 6-(N-(3-(benzoquinone) Oxy))_2_((4,4,5,5-tetradecyl-1,3,2-dioxaboran-2-yl)methyl)propyl)methyl-decylamino)_2_(3_fluorobenzene 5-)cyclopropyl-N-methylbenzofuran-3-carboxamide (0.96 g, 980/〇 yield). Step 14 ·· 2-(3-Fluorophenyl)-5-cyclopropyl-6-(1((2-)-based, 1,2-oxo- 154007.doc-153- 201221131 4-based) Methyl)methylsulfonylamino)_N-methylbenzofuran_3_formalamine 6_(N_(3_(benzyloxy)-2-((4,4,5,5-tetramethyl) -1,3,2-dioxaboron-2-yl)methyl)propyl)methylsulfonylamino)_2_(3-fluorophenyl)-5-cyclopropyl-N-mercaptobenzofuran _3-decalamine (〇96 g, 139 mm〇l) was dissolved in THF (15 mL). Palladium/activated carbon (1 〇〇/〇, 33 〇 mg) was added and the mixture was stirred at room temperature under hydrogen (40 psig) for 48 hours. The mixture was filtered and concentrated. The residue was taken up in EtOAc (15 mL)EtOAcEtOAcEtOAc. The mixture was stirred for 3 hours, then filtered and concentrated in vacuo. The crude product was purified by reverse phase HPL (: purified to give 2_(3·fluorophenyl)_5_cyclopropyl_6_(ν·((2_ hydroxy-1, 2- oxy boron -4-) as a white solid Methyl)methylsulfonylamino)indole-methylbenzofuran-3-carboxamide (95 mg, 14 〇/〇 yield iH NMR (3〇〇ΜΗζ, CD3OD) 6=7.75 ( m, 3H), 7.55 (q, 1H), 7.23 (m5 1H), 7.11

ES+=501(M+1) Example 36 5-Cyclopropyl-2-(3-fluorophenyl)-6-(N-((l-yl) 4,3-dihydrobenzo[e][12 Oxaborolide-5-yl)methyl)methylsulfonylamino)_N-methylbenzofuran-3-cartoamine

154007.doc •154· 201221131 Step 1: 5-((N-(5-Cyclopropyl-2-(3-fluorophenyl)-3-(methylamine-carbamoyl)benzofuran-6-yl) ) methylsulfonamide) methyl iodobenzoic acid methyl vinegar heated at 80 ° C under nitrogen atmosphere 5-cyclopropyl-2-(3-fluorophenyl)-N-fluorenyl-6- (曱Methylsulfonylamino)benzofuran-3-carbamide (〇8 g, 丨99 mmol), methyl 5-(bromomethyl)_2-methyl benzoate (1 g, 2·82 mm〇l, U25284/82/1), a solution of potassium carbonate (0.823 g, 5.97 mmol) and hydrazine (0.33 g, 1.99 mmol) in anhydrous DMF (10 mL). After filtration, the residue was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) Cyclopropyl-2-(3-fluorophenyl)-3-(decylamine-methylhydrazino)benzofuran-6-yl)nonylsulfonylamino)methyl)-2-homobenzoic acid Vinegar (0.65 g, 0.961 mmol, 50%) Step 2: 5-((N-(5-cyclopropyl-2-(3-fluorophenyl)-3-(methylaminemethyl) benzo) Furan-6-yl)methylsulfonylamino)methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxosept-2-yl) benzoic acid hydrazine vinegar heated at 100 ° C under nitrogen atmosphere 5- ((N -(5-cyclopropyl-2-(3-fluorophenyl)-3-(decylaminemethylmercapto)benzofuran-6-yl)methylsulfonylamino)indolyl) Methyl benzoate (650 mg, 0.961 mmol), PdCl2(dppf)-CH2C12 adduct (97 mg, 0_〇96 mmol), bis(pinadol) diboron (0.366 g, 1.44 mmol) and acetic acid A solution of potassium (283 mg, 2.883 mmol) in EtOAc (EtOAc)EtOAc. 5-((N-(5-cyclopropyl-2-(3-fluorophenyl)-3-(decylamine)methyl)benzofuran-6-yl)nonylsulfonylamino)曱3)·(2-(4,4,5,5-tetramethyl 154007.doc •155· 201221131 yl-1,3,2-dioxaboron·2·yl)methyl benzoate (〇3 g, 〇443, 46%) 〇Step 3: 5-cyclopropyl·2_(3•fluorophenyl)6(Ν_((1_hydroxy_13_dihydrobenzo[c][l,2]oxaboron Heterocyclopentene-5-yl)methyl)methylsulfonylamino)-indole-methylbenzofuran-I-carboxamide 〇°C down to 5-((#-(5-cyclopropyl-2-(3-fluorophenyl)-3-(methylaminoindolyl)benzofuran-6-yl)methylsulfonate) Amino)hydrazino)_2_(4,4,5,5•tetradecyl·l3,2·dioxaboron-2-yl) methyl bromide (300 mg, 0.443 mmol) in THF (15 ml LiBH4 was added to the solution in the solution (2 Μ in THF, 0.443 m b 0.886 mmol), and the reaction solution was stirred at room temperature for 2 hours and then poured into water. The solution was extracted with EtOAc and the org. After removal of the solvent, the crude product was purified by reverse phase to give 5- <RTIgt; </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; [c][l,2]oxaborol-5-yl)methyl)methylsulfonylamino)-N-methylbenzofuran-3·decylamine (93.8^, 〇. 171 mmo 32.6%). NMR (300 MHz, sterol-d4) δ: 7 7 b 7 48 (m, 5 Η), 7.30-7.18 (m, 3 Η), 7.03 (s, 1 Η), 5.06-4.87 (m, 4 H ), 3.18 (s, 3 H), 2.95 (s, 3 H), 2·23 (m, 1 H), 〇 98_〇 31 (m, 4 H). LCMS (/z, ES+) = 548.9 (M+l) 〇 Example 37 2-(4-Phenylphenyl)-5-cyclopropyl-6-(N-((l-hydroxy_i,3_2) Hydrobenzoxanthene] 2] oxaborole-5-yl)methyl)methylsulfonylamino)N-methylbenzoin-3-carbamide 154007.doc -156 - 201221131

Step 1. 5-((N-(5-Cyclopropyl-2-(4-chlorophenyl)-3-(methylaminemethanyl)benzofuran-6-yl)decylsulfonylamino)曱 ) ) ) 碘 碘 碘 碘 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在Benzofuran-3-3-decylamine (〇8 gi 91 mmol), 5-(bromomethyl)-2-Ebenzoic acid methyl ester (1 g, 2 82 _〇ι, U25284/82/1), carbonic acid A solution of potassium (0.791 g, 5.73 mmol) and κ (0.317 g ' 1.91 mm 〇l) in anhydrous dmF (10 mL) for 30 min. The reaction solution was quenched with water (30 mL). After filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na 2 S 4 . After removal of the solvent, the residue was purified by column chromatography to give 5 _ ((N-(5-cyclopropyl-2-(4-chlorophenyl))-3-) Amidoxime)benzofuran-6-yl)nonylsulfonylamino)hydrazino)-2-iodobenzoate oxime (〇75 g, 1〇8 mmol, 57%). Step 2: 5-((N-(5-cyclopropyl-2-(4-carbophenyl)-3-(methylaminemethanyl)benzobenzopyranyl)methylsulfonylamino) Methyl)_2-(4,455_tetramethyl·132_monooxybutan-2-yl)benzoic acid methyl vinegar 5-((#_(5-cyclopropyl-2) at 100 ° C under nitrogen atmosphere -(4-Phenylphenyl)-3-(methylamine-mercapto)benzofuran-6-yl)methylsulfonylamino)methyl)-2-hydrazinobenzoate (750 mg, 1.08 Ment), bis (frequency), diboron (0.412 g, 1.62 mmol), potassium acetate (318 mg, 3.24 mmol) and 154007.doc -157-201221131

A solution of PdCl2(dppf)-CH2Cl2 adduct (112 mg '0.11 mmol) in anhydrous DMF (15 mL) was warmed overnight. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjjj Mercapto)benzofuran-6-yl)nonylsulfonylamino)hydrazino)_2_(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl Methyl benzoate (〇 39 g, 〇.563 mmol, 36%). Step 3: 5-Cyclopropyl-2-(3-phenylphenyl)-6-(Ν-((1-hydroxy-1,3-dihydrobenzo[c][l,2]oxa heterocycle) Pentyl) fluorenyl)methyl hydrazinyl)-N-methylbenzofuran-3-carboxamide was treated with LiBH4 (2 in THF, 0.563 mL, 1.120 mmol) at 〇 °C. (#-(5-cyclopropyl-2-(4-carbophenyl)-3-(methylaminecarbamimidyl)benzocarbonyl)-6-yl)methylamino)indolyl) _2_(4,4,5,5-Tetramethyl-1,3,2-dioxy-decyl-2-yl) a solution of methyl benzoate (390 mg, 0.563 mmol) in THF (15 mL). The resulting solution was stirred at room temperature for 15 hours and then poured into water. The solution was extracted with EtOAc and the org. After removal of the solvent, the crude product was purified using preparative H.sub.p.c. to afford to afford 5- <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Dihydrobenzo[c][i,2]oxaborol-5-yl)methyl)methylsulfonylamino)-indole-methylbenzofuran_3_formamide (9 〇 4 mg, 〇16 〇 〇 28%).咕NMR (300 MHz, methanol) 4) &amp; 7 86 7 83 (m, 2 Η), 7.61-7.50 (m, 4 Η), 7.30-7.22 (m, 2 Η), 7.03 (s, 1 Η) , 5.51-4.87 (m, 4 Η), 3.18 (s, 3 Η), 2.95 (s, 3 Η), 2.23 (m, 1 Η), 0.98-0.31 (m, 4 Η) 〇LCMS( m/z , ES+)=564.7 I54007.doc -158- 201221131 (M+1)° Example 38 5-Cyclopropyl-2-(3,4-difluorophenyl)_6·(Ν-((1•hydroxy-1) ,3-dihydrobenzo[c][l,2]oxapene heterocyclopenten-5-yl)methyl)methylsulfonylamino)-N-methylbenzo-bate-3. Amine

Step 1: 5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(methylamine f-yl)benzofuran-6-yl) methyl) 5-Aminopropyl-2-(3,4-difluorophenyl)-N-methyl-6-(methylsulfonamide) under a nitrogen atmosphere Benzofuran-3-carboxamide (0.75 g, 1.8 mmol) was dissolved in acetonitrile (40 ml), followed by the addition of 5-(derivative)·2_iodobenzoate methyl ester (0.766 g ' 2 ) · 16 mmol) and propylene carbonate (0.745 g, 5.4 mmol). The reaction mixture was heated to 70 ° C and stirred until TLC indicated the reaction was completed. EtOAc (50 ml) / water (50 ml) (ml) extraction, washing with brine (100 ml), 'back-extraction, dried over sodium sulfate, and flash chromatography (EtOAc··hexane = 1:3) to give a white solid. Propyl 2-(3,4-difluorophenyl)-3-(decylamine decyl)benzofuran-6-yl)nonylsulfonylamino)mercapto)-2-iodobenzoic acid Methyl ester (1. g, 83%). Step 2: 5-((N-(5-Cyclopropyl-2-(3,4-difluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonate Amidino)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzoic acid methyl vinegar 154007.doc •159· 201221131 5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(decylamine)methyl)benzofuran-6-yl)sulfonylsulfonate under nitrogen Hydrazinyl hydrazinyl hydrazide (1 g, 1.4 mmol) was dissolved in anhydrous dioxane (25 ml) followed by HBPin (5.37 g, 42 mmol), triethylamine (1 g , 9.8 mmol), dicyclohexylphosphinobiphenyl (5 2.5 mg, 0.14 mmol). The mixture was immersed in a l ° ° C oil bath and pdOAc 2 (i 6.8 mg, 0.07 mol) was added rapidly. The mixture was allowed to be mixed until complete reaction was observed as observed by LCMS. The mixture was poured into EtOAc (3 mLEtOAc) The residue was purified by column chromatography (EtOAc EtOAc EtOAc:EtOAc) )_3_(Methylaminodecyl)benzofuran-6-yl)nonylsulfonylamino)methyl)_2_ (4,4,5,5-tetradecyl-l,3,2-dioxy Boron-2-ylbenzoate decanoate (850 mg, 850/〇). Step 3: 5-Cyclopropyl-2-(3,4-difluorophenyl)-6-(1((1-hydroxy-1,3-dihydrobenzo[c][l,2]oxa) Boronol-5-yl)methyl)methylsulfonylamino)_N_methyl benzofuranylamine is slowly added to LiBH4 at -5 °C (2 Μ in THF, 1.2 ml, 2.4 Ment) to 5-((N-(5-cyclopropyl-2-(3,4-difluorophenyl)-3-(methylaminemethanyl)benzofuran-6-yl)decylsulfonate Hydrazinyl) fluorenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl) benzoate (850 mg, 1.4 mmol) In a solution of THF (15 ml). The mixture was stirred for 15 min and poured with EtOAc EtOAc (EtOAc (EtOAc (EtOAc) 5-cyclopropyl-2-(3,4-difluorophenyl)-6-(Ν-((1-hydroxy-1,3-I54007.doc 201221131 dihydro cumin [C][l, 2] Oxaborolide-5-yl)indolyl)methylsulfonylamino)-N-methylbenzofuran-3-indoleamine (330 mg, 48%). LCMS (m/z, ES+) = 566.9 (M+1). 'H NMR (300 MHz, CD3OD) 6=7.86-7.69 (m, 2H), 7.61 (S, 1H), 7.54-7.36 (m, 2H), 7.29-7.21 (m, 2H), 7.03 (s, 1H) ), 5.04-4.87 (m, 4H), 3.17 (s, 3H), 2.94 (S, 3H), 2.28-2.24 (m, 1H), 0.99-0.75 (m, 3H), 0.34-0.32 (m, 1H) ). Example 39 5-Cyclopropyl·6-(Ν-((1·hydroxy-1,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl) Methylsulfonylamino)-N-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide

Step 1: 5-((Ν·(5-cyclopropyl-3-(methylaminemethanyl)-2-(4-(trifluoromethyl)phenyl)benzofuran-6-yl)indole 5-Hydroxypropyl-N-methyl-6-(indolylsulfonylamino)-2-(4-(three) sulfamoylamino)methyl)-2-iodobenzoic acid methyl ketone under nitrogen Fluoromethyl)benzyl)benzoxylf _3_cartoamine (〇.5 g, 1.1 mmol) dissolved in acetonitrile (20 ml) 'then added 5 · (bromomethyl) · 2-iodobenzene Methyl decanoate (0.461 g '1.3 mm 〇l) and potassium carbonate (〇 455 g, 3 3 mmol). The reaction mixture was heated to 70. (: and stirring until the reaction was complete by TLC. The mixture was diluted with EtOAc (30 ml) / water (30 ml), EtOAc (3x30 ml) 154007.doc. 161 - 201221131 taken with brine (40 ml) Washing, 'back-extracting, drying over sodium sulfate, and flash chromatography (EtOAc:hexane = 1 : 3) to give the product as a white solid (5-((5-cyclopropyl-3-(decylamine) Indenyl)-2_(4-(trifluoromethyl)phenyl)benzofuran-6-yl)methyl-decylamino)indolyl)_2_phenyl phthalate (〇7, 87%) 〇Step 2: 5-((N-(5-cyclopropyl-3-(methylaminemethanyl) μ2_(4_(trifluoromethyl)phenyl)benzofuran-6-yl)decylsulfonate Amidino) indenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxos-2-yl)acetoic acid methyl acetonate 5--(under nitrogen) N-(5-Cyclopropyl_3_(methylamine-mercapto)_2_(4-(trifluoromethyl)phenyl)benzofuran-6-yl)indolyl hydrazide-yl) fluorenyl)_2_ Methyl benzoate (700 mg, 0.96 mmol) was dissolved in anhydrous dioxane (2 〇ml) and then HBPin (3.48 g, 28.6 mmol), triethylamine (680 mg, 6.7 mmol) and Cyclohexylphosphinobiphenyl (35 mg, 〇"mm〇1). The mixture was immersed in a l ° ° C oil bath and quickly added pdOAcjn 2 mg, 0. 05 mol). The mixture was stirred until the reaction was judged complete by lc-MS and poured into 20 ml of water. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. 5-((n-(5-cyclopropyl-3-(methylaminoindenyl))-2-(4-(trifluoromethyl)phenyl)benzofuran-6-yl)methylsulfonate Amino)mercapto)-2·(4,4,5,5-tetramethyl-,3,2-dioxaboran-2-yl)benzoic acid methyl ester (650 mg, 89%). 3 : 5-cyclopropyl-6-(Ν-((1-hydroxy-ij-dihydrobenzo[c][12]oxalolepent-5-yl)methyl)methylsulfonate Amino)·Ν_methyl_2_(4_(trimethylmethyl)phenyl)benzofuran-3-carboxamide 154007.doc -162· 201221131 Slowly add UBH4 at -5 °C (2 Μ In THF, 〇·9 ml, 1.8 mmol) to 5-((N-(5-cyclopropyl-3_(methylaminemethylmercaptotrifluoromethyl)phenyl)benzofuran-6-yl)) Sulfosamine)methyl)_2_(4,4,5,5-tetramethyl-1,3,2-oxygen Taste-2-yl) benzoic acid methyl ester (650 mg, 0.9 mmol) in THF Shen (15 ml) in the. The mixture was stirred for 15 min and poured with EtOAc EtOAc (EtOAc (EtOAc. 5-cyclopropyl·6-(Ν-((1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl) Mercaptosulfonylamino)-N-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide (200 mg, 37%). LCMS (m/z, ES+) = 598.8 (M+1). 4 NMR (300 MHz, CD3OD) 5=8.03- 8.00 (d, 2H), 7.80-7.77 (d, 2H), 7.63-7.51 (m, 2H), 7.30-7.22 (m, 2H), 7.04 (s, 1H), 5.03-4.88 (m, 4H), 3.18 (s, 3H), 2.94 (S, 3H), 2.29-2.22 (m, 1H), 1.00-0.76 (m, 3H), 0.35-0.31 (m, 1H). Example 40 5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_6·(Ν-((1-hydroxy-1,3-dihydrobenzo[c][l,2 Oxetylene heterocyclopentene·5-yl)methyl)methylsulfonylamino)_N_methylbenzofuran-3-carboxamide

Step 1: 3-(4-Xinylphenyl)_3_oxoxypropionic acid ethyl acetoacetate 154007.doc -163- 201221131 To 4-benzoic acid (40.0 g, 0.199 mol) in DCM (300 mL) Ethylene dioxane (27 mL, 311·311 mol) was added to the solution, followed by DMF (0.5 mL) dropwise. The reaction mixture was refluxed for 2 hours. The resulting clear solution was concentrated in vacuo. An acid chloride in the form of a yellow liquid is obtained. Add TEA (76 mL) to a solution of malonic acid monoethyl sulphate (38 g '0.222 mol) in MeCN (550 mL) and cool in ice-salt bath, add MgCl2 (28 4 g, 0.299 mol) ) and the resulting mixture was stirred at the temperature for 3 hours. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and mixed overnight. The mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2 N EtOAc (600 mL). The mixture was stirred in an ice bath for 5 hours, then transferred to a sep. funnel and extracted with EA (3×200 mL). The combined organic layers were washed with EtOAc EtOAc (EtOAc m. Ethyl oxypropionate (48.4 g, 89%). It was used in further steps without purification. Step 2: 2-(4-Bromophenyl)-5-hydroxybenzopyran-3-carboxylic acid ethyl acetate was stirred in absolute ethanol (75 mL) with zinc oxide (26.8 g, 0.197 mol), followed by drying. The glass jut was heated to 95 ° C (reflux) under a nitrogen atmosphere. Ethyl 4-bromobenzylideneacetate (5 〇g, 0.184 mol) was added in a single portion. Then phenylhydrazine (21.5 g, 0.199 mol) was added dropwise over 2 hours in anhydrous MTBE (5 50 mL). Solution. This is accompanied by the simultaneous distillation of the MTBE from the reaction mixture, so the reactant volume remains approximately constant. Maintain 145-155 during most of the additions. (: bath temperature and internal temperature of 75-95 ° C. Add more anhydrous ethanol (75 mL) in the middle of the addition, because 154007.doc • 164 - 201221131 The reaction mixture becomes slightly and suspected - some original volume Ethanol was lost via steaming. After complete addition, heating was continued for 3 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (25 mL). Insoluble solids and the organic layer was then separated, the bars were washed with more water, dried and evaporated under vacuum. Residual &amp; solids were slurried in warm di-methane and the mixture was cooled to room temperature and left overnight by freezing. Further cold. The tan solid was filtered from a dark brown solution and washed with EtOAc EtOAc (EtOAc) -5-Isopropoxybenzofuran-3_carboxylic acid, ethyl 2-(4-bromophenyl)·5-hydroxybenzofuran-3-carboxylate was treated with 2-iodopropane (22 mL) (26.5 g, 0.073 mol) of NMP (300 mL) followed by addition of carbonic acid planer (47.8 g, 0.147 mol). The reaction mixture was at 6 〇. The mixture was stirred for 4 hours in an 油c oil bath and then cooled to ambient temperature. The reaction mixture was treated with a 5% ammonium solution and stirred for 15 minutes. The mixture was then diluted with water and extracted with hexanes. The organic layer was washed with water and dried over anhydrous sodium sulfate. , transition and concentrated in vacuo to give the compound 2-(4-bromophenyl)-5-isopropoxybenzene and benzoic acid ethyl ester (30 g, 102%). Step 4: 2- 4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran_3_carboxylic acid ethyl acetate 2-(4-bromophenyl)-5-isopropoxybenzofuran_3- Ethyl citrate 4 (3 〇g, 0_073 mol) was dissolved in air (60 mL) and the resulting solution was cooled in an ice bath. Nitric acid (49 mL) was also dissolved in air (60 mL) in ice Cooling in a bath. Add the acid solution dropwise to the solution of the compound 2-(4-diphenyl)-5-isopropoxybenzopyrene-N-acetic acid in ethyl acetate over 0.5 hours, and then in 〇 〇 154007.doc -165- 201221131 The reaction mixture was stirred for 0.5 hours. The reaction mixture was diluted with water (1 mL) and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated a brown oil which was pulverized in 15 mL of MTBE and then filtered to afford 2_(4-bromophenyl)·5-isopropoxy-6-nitrobenzofuran_3_carboxylic acid as an orange solid. Ethyl ester (14 5 g, 44 6%) Step 5: 2-(4-(4-Fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzopyran-3-yl Ethyl acetoacetate Ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofurancarboxylate (13.2 g ' 29.45 mm 〇i) was dissolved in toluene (8 mL). Adding di-tert-butyl (2',4',6,-triisopropylbiphenyl-2-yl)phosphine (28,4712111111〇1), potassium phosphate (12.5 g '58.9 mmol) and palladium diacetate ( 529 mg, 2.356 mmol). The resulting solution was stirred overnight under nitrogen at rt. The reaction was cooled to /m and washed with water (3×50 mL); Purified by recrystallization from EtOAc (1 50 mL) to give purified product (1 1 g, 79%) as a pale yellow solid. Step 5: 2-(4-(4-fluorophenoxy)benzene _5_hydroxy_6_nitrobenzofuran _ ethyl formate 2-(4-(4-fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzofuran _ 3 - Formic acid (li. ig ' 23 15 mm 〇l) was dissolved in dry DCM (150 mL) and cooled in an ice-bath under nitrogen atmosphere. The trichloro side (35 mL ' 34.7 mmol) was added over 2 min. After the complete reaction, the mixture was quenched by pouring into an ice/water mixture. The reaction mixture was poured into ice/water mixed with DCM. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under vacuum to give the compound 2-(4-(4-fluorophenoxyl 154007.doc 201221131)phenyl)-5-hydroxy-6-nitrobenzofuran_3·carboxylic acid ethyl ester (10·4 g , quantitative yield). 6 : Ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-(trifluorosulfonylsulfonyloxy)benzofuran-3-carboxylate under ice in ice Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3-decanoate (10.4 g, 23.15 mmol) and DMAP (0.292 g) , 2.39 mmol), trifluoromethanesulfonic anhydride (5.68 mL, 34.4 mmol) was added to a solution of anhydrous DCM (350 mL) and anhydrous TEA (4.85 mL). The reaction mixture was stirred under nitrogen at 30 ° C for 30 min. It was then quenched with water (200 mL) and EtOAc (EtOAc) (EtOAc (EtOAc) Drying with sodium, filtration, and EtOAc (EtOAc): Ethyl benzofuran-3-indoleate (13.25 g, 100%) which was used without further purification. Step 7 ················· Phenyl)-6-nitrobenzo-bite 3-carboxylic acid ethyl acetate to 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-(trifluoromethanesulfonyl) Oxy)benzene Ethyl furan-3-carboxylate (13.25 g, 23.27 mmol), KF (4.73 g, 81.45 mmol), NaBr (2.54 g, 24.67 mmol), cyclopropyl acid (3.0 g, 34.91 mmol) and Pd (Ph3P) To a mixture of 4 (1.34 g, 1.16 mmol) was added toluene (130 mL) and water (3 mL). The reaction flask was evacuated for 3 minutes and then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hours and then cooled to ambient. The reaction mixture was diluted with EtOAc (150 mL) EtOAc EtOAc (EtOAc) The residue was purified by column chromatography (EtOAc/EtOAc/EtOAc/EtOAc/EtOAc/EtOAc Ethyl)phenyl)_6-nitrobenzofuran_3_carboxylic acid ethyl ester (8.4 g, 78%). Step 8: 6-Amino-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)benzoxyl-3-carboxylic acid ethylacetate to 5-cyclopropyl-2-( Add ίο% palladium to a solution of ethyl 4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran_3_carboxylate (8.4 g, 18.2 mmol) in ethyl acetate (4 mL) / activated carbon (1.56 phantom and hydrazine N HCl solution (2 3 mL). The mixture was stirred at 0.4 MPa under stirring for 8 hours at room temperature. The reaction mixture was filtered over celite and evaporated to give a brown solid. Amine (8 g, 1 〇〇〇/0) 〇Step 9: 5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N_(methylsulfonylmethyl) Ethylsulfonyl)benzofuranate ethyl acetoacetate at &lt;15 ° C under &amp; atmosphere to 6 · amino-5-cyclopropyl-2-(4-(4-fluorophenoxy) Add hydrazine (6.91 mL, 46.35 mmol) to a solution of ethyl phenyl)benzofuran-3-carboxylate (8 g, 18·54 mm 〇1) in anhydrous di-methane (180 mL). Methane sulfonium gas (5 〇 5 mL, 64.9 mmol) was added dropwise. The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (1 mL) and DCM (3x) L5 〇 mL). The organic layer was combined, dried with NaHjjjjjjjjjjjjjjjjjjjjjjjjjjjj -6-(N-(methylsulfonyl fluorenyl)methyl 154007.doc 201221131 sulfamoylamino)benzofuran-3-carboxylate (9.5 g, 87%) Step 10 · 5-ring Propyl-2-(4-(4-fluorophenoxy)phenyl)_6-(methyl-hydroxylamino)benzofuran-3-carboxylic acid was added with potassium hydroxide (13.6 g, 243 mmol) under nitrogen. ) to 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_6·(Ν_(sulfonylhydrazinyl)methylsulfonylamino)benzofuran-3·• Ethyl formate was added to a solution of ethanol (7 mL) and water (35 mL). The reaction was refluxed for 1 hour and then concentrated in vacuo. # The remaining solid was dissolved in water and the solution was taken with 2 N HCl (1 4 1 mL) acidified until a precipitate formed. The solid was filtered and dried to give 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(sulfonylsulfonate) as a white solid. Amidinosylfuran-3-carboxylic acid (9 g, quantitative yield). This material was used without further purification. 11 : 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-(methylsulfonylamino)benzofuran-3-carboxamide Treatment of 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_6_ (nonylsulfonyl) with DIPEA (5.86 g '45.23 mmol) and HATU (9.42 g, 24.67 mmol) A solution of the amino)benzofuran-3-carboxylic acid (9.9 g, 20.56 mmol) in dry DMF (50 mL). After 15 minutes, 2 M decylamine in THF (41.12 mL &apos; 82.24 mmol) was added dropwise and the mixture was stirred for further 2 hr and then diluted with water (200 ml). The mixture was extracted with EtOAc (3×250 mL).EtOAc. Ν-Methyl-6-(fluorenyl hydrazino)benzofuran-3-decylamine (10 g, 98%). Step 12 ·· 5-((N-((5-cyclophenoxy)phenyl)-3) (Yinji 154007.doc •169 201221131 Aminyl) Benzofuran-6-yl)methyl)methylsulfonylamino)hydrazinyl)_2_ molybdate methyl vinegar Adding carbonic acid clock (418 mg, 3.03 mmol), KI (168 mg, 1.01 mmol) and 5-(bromodecyl)·2·iodobenzoate (717 mg, 2.02 mmol) to 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)- N-methyl-6- (methyl continuation of amino groups). A solution of flavonoid-3-anthracene (〇·5 g, 1.01 mmol) in water-free DMF (8 mL). The reaction mixture was stirred at room temperature for 3 〇 min diluted with water (30 mL) and filtered. The residue was dissolved in ea, dried <RTI ID=0.0></RTI> to <RTI ID=0.0> ((N_((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_3-(decylamine)methyl)benzofuran-6-yl)indolyl)methylsulfonate Methylamino) decyl)-2-benzoic acid methyl ester (365 mg, 46%) ° Step 13: 5-((N-((5-cyclopropyl-2-(4-(4-fluoro))) Phenoxy)phenyl)-3-(decylaminecarbamimidyl)benzofuran-6-yl)methyl)methyl hydrazinyl)methyl)_2_ (4,4,5,5-tetra Treatment of 5-((N-((5-cyclopropane-propyl)) with Pd(dppf)2Cl2 (54 mg, 0.047 mmol) under N2 atmosphere 2-(4-(4-fluorophenoxy)phenyl)·3·(methylamine-mercapto)benzofuran-6-yl)indolyl)methylsulfonylamino)methyl) _2_Iodobenzoic acid methyl vinegar (365 mg, 0.466 mmol), 4,4,4 ',4 ',5,5,5 ',5 octamethyl-2,2'-linked (1,3,2- Borax flavor) (237 mg, 0.933 mmol) and KOAc (137 mg, 1.4 dioxane (2 mL) and the mixture was stirred in the hour. And the crude residue was purified by column chromatography (first EA/PE = 1:5, then εα/ρεη: 2) to give 5_((N_((5 cyclopropyl) I54007.doc •170· 201221131 2 -(4-(4_ phenoxy)phenyl)_3-(decylaminemethyl)benzo M-6-yl)methyl)indolyl hydrazino)methyl is 4,4, 5,5_tetradecyl (1)·dioxosimidin-2-yl)methyl benzoate (0.345 g, 94%) Step 14: 5-cyclopropyl-2-(4-(4-fluorophenoxy) Phenyl) phenyl) winter (Ν_((I)-1,3-1,3-hydrobenzo[c][l,2]oxaborolan-5-methyl)methyl)methylsulfonylamino )-N-methylbenzo-fifting -3-anthracene

5-((N-((5-cyclopropyl-2-(4-(4-)-fluoro) was treated dropwise with OM: 2M LiBH&lt;THF (〇.449社,〇〇龙〇1) Phenoxy)phenyl)_3_(methylaminoindenyl)benzofuran-6-yl)indolyl)methylsulfonylamino)indenyl)_2_ (4,4,5,5-tetradecyl) -1,3,2-dioxosin-2-yl phthalate (0.345 g, 0.449 mmol) in THF (15 mL). The mixture was stirred for 15 hours. The reaction mixture was then quenched by the addition of a solution of water / EA (1:1, 25 mL). EtOAc (3 X 20 mL) was evaporated and evaporated. The residue was purified by preparative HPLC to give 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-((-- 1-hydroxy-l) as a white solid. ,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)methylsulfonylamino)-N-mercaptobenzofuran-3-formamidine Amine (61 mg, 20%). NMR (300 MHz, CDC13) 5=7.86-7.83 (d, 2H), 7.56-7.52 (t, 2H), 7.39-7.00 (m, 9H), 4.99 (s, 4H), 3.16 (s, 3H), 2.92 (s, 3H), 2.23 (m, 1H), 0.98 (m, 1H), 0.92-0.88 (m, 2H), 0.35-0.33 (m, 1H). LCMS (m/z) ES+=641.2 (M+1) </RTI> 41 (+)-5-cyclopropyl-2-(4-fluorophenyl)-6-[[(l-hydroxy-3-methyl-) 1,3-Dihydro-2,1-benzoxylene heterocyclopenta-5-yl)methyl](A)-amino]-N-methyl 154007.doc -171 - 201221131 1-benzofuran-3-carboxamide

Step 1: 2-Bromo-N,5-dimethyl-N-(methyloxy)benzamide can be 2-iso-5-methylbenzoic acid (9.23 g, 42 9), with stirring. N, 〇-dimethyl-based amine (5.23 g' 53.7 mm〇1), EDC (1〇7〇55.8 mmol), HOBT (8.54 g '55 8 on call and triethylamine (1) % mL, 86«^ 〇 1) The solution in dichloromethane (300 〇^) is maintained overnight. The mixture was poured into aq. The residue was purified by column chromatography to give EtOAc (EtOAc): LCMS (m/z, ES+) = 259 (M+H) Step 2: 1-(2-bromo-5-methylphenyl)ethanone &lt;RTI ID=0.0&gt; a solution of N,5-dimethyl-N-(methyloxy)benzamide (10.45 g, 40.5 mmol) in tetrahydrofuran (300 mL) and stirred at room temperature Maintain for 6 hours. The mixture was cooled to 0 ° C, EtOAc (EtOAc m. Purification afforded 1-(2-di-5-indolyl) ethyl ketone as a yellow oil (7.46 g, 35.0 mmol, 86% yield 154007.doc -172.201221131). LCMS (w/z, ES+) = (M+H) Step 3: 1-(2-bromo-5-methylphenyl)ethanol is maintained at 〇 °c under the conditions of maintenance. A solution of acetamidine (7 2 g, 33.8 _ 〇 1) in methanol (100 mL) was taken portionwise with EtOAc (32 g, 84 mmol). The mixture was maintained under stirring for 3 hours and diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer is separated and dried over sodium sulfate

Dry, filter, and concentrate to a residue under reduced pressure to give 1-(2-bromo-5-mercaptophenyl)ethanol (6.06 g, 28 2 〇 ,1, 83 〇 / 〇 Rate H NMR (DMSO-d6) δ: 7.33-7.47 (m, 2H), 6.98 (d, J=8.0

Hz, 1H), 5.35 (d5 J=4.1 Hz, 1H), 4.79-4.98 (m, 1H), 2.28 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). Step 4: 1-Bromo-4-methyl-2·(1-{[(methyloxy)methyl)oxy}ethyl)benzene with DIPEA (19.70 mL, 113 mmol) and MOM-Cl (4.28) mL, 56.4 mmol) of 1-(2-bromo-5-methylphenyl)ethanol (6 〇 65 g, 28 2 mmol) in di-methane (150 mL) and stirred at room temperature Maintain for 3 hours. The mixture was poured into saturated ammonium chloride and the organic layer was combined with celite and concentrated to give a residue, which was purified by column chromatography to yield 1-bromo-4-indolyl- (1-{[(indolyloxy)methyl)oxy}B

Base) stupid (3.30 g, 12.73 mmol, 45.2% yield). NMR (DMSO-d6) δ: 7.44 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 6.96-7.13 (m, 1H), 4.96 (d, J = 6.4 Hz, 1H), 4.59 ( d, J = 6.8 Hz, 1H), 4.44 (d, J = 6.6 Hz, 1H), 3.20 (s, 3H), 2.29 (s, 3H), 1.34 (d, J = 6.4 Hz, 3H). Step 5: 1-Bromo-4-(bromomethyl)-2-(l-{[(methyloxy)methyl]oxy}ethyl 154007.doc •173· 201221131 base) benzene at 8 (TC) Maintaining Momomethyl-2(1_{[(methyloxy)methyl)oxy}ethyl)benzene (1.5 g, 5.79 mmol), NBS (1.082 g, 6.08 匪〇1) and AIBN (G.G48 g, 0.289 mm.!) in a bath of carbon tetrachloride (35 mL) for 5 hours. The mixture was cooled to room temperature, poured into saturated sodium bicarbonate and diluted with an additional gas. The layers were separated, dried over sodium sulfate; concentrated to a residue under reduced pressure, and passed through a plug of sulphur dioxide, and used in the subsequent chemical conversion 粗27 g, 2 254 mm〇1, 38.9% Yield). Step 6: 6-[{[4-Bromo-3-(1_{[(methyloxy)methyl)oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino]-5 -cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide maintained at 5 ° C under stirring for 5_cyclopropyl_2_(4_ Fluorophenyl)_N_methyl_6-[(methioninyl)amino]-1-benzofuran_3_decylamine (950 mg, 2.361 mmol), 1-bromo-4-(bromomethyl) _2_(1·{[(Methyloxy)methyl)oxy}ethyl)benzene (1197 mg, 3.54 mmol, crude residue from step 5) and potassium carbonate (652 mg ' 4.72 mmol) in acetonitrile The mixture in (25 mL) was 3 hours. The cooled mixture was poured into saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was separated by <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; -{[(Methoxy)methyl]oxy}ethyl)phenyl]methyl}(nonylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)· Ν-Methyl-1-benzofuran-3-decylamine (920 mg ' 1.395 mmol, 59.1% yield). LCMS (m/z, ES+)=661 (M+H) 154007.doc •174· 201221131 Step 7: 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(1-) -3-methyl-1,3-dihydro-2,1-benzoxepallidene-5-yl)methyl](methyl sulfhydryl)amino]_N-methyl-1 -Benzo-fus _-3·Artemisamine 6-[{[4-bromo-3-(1-{[(methyloxy)methyl)oxy}ethyl)benzene at 90 ° C Alkyl]methyl}(anthracenyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-cartoamine 200 mg, 0.303 mmol), acetic acid unloading (119 mg '1.213 mmol), bis(pinacolyl)diboron (135 mg, • 〇531111111〇1) and ? (1::12@??〇-(:112(:12 adduct (18.57 1118, 〇.〇23 mmol) in 1,4-dioxane (4 mL) was maintained overnight. Cooling mixture' Filtered through diatomaceous earth and washed the diatomaceous earth with ethyl acetate. Concentrate the liquid to produce about 70% 5-cyclopropyl·2-(4-fluorophenyl)-N-indenyl-6-[{ [3-(1_{[(Methyloxy)methyl)oxy}ethyl)-4-(4,4,5,5-tetradecyl-indole, 3,2·dioxane 咮-2 -based) phenyl]methyl}(nonylsulfonyl)amino]]•benzofuran_3_carbamoamine crude residue. Using 5·〇N HC1 (aqueous solution) (3.〇3 mL, 15.15 (mmol) and polymer-supported phthalic acid (582 mg, 1.515 mmol) were treated with a crude residue (214 mg, 0.303 mmol) in tetrahydrofuran (5 mL) and maintained at 65 ° C for 3 hours. Filtration with celite, and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and then concentrated to dryness under reduced pressure and purified by column chromatography to give a yellow foam. 5_cyclopropyl_2_(4_fluorophenyl)_6_[[(1_hydroxy·3_indolyl-1,3-dihydro-2,1_benzoaoxaborole_5 _基)曱Alkyl]-N-indenyl]-benzofuran_3·decylamine (65 mg, 〇116 mmol '38.1% yield). lH nMR (DMSO-d6) δ: 8.76 (s,1H), 8·〇9 (br. s., 1H), 7.92 (dd, J=8.8, 5.5 Hz, 2H), 7.54-7.70 154007.doc -175- 201221131

(m, 2H), 7.33 (t, J=9.0 Hz, 2H), 7.23 (d, J=6.4 Hz, 2H), 6.99 (s, 1H), 5.12 (q, J=6.4 Hz, 1H), 4.92 (br. s.5 2H), 3.04 (s, 3H), 2.82 (d, J=4.5 Hz, 3H), 2.17-2.26 (m, 1H), 1.30 (d, J=6.4 Hz, 3H), 0.68 -0.98 (m, 3H), 0.36 (m, 1H). LCMS (m/z, ES+) = 563 (M+H) </RTI> <RTI ID=0.0></RTI> </RTI> 5- <RTIgt; 5- </RTI> </RTI> <RTIgt; 1,2]oxaborol-5-yl)methyl)methylsulfonylamino)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1.2 2-Amino-3-indol-5-methylbenzoic acid vinegar Add Pd(OAc)2 (880 mg, 3.92 mmol), DPPF (3.26 g, 5.88 mmol) and Et3N (2.2 g' 20.58 mmol) To a solution of 2-bromo-6-fluoro-4-mercaptoaniline (4.0 g ' 19.6 mmol) in DMSO (132 mmol) and MeOH (EtOAc) The mixture was heated to 8 ° C under 1 -5 MPa - carbon oxide and stirred for 16 hours. The mixture was cooled to room temperature and filtered. The mixture was diluted with EtOAc (200 mL) EtOAc (EtOAc) (EtOAc) Methyl 2-amino-3-fluoro-5-methylbenzoate (2.7 g, 75%) was obtained. Step 2 ·· 2-Bromo-3-fluoro-5-methylbenzoic acid methyl ketone 2. Dissolve methyl 2,amino-3-fluoro-5-methylbenzoate in MeCN (20 mL) 154007.doc -176 · 201221131

In the middle, after cooling to (re), i48 mL of HBr (47% in water) was added dropwise over 10 minutes, followed by dropwise addition of water containing NaN〇2 (91 〇mg, 13.2 mmol) over 1 hour. 'Stir the solution for 5 minutes and add CuBr (2 〇 1 mg, 138 axis) over a period of 30 minutes. The mixture is heated to 70. (:, for several hours, then cooled to 〇t, added water (2 〇 mL) and the mixture The mixture was extracted with EtOAc (3×50 mL). EtOAc (EtOAc) Purification of % ethyl acetate in petroleum to purify to give 2-bromo-3-fluoro-5-methylbenzoic acid decyl ester u 39 g, 46 〇 / 〇). Step 3: 2-bromo-5-(bromomethyl) )-3-fluorobenzoic acid formazan methyl 2-methyl 5-methylbenzoate (1.39 g, 5.63 mm 〇l), benzamidine peroxide (72.6 mg, 0.3 mmol) and N-bromobutane The imine g, 6.2 mmol) was dissolved in 30 mL 〇: 〇: 14 and heated to reflux for 2 days. The reaction was cooled and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=20: 1) Purification to produce 2-bromo-5-(bromomethyl)_3_fluoro Methyl benzoate (1_9 g, 104%) Step 4: 2-Bromo-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)·3·(methylamine) Methyl 2-bromo-5-(bromomethyl)-3-fluorobenzoic acid methyl ester with methyl bromobenzoic acid methyl ketone (8〇8 mg , 2 48 mm〇1) Treatment of 5-cyclopropyl-2-(4-fluorophenyl)-N-indolyl-6·(nonylsulfonylamino) stupid and cough %-3 a suspension of decylamine (500 mg ' 1.24 mmol), KI (10.3 mg, 0.06 mmol) and K2C03 (513 mg, 3.72 mmol) in anhydrous DMF (15 mL) and stirred at room temperature under nitrogen The mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). EtOAc EtOAc EtOAc EtOAc EtOAc The Na2S04 was dried and evaporated. The crude product was purified by column chromatography (EA:PE = 1:2) to yield 2-bromo-5-((N-(5-cyclopropyl-2-(4-fluorophenyl) )-3-(methylamine-mercapto)benzofuran-6-yl)methylsulfonylamino)hydrazino)-3-ylfluorobenzoate (45 mg, 56%). Step 5: 5 -((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine formazan) Benzo[0,0,0,0,6-yl)methyl-decylamino)methyl)-3- 1-2-(4,4,5,5-tetramethyl-1,3,2-dioxo 2-B-5-((N-(5-cyclopropyl-2-(4-fluorophenyl))-(methylamine A) Methyl benzo)pyran-6-yl)methyl hydrazinyl) fluorenyl methyl fluoroformate (450 mg, 0.69 mmol) was dissolved in dioxane (2 mL). Adding bis(pinacolyl) II (3 53 mg ' 1.39 mmol), potassium acetate (196 mg, 2.07 mmol) and 1, plant-bis(diphenylphosphino)ferrocene _ dichlorination (11 ) (80 mg '0·07 mmol) and at 1〇〇. The mixture was poured into a mixture of EtOAc (3 mL) and EtOAc (3 &lt;&gt;&gt; The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc Phenyl)·3_(decylamine fluorenyl)benzoindole. South-6-yl)methyl-amino-methyl)_3_-- 2-(4,4,5,5-tetramethyl -1,3,2-Dioxypyridin-2-yl)benzoic acid methyl vinegar (340 mg, 710/〇) Step 6: 5-cyclopropyl-6-(N-((7-fluoro-1) -hydroxy-1&gt;3-dihydrobenzo[c][12]oxaborol-5-yl)methyl)methyl hydrazinyl)_2-(4-phenylphenyl)- Benzo benzofuramide 154007.doc -178- 201221131 Slowly add LiBH4 (2 Μ in THF, 0.74 nU, heart i · 47 mmol) to 5-((N-() in -5 °C 5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonylamino)methyl)_3_fluoro_2_( Ethyl 4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzoate (340 mg, 0.49 in THF (15 ml) The solution was then warmed to room temperature and stirred for 3 h. The mixture was poured with EtOAc EtOAc (EtOAc (EtOAc) Purification by reverse phase φ HPLC to give 5-cyclopropyl+hydroxy-1,3-dihydrobenzo[c][l,2]oxaborol-5-yl) as a white solid.曱 base) 曱 基 绩 胺 ) ) ) -2- -2- -2- -2- -2- 。 。 。 。 。 。 。 。 。 。 。 。 。 。 ( ( ( ( ( ( ( ( ( ( 。 。 LCMS (m/z) ES+ = 567.2 (M+1). NMR (300 MHz, CD3OD)=7.92-7.88 (m, 2H), 7.62 (S, 1H), 7.27-7.21 (m, 2H), 7.10-7.89 (m, 3H), 5.04-4.92 (m, 4H) , 3.17 (s, 3H), 2.92 (S, 3H), 2.28-2.24 (m, 1H), 1.03-0.85 (m, 3H), 0.41-0.35 (m, 1H) • Example 43 5-cyclopropyl- 6-(N-((4-fluoro-1-hydroxy-1,3-dihydrobenzooxaborole-5-yl)methyl)methylsulfonylamino)-2-(4) -fluorophenyl)-N-methylbenzofuran_3_formamide

Step 1: 6-Bromo-2-fluoro-3-iodobenzoic acid 154007.doc .179- 201221131 Add 4-bromo-2-fluoro-1-mothene (20 g, 66.4 mmol) at -78 °C A solution of LTMP (9.8 g, 73.1 mmol) and n-BuLi (45.7 mL, 73.1 mmol) in THF (100 mL). After stirring at -78 ° C for 40 minutes, the mixture was saturated with a gas of C 2 vapor. The mixture was stirred at -75 °C for 30 minutes and allowed to warm to -20 ° C. then was carefully hydrolyzed with aqueous sulfuric acid (1.5 Μ, 100 mL). The water was separated and extracted with diethyl ether (3×100 mL). Concentrate the combined organic layers. The residue was filtered and washed sequentially with water, benzene and hexane. Drying in vacuo to give 6-bromo-2-fluoro-3-iodobenzoic acid (17 g, 75%). Step 2: 6-bromo-2-fluoro-3-iodobenzoic acid methyl acetonate 2.22 g, 15.66 mmol) of a solution of 6-bromo-2-fluoro-3-benzolic acid (4.5 g, 13.05 mmol) and potassium carbonate (2.7 g, 19.58 mmol) in acetonitrile (45 ml) Stir overnight at 〇 °C. The mixture was concentrated in vacuo and diluted with EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc (EtOAc m. Methyl benzoate (4.3 g, 92%). Step 3: 6-Bromo-2-fluoro-3-vinylbenzoic acid hydrazine vinegar under nitrogen to 6-bromo-2-fluoro_3_iodobenzoate (43 g, 1198 mmol) in anhydrous DMF ( Pd(pph3)4 (715 mg, 0.62 mm〇l) and vinyl (tributyl)tin (45(6), 14 48 mmol) were added to the solution in 20 mi). The mixture was degassed with N2 for 5 minutes and heated at 8 Torr: for 24 hours. After cooling, the mixture was partitioned between diethyl ether and brine. The organic phase above the 1% aqueous KF solution was stirred for 4 hours. The ether layer was separated, washed with water and brine 154007.doc: 180· 201221131 and dried over sodium sulfate. The solvent was removed and the residue was purified by EtOAc EtOAc EtOAc (EtOAc) /0). Step 4: 6·Bromo-2-de-(3-mercapto)benzoic acid methyl acetate to cool 6-bromo-2-fluoro-3-vinylbenzoic acid decyl ester (4〇g, 152 mm〇1) The solution in CH2Cl2 / MeOH (15 ml / 15 ml) was taken to _78. And saturated with gas 〇3 flow. The mixture was stirred for 30 minutes and then NaBH4 (1 g, 23.9 • mmo1) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. Add water. The solution was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate &lt;[&gt;&lt;[&gt;&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Methyl benzoate (2.09 g, 52%). Step 5: 6-Bromo-3-(methyl)-2-fluorobenzoic acid methyl acetonate 6-Bromo-2-fluoro-3-(hydroxyindenyl)benzoic acid methyl ester (39 mg, 1.48 mmol) Dissolved in DCM (20 ml) and slowly added a solution of pph3 (579 mg, 2.22 mmol) in DCM (5 ml). Mix the mixture at room temperature for 5 hours and add water. The organic layer was separated and washed with EtOAc EtOAc (EtOAc) Methyl 2-fluorobenzoate (350 mg, 73%) » Step 6: 6·Bromo-3-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-) Methylaminomethyl benzofuran-6-yl)methylsulfonylamino)methyl)-2-fluorobenzoic acid methyl 6-bromo-3-(bromoindolyl)-2-fluorobenzoic acid Ethyl ester (350 mg, 1.07 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonylamino) Ben and 0 Fu Nan-3 - Methionamine (430 mg, 1.07 mmol), bismuth clock (9 mg, 0.054 mmol) and potassium carbonate (443 mg, 3-21 mmol) were dissolved in DMF (10 154007.doc -181 - 201221131 ml). The mixture was mixed for 0 5 hours and then water was added. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. (N-(5-cyclopropyl_2_(4-fluorophenyl)·3·(methylamine methyl)benzofuran-6-yl)nonylsulfonylamino)methyl)_2_fluoro Ethyl benzoate (510 mg, 73%). Step 7: 3-((N-(5-cyclopropyl_2_(4-fluorophenyl)_3•(methylaminemethanyl)benzene# σ4-6-Μ) f S^m^S) f M)-2-M,-6-(4,4,5,5-m fS-1'3,2-dioxaboran-2-yl)benzoic acid methyl acetonate 6-bromo- under nitrogen atmosphere 3-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine decyl)benzofuranyl) decylsulfonylamino)methyl)_2_ Methyl fluorobenzoate (406 mg, 0.71 mmol), PdCl2 (dppf) (25.6 mg, 0.035 mmol), B2PIN2 (272 mg, 1.07 mmol) and acetic acid (209 mg, 2.13 mmol) dissolved in dioxane (12 In ml). The mixture was stirred at 95 ° C for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc (20 mL)EtOAc. The organic layer was separated and washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Keto-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonylamino)methyl)-2-fluoro-6-(4, Methyl 4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)benzoate (300 mg, 61%) » Step 8 · 5-cyclopropyl-6-( N-((4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaborer-5-yl)methyl)methylsulfonylamino) -2-(4-Fluorophenyl)-nonyl benzofuran-3-carboxamide was slowly added with LiBH4 (2 Μ in THF) at 〇 °C (0.64 ml' 1.28 154007.doc -182- 201221131 mmol ) to 3-((N-(5-cyclopropyl_2.(4-fluorophenyl)3•(methylamine-mercapto)benzofuran-6-yl)indolylsulfonyl)) Base)_2_Fluoryl_6_(4,4,5,5-tetramethyl), 3'2-dioxaboron-2-ylbenzoate (300 mg, 0.43 mmol) in THF (1 〇) In the solution in ml). After stirring for 2 hours, the mixture was poured with EtOAc EtOAc EtOAc EtOAc. 5-cyclopropyl·6_(Ν-((4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaborol-5-yl)) (Mercapto)sulfonylamino)_2_(4.fluorophenyl)-N-methylbenzofuran_3·decylamine (65 mg, 27%). LCMS (w/z, ES+) = 567.1 (M + 1). 4 NMR (300 MHz, CDC13) 6=7.93-7.88 (dd, 2H), 7.61 (s, 1H), 7.32-7.22 (m, 4H), 7.02 (s, 1H), 5.15-4.92 (m, 4H) , 3.19 (s, 3H), 2.93 (s, 3H), 2.28-2.23 (m, 1H), 0.98 (m, 1H), 0.82-0.76 (m, 2H), 0.29 (m, 1H) LCMS ( m/ z) ES+=567.1 (M+1) Example 44 and 45 φ 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[(3S)-l-hydroxy-3-methyl-1) ,3-dihydro-2,1-benzoxoxaborole-5-yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3- Methionamine and 5-cyclopropyl-2-(4-fluorophenyl^6-[{[(3R)-l-yl-yl-3-methyl-1,3-dihydro-2,1-benzene) Oxaoxacyclopenta-5-yl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

154007.doc -183- 201221131 Supercritical C〇2 column chromatography with a palm-shaped stationary phase (40 〇/. Me0H/C02, 140 bar, 40 ° C, 2 ml/min, 〇Z column) Resolution of racemic 5_cyclopropyl_2_(4-fluorophenyl)-6-[{[1_-based _3-fluorenyl-i,3_dihydro 2,1-stupidyloxy) ]Methyl}(methylsulfonyl)amino]]-1-pyranfuran-3-indene, $ ° is not specified for absolute configuration. First dissolving enantiomer. i nmr (sterol-d4) δ: 7.88 (dd J=8.7' 5.4 Hz, 2H), 7.58 7 29 (m 4m ^ (s, 1H), 7.45-7.54 (m , 2H), 7.11 7.29 (m, 4H), 7.01 j 1H) 4 92 S 04 / , 3.7 Hz, 1H), 5.17 (q, J = 6.4 Hz 1H), 4.92-5.04 (m, 2h) fly] j Ί 1Ί (1U, (s, 3H), 2.90 (s, 3H), 2.12 2.27 (m, 1H), 1.24" n 〇. lm, 3H), 0.89-1.01 (m, 1H), 0.63 0.83 (m, 2H), 〇.2〇_〇vm5 1H) 〇LCMS (m/z, ES+)=56 (M+H). f

Second Dissociation Enantiomers] 祖·H NMR (methanol-d4) δ: 7.88 (dd, 58 1H), 7.45-7.54 (m, 2H), 7.11- 7.29 (m, 4H), 7.01 (d卜13·7 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 4.92-5.04 (m, 2H) 3 1 . (s, 3H), 2.90 (s, 3H), 2.12- 2.27 (m , 1H), 1.24-1 40 ( vm, 3H)} 0.89-1.01 (m, 1H), 0.63-0.83 (m, 2H), 0.2〇-〇3c ( ° (m, 1H) 〇LCMS (m/z , ES+)=563 (M+H). 8.7, 5.4 Hz, 2H), 7.

Example 46 5-Cyclopropyl-2-(4-fluorophenyl[c][l,2]oxaborolanebenzo-3-anthracene) via-1,3-di Nitrobenzox, yl)ethyl)methylsulfonylamino)-N-methyl J54007.doc

S •184· 201221131

Step 1: 2-Bromo-5-disc benzoic acid methyl vinegar was heated at 80 ° C for 2_bromo-5-iodobenzoic acid (2 g$ mm〇1), K2C03 (1.5 g> ii mm〇l)^ Mel (0.82 g» 5.g mmol)^MeCN solution for 48 hours. The reaction mixture was poured into water and then extracted with EtOAc (EtOAc m. The solvent was removed under reduced pressure to give 2-yield-5-ylidene succinic acid (2 2 g, 6 5 _ 〇, 95% yield). Step 2: 2-Bromo-5-vinylbenzoic acid methyl vinegar Heating 2-bromo-5-iodobenzoate (1.5 g, 4 4 mm〇i) at 120 ° C,

A solution of Bu3SnC2H4 (1.81 g, 5.3 mmol) and Pd(PPh3)4 (0.51 g, 0.44 mmol) in DMF (10 mL) was applied for 12 hours. The reaction mixture was diluted with H.sub.2 O /EtOAc (100 mL / 200 mL). The organic layer was washed with brine (2×2 mL) and dried over anhydrous Naz. After the solvent was removed, the crude material was purified eluting with EtOAc EtOAc (EtOAc) Step 3 · 2 - Desert - 5-(1-Aethyl)benzoic acid 2-Bromo-5-vinylbenzoate (137 g, 4 28 mmol) in HBr (48% aqueous) at 90 °C The solution in 20 mL) was allowed to stand for 2 hours and then poured into ice water (200 mL). The aqueous solution was extracted with DCM (3M EtOAc). The combined organic layers were dried over anhydrous NazSCU. After the solvent was removed, the crude material was purified eluting with EtOAc s s s s s s s s s s s s s s s s s s s s s s s s 97% yield). Step 4: 2-Bromo-5-(1-bromoethyl)benzoic acid methyl vinegar was heated at 80 ° C - 2--5-(1-diethyl)benzoic acid (1.2 g, 3.92 mmol), K2CO3 (1.08 A solution of g ' 7.84 mmol) and Mel (0.56 g, 3.92 mmol) in MeCN (50 mL) for 24 h. The reaction mixture was dissolved in water / EtOAc (EtOAc (EtOAc) The combined organic layers were washed with H.sub.2 (2.times.50 mL) and dried over anhydrous Na? After the solvent was removed, the crude product was purified by column chromatography to yield 2-&gt;yield-5-(1-bromoethyl)benzoic acid as a yellow solid (950 mg, 2.97 mmol, 75%) Yield). Step 5: 2-Bromo-5-(1-(indolyl-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)) Methylsulfonylamino)ethyl benzoic acid methyl vinegar heated at 80 °C - -5 - (1-diethyl) benzoic acid methyl gram (950 mg, 2.97 mmol), 5-cyclopropyl 2-(4-Fluorophenyl)-N-mercapto-6-(indolylsulfonylamino)benzofuran-3-carboxamide (1.18 g, 2.96 mmol) and K2CO3 (0.819 g, 5.94 mmol) solution in MeCN (10 mL) for 3 h. After the reaction solution was cooled to room temperature, it was poured into water (200 mL) and then EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After removal of the solvent, the residue was purified with EtOAc EtOAc EtOAc EtOAc 3-(Methylaminoindenyl)benzocypano-6-yl)methyl acrylamino)ethyl)benzoic acid (850 mg, 1.32 mmol, 44% yield). Step 7 ··· 5-(1-(Ν-(5-cyclopropyl-2·(4-fluorophenyl)-3-(methylaminecarbamyl) 154007.doc -186- 201221131 Benzofuran- 6-yl)methylsulfonylamino)ethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzoic acid methyl vinegar 2-Bromo-5-(1-(Ν-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminoindenyl)benzofuran) under nitrogen at 100 ° C -6·yl)nonylsulfonylamino)ethyl)benzoic acid 6 (850 mg, 1.32 mmol), Pd(dppf)Cl2 (78.5 mg, 0.07 mmol), Pin2B2 (223 mg, 0.88 mmol) and KOAc (364 mg ' 2.64 mmol) was stirred in a solution of EtOAc (3 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After removal of the solvent, the residue was purified by column chromatography to give 5-(1 - (5-cyclopropyl-2-(4-fluorophenyl)-3-) as a white solid. Amidoxime)benzofuran-6-yl)methyl arylamino)ethyl)-2-(4,4,5,5-tetradecyl-1,3,2-dioxy odor · 2·yl) benzoic acid vinegar (650 mg, 1.02 mmol, 78% yield). Step 8: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(Ν-(1-(1-hydroxy-1,3-dihydrobenzo[c][l, 2]oxa) Boronheap-5-yl)ethyl)methylsulfonylamino)-N-methylbenzol-f-amyl-3-cartoamine at 〇°C to 5·(1-(#-( 5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine oxime) benzofuran-6-yl)nonylsulfonylamino)-2-(4,4, Adding LiBH4 to a solution of 4,5,5-tetramethyl-1,3,2-dioxosole-2-yl)benzoate (650 mg, 1.02 mmo) in THF (10 mL) 2 mL, 2 mmol) and the resulting solution was stirred at room temperature for 2 hours. The reaction solution was poured into ice water (loo mL) and extracted with Et EtOAc (3 X 1 〇〇 ml). The combined organic layers were dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by reverse phase HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(iV-(l-(l-hydroxy)- 154007 as a white solid. .doc •187· 201221131 1'3-Dihydrobenzo[c][l,2]oxaborol-5-yl)ethyl)methylsulfonylaminononylbenzofuran-3 - carbamide (5 〇 mg, 0.089 mmol, 12% yield) NMR (300 MHZ, CD3 〇D) δ: 7.98-7.89 (m, 2H), 7.74 (s, 1H), 7.74-7.69 (d , 0.5H), 7.52-7.55 (d, 0.5H), 7.32-7.16 (m, 3H), 7.16-7.09 (m, 2H), 6.89 (s, 1H), 5.71-5.66 (m, 1H), 5.14 -4.95 (m, 2H), 3.18 (s, 2H), 2.96-2.94 (d, 3H), 2.86 (s, 1H), 2.56-2.51 (m, 1H), 1.78-1.76 (d, 2H), 1.58 -1.56 (d, 1H), 1.17-1.15 (m, 1H), 0.85-0.73 (1 m, 1.5H), 0.49-0.43 (m, 0.5H), 0.17-0.02 (m, 1H). LCMS (w /z, ES ) = 567(M+1) 〇 Example 47 5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl) Winter (Ν·((2·hydroxy-4-oxo boron) -4-yl)methyl)methyl-branched amino-methyl benzophenone·3_cartoamine

'ΟΗ Step 1: 6-(Ν-(2·(Benzyloxymethyl)allyl)methylsulfonylamino)_5_cyclopropyl-2-(4-(4-fluorophenoxy) Phenylmethylbenzofuran-carboxamide was heated at 40 ° C under nitrogen atmosphere with 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6 -(fluorenyl hydrazino)benzofuran-3-formamide (〇6 g '1.213 mmol), rabbit acid unloading (0.502 g, 3.64 mmol), hydrazine (0.201 g, 1.211 mmol) and (2- a solution of bromomethylallyloxymethyl)benzene (〇585 g, 2.426 mmo, U25279/75/1) in anhydrous DMF (8 mL) 30 &gt; 188-154007.doc 201221131 minutes. After the filtration, the residue was dissolved in EtOAc. EtOAc was evaporated. N-(2-(benzomethoxymethyl)allyl) decylsulfonylamino)_5•cyclopropyl_2_(4·(4-fluorophenoxy)phenyl)_N-methylbenzene And furan_3_formamide (0.49 g, 0.748 mmol, 62%) ° Step 2: 6-(N-(3-(benzyloxy)-2-((4,4,5,5-four) Methyl-1,3,2-dioxy#咮-2-yl) fluorenyl) propyl)methylsulfonylamino)_5_cyclopropyl sulfooxy) strepyl)-N-methyl stupid and bitten with carbamide at room temperature under nitrogen Chlorocarbonyl bis(triphenylphosphine) oxime 0) (52 mg, 0.075 mmol), 6-(N-(2-(benzophenoxyfluorenyl) propyl)methylsulfonamide -5-cyclopropyl-2-(4-(4-fluorophenoxy)phenylmercaptobenzofuran-3-decylamine (490 mg, 0.748 mmol) and pinacol borane (479 mg) , 3,74 mmol) in THF (15 mL) was stirred overnight. After the solvent was removed, the crude material was purified by column chromatography to yield 6- (N. 2-((4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)methyl)propyl)nonylsulfonylamino)_5_ ring Propyl-2-(4-(4-fluorophenoxy)phenyl)_ N-methylbenzoindol-3-carboxamide (0.5 g, 0.638 mmol, 85%). Step 3: 5- Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N-((2-hydroxy-1,2-oxaboromid-4-yl)methyl)methylsulfonate醯Aminomethylbenzofuran_3_ decylamine 6((((()))(((((()))) 4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)indolyl)propyl)methylsulfonylamino)-5-cyclopropyl-2-(4- (4-fluorophenoxy)phenyl)-indole_methylbenzopyrene 154007.doc •189· 201221131 -3--3-carbamidamine (0.5 g, 0.639 mmol) and Pd/C (188 mg) in THF ( The solution in 15 mL) was stirred overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was dissolved in THF (15 mL) and EtOAc (EtOAc) The suspension was stirred overnight at rt, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase EtOAc (EtOAc) toield , 2-oxoboron-4-yl)indolyl)methylsulfonylamino)-N-mercaptobenzofuran-3-carboxamide (75 mg, 0.126 mmol, 20%). 4 NMR (300 MHz, methanol-d4) δ: 7.90-7.87 (d, 2 H), 7.72-7.68 (d, 1 H), 7.21-7.06 (m5 7 H), 3.85-3.63 (m, 4 H) , 3.09 (s, 3 H), 2.96 (s, 3 H), 2.48-2.44 (m, 2 H), 1.11-0.70 (m, 6 H). LCMS (m/z, ES+) = 593.1 (M+H). Example 48 5-Cyclopropyl-6-(N-((6-fluoro-1-hydroxy-i,3-dihydrobenzo[CH2]oxaborol-5-yl)methyl)methyl Sulfonamide fluorophenyl)_N_methylbenzofuran-3-carboxamide

Step 1: 4-Fluoro-2-hydroxy-5-methylbenzoic acid 4-Fluoro-3-mercaptobenzoic acid (7 g, 45 mmol) (Alfa) at 11 5 ° C at 10 MPa 〇2 , Pd(OAc) 2 (lg, 4.5 mmol), KOAc (8.8 g, 90 mmol) and benzoquinone (10.8 g '45 mmol) in DMA (200 mL) 154007.doc • 190 - 201221131 Stir overnight. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. After the solvent was removed, the crude product was purified by column chromatography to afford 4?????????????????~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Step 2: 4-Fluoro-2-hydroxy-5-methylbenzoic acid methyl vinegar heated at 80 ° C 4-fluoro-2-hydroxy-5-mercaptobenzoic acid (2 g, 117 mmol) and concentrated H 2 SO 4 (0.15 mL) a solution in MeOH (20 mL) EtOAc. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water / EA (100 mL / 1 〇〇 mL). The separated organic layer was dried over anhydrous Na 2 EtOAc. After the solvent was removed, the crude was purified eluting with EtOAc EtOAc EtOAc . Step 3: 2-(T-butyldimethylsilyloxy)-4_fluoro-5-methylbenzoic acid methyl vinegar Stirring 4-fluoro-2-hydroxy-5-nonylbenzene at room temperature A solution of methyl formate (L5 g, 8.15 mmol), TBSC1 (1.8 g, 12.2 mmol) and imidazole (ii g, 16 3 mmol) in DMF (50 mL) The reaction mixture was poured into EtOAc (3 mL) The combined organic layers were dried over anhydrous Naj. After the solvent was removed, the crude product was purified by column chromatography to yield ethyl 2-(t-butyl-didecyl decyloxyfluoro-5-mercaptobenzoic acid methyl ester (2 g, 6_7) Ment, 80% yield) Step 4: 5-(Bromomethyl)-2-(t-butyldimethylmethylalkyloxy)_4_ benzoic acid methyl ester to 2-(t-butyl 2 Addition of NBS (1.15 g) to a solution of CC (50 mL) in an ester (2 g, 6.7 mmol). '6.5 mmol) and benzoquinone peroxide (33.5 mg, 0.0335 mmol). The flask was purged several times with nitrogen and the reaction solution was heated at 8 (TC) for 12 hours. The reaction mixture was poured into EA/water (1 〇〇mL/100 The organic layer was separated and washed with water (3×50 mL) and dried over anhydrous Na.sub.sub.sub.sub.sub.4. After the solvent was removed, the crude product was purified by column chromatography to yield 5 2-(tert-butyl dimethyl fluorenyloxy)-4-fluorobenzoic acid decyl ester (2.1 g, 5.6 mmol, 75% yield). Step 5: 2-(t-butyl Dimethyl decyloxy)_5_((n_(5_cyclopropyl-2-(4-fluorobenzene) --3-(decylamine-mercapto)benzofuran-6-yl)decylsulfonylamino)methyl)-4-fluorobenzoic acid methyl vinegar heated at 80 ° C 5-cyclopropyl -2-(4-Fluorophenyl)-N-mercapto-6-(methylsulfonylamino)benzoxan. South-3-carbamamine (2 g '4.9 mmol), 5-(bromo) Methyl) 2- 2-(2-butylmethylsulfanyloxy)-4-fluorobenzoic acid vinegar (1.8 g, 4.9 mmol) and K2C03 (1.35 g, 9.8 mmol) in MeCN (100) The solution was stirred for 2 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc) The residue was dried over anhydrous Na.sub.2.sub.4. ·(5-Cyclopropyl_2_(4-fluorophenyl)_3_(methylamine-mercapto)benzofuran-6-yl)nonylsulfonylamino)methyl)_4_fluorobenzoate (0.95 g, 1.3 6 mmol, 30% yield) Step 6: 5·((Ν-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminocarbamoyl) Benzofuran·6·yl)methylsulfonamide Methyl)_4_fluorohydroxybenzoic acid methyl vinegar 154007.doc -192- 201221131 Stirring 2-(t-butyldimethylmethylalkyloxy)_5_((Ν·(5·cyclopropyl) at room temperature -2-(4-Fluorophenyl)_3_(methylamine-mercapto)benzofuran-6-yl)methylsulfonylamino)methyl)_4·fluorobenzoate (0.95 g, 1.36 mmol) And a solution of HCl (5 N aqueous solution '2 mL) in THF for 12 h. The reaction mixture was concentrated under reduced EtOAc (EtOAc)EtOAc. The solvent was removed under reduced pressure to give 5 (((-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine)methyl) benzofuran as a white solid. -6-yl)methylsulfonylamino)methyl)_4_fluoro-2-hydroxybenzoate (540 mg, 0.92 mmol, 67% yield). Step 7: 5-((N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)decylsulfonylamino )methyl)_4_fluoro-2-hydroxybenzoic acid methyl vinegar to 5-(C/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methyl) at 〇 °C Amidino)benzofuran-6-yl)nonylsulfonylamino)hydrazino)_4_fluoro-2-hydroxybenzoate (540 mg, 0.92 mmol) and DIEA (237 mg, 1.84 mmol) Tf2(R) (387 mg, 1.84 mmol) was added dropwise to a solution in DCM (50 mL). After the addition, the reaction mixture was allowed to warm to room temperature and the sand was dropped for 2 hours. The reaction mixture was poured into EtOAc (3 mL &lt The combined organic layers were dried over anhydrous Na.sub.2. After removal of the solvent, the crude product was purified by column chromatography to yield 5-[(V-(5-cyclopropyl-2-(4-fluorophenylmethylamine)methyl) benzene as a white solid. And furan-6-yl) decylsulfonylamino)hydrazino)-4-fluoro-2-hydroxybenzoic acid methyl ester (450 mg, 0.64 mmol, 68 ° / yield). Step 8: 5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine-carbamoyl)benzofuran-6-yl)decylsulfonylamino )methyl)-4_fluoro_2-(445,5_tetramethyl_154007.doc •193· 201221131 1,3,2-dioxaborin-2-yl)benzoic acid vinegar at 100° 5-((i-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine-carbamoyl)benzofuran-6-yl)methyl) under nitrogen atmosphere Sulfonamide) mercapto)-4-fluoro-2-p-benzoic acid vinegar (450 mg, 0.64 mm 〇G, Pd(dppf)Cl: 2 (24 mg '0.032 mmol), Pin2B2 (243 mg, A solution of 0.96 mmol) and EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) The organic layer was dried over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub. )-3-(methylamine-mercapto)benzofuran-6-yl)nonylsulfonylamino)fluorenyl)_4_fluoro-2-(4,4,5,5-tetramethyl- 1 , 3,2-dioxos-2-yl)benzoic acid vinegar (250 mg, 0.36 mmol, 35% yield). Step 9: 5-cyclopropyl-6·(Ν-((6-fluoro-1·hydroxy-13-dihydrobenzo[(:][1,2]oxacyclopent-5-yl) )methyl)methylsulfonylaminofluorophenyl)_ Ν-methylbenzoin. Furumidamide to 5_((沁(5_cyclopropyl_2_(4)) at 〇 °C for 10 minutes ·Fluorophenyl)3_(decylamine decyl)benzopyrano-6-yl) fluorenyl hydrazino)methyl)_4_fluoro _ 2·(4,4,5,5·4 Add mUBH4 (〇37 mL '0.74 mmob 2 Μ to the solution of thiol-H2-dioxaboron-2-yl)benzoate (mo mg '0.36 mmol) in Thf (25 mL) The mixture was stirred in THF for 3 hrs. The reaction mixture was poured into ice/water (50 mL) and the aqueous layer was extracted with Et.sub. After the solvent, the crude product was purified by reverse phase HPLC to give a white solid. </ br> 154007.doc • 194· 201221131 propyl _6_(N_((6·Fluoro-Siliary-1,3-dihydro stupid) (4) Π, 2] oxazapine pentene-5-yl)methyl)methylsulfonylamino)_2_(4.fluorophenyl)_Ν_ΤΤ I 本和夫夫喃-3-decylamine ( 79 mg ' 〇 · 14 mmol, 37% yield. Lu ' H nmr (300 MHz, CDC13) δ: 7.85-7.80 (m, 2Η), 7.31-7.13 (m 6 5.78-5.76 (m,1H), 5.19-4.97 (m,4H),3.08 (s' 3H ) 2 98' 2.86 (d, 3H), 2.20 (ηΐ} 1H), 1.05-0.90 (m, 3H), 〇.5〇, 1H). LCMS (m/z, ES+) = 564 (M+H). 'Example 49 5-Cyclopropyl-2-(4-fluorophenyl)_6_(N_(2_(1_hydroxy·13 dihydrobenzo[〇][1,2]oxaboron _5 _ base) ethyl)methylsulfonylamino) _ heart methyl benzoate bite -3 - ugly amine

Step 1 ·························································· To the solution was added lithium 2,2,6,6-tetradecylpiperidine (5.2 g, 35.5 mmol) and the reaction mixture was stirred at -80 °C for 40 min. Next, DMF (20 mL) was added and the reaction solution was stirred at -90 °C for 2 Torr. The solution was warmed to room temperature and HCl (1 N, 2 〇 mL) was added dropwise. The aqueous layer was extracted with EtOAc (180 mL). The combined organic layers were dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure gave 2-bromo-5-indole benzine (丨2.4 g, 154007.doc -195 - 201221131 40 mmol, 113%) ° Step 2 · (2-bromo-5-phenylene) To a solution of 2-bromo-5-iodobenzaldehyde (12.4 g &lt;RTI ID=0.0&gt;&gt;;;;;;;;;;;;; After the addition, the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with water (2 mL) and EtOAc (60 mL). The organic layer was separated and dried over anhydrous Na.sub.2.sub.4. After the solvent was removed, the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Step 3: (2-Bromo-5-mothromoxy) (t-butyl) dimethyl oxime at 0C to (2-bromo-5-iodophenyl)methanol (3.5 g, ii 2 mm 〇 i) and a solution of the imidazole (1.53 g, 22.4 mmol) in DCM (85 mL) was added TBSC1 (2.03 g, 13.4 mmol). The solution was stirred at room temperature for 3 minutes and then diluted with water (20 mL). The organic layer was washed with brine (2 mL) and dried over anhydrous NazSO. After removal of the solvent, the crude material was purified by flash column chromatography to yield (2·bromo-5-iodobenzyloxyt-butyl butyl) dimethyl sulfoxide (4.48 g '10.5 mmol) , 94% yield). Step 4: (5-allyl-1-bromobenzyl) (t-butyl)didecyl oxime at room temperature to (2-bromo-5-iodobenzyloxy) (third Butyl) dimethyl decane (10 g '23.5 mmol) and hydrazine (triphenylphosphine) Add allyl (tributyl) tin to a solution of (1.38 gi 2 mm 〇1) in DMF (100 mL) (9 37 g, 28.2 mmol). The reaction solution was stirred at room temperature for 48 hours and then diluted with water (5 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na? After removal of the solvent, the crude product was purified by flash column chromatography to yield 154007.doc - 196 - 201221131 (5 - allyl. 2 - benzyloxy) (t-butyl) Dimethyl zebra (7 g '20.5 mmol, 87% yield). Step 5. 2-(4-Bromo-3-((t-butyldimethylmethylsulfanyloxy)methyl)phenyl)ethanol saturates the methyl group (5-allyl) with a hydrazine 3 stream at -78C A solution of 2bromophenoxy κ 2 butyl) dimethyl decane in CH 2 Cl 2 / MeOH (30 ml / 30 ml). The mixture was stirred for 30 minutes until the reaction mixture turned blue. The solution was purged with n2 for 30 minutes and then NaBH4 (1.2 g, 30.9 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After adding water (5 mL), the solution was extracted with EtOAc (3 &lt; The combined organic layers were washed with brine (5 mL) and dried over anhydrous Naj. After removal of the solvent, the crude product was purified by reverse phase HPLC to give 2-(4-di--3-((t-butyldimethyl- syloxy) phenyl)phenyl) as a colorless oil. Ethanol (4 〇〇 mg, 1.16 mmol, 5.6%) ° !H NMR (300 MHz, CDC13) δ: 7.44-7.46 (m, 2H), 7.00-7.04 (m, 1H), 4.75 (s, 2H), 3.87-3.91 (t, 2H), 2.86- # 2.90 (t, 2H), 0.99 (s, 1H) ° Step 6. (2 -Bromo-5-(2-diethyl)benzyloxy) (Part Tributyl) dimethyl sulfoxide is stirred at room temperature under nitrogen atmosphere with 2-(4-bromo-3-((t-butyldimethyl oxalyloxy)methyl)phenyl) A solution of ethanol (410 mg, 1.12 mmol), PPh3 (632 mg, 2.24 mmol) and NBS (418 mg, 2.24 mmol) in di-methane (20 mL) for 1 min. The reaction solution was poured into aq. EtOAc (EtOAc m. The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na. After removal of the solvent 154007.doc -197- 201221131, the crude product was purified by column chromatography to give (2-bromo-5-(2)-bromoethyl)benzyloxy) (t-butyl) dimethyl Decane (373 mg, 〇92 mm〇1, 77% yield). Step 7: 6-(N-(4-Bromo-3-((t-butyldimethylmethylsulfanyloxy)methyl)phenethyl)methylsulfonylamino)-5-cyclopropyl_ 2. (4-Fluorophenyl)_N-methylbenzopyran-3-carbamide was heated at 80 ° C under nitrogen atmosphere with 5 - cyclopropyl 2 - ( 4 - fluorophenyl ) 沁 methyl -6-(methylsulfonylamino)benzofuran_3_decylamine (33 〇, 〇83 mmol), (2-bromo-5-(2-bromoethyl)phenyl fluorenyloxy) Tributyl) dimethyl astaxane (373 mg, 0.92 _〇1), κΐ (7 mg, 〇.〇4 mmol) and K2C03 (372 mg, 2.7 mmol) in anhydrous DMF (15 mL) The solution was 2 hours. The reaction solution was diluted with water (30 mL) andEtOAc. The combined organic layers were washed with water (50 mL) and brine (50 mL) and then dried over anhydrous Na? After removal of the solvent, the crude product was purified by column chromatography to yield 6-(N-(4-di-dimethyl-3-((t-butyldimethyl)) () ethyl) methyl ethyl hydrazide) _5_cyclopropyl 2 - (4-fluorophenyl) - methyl benzofuran · 3 · decylamine (344 mg, 〇 47 mm () 1 , 57% yield). Step 8: 6-(N-(3-((tert-butyldimethyl)alkyl)methyl)_4_(4,4,5,5-tetramethyl-H2·dioxaboron-2 -yl)ethylidene)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran_3-formamide under reflux in a nitrogen atmosphere 6-(7V-(4-Bromo-3·((Tertiary butyl dimethyl oxalate)oxy) phenylhexyl)methyl arylamino)_5_cyclopropyl_2 ·(4_fluorophenyl)-iV-mercaptobenzofuran_3_formamide (344 mg, 〇47 154007.doc 201221131 bis(pinacolyl)diboron (238 mg, 0.94 mmol), acetic acid clock (138 mg '1.41 mm〇i) &amp; PdCl2(dppf)_CH2Cl2 (57 mg, 0.05 mmol) was heated overnight in a solution of 1 ° of sulphur (15 mL). After cooling to room temperature, the reaction mixture was poured into water. (50 mL) and EtOAc (3×50 mL) EtOAc (EtOAc m. ((dibutyldimethyl fluorenyloxy) fluorenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborium. East-2-yl Phenylethyl)methyl Sulfhydrylamino)_5_cyclopropyl-2-(4-fluorophenyl)-octamethylbenzofuran-3-carboxamide (355 mg, 0.46 mmol, 97% yield). Step 9: 5 -cyclopropyl-2-(4-fluorophenyl)-6-(Ν-(2-(1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaboron) Alkenyl)ethyl)methylsulfonylamino)_N_methylbenzofurancarboxamide 6-(#-(3-((三三*) dimethyl decyloxy) )methyl)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborin-2-yl)phenethyl)methylsulfonylamino)-5-cyclo Propyl-2-(4-fluorophenylmethylbenzofuran-3-carboxamide (355 rag '0.46 mmol) and 4·methylbenzenesulfonate pyridine (230 mg, 0.92 mmol) in EtOH (15 The solution was heated over EtOAc (EtOAc) (EtOAc m. Purification by preparative HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(#-(2-(1-hydroxy-1,3·dihydrobenzo[c]] as a white solid. [Factory 2] oxaborole-5-yl)ethyl)indolylsulfonylamino)_#_mercaptobenzofuran_3 _ guanamine (16 〇 mg '0.28 mmol, 620 / 〇 yield). iH NMR (methanol-d4) δ: 7.84 154007.doc •199· 201221131 (m, 2H), 7.45 (d, 2H), 7.18 (m, 5H), 4.88 (s, 2H), 3.95 (m, 2H) , 2.95 (s, 3H), 2.85 (s, 3H), 2.82 (m, 2H), 2.26 (m, 1H), 0.99 (m, 1H), 0.83 (m, 2H), 0.39 (m, 1H). LCMS (m/z, ES+) = 563.0 (M+H) Example 50 5-{[5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]benzo Furan-6-yl}(M-)-amino}methyl}-1-yl-l-1,3-dihydro-2,1-benzoxoxaborole-7-carboxylate

Step 1: 2,6-Dibromo-p-toluidine From the treatment of thief (7.72 mL '0.150 mol), the di- ox (12.78 mL) was cooled to obtain an orange-yellow complex. The guanidine amine (16.07 g, 0.15 mol) was then cooled in ice water. The solution in the cauterization (120 mL) was taken to 8 ° C and treated with the above prepared complex as a portion. The internal temperature was maintained at 14 throughout the addition. 〇The following. After the addition, the solution was stirred for another 1 minute, followed by filtration to collect a solid. The filter cake was washed sequentially with 50 mL water, dilute NaOH and 10 mL water to give a portion of off-white solids. The filtrate was neutralized with more dilute Na?H, concentrated and filtered to afford another crop. The combined solids were recrystallized from hot ethanol to give 2,6.dibromo-p-indoleamine (15.34 g, 0.058 m 〇i, 38 6 〇 / yield) as an off-white solid. 4 NMR (400 MHz, 154007.doc 201221131 chloroform δ: 7.21 (s, 2 H), 3.71-4.70 (br, 2 H), 2.17-2.26 (s, 3 H). Step 2: 2-Amino-5 -Methyl-1,3-phthalic acid dimuth vinegar maintains 2,6-di-p-aniline (5 g, 18-87 mmol) at 80 ° C under a CO atmosphere (about 70 psi) A solution of TEA (2.101 g, 20.76 mmol), acetic acid (0.847 g ' 3.77 mmol) and dppf (3_14 g, 5.66 _〇l) in DMSO (30 mL) and methanol (20 mL). • The mixture was filtered with EtOAc (EtOAc)EtOAc. 2•Amino·5_methyl-1,3-benzonic acid diterpene (1_85§, 8.29 111111〇1, 43.9% yield) as a yellow solid. 4 NMR (400 MHz, gas - Hook δ: 8.13 (br. s., 1 H), 7.93 (s, 2 H)' 7.61 (br. s., 1 H), 3.89 (s, 6 H), 2.24 (s, 3 Η). Step 3: Dimethyl 2-bromo-5-methyl-1,3-phthalate to cool 2-amino-5-mercapto-l,3-benzoic acid dinonyl ester (15 g, 6 72Mm 〇 l) a solution of acetonitrile (2 〇 mL) to 0 ° C, followed by dropwise addition of 48% aqueous solution of arbromobromide (7 6 〇, 67 2 mmol) via a dropping funnel over 10 minutes, followed by 3 2 mL of water containing sodium nitrite (〇5丨〇吕, 7.39 mmol) was added dropwise over a few minutes. After the addition, the mixture was stirred for another 10 knives at 〇〇c and then the desertification was added portionwise for 3 minutes. Copper (11^1 邑, 773 mmoip) The solution was stirred overnight at room temperature and then stirred under EtOAc for EtOAc. EtOAc was evaporated. Purification by column chromatography to yield 2-bromo-5-mercapto-1,3-benzoic acid dimethyl ester (1.55 g, 5.40 154007.doc •201 · 201221131 mmol '80%) Rate) 4 NMR (400 MHz, gas-d-d) δ: 7.56 (s, 2 H), 3.92 (s, 6 H), 2.36 (s, 3 H). Step 4: 2-bromo-5-( Bromomethyl)-1,3-phthalic acid diacetate dimethyl 2-bromo-5-methyl-i,3-phthalate (1.5 g, 5.22 mmol), NBS (1.023 g, 5· 75 mmol) and hydrazine (0.043 g, 0.261 mmol) dissolved in CC14 (20 mL) Reflux for 5.5 hours. The solid was removed by vacuum filtration and the filtrate was concentrated and purified to purified crystals crystals 0.63 g, 1.721 mmo, 32.9% yield). H NMR (400 MHz, gas δ: 7.75 (s, 2 H), 4.44 (s, 2 Η), 3.97 (s, 6 Η). Step 5: 2-bromo-5-{[{5-ring Propyl-2-(4-fluorophenyl)-3-[(methylamino)methyl]-1-benzofuran-6-yl}(methyl hydrazino)amino]methyl b 1,3 _Dimethyl phthalic acid in a A atmosphere, 2-bromo-5-(bromoindolyl)-1,3·dibenzoic acid dimethyl vinegar (0.6 g, 1.639 mmol), 5-cyclopropyl-2 -(4-Fluorophenyl)-indenyl_6_[(Metforminyl)amino]-1-benzoxofan-3-cartoamine (0.51 g, 1.267 mmol), potassium carbonate (0.175 g) , 1.267 mmol) and a mixture of potassium iodide (〇.〇 21 g, 0.127 mmol) in DMF (6 mL) warmed to 3 (c) for 3 h. The solid was removed by filtration and the filtrate was diluted with water. Extraction 'and the organic layer was dried by NazSO 4 'transition, concentrated and purified by column chromatography to give a viscous light yellow oil of 2-yel-5- {[{ 5-cyclopropyl-2-(4_fluoro) Phenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}-1,3-benzene diacetate (0.85) g, 1.236 mmol, 98% yield). iNMR (400 MHz, gas δ: 7.87 (1 (1,7=8.0) , 5.7 154007.doc -202· 201221131

Hz, 2 Η), 7.59 (s, 2 Η), 7.27 (s, 2 Η), 7.14-7.23 (m5 2 Η), 5.78 (br. s., 1 H), 4.87 (q, 2 H), 3.93 (s, 6 H), 3.06 (s, 3 H), 3.00 (d, 7=4.7 Hz, 3 H), 2.09-2.22 (m, 1 H) , 1.00-1.14 (m, 1 H), 0.83 -0.97 (m, 2 H), 0.52 (d, /=5.1 Hz, 1 H). Step 6: 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]benzovv-6-yl} Amino]mercapto}-2-(4,4,5,5-tetradecyl-1,3,2-dioxaboran-2-yl)-1,3-benzenedicarboxylic acid diterpene vinegar 2-Bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)_3-[(decylamino)carbonyl]-1-benzofuran-6-yl} under N2 atmosphere , 醯 ) ) ) ) ) [ [ [ [ [ [ [ [ [ 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Octamethyl-2,2,-linked-1,3,2-dioxaboron. East (0.628 g, 2.473 mmol), Pd(dppf)Cl2-CH2Cl2 (〇.l〇l g' 0.124 mmol) and acetic acid clock (0.364 g ' 3.71 mmol) in 1,4-two-degree cauterization (20 mL) The solution in the solution was refluxed overnight. The solution was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, evaporated and purified eluting eluting eluting (Methylamino) benzyl]-1-benzo[beta]. _6-yl}(indolyl)amino]methyl}-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)- Dimethyl 1,3-benzenedicarboxylate (0.26 g, 0.354 mmo, 28.64% yield). [(:-]^8(milk/7, £8+) = 735 (]^+11). Step 7: 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3 -[(methylamino)carbonyl]-1 - benzoheptan-6-yl}(methylsulfonyl)amino]methyl-hydroxy-13-dihydro-2,1-benzoxa-boron Cyclopentene_7-carboxylic acid methyl vinegar was treated with 4.15 mL of LiBH4 (0.202 mL, 8.31 mmol, 2.0 M in THF) 5-{[{5-cyclopropyl-2-(4-fluorophenyl)_3-[( Amidino)carbonyl]_1_stupid 154007.doc 203 · 201221131 and furan-6-yl}(sulfonyl)amino]methyl b 2·(4,4,5,5-tetramethyl·1 , 3'2-dioxaboron-2-yl)·m, a solution of dimethyl dimethyl phthalate (〇26 g, 〇^4 mmol) in anhydrous tHF (2 〇mL), and in the chamber Stir under temperature until the starting material is completely consumed. The mixture is poured into ice water and extracted with EtOAc (EtOAc). [{5-Cyclopropyl-2-(4-fluorophenyl)_3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(nonylsulfonyl)amino]methyl}_丨_Hydroxy-1,3-dihydro-2,1-benzoxoxaborole-7-carboxylate (28 5 mg, 0.047 mmo 13.25% yield. NMR (400 MHz, gas-like δ: 8.41 (s, 1 H), 7.95 (s, 1 H), 7.79-7.86 (m, 2 H), 7.47 (s, 1 Η ), 7.24 (s, 1 Η), 7.19 (t, 2 Η), 5.75 (d, 1 Η), 5.05-5.15 (m, 3 Η), 4.87 (d, 1 Η), 3.95 (s, 3 Η) ), 3.07 (s, 3 Η), 2.99 (d, 3 Η), 2.14-2.24 (m, 1 Η), 2.02 (s, 1 Η), 1.00- 1.12 (m, lH), 0.85-0.98 (m , 2H), 0.49-0.60 (m, lH) ° LC-MS (m/z, ES+) = 607 (Μ + Η). Example 51 5-cyclopropyl-2-(4-fluorophenyl)-6 -[{[l-yl-7·(monomethyl)·ι,3-dihydro-2,1-benzoxoxaborole-5-yl]methyl}(methanesulfonic acid) Amino]methyl-1-benzo-cough-3-carbamamine

154007.doc • 204· 201221131 5-Cyclopropyl-2-(4-fluorophenyl)_6_[{[i-hydroxy-7_(hydroxymethyl)_13_dihydro-2,1-benzoxylene boron Heterocyclic pentene-5-methyl]methyl}(methylsulfonyl)amino]-Nmethyl-1-benzol-vv-3-amine to 5-{[{5-cyclopropyl-2 -(4-fluorophenyl)-3-[(methylamino)carbonyl]-1. stupid and acetyl-6-yl}(methylsulfonyl)amino]mercapto}_丨_hydroxy_丨, Add 3⁄4 mL of LiBH4 (62.9 mg, 2.89) to a solution of 3H-dihydrobenzoindole and oxaborole-7-carboxylate (35 mg, 0.058 mmol) in dry THF (5 mL) Methyl acetate, 2.0 M in THF) and stirred at room temperature until complete consumption of starting material. The solution was washed with water, EtOAc (EtOAc) (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH {[1-Hydroxy-7-(hydroxyindenyl)-l,3-dihydro-2,1-benzooxaborole-5-yl]methyl}(methylsulfonyl)amino ]_ N-Methyl-1-benzofuran-3-carboxamide (14.5 mg, 0.025 mmol, 43.4% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.89 (br·s., 1 Η), 8.35-8.50 (m, 1 Η), 8.14-8.20 (m, 1 Η), 7.80-8.01 (m, 3 Η) ), 7.39 (t, 2 Η), 7.29 (s, 1 Η), 7.18 (s, 1 Η), 6.89 (s, 1 Η), 5.43 (br. s., 1 H), 5.00 (d, 1 H), 4.91 (s, 2 H), 4.84 (d, 1 H), 4.66 (s, 2 H), 3.21 (br. s., 4 H), 2.79 (d, J=3.5 Hz, 3 H) , 2.27-2.38 (m, 1 H), 0.86-1.00 (m, 1 H), 0.68-0.86 (m, 2 H), 0.12-0.26 (m, 1 H). LC-MS 〇/z, ES+) = 579 (M+H). Example 52 6-(N-((7-Chloro-1-hydroxy-1,3-dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)methyl Sulfonamide)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzopyrene·3_cartoamine 154007.doc -205- 201221131

Step 1: 2 - -6-gas-4-methylaniline to 2-acet-4-methylaniline (5.0 g, 35.3 mmol) in acetic acid (15) at 15 ° C under nitrogen atmosphere. NBS (6.9 g, 3 8·3 mmol) was added to the solution in mL). After the addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (150 mL) andEtOAc. The organic layer was washed with water (2×150 mL) and Na.sub.2CO.sub.3 (10% aq. After removal of the solvent, the crude material was purified eluting with EtOAc EtOAc EtOAc EtOAc Step 2: 2-Amino-3-gas-5-methylbenzoic acid methyl vinegar was heated at 80 ° C under 2.2 MPa - carbon oxide to heat 2-bromo-6-chloro-4-mercaptoaniline (3.5 g, A solution of 16 mmol), Pd(OAc) 2 (0.72 g, 3.2 mmol), dppf (2.69 g, 4.8 mmol) and EtN3 (1.62 g, 16 mmol) in DMSO (105 mL) and MeOH (69 mL). The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (300 mL) and washed with water (3×200 mL) and brine (200 mL) and dried over anhydrous Na? After the solvent was removed, the crude product was purified by column chromatography to yield ethyl 2-amino 3- 3--5-methylbenzoic acid as a white solid (3.15 g, 15.8 mmol, 98% yield ). Step 3: 2-Bromo-3-chloro-5-methylbenzoic acid hydrazine at 〇 ° C for 10 minutes to 2_Amino_3_gas_5-methylbenzoic acid methyl ester 154007.doc 201221131 (3.15 g' 15·8 mmol) HBr (47% aqueous solution, 19.5 mL) was added dropwise to a solution of MeCN (20 mL). Water containing NaN02 (1.12 g, 17.4 mmol) (5 mL) was added dropwise at 0 °C over 1 hour. After the addition, the solution was stirred at 〇 ° C for 5 minutes, and then CuBr (2.64 g ' 18 2 mm 〇i) was added in several portions over 30 minutes. The reaction mixture was heated at 70 ° C for 1 hour. Cool to 〇. After hydrazine, water (3 〇 mL) was added and extracted with Et EtOAc (3×30 mL). The combined organic layers were washed with cold water (7 mL) and dried over anhydrous Na.sub.2. After removal of the solvent, the crude material was purified with EtOAc EtOAc EtOAc EtOAc rate). Step 4: 2-Bromo-5-(bromomethyl)-3-chlorobenzoic acid methyl ketone was heated under reflux with methyl 2-bromo-3-chloro-5-mercaptobenzoate (3.1 g, 11.8 mmol) A solution of benzamidine peroxide (145 mg, 〇6 mmol) and λ/·-bromobutadienimide (2.31 g '13.0 mm〇i) in cci4 (50 mL) for 48 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. Vinegar (1.54 g' 4.5 mmol, 38% yield). Step 5: 2-Bromo-3-chloro-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6- Methyl sulfonylamino)methyl)benzoic acid methyl ketone stirred at room temperature under nitrogen atmosphere 5_cyclopropyl_2_(4·fluorophenyl)_#•methyl-6-(methyl Sulfonamide)benzofuran_3_formamide (6〇〇mg, mmol), 2-bromo-5-(bromomethyl)_3_chlorobenzene f acid methyl ester (769 mg, 225 mmol), A solution of KI (12 mg '〇_〇7 mm〇1) and K2C〇3 (621, mmol) in anhydrous DMF (25 mL) was incubated for a few hours. The reaction solution was diluted with EtOAc EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water (75 mL) brine brine After the solvent was removed, the crude was purified by column chromatography to give 2-bromo-3-chloro-5-((1-(5-cyclopropyl-2-(4-fluorobenzene) as a white solid. Methyl 3-(methylaminoindenyl)benzofuran-6-yl)methylsulfonylamino)methyl)benzoate (700 mg, 1.05 mmol, 71% yield). Step 6: 3-Gapent-5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl) benzofuran-6-yl)methyl Sulfonamide)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzoic acid methyl ketone 2-bromo-3- gas -5-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminoindolyl)benzofuran-6-yl)indolylsulfonylamino)indole Ethyl benzoate (7〇〇mg '1.05 mmol), bis(pinacolyl)diboron (533 mg, 2.1 mmol), potassium acetate (308 mg '3.15 mmol) and PdCl2(dppf)-CH2Cl2 ( A solution of 115 mg '0.1 mmol) in dioxane (25 mL) was degassed and refilled with nitrogen three times and then warmed overnight at 10 °C. After the reaction solution was cooled to room temperature, it was poured into water (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) dried over anhydrous Na. After the solvent was removed, the residue was purified by column chromatography to yield white crystals of 3-chloro-5- ((-- 5- 5-propylpropyl-2-(4-fluorophenyl)-3- (methylamine-mercapto)benzofuran-6-yl)methylsulfonylamino)hydrazino)-2·(4,4,5,5-tetramethyl-1,3,2-dioxo Methyl boron Boron-2-yl)benzoate (115 mg, 0.16 mmol, 1 5% yield). Step 7: 6-(Ν·((7-Gaxo-1-hydroxy-1,3-dihydrobenzo[c][i,2]oxaborol-5-yl)methyl) A Baseline 醢aminocyclopropyl-2-(4·fluorophenyl)· 154007.doc •208- 201221131 N-mercaptobenzofuran-3-decylamine

3-A-5-((N-(5-cyclopropyl_2-(4-fluorophenyl)·3·(methylaminoindenyl)benzofuran-6-) at -5 °C Ethyl sulfonylamino)methyl)_2_(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl) benzoic acid decyl ester (115 mg, To a solution of THF (15 mL), EtOAc (EtOAc m. After the addition, the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was poured into EtOAc (3 mLEtOAc) The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na. After removal of the solvent, the crude product was purified by reverse-phase HPLC to yield hydroxy-(1,2-dihydrobenzo[c][l,2]oxaborole _5_ as a white solid. Methyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-#-methylbenzofuran-3-decylamine (75 mg ' 0.12 mmob 18 %Yield). NMR (methanol-&lt;14) 5: 7.94-7.89 (m, 2H), 7.65 (S, 1H), 7.29-7.19 (m, 4H), 7.03 (s, 1H), 5.06-4.86 (m, 4H ), 3.32 (s, 3H), 2.93 (S, 3H), 2.28-2.26 (m, 1H), 1.03-0.81 (m, 3H), 0.34-0.32 (m, 1H). LCMS (/z, ES+) = 583.1 (M+H) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 1H-2,1-benzoxoxaborole-6-yl)methyl](methylsulfonyl)amino]_N-methyl-1-benzofuran-3-carboxamide

154007.doc 201221131 Step 1: 2-Bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[( ▼-amino)-yl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]methyl benzoic acid methyl vinegar heated 5-cyclopropyl-2-(4-fluorophenyl)-#-methyl-6-[(sulfonyl) Amino]-1-benzol-f-butan-3-cartoamine (5.00 g, 12.4 mmol), 2-di-5-(glymethyl) benzoic acid decyl ester (7.65 g ' 24.85 mmol, purity 60 % (according to LCMS)) and a mixture of potassium carbonate (3.43 g, 24.85 mmol) in acetonitrile (1 mL) to 50 ° C for 4 h. To this mixture was added additional 2-methyl-5-(bromoindolyl)benzoate methyl 〇〇 g, 3 25 mm 〇i, purity 60% (according to LCMS) and heating was continued for a further 3 hours. The mixture was cooled to room temperature and filtered and concentrated to remove most of the acetonitrile. The residue was diluted with water and extracted with EtOAc (EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate Purification by gas chromatography (containing hydrazine to 1 〇〇% ethyl acetate) gave 2-bromo-5-{[{5-cyclopropyl-2-() as a pale yellow foam. 4-fluorophenyl)-3-[(indenyl)anthracene]_ι_benzofuran_6_ylindole (anthracene)amino]mercapto}methyl benzoate (6.59 g, 84%). 4 NMR (gas-d) δ: 7.86 (dd, J=8.7, 5.3 Hz, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.15- 7.26 (m, 5H), 5.76 (m, 1H), 4.92-5.00 (m, 1H), 4.72-4.79 (m, 1H), 3.89 (s, 3H), 3.04 (s, 3H), 2.99 (d, J = 4.9 Hz, 3H), 2.11-2.21 (m, 1H), 1.01-1.10 (m, 1H), 0.87-0.98 (m, 2H), 0.54 (q, 1H). LCMS (m/z, ES+) = 629 (M+H). Step 2: 6-[{[4-Bromo-3-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]·5·cyclopropylfluorophenyl)-N-methyl- 1-benzofuran-3-decylamine treated with lithium borohydride solution (18.5 mL, 2.0 Μ in THF) 2-Moist - 154007.doc -210- 201221131 5- {[{5-cyclopropyl- 2-(4-Fluorophenyl)_3-[(methylamino)carbonyl]_ι·benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoic acid methyl ester (4 66 g, 7 4 mmol) a solution in THF (100 mL) and methanol (1 mL). After stirring for 16 h, the reaction was quenched with EtOAc EtOAc EtOAc. The reaction mixture was concentrated to remove most of the THF. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated tolululululululululululululululululululu 5-ylcyclopropyl-2·(4-fluorophenyl)_Λ/·-methyl-1-benzofuran_3-carbamamine (2.84 g, 64 〇/〇). A NMR (gas δ: 7_86 (dd, J=8.7, 5.3 Ηζ, 2Η), 7.45 (d, J=8.1 Ηζ, 1H), 7.37 (d, J=1.7 Hz, 1H), 7.26 (br. s ., 2H), 7.19 (t, J=8.6

Hz, 2H), 7.07 (dd, J=8.2, 2.0 Hz, 1H), 5.75 (d, J=4.5 Hz, 1H), 4.89-5.05 (m, 1H), 4.61-4.81 (m, 3H), 2.91 -3.09 (m, 6H), 2.12-2.26 (m, 1H), 0.80-1.13 (m} 3H), 0.44-0.63 (m, 1H) ° LCMS {m/z, ES+) = 601 (M+H) ° Step 3: 6-[[(4-bromo-3-carboxyphenyl)methyl](methylsulfonyl)aminodi 5_cyclopropyl-2-(4-fluorophenyl)_N- Treatment of 6-[{[4-bromo-3-(sulfenyl)phenyl) with methyl-1-benzofuran-3-carboxamide with mono-oxidation (0.88 g, ΐ〇·ι mm〇i) Methyl}(methylsulfonyl)amine bromide 5_cyclopropyl_2_(4-fluorophenyl)_#_ fluorenyl-1-benzhydrin-3 - anthraquinone (0.61 g,l .oi mmol) A solution of dioxane (100 mL) and allowed to stir at room temperature overnight. The reaction mixture was filtered through a pad of Celite, and rinsed with di-hexane and ethyl acetate. The filtrate was concentrated and the residue was purified EtOAc EtOAc EtOAc EtOAc (Methanesulfon 154007.doc •211 - 201221131 fluorenyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-#-mercapto-1-benzofuran-3-carboxamide 0.48 g, 79%). NMR (gas δ: 10.29 (s, 1H), 7.85 (dd, J = 8.7, 5.3 Hz, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H) , 7.44-7.57 (m, 1H), 7.25 (s, 1H), 7.19 (t, J=8.6 Hz, 2H), 5.64-5.85 (m, 1H), 4.89-5.05 (m, 1H), 4.72-4.89 (m, 1H), 2.89-3.13 (m, 6H), 2.09-2.25 (m, 1H), 0.99-1.15 (m, 1H), 0.80-0.99 (m, 2H), 0.40-0.62 (m, 1H) LCMS (m/z, ES+) = 599 (M+H).

Step 4: 6-[{[4-bromo-3-(2-o-oxyethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-(4-1 benzene) Gasoline (methyloxymethyl)triphenyl scale (0.49 g, 1.42 mmol) and potassium butoxide (yield) Treatment of 6-[[(4-bromo-3-carboxyphenyl)indolyl](nonylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorobenzene) with 0.16 g, 1_42 mmol) A solution of methyl-1-benzofuran-3-indolamine (0.71 g, 1.18 mmol) in DMF (15 mL). The reaction was stirred at room temperature overnight then additional (3 methoxymethyl)triphenyl hydrazide (0.16 g, 0.47 mmol) and potassium butoxide (0.053 g, 0.47 mmol) 6 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was washed with water (2 mL) and brine (1x) The residue was dissolved in THF (15 mL)EtOAc. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate Purification by gas chromatography (containing 0 to 100% ethyl acetate in hexanes) to give 6-[{[4-bromo-3-(2- </RTI> ethoxyethyl)benzene as a pale yellow oil Methyl}(methylsulfonyl)amine 154007.doc • 212- 201221131 yl]-5-cyclopropyl-2-(4-fluorophenyl)-iV~mercapto-1-benzoaphthyl -3 - an amine (0.42 g, 58%). NMR (chloroform δ: 9.66 (t, J = 1.5 Hz, 1H), 7.81-7.95 (m5 2H), 7.47-7.57 (m, 1H), 7.24 (d, J = 2.5 Hz, 2H), 7.16-7.23 ( m, 2H), 7.09 (dd, J=8.2} 2.2 Hz, 1H), 7.03 (d, J=2.1 Hz, 1H), 5.87 (d, J=4.5 Hz, 1H), 4.93 (d, J=14.4 Hz, 1H), 4.71 (d, J=14.3 Hz, 1H), 3.81 (dd, J=3.1,

1.5 Hz, 2H), 3.03 (s, 3H), 2.96-3.02 (m, 3H), 2.08-2.20 (m, 1H), 0.98-1.12 (m, 1H), 0.83-0.97 (m, 2H), 0.48 -0.62 (m, 1H) 0 LCMS (w/z, ES+) = 613 (M+H). Step 5: 6-[{[4-Bromo-3-(2-{[(methyloxy)methyl)oxy}ethyl)phenyl]methyl}(methylsulfonyl)amino]- 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide cooled 6-[{[4-bromo-3-(2- oxooxy) Ethyl)phenyl]fluorenyl}(sulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-iV~mercapto-1-benzo[beta]#3_ A solution of the amine (0.42 g, 0.69 mmol) in methanol (10 mL) was taken to EtOAc (EtOAc) The reaction was allowed to warm to room temperature. After 1 hour, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine~ dried over sodium sulfate and concentrated. The residue was dissolved in dioxane (10 mL) and cooled to (TC. solution was mEA ( 〇 14 mL, 0.82 mm 〇l) and gas methyl methyl shunt (62 吣, 〇82 with 〇1) The reaction mixture was allowed to warm to room temperature overnight (&lt;&gt;&gt; and poured into water and extracted with dichloromethane (2 χ). The combined organic layers were washed with water (1 χ) and brine (1×), followed by sulfuric acid The sodium is dried and concentrated, and purified by Shihic acid chromatography (containing hydrazine to spectrum. Ethyl acetate in acetonitrile) to give 6-[{[4_ 154007.doc -213- 2012-21131 bromo-3-( 2-{[(methyloxy)indenyl]oxy}ethyl)phenyl]indolyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl) -#-Methyl-1-benzofuran-3-3-decylamine (0.38 g, 84%). LCMS (w/z, ES+) = 659 (M+H) 〇 Step 6.5. 2-(4-^phenyl)-6-[[(l-trans)-3,4-dihydro 2J-benzooxaborolen-6-yl)methyl](sulfonyl) Amino]_N_methyl-1-benzofuran-3-carboxamide in 6-[{[4-bromo-3-(2-{[(methyloxy))) in a thick-walled glass pressure vessel Mercapto]oxy}ethyl)phenyl]methyl}(nonylsulfonyl)amino]-5-ring Benzyl-2-(4-carbene)-iV-methyl-1-benzox-ammon-3-amine (0.38 g, 0.58 mmol), acetic acid (113 mg, 1.1 5 mmol), double (pinacol root) dipterin (190 mg '0.75 mmol), sodium bromide (59 mg, 0.58 mmol) and dioxobis(tricyclohexylphosphine) (Π) (43 mg, 0.058 mmol) at 1, The mixture in 4-dise hospital (10 mL) was degassed' and then heated under stirring for 95 hours under stirring. The reaction mixture was cooled to room temperature, filtered through a pad of Celite and concentrated. Treated in 1,4- bis., sulphur (40 mL) and treated with 5 N HCl (20 mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with water and concentrated to remove most organics. The organic layer was washed with water (2x) and brine (1x) then dried over sodium sulfate and concentrated. Purification of methanol (di-methane methane) followed by a second purification by reverse phase HPLC to give 5-cyclopropyl.2~(4.fluorophenyl)_6[[(1) hydroxy-3, as a white foam. 4-dihydrobenzoxaazepine Hexene_6_yl)subunit](methylheptyl)amino]-iv-mercaptobenzofuran_3_formamide (188, 58%). 丨H NMR (methanol-state δ: 7.85 -7,96 (m,2H), 7.58 (s, 154007.doc 201221131 1H), 7.49 (d, J=7.5 Hz, 1H), 7.24 (t, J=8.8 Hz, 2H), 7.04-7.13 (m , 2H), 7.02 (s, 1H), 4.92-4.98 (m, 1H), 4.77-4.84 (m, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.15 (s, 3H), 2.92 ( s, 3H), 2.83 (t, J=5.9 Hz, 2H), 2.16-2.34 (m, 1H), 0.90-1.05 (m, 1H), 0.68-0.86 (m, 2H), 0.25-0.41 (m, 1H). LCMS (w/z, ES+) = 564 (M+H). Example 54 5-Cyclopropyl-N-ethyl-6-[[(7-fluoro-1-hydroxy-1,3-dihydro-2,1-benzooxazepine heterocyclopenten-5-yl) )methyl](methylsulfonyl)amino-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide

Step 1: 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-decylamine in ice Cooling 5-cyclopropyl-2-(4-fluorophenyl)-6-[(oxasulfonyl)amino]-1-benzofuran-3-indole (5 g, 12.84 mmol) in a bath Solution in DMF (30 mL). DIEA (8.97 mL, 51.4 mmol) and ethylamine hydrochloride (1.571 g, 19.26 mmol) were added to this solution. After 1 minute of mixing, 2,4,6-tripropyl-i,3,5,2,4,6-trioxatriphosphine 2,4,6-di was added over 2 minutes. Oxide (11.47 mL, 19.26 mmol) and the reaction was stirred for 4 min. The reaction did not proceed and was poured into the water and mixed for 2 〇 minutes. The suspension was filtered and dried under vacuum to give a brown solid: </ s </ s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s. Mercapto)amino]-1-benzofuran-3-decylamine (4.14 g, 9.94 mmol, 77% yield).丨H NMR (DMSO-de) δ: 9.31 (br. s., 1H), 8.52 (t, J=5.57 Hz, 1H), 7.95 (dd, J=5.37, 8.70 Hz, 2H), 7.60 (s, 1H), 7.38 (t, J=8.89 Hz, 2H), 7.14 (s, 1H), 3.27-3.40 (m, 2H), 3.05 (s, 3H), 2.25-2.38 (m, 1H), 1.14 (t , J = 7.13 Hz, 3H), 0.95-1.04 (m, 2H), 0.63-0.74 (m, 2H). LCMS (7«/z, ES+) = 417. Step 2: 2-Bromo-5-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-bromo-afu-6- Alkyl]methyl benzoic acid vinegar vinegar heated 5-cyclopropylethyl-2-(4-fluorophenyl)-6-[(sulfonyl)amino group μ 1-Benzo-Of0-N--3-decylamine (0.50 g ' 1.20 mmol), 2-bromo-5-(bromomethyl)-3-fluorobenzoic acid methyl ester (0·47 g, 1.44 mmol) A mixture of carbonic acid (0.33 g, 2.40 mmol) in acetonitrile (20 mL) was taken to 5 ° C for 15 h. The mixture was cooled to room temperature and filtered. The mash was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water (EtOAc) and brine. Purification by gelatin chromatography (containing hydrazine to 1% by weight of ethyl acetate) gave 2-bromocyclopropyl-3-[(ethylamino)carbonyl as pale yellow foam. ]_2_(4.Fluorophenyl)-indole benzofuran-cardiyl](methyl aryl)amino]indolyl}-3-fluorobenzoic acid decyl ester (〇.72 g, 91%).咕NMR (C(4) δ: 8.00-8.08 (m,2H)' 7.73 (s,1H), 7.56-7.64 (m, 2H), 7.44 (dd, J=9.2, 1.8 Hz, 1H), 7.29 (t, J=8.8 Hz, 2H), 7.09 (s, 1H), 5.06-5.13 (m, iH), 4.90-4.98 (m, 1H), 3.85 (s, 3H), 3.45 (quin, J=6.7 Hz, 2H ), 3.23 (s, 154007.doc -216- 201221131 3H), 2.29-2.39 (m5 1H), 1.20 (t, J=7.2 Hz, 3H), 0.93-1.02 (m, 1H), 0.74-0.89 (m , 2H), 0.23-0.32 (m, 1H). LCMS (m/z, ES+) = 661 (M+H). Step 3: 5-cyclopropyl-N-ethyl·6-[[(7- Fluor-1-hydroxy-1,3-dihydro-2,1-benzooxaborole-5-yl)methyl](methylsulfonyl)amino]-2-(4-fluoro 2-bromo-5-{[[5-cyclopropyl-3-[(ethylamino)carbonyl) in a thick-walled glass pressure vessel ]-2-(4-Fluorophenyl)-1-benzofuran-6-yl](methylsulfonyl)amino] decyl}-3-fluorobenzoate decyl ester (0.72 g, 1.09 mmol) Potassium acetate (0.21 g ' 2.18 mmol), bis(pinacolyl)diboron (0.36 g, 1.42 mmol), sodium bromide (112 mg, 1.09 mmol) and dichlorobis(tricyclohexylphosphine) 11) (80 mg, 0.11 mmol) in 1,4-dioxacin (10 mL) The mixture was degassed, then heated at 95 ° C for 22 hours with stirring. The reaction mixture was cooled to room temperature. Filtered through Celite, and concentrated by chromatography (with 0 to 100% acetic acid) Purification of the ester of hexane) gave 5_{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1 -benzofuran as a colorless oil „南_6_基】(Met) Amino]Methyl}-3-Any-2-(4,4,5,5-tetramethyl-i,3,2-dioxaborazole-2 -yl) decyl benzoate (0.75 g, purity 67% (according to LC/MS)). This material was dissolved in THF (15 mL) and cooled in an ice bath with &lt;RTI ID=0.0&gt; The mixture was treated with EtOAc (EtOAc)EtOAc. Purification by gelatin chromatography (dichloromethane containing hydrazine to 100% ethyl acetate followed by hydrazine to 3.5% decyl alcohol), followed by cyclohexane to give 5-cyclopropane as a white solid. 154007.doc -217- 201221131 yl-iV-ethyl-6-[[(7-a-1-1-yl-1,3-dihydro-2,1-benzoxanthene-5) -yl)methyl](nonylsulfonyl)amino]-2-(4-fluorophenyl)4-benzopyrene-3-carboxamide (297 mg, 39./〇 (after 2 steps) ). 4 NMR (DMSO-d6) δ: 9.24 (s, 1H), 8.51 (t, J = 5.6 Hz, 1H), 7.93 (dd, J=8.7, 5.4 Hz, 2H), 7.87 (s, 1H), 7.38 (t, J=8.8 Hz, 2H), 7.19 (Sj 1H), 6.96 (d, J=8.8 Hz, 1H), 6.91 (s, 1H), 5.02 (d, J=14.6 Hz, 1H), 4.93 ( s, 2H), 4.85 (d, J=14.7 Hz, 1H), 3.27-3.38 (m, 2H), 3.18-3.27 (m, 3H), 2.22-2.36 (m, 1H), 1.11 (t J=7.2 Hz, 3H), 0.87-1.02 (m, 1H), 0.67-0.84 (m, 2H), 0.12-0.26 (m, 1H). LCMS (m/z, ES+) = 581 (M+H). Example 55 5-Cyclopropyl-2-(4-fluorophenyl)-6-(Ν-(2-(1·hydroxy-l,3-dihydrobenzo[c][l,2]oxaboron Heterocyclopenten-3-yl)ethyl)methylsulfonylamino)_N_methylbenzobenzoin-3-cartoamine

Step I · 1-(2-indifferent) propan-2-indole-I-alcohol at 0 ° C under N 2 atmosphere for 1.5 hours to 2-bromobenzaldehyde (1 〇.〇g, 54 mmol, Vin-MgBr (33.8 mL, 1.6 mol in THF) was added dropwise to a solution of EtOAc (90 mL). The reaction mixture was slowly warmed to room temperature and kept stirring for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water 154007.doc - 218. After removal of the solvent, the crude material was purified eluting with EtOAc EtOAc EtOAc. Yield). Step 2: (1-(2-Bromophenyl)allyloxy)(t-butyl)dimethylhydrazine is calcined at room temperature to 1-(2-bromophenyl)propan-2-enol ( 9 16 g, 43 mm 〇 1) To a solution of DMF (60 mL) was added butyl dimethyl dimethyl hexane (7.77 g, 51.6 mmol) and imidazole (5.85 g, 86 mm 〇1). The mixture was stirred at room temperature for 3 hours and then diluted with water (1 〇〇 mL) and used

Extract with EtOAc (3 x 100 mL). The combined organic layers were washed with water (15 mL) and brine (150 mL) and dried over anhydrous Na? After the solvent was removed, the crude product was purified by column chromatography to yield (y-(2-bromophenyl)-s-propyloxy) (t-butyl) dimethyl succinic (13.85 g. , 42 mmol, 98% yield). Step 3: 3-(2-Bromophenyl)-3-(t-butyldimethylmethylalkyloxy)propan-1-ol to (1-(2-bromophenyl)allyl at room temperature Add IX) BBN (5.7 g, 23.4 mmol) to a solution of (t-butyl) dimethyl hydrazine (12.8 g '39 mmol) in THF (250 mL) and stir the reaction mixture at room temperature Overnight. The reaction mixture was quenched with NaOH (1 mL aqueous solution, 180 mL). After stirring for 15 minutes, H 2 〇 2 (30%, 45 0 mL) was added dropwise to the reaction solution. After the addition, the reaction solution was stirred at room temperature for 30 min and extracted with EtOAc (3×400 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL) and dried over anhydrous Na? After removal of the solvent, 154007.doc • 219-201221131 The crude product was purified by column chromatography, and the product was purified by column chromatography to yield 3-(2-bromophenyl)-3- (Second butyl dimethyl decyloxy) propiol oxime 19, μ $ mmol, 85% yield). Step 4. (3-Di-(2-diphenyl)propoxy-tert-butyl) dimethyl oxime was calcined to 3_(2-bromophenyl)_3_ under a nitrogen atmosphere at 〇 °C a solution of the third butyl dimethyl decyloxy) propan-1-ol (5. 〇g, 14 5 〇 1) and NBS (5 16 LV, 29 mm 〇 1) in DCM (50 mL) DCM (15 mL) containing pph3 (76 g, 19.2 mmol) was added. The reaction mixture was stirred at room temperature for 5 min and then poured into ice water (5 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na. After the solvent was removed, the crude product was purified by column chromatography to yield (3-bromo-1-(2-bromophenyl)propoxy) (t-butyl) dimethyl decane as a colorless liquid. 3 5 g, 8.6 mmol, 59% yield). Step 5: 6-(N-(3-(2-Bromophenyl)-3-(t-butyldimethylmethylalkyloxy)propyl)methylsulfonylamino)-5-cyclopropyl -2·(4-Fluorophenyl)-indole·methylbenzofuran-3-carboxamide was heated at 80 ° C under nitrogen atmosphere with 5-cyclopropyl-2-(4-fluorophenylmethyl) -6-(曱基绩生胺基)benzobenzoin-3-cartoamine (2.5 g, 6.2 mmol), (3-bromo-1-(2-bromophenyl)propoxy) (third a solution of butyl) dimethyl zebra (3_5 g, 8.6 mmol), KI (51 mg, 0.31 mmol) and K2C03 (2.57 g ' 18.6 mmol) in anhydrous DMF (25 mL). (100 mL) was diluted and extracted with EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjj Column chromatography purification 154007.doc -220 - 201221131 yielded 6-(#-(3-(2-bromophenyl)-3-(t-butyldimethyl decyloxy)propane as a yellow solid. Methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-indole/methylbenzoindole. Southern-3-carbamamine (3.4 g, 4.7 mmol, 75 % yield). Step 6: Third Butyl bis-indenyl decyloxy)-1(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)phenyl)propyl) 5-sulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide 6-(# under nitrogen atmosphere at 95 ° C -(3-(2-bromophenyl)-3-(t-butyldimethylmethylalkyloxy)propyl)methylsulfonylamino)_5·cyclopropyl-2-(4-fluorobenzamide Alkyl benzophenone-3 - anthraquinone (3.4 g, 4.7 mmol), bis(pinadol) shed (3.39 g, 9.4 mmol), acetic acid; if (1.38 g, 11.4 mmol) and PdCl2 (dppf)-CH2Cl2 (540 mg, 0.47 mmol) in EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water (150 mL) and brine (150 mL) and then dried over anhydrous Naj. (iv_(3_(T-butyldidecylfluorenyloxy)-3-(2-(4,4,5,5-tetradecyl-H2-dioxaboryl-2-yl)phenyl) Propyl)methylsulfonylamino)-5· Cyclopropyl-2-(4-fluorophenyl)-mercaptobenzofuran-3-indoleamine (1.02 g, i.33 mm 〇 1 ' 28% yield). Step 7: 5-cyclopropyl_2_(4-fluorophenyl)_6_(Ν·(2_(ι-carbyl·ΐ3_diazabenzooxaborole)-3-yl)ethyl) Methyl-amino)N-methylbenzofuran-3-carboxamide 6-(N-(3-(t-butyldimethyl oxalate)oxy) is small at 30 ° C (2_ 154007.doc •221 - 201221131 (4'4,5'5-Tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)propyl)methylsulfonylamino)-5 -cyclopropyl_2_(4-fluorophenyl)_N_methylbenzofuran·3_decylamine (1.02 g, 1.33 mm〇1), 4-methylsulfonate pyridinium (〇67 g2 μmmol And a solution of 1 M HCl (Ql mL) was stirred overnight. After removing the solvent, the residue was dissolved in Et EtOAc (5 〇 mL) and washed with H.sub.2 (2 〇). The organic solution was dried over anhydrous NkSCU. After removal of the solvent, the residue was purified by reverse-phase HPLC to yield 5- <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; And [c][1,2]oxazacyclopent-3-yl)ethyl)decylsulfonylamino)_αγ·methylbenzofuran_3_decylamine (650 mg ' 1.15 mm 〇l, 86°/〇 yield). iH NMR (sterol_d4) δ. 7.86-7.80 (m, 2H), 7.67-7.50 (d, 1H), 7.50-7.41 (m, 2H) 7.35-7.26 (m, 2H), 7.22-7.14 (m , 3H), 5.83-5.82 (d, 1H), 5.29-5.19 (m, 2H), 4.01-3.83 (m, 2H), 3.06-2.97 (m, 6H) 2.34-2.25 (m, 2H), 1.86- 1.71 (m, 1H)} 1.04-0.89 (m, 3H) 0.68-0.61 (m, 1H). LCMS (m/z, ES+) = 563 i (m + h) ' </ RTI> 56 5-cyclopropyl-2-(4-fluorophenyl)·6·(Ν-((1-hydroxydihydroindole)川以】 Oxacyclohexyl-3-yl)methyl)methyl-nonylamino)-Ν-methylbenzofuran-3-carboxamide

Step 1: 2·Bromo-1-(2-bromophenyl)ethanone 154007.doc -222- 201221131 Heating 1-(2-bromophenyl)ethanone under reflux (2〇g, i〇i mm〇 1 , sigma), &gt; a solution of stannized copper (9.63 g, 43.63 mmol) and diazonium (16.7 mol) in EA (100 mL) and DCM (100 mL) for 24 hours. The resulting reaction mixture was cooled to room temperature &lt;&apos;&gt; filtered and extracted with EtOAc (EtOAc). The organic layer was washed with brine (100 mL) and dried over anhydrous Na? After the solvent was removed, the crude product was purified by column chromatography to yield 2-bromo-1-(2-bromophenyl)-ethyl (i4g, 50 mmol, 50% yield) as white solid. Step 2: 6-(Ν-(2-(2·Bromophenyl)-2-oxoethyl)methanesulfonylamino)_ 5-cyclopropyl-2-(4-fluorophenyl) -N-methylbenzofuran-3-carboxamide is stirred at room temperature 5·cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(sulfonyl)amine 1-benzofuran-3-indoleamine (1.5 g, 3.7 mmol), 2-bromo-1-(2-bromophenyl)ethanone (2.0 g, 7.4 mmol), potassium carbonate (1.53 g) , 11 · 1 mmol) and a solution of potassium hydride (610 mg, 3.7 mmol) in DMF (50 mL) for 4 h. The solution was cooled to room temperature and diluted with EtOAc and water. The organic layer was dried over anhydrous NajO4. After the solvent was removed, the crude product was purified by column chromatography to yield 6-(N-(2-(2-bromophenyl)-2-oxoethyl)sulfonylsulfonium as a white solid. Amino)-5-cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran-3·decylamine (1.3 g '2.2 mmol, 59% yield). LCMS (w/z, ES+) = 599 (M+H) Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2- </RTI> -2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)indolyl Drink 3-carbamamine 6-(N-(2-(2-bromophenyl)-2-oxoethyl)methyl amide amino)-5-ring 154007.doc •223 · 201221131 C 2-(4-fluorophenyl)-N-methylbenzofuran·3-formamide (1 3 g, 2 2 mmol), potassium acetate (646 mg, 6.6 mmo), double (frequency) A solution of the alcoholic) diboron (1.1 g, 4.4 mmol) and PdCl 2 (dPPf)-CH 2 Cl 2 adduct (160 mg, 0.22 mmol) in 1 '4-dioxane (50 mL) was degassed with nitrogen It was refilled 3 times and heated overnight at 100 °C. The reaction solution was cooled to room temperature. Water (100 mL) was added and the solution was extracted with EtOAc EtOAc. The combined organic layers were dried over anhydrous NaaSO4. After the solvent was removed, the residue was purified by column chromatography to yield 5-cyclopropyl-2((4-fluorophenyl)-N-methyl-6-(N-(2- side) as a white solid. Oxyl 2-(2-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)phenyl)ethyl)methyl-nonylamino)benzene And furan_3_formamide (2 〇g, 3.0 mmo 142% yield). LCMS (m/z, ES+) = 647 (Μ+Η) Step 4: 6-(N-(2-(2) -Bromophenyl)-2-hydroxyethyl)methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-:N-methylbenzofurancarboxamide in several portions To 6-(N-(2-(2-bromophenyl)-2-oxoethyl)indolyl arylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N Add a solution of methyl benzofuran-3-carboxamide (2.0 g, 3.44 mmol) in THF (40 mL) MeOH (10 mL)EtOAc. After stirring for 3 hours, the reaction mixture was taken with EtOAc EtOAc (EtOAc (EtOAc) (EA: PE = 1:2) was purified to give 6-(N-(2-(2-bromophenyl)-2-hydroxy) as a white solid. Ethyl)nonylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-indole-mercaptobenzofuran-3-carboxamide (500 mg, 0.83 mmol, 26% yield) Rate) Step 5: 5-cyclopropyl-2-(4-fluorophenyl)-6-(Ν-((1-hydroxy-1J-dihydrobenzene 154007.doc 201221131 and [c][l,2 Oxaborolide-3-yl)methyl)nonylsulfonylamino)_N_methylbenzopyran-3-carboxamide 6_(N_() under nitrogen atmosphere at 80 ° C 2-(2-bromophenyl)-2-hydroxyethyl) fluorenylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- Indoleamine (0.5 g ' 〇.83 mmol), bis(pinacolyl)diboron (0.421 g ' 1.66 mmol), potassium acetate (0.244 g, 2.49 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct ( The solution was stirred in EtOAc (3 mL) EtOAc (EtOAc) -% propyl-2-(4-fluorophenyl)-6-(Ν-((1-)-yl-1,3-dihydroindol [c][i,2] oxaborole · 3-yl)methyl)methylsulfonylamino)-N-mercaptobenzopyran-3- Amides (42 mg, 0.07 mmol, 9% yield). NMR (methanol_d4) δ: 7.94-7.87 (m, 2H), 7.70-7.61 (m, 2H), 7.4-7.09 (m, 4H), 5.40-5.29 (m, 1H), 4.48-3.70 (m, 2H), 3.18-2.93 (m, 6H), 2.44-2.30 (m, 1H), 1.15-0.96 (m, 3H), 0.80-0.72 • (m, 1H). LCMS (m/z, ES+) = 549.1 (M+H) </RTI> <RTI ID=0.0></RTI> </RTI> 5- <RTIgt; 5- </RTI> <RTIgt; Dihydrobenzo[c][l,2]oxaborol-5-yl)methyl)methylsulfonylamino)-N-methyl benzofuran-3-carboxamide

154007.doc -225 - 201221131 Step 1: 4-Methyl-2-(trifluoromethyl)aniline 4-mercapto-1-nitro-2-(trifluoro) at 25 ° C under 0.3 MPa of hydrogen A

Benzene (6.0 g, 29 mmol, Alfa), 10% Pd/C (0.6 g), and EtOAc (1 N aqueous solution &lt;RTIgt; The reaction mixture was filtered and evaporated under reduced pressure toielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel . Step 2: 2-Bromo-4-methyl-6-(trifluoromethyl)aniline to 4-mercapto-2-(trimethylhydrazinyl)aniline in several portions at 15 ° C under nitrogen atmosphere ( NBS (5.87 g '33 mmol) was added to a solution of 5 _2 g, 30 mmol) in EtOAc (50 mL). The mixture was diluted with water (150 mL) and EtOAc (EtOAc. The combined organic layers were washed with water (2×150 mL) and Na.sub.2CO.sub.3 (10% aq. After removal of the solvent, the crude material was purified eluting elut elut elut elut eluting eluting eluting eluting eluting eluting Yield). Step 3: 2-Amino-5-methyl-3-(trifluoromethyl)benzoic acid methyl vinegar was heated at 80 ° C under 2.0 MPa - carbon oxide to heat 2-bromo-4-methyl-6- ( Trimethyl sulfhydryl) aniline (5.27 g, 21 mmol), Pd(OAc) 2 (0.94 g, 4.2 mmol), dppf (3.49 g, 6.3 mmol) and Et3N (2.23 g, 22 mmol) in DMSO (120 mL) And a solution in MeOH (80 mL) for 16 h. The reaction mixture was cooled to room temperature and dried overnight. The filtrate was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. After the solvent was removed, the crude product was purified by column chromatography to yield 2-amino-5-methyl_3_(trifluoromethyl)benzoic acid methyl acetonate as white 154007.doc •226· 201221131 color solid. (4 35 g, 18·7 mmol, 90% yield). Step 4: 2-bromo-5-methyl-3-(trifluoromethyl)benzoic acid methyl acetonate at 0 C for 1 〇 to 2_amino-5-methyl-3•(trifluoromethyl)benzene HBr (47% in water, 231 mL) was added dropwise to a solution of EtOAc (4.35 g, 18.7 <RTIgt; </RTI> <RTIgt; Next, water (5 mL) containing NaN02 (1.42 g, 2 〇·6 mm〇i) was added dropwise at 〇 &lt;t for 1 hour. • After the addition, the solution was stirred at 〇 ° C for 5 minutes, and then CuBr (3 - 12 g, 21.5 mmol) was added in several portions over 30 minutes. The mixture was heated at 70 ° C for 1 hour. After cooling to 〇eC, water (40 mL) was evaporated. The combined organic layers were washed with cold water (1 mL) and dried over anhydrous Na? After removal of the solvent, the~~~~~~~~~~~~~~~~~~~~~~~~~ %Yield). Step 5: 2-Bromo-5-(bromomethyl)-3-(trifluoromethyl)benzoic acid methyl ketone • Heating 2-bromo-5-methyl-1,3-(trifluoromethyl)benzene under reflux A solution of methyl decanoate (1_94 g, 6.53 mmol), benzamidine peroxide (8 mg, 〇〇3 mm〇1) and bromobutanimide (1.28 g' 7.18 mmol) in 25 mL CC14 hour. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc Step 6: 2-Bromo-6-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(indolyl)methyl)benzofuran-6-yl)methyl Sulfonamide)methyl)-3-(trifluoromethyl)benzoic acid methyl vinegar 154007.doc •227· 201221131 Under the nitrogen to give 5-cyclopropyl-2-(4-fluoro) Phenyl)-N-methyl-6-(methylsulfonylamino)benzofuran-3-carboxamide (5 mg, j 24 mmol), 2·bromo-5-(bromomethyl)_3_( A solution of methyl trifluoromethyl)benzoate (932 mg, 2.24 mmol), KI (10 mg, 0.06 mmol), and K2CO3 (513 mg, 3.72 mmol) in anhydrous DMF (15 mL) The reaction mixture was diluted with water (45 mL)EtOAc. The combined organic layers were washed with water (50 mL) and brine (50 mL) and then dried over anhydrous Na? After the solvent was removed, the crude product was purified by column chromatography to yield 2-di-6-((N-(5-cyclopropyl-2-(4- phenyl)) Amine oxime base) benzopyrano-6-yl)methyl schistosamine)methyl)_3_(tris-methyl)benzoic acid methyl vinegar (520 mg, 0.75 mmol, 60% yield) . Step 7. 6-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminemethanyl)-car oxime-6-yl)methylsulfonamide ))methyl)_2_(4,45,5-tetramethyl·ΐ3,2_monoboroin-2-yl)-3-(trifluoromethyl)benzoic acid formazan 2-bromo-6-( (N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminoindolyl)benzofuran-6-yl)nonylsulfonylamino)indolyl)_3_( Methyl trifluoromethyl)benzoate (450 mg, 0.64 mmol), bis(pinacolyl)diboron (325 mg, 1.28 mm〇l), potassium acetate (188 mg, mm〇1) and pdcl2 (dppf) The solution of CH2C12 (69 mg, 0.06 mmol) in dioxane (25 mL) was degassed and refilled with nitrogen three times and then heated overnight at 10 〇t. After cooling to room temperature the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with reverse phase HPL C to give 6-((-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine)methyl) benzofuran -6 as a white solid. _ base) methylsulfonylamino)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)_3_ (three gas 154007. Doc-228 - 201221131 decyl benzoate (15 mg, 0.02 mmol, 3% yield). Step 8: 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N_((1-hydroxy-7-(3-methyl)-1,3-dihydrobenzo[c][l , 2] oxaborole _5-yl)methyl)methyl-branched amino-methyl benzo---------------------------------------------------- (5-cyclopropyl-2-(4-fluorophenyl)_3·(decylamine decyl)benzofuran-6-yl) fluorenyl hydrazide-yl) fluorenyl)_2_(4,4, 5,5-Tetramethyl-1,3,2-dioxaborin-2-yl)-3-(trifluoromethyl)benzoate (15 mg, • 〇.02 mmol) in THF ( The solution in 5 mL) was added dropwise to THF, 0.03 mL '0.06 mmol). After the addition, the reaction mixture was allowed to stand at room temperature for 1 hour. The mixture was poured into ice water (5 mL) andEtOAcEtOAc The combined organic layers were washed with brine (1 mL) and dried over anhydrous Na. After removal of the solvent, the residue was purified by preparative HPLC to afford 5- <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Fluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaboranium-5-yl)indenyl)methylammonium)-mercaptobenzophenone. South _3_ formazan (5 mg, 〇.008 mmo1, 40% yield). 1h NMR (methanol-d4) δ: 7.85-7.80 (m, 2H), 7.52-7.47 (d, 2H), 7.27-7.15 (m, 4H), 5.74-5.72 (d, 1H), 5.06-5.03 (m , 4H), 3.05-2.97 (m, 6H), 2.22-2.13 (m, 1H), 1.06-1.03 (m, 1H), 0.90-0.85 (m, 2H), 0.53-0.51 (m, 1H). LCMS (speaking / z, ES+) = 617.2 (M+H). Examples 58 and 59 5-Cyclopropyl-2-(4-fluorophenyl)-6-[{2-[(3S)-l.hydroxy-1,3-dihydro-2,1-benzoxylene Boronheap-3-yl]ethyl}(methylsulfonyl)amino]_N_methylbenzofuran-3-carboxamide and 5-cyclopropyl-2-(4-fluorophenyl) )·6-[{2-丨(3R)- 154007.doc •229- 201221131 1-hydroxy-1,3·dihydro-2,1-benzoxoxaborole_3_yl] B (methanesulfonyl)amino]-indole-methyl-1·benzofuran_3_formamide

Supercritical c〇2 column chromatography with a palm-shaped stationary phase (1%

MeOH (10o/〇CHC13)/C02 '140 bar '40°C, 2 ml/min 〇j_H) Analyze racemic 5-cyclopropyl·2-(4-fluorophenyl)_6·[{2-1 -hydroxy-i,3-dihydro-2,1-benzoxoxaborole_3_yl]ethyl hydrazine (methylsulfonyl)amino]-methyl-1-benzofuran _ 3_carbamamine. Absolute configuration based on VC:D spectroscopy, rational energy level: ONIOM method, b3pw 91/6-311+g (2df) applied to S〇2 ' and B3LYP/6-3 11 G (d, p) application In the rest of the molecule. Enantiomer No. 1 (3iS): iH NMR (sterol·&amp;) δ: 7 84 7 92 (m, 3H), 7.68 (d, J = 16.8 Hz, 1H), 7.58 (d, J= 7.2 Hz, 1H), 7.34- 7.41 (m, 1H), 7.15-7.31 (m, 4H), 7.13 (s, 1H), 5.19-5.31 (m, 1H), 3.73-4.09 (m, 2H), 3.09 (d, J = 9.2 Hz, 3H), 2.91 (s, 3H), 2.18-2.48 (m5 2H), 1.56-1.81 (m, 1H), 0.80-1.09 (m, 3H), 0.48-0.70 (m, 1H) ° LCMS (m/z, ES+) = 563 (M+H) 2 (yield): H NMR (methanol ss: 8 42 (d, J 4.5 Hz, 1H), 7.83 -7.93 (m, 3H), 7.68 (d, J=16.6 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.33-7.41 (m&gt; ih), 7.15-7.31 (m, 4H), 7.13 (s, 1H), 5.18-5.32 (m, 1H), 3.85-4.08 (m, 2H), 154007.doc 201221131 3.09 (d, J=9.4 Hz, 3H), 2.85-2.94 (m, 3H), 2.18-2.48 (m, 2H), 1.56-1.81 (m, 1H), 0.85-1.07 (m, 3H), 0.49-0.69 (m, 1H). 563 (M+H). LCMS (m/2, ES+ ) = 563 (Μ + H). Example 60 5-Cyclopropyl-2-(4-fluorophenyl)-6-indole ({1-hydroxy-7-[(trifluoromethyl)oxy]-1 ,3-dihydro-2,1-benzooxaborole-5-yl}methyl)(methylsulfonyl)amino]-N-methyl-1-benzo[n] _ 3_Metamine

Step 1: {4-Methyl-2-[(trifluoromethyl)oxy]phenyl}amine 4·/odor-2_[(di IImethyl)oxy]phenylamine (20.0 g, 78 mmol), A mixture of PdCl2(dppf)-CH2Cl2 adduct (3.19 g, 3.91 mmol) and trimethylboroxane (24.5 g, 195 mmol) in 1,4-dioxane (300 mL) The gas' was then heated to an internal temperature of 8 ° C for 1 hour. The reaction mixture was cooled to room temperature, filtered over a pad of Celite and concentrated. Purification by gelatin chromatography (containing 0 to 1% 0% of methane in hexanes) afforded (4-methyl-2-[(trifluoromethyl)oxy]phenyl}amine as a colorless oil. 13 % §, 89%). H NMR (gas _d) δ: 6 96 (s, 1H), 6 9 〇 (d, J = 8 Hz, 1H), 6.72 (d, J = 8.l Hz, 1H), 3.79 (br .s., 2H), 2.26 (s, 3H). ' Step 2: {2-Molyl-4-methyl·6·[ΡΙmethyl)oxy]phenyl}amine to cool {4_methyl[(trifluoromethyl)oxy]phenyl}amine (12.20 g,63.8 154007.doc •231 · 201221131 mmol) in acetonitrile (100 mL) to 〇°c. NBS (11.93 g, 67.0 mmol) was added to the bath over several minutes over several minutes. After 30 minutes, the reaction mixture was diluted with water and ethyl acetate and then stirred for 1 hour. After further dilution with water and ethyl acetate, the layers were separated. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (1×) and brine (1×) then dried over sodium sulfate. Fluoromethyl)oxy]phenyl}amine oxime 7 32 g, 100% yield). NMR (gas-d) δ: 7.19 (s, 1H), 6.94 (s, 1 Η), 2.25 (s, 3 Η). Step 3: 2-Amino-5-methyl-3-[(trifluoromethyl)oxy]benzoic acid methyl acetonate with {2-bromo-4-indolyl-6-[(trifluoromethyl) with carbon monoxide )oxy]phenyl}amine (17.32 g, 64.1 mmol), dppf (3.20 g, 5.77 mmol), triethylamine (11.2 mL, 80 mmol) and palladium acetate (〇·86 g, 3.85 mmol) at 1: 1 The mixture in methanol/DMSO (120 mL) was pressurized to 60 psig and heated in a 8 〇〇c bath for 22 hours. Additional carbon monoxide was added as the pressure dropped over the first 6 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was washed with brine (2 Torr) then dried over sodium sulfate and concentrated. Purification by the use of zea gel chromatography (containing hydrazine to 30% acetic acid to purify) to produce 2-amino-5-mercapto-3-[(trifluoromethyl)oxyl as a yellow oil Methyl benzoate (11.98 g, 75%). NMR (chloroform-d) δ: 7.63 (d, J=ll Hz, 1H), 7.13 (s, 1H), 5.40-6.09 (m, 2H), 3.89 (s, 3H), 2.26 (s, 3H). LCMS (w/z, ES+) = 250 (M+H). Step 4: 2-Bromo-5-methyl-3-[(trifluoromethyl)oxy]benzoic acid in acetonitrile to cool 2-amino-5-methyl-3-[(trifluoromethyl)oxy a solution of methyl benzoate (丨3.1 154007.doc -232· 201221131 g, 52.6 mmol) in acetonitrile (200 mL) to _5 〇C over a period of 3 hrs with concentrated aqueous HBr (65 mL, 47%) deal with. A solution of sodium nitrite (4·53 g' 65.7 mmol) in 20 mL of water was added dropwise over 30 minutes maintaining the temperature below 0 °C. Copper bromide (9.80 g, 68_3 mmol) was added to this solution over several minutes in several portions. After another 15 minutes, the reaction mixture was allowed to warm to room temperature and then slowly heated to 75. The internal temperature of the crucible lasts for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water (1 mL) and brine (1x) Purification by chromatography on silica gel (containing hydrazine to 2 〇. / ethyl acetate) gave 2-bromo-5-methyl-3-[(trifluoromethyl)oxyl as a yellow oil. Base] decyl benzoate (9.79 g, 60%). An impure fraction containing slightly higher Rf impurities provides another 4.82 g (29%, purity 80 Å/〇) product. iH NMR (chloroform-d) δ: 7.48 (s, 1H), 7.25 (br.s., 1H), 3.95 (s, 1H), 2.38 (s, 3H). ' Step 5. 2-Mo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)_3_[(methylamino)carboxyl]yl]-1-benzofuran-6-yl} (Methanesulfonyl)amino]methyl(trifluoromethyl)oxy]benzoic acid methyl ketone treated with NBS (3.72 g, 20.93 mmol) and alboxidized (〇21 g, 〇_87 mmol) a solution of methyl 2-bromo-5-methyl_3_[(trifluoromethyl)oxy]benzoate (5.46 g, 17.44 mmol) in 1,2-diethane (250 mL) Heat for 21 hours. The reaction mixture was cooled to room temperature and diluted with methane, then washed with water (2×). The organic layer was washed with brine (1 mL) dried over sodium sulfate and concentrated to yield &lt;RTI ID=0.0&gt;&gt; ) oxy] benzoic acid hydrazine 154007.doc -233 - 201221131 vinegar (according to LC/MS). Heating 5-cyclopropyl-2-(4-fluorophenylmethyl_6·[(methylsulfonyl)amino]-1-benzopyrano-3' decylamine (ο?〗 g, ο % mmol), methyl 2-bromo-5-(bromomethyl)-3-[(trifluoromethyl)oxy]benzoate (3.3 g or more crude product, 1.86 mmol) and potassium carbonate (〇52 g, 3 73 mmol) of the mixture in acetonitrile (25 mL) to 60 ° 〇, for 15 hours, then increase the temperature to 70 ° C for 2-5 hours. Cool the reaction mixture to room temperature, pour into water and use ethyl acetate (2x) extraction. The combined organic layers were washed with brine (1 EtOAc) then dried over sodium sulfate and concentrated, and purified by silica gel chromatography (0 to 100% ethyl acetate) to give an orange oil. 2 indifferent _ ® {[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-indole_benzofuran_6_yl} (A) Methylamino] decyl}-3-[(trifluoromethyl)oxy]benzoic acid methyl ester (O.SOg'STo/Oo'HNMMDMSO-dMiqm'lH),?, 7.98 (m, 2H), 7.82 -7.89 (m, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.33-7.45 (m, 2H), 6.88-6.95 (m, 1H), 5.01- 5.13 (m , 1H), 4.76-4.88 (m, 1H), 3.78-3.89 (m, 3H), 3.22- 3.30 (m, 3H), 2.73-2.87 (m, 3H), 2.08-2.25 (m, 1H), 0.71- φ 100 (m, 2H), 0.49-0.66 (m, 1H), 0.02-0.23 (m, 1H) LCMS (m/z, ES+) = 713 (M+H). Step 6·· 6-[({4-bromo-3-(hydroxymethyl)-5-[(trifluoromethyl)oxy) (phenyl)fyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzo- ak °4-s- ψ Mm cooling 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino))]-1-benzoindole in an ice bath 6-yl}(anthracenyl)amino]methyl}_3-[(trifluoromethyl)oxy]benzoic acid methyl ester (0.50 g, 0.70 mmol) in tetrahydrofuran (10 154007.doc •234-

A solution of S 201221131 mL) and decyl alcohol (1 mL) was treated with lithium borohydride (〇88 i75 mmol, 2.0 Μ in THF). After 3 minutes, the reaction was allowed to warm to rt and stirred for additional 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate Purification by gelatin chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[({4-bromo-3-(hydroxyindole).5-[(trifluoro) as a yellow solid. Mercapto)oxy]phenyl}methyl)(methyl#sulfonyl)amino]_5·cyclopropyl·2·(4-fluorophenyl)-#-fluorenyl·ι_benzofuran·3 - guanamine (0.34 g, 71%). NMR (DMSO-d6) δ: 8.41 (m, 1H), 7.89-7.99 (m, 2H), 7.83-7.89 (m, 1H), 7.51 (m, 1H), 7.34-7.44 (m, 2H), 7.27 (s,1H), 6.92 (s,1H), 5.62 (t, J=5.5

Hz, 1H), 5.02 (d, J=14.6 Hz, 1H), 4.84 (d, J=14.6 Hz, 1H), 4.42-4.55 (m, 2H), 3.18-3.28 (m, 3H), 2.75-2.89 (m, 3H), 2.14-2.29 (m, 1H), 0.50-1.01 (m, 3H), 0.08-0.28 (m, 1H)-LCMS (m/z, ES + ) = 685 (M+H). ® Step 7: 6-[({4-Bromo-3-({[(methyloxy)methyl)oxy)indolyl)_5_[(trifluoromethyl)oxy]phenyl}methyl) (Methanesulfonyl)amino]_5_cyclopropyl-2-(4-fluorophenyl)-N-indenyl-1- benzoate and decylamine with DIEA (0.26 mL, 1.49 mmol) and chlorine Treatment of 6_[({4_bromo-3-(hydroxymethyl))-5-[(trifluoromethyl)oxy]phenyl}indolyl) with m-methyl ether (0.11 mL ' 1.49 mmol) Amino]_5_cyclopropyl-2-(4-fluorophenyl)-iV-methyl-1-benzofuran_3-formamide (0 34 g, 0.50 mmol) in THF (10 mL) The solution 'was then heated in a 5 °c bath for 22 hours. The reaction was cooled to room temperature and diluted with water then extracted with ethyl acetate (2×). 154007.doc • 235-201221131 The organic layer was washed with brine, dried over sodium sulfate and evaporated. Purification by gelatin chromatography (containing 0 to 100% ethyl acetate in hexane) afforded 6·[({4-bromo-3-({[(methyloxy))]] Oxy}indenyl)5 [(trifluoromethyl)oxy]phenyl}methyl)(methanesulfonyl)aminocyclopropyl_2_(4-fluorophenyl)-JV-mercapto-1- Benzofuran _3_ guanamine (〇3〇g, 83%).咕NMR (DMSO-d6) δ: 8.34-8.45 (m, 1H), 7.88-7.97 (m, 2H), 7.81-7.87 (m, 1H), 7.31-7.45 (m, 4H), 6.87-6.94 (m ,1H), 5.01 (d, J=14.4 Hz, 1H), 4.84 (d, J=14.5 Hz, 1H), 4.59-4.66 (m, 2H), 4.53 (s, 2H), 3.14-3.28 (m, 6H), 2.72-2.88 (m, 3H), 2.10-2.27 (m, 1H), 0.53-0.98 (m, 3H), 0.08-0.27 (m5 1H). LCMS (m/z, ES+) = 729 (M+H). Step 8: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[({l-hydroxy-7-[(trifluoromethyl)oxydihydro-2,1-benzoxylene Benzene heterocyclic pentyl)methyl)(methine)amino]-~Ν-methyl-1-benzox-missing methotrexate in thick-walled glass pressure vessels 6-[({4 -Bromo-3-({[(methyloxy)methyl)oxy)methyl)-5-[(trifluoromethyl)oxy]phenyl}indolyl)(sulfonyl)amino ]-5-cyclopropyl-2-(4-fluorophenylindenyl-1-benzofuran_3_decylamine (0.28 g, 0.38 mmol), potassium acetate (75 mg, 0.77 mmol), double ( Pinacol-based) shed (146 mg, 0.58 mmol), sodium bromide (39 mg, 0.38 mmol) and dichlorobis(tricyclohexylphosphine)palladium(II) (28 mg, 〇〇38 mmol) in 1 The mixture in 4-dioxane (1 mL) was degassed and then heated under stirring at 95 C for 20 hours. The reaction mixture was cooled to room temperature, filtered over Celite pad and concentrated. Chromatography (purification of hydrazine to 1% by weight of ethyl acetate) - yielding 5-cyclopropyl·2-(4-fluorobenzene 154007.doc •236· 201221131 base)-N in the form of a yellow oil -methyl·6·[({3-({[(methyloxy)methyl)] (Methyl)-4_(4,4,5,5-tetradecyl-1,3,2-dioxan-2-yl)-5-[(trifluoromethyl)oxy] }methyl)(methylsulfonyl)amino]-1-benzobenzoin-3. formamidine (0.29 g 'purity 71% (according to LC/MS)). Dissolve this oil in thf ( 15 mL) and treated with 1 n HCl (5 mL) and then heated under reflux. After 16 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x). (2χ) and brine (ix) washing, followed by drying over sodium sulfate and concentration. Chromatography by chromatography (containing hydrazine to 1% by weight of ethyl acetate in dichloromethane followed by 0 to 3.5% methanol) Purification of methane) followed by a second purification by reverse phase HPLC followed by lyophilization to give 5-cyclopropyl-2-(4-fluorophenylhydroxy-7-[(trifluorofluorene) as a white solid. Alkyloxy-1,3-dihydro-2,1-benzooxaborole-5-yl}methyl)(methylsulfonyl)amino]mercapto-1-benzo Furan_3_carbamamine (41.4 mg '17% (after 2 steps)). 4 NMR (sterol_d4) δ: 7.80-7.91 (m, 2H)S 7.57 (s, 1H), 7.14-7.26 ( m, 3H), 7.08 (m, 1H), 6.98 (s, 1H), 4.81-5.05 (m, 4H), 3.13 (s, 3H), 2.88 (s, 3H), 2.16 (m, 1H), 0.84-1.04 (m, 1H) ), 0.59-0.84 (m, 2H), 0.17-0.37 (m, 1H). LCMS (w/z, ES+) = 633 (M+H). Example 61 6-(N-(2-(7-Chloro-1-hydroxy-1,3-dihydrobenzinooxaborole-3-yl)ethyl)methylsulfonylamino) -5-cyclopropyl_2_(4-fluorophenyl)-indole·methylbenzofuran-3-carboxamide 154007.doc -237· 201221131

Step 1: l-(2-H-phenylphenyl)propan-2-phenan-1-ol to 2-bromo-3-gasbenzaldehyde (3 g, 137 mmol, Ouhe) at -50 ° C under nitrogen atmosphere The solution was dissolved in anhydrous THF (100 mL) (methanol) (15 mL, 1 M) and the mixture was stirred at room temperature for 2 hr. The reaction was quenched with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. . After removal of the solvent, it gave 1-(2-bromo-3-phenylphenyl)propane-, ene-indole alcohol as a colorless oil (3.5 g. Step 2: (1-(2-Bromo-3-phenylphenyl)allyloxy)(t-butyl)dimethyl group at 1 °C under nitrogen atmosphere to 1-(2-bromo-3-chloro To a solution of phenyl)propene oxime-ol (3_5 g' 14.17 mmol) and imidazole (2.41 g, 35.43 mmol) in anhydrous DMF (20 mL) was added DMF containing TBSC1 (3.2 g, 21.25 mmc &gt; 1) l〇mL). Then, the reaction solution was stirred at room temperature for 3 minutes. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc (aq. sat.) and brine (aq. After the solvent was removed, the crude product was purified by column chromatography to yield (1_(2-bromo-3-phenylphenyl) allyloxy) (t-butyl) decyl decane as a colorless oil. 4 g, 11.05 mmo b 78%). 154007.doc -238- 201221131 Step 3: 3-(2-Bromo-3-phenylphenyl)-3-(t-butyldimethylmethylalkyloxy)propan-1-ol at room temperature under nitrogen Stir (1-(2-bromo-3-phenylphenyl)allyloxy) (t-butyl) dimethyl decane (4 gU 〇 5 mmol) and 9-BBN dimer (2.97 g') under an atmosphere 12.15 mmol) in anhydrous THF (80 mL) for 4 h. Next, Na〇H (3 N aqueous solution, 40 mL) was added at 〇 ° C, followed by hydrogen peroxide (30%, 40 mL). The reaction was stirred at room temperature for 1.5 hrs and extracted with EtOAc (3×5 EtOAc). The combined organic layers were washed with water and brine (aq) and dried over anhydrous Na? After the removal of the solvent, the crude product was purified by column chromatography to give 3-(2-bromo-3-phenylphenyl)-3-(t-butyl-di-decyl-decyl-alkyloxypropane) as a colorless oil. "·Alcohol (33 g, 8.73 mmol, 79%) ° Step 4. (3-Bromo-1-(2-bromo-3-phenylphenyl)propoxy)(t-butyl)dimethyl sulphur Burning at 〇 ° C under nitrogen atmosphere to 3·(2_bromo-3-phenylphenyl)-3-(t-butyl fluorenylmethyl oxanyloxy)propan-1-ol (3.3 g, 8.73 mmol) and Ph3P (4.57 g, 17.46 mm〇l) were added NBS (3,26 g, 18.333 mmol) in anhydrous DC:M (5 mL) and stirred at room temperature bj The reaction mixture was quenched with water (40 mL). EtOAc was evaporated. (2-Di-3-chlorophenyl)propoxy)(t-butyl)-methyl-stone (3.3 g, 7.62 mmol, 87%). Step 5: 6-(N-(3-( 2-Bromo-3-chlorophenyl)-3-(t-butyldidecylmercaptooxy)propyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluoro Phenyl 154007.doc -239- 20122 1131-benzofuran-3-carboxamide was heated at 80 ° C under nitrogen atmosphere with 5-cyclopropyl-2-(4-fluorophenyl)-N-indenyl-6-(methylsulfonylamino) Benzofuran·3_formamide (1 g, 2 485 mmol), (3-bromo-1-(2-bromo-3·henylphenyl)propoxy)(t-butyl)dimethyl A solution of decane (1.39 g ' 3.23 mmol), potassium carbonate (1.03 g, 7.455 mmol) and hydrazine (0. 41 g, 2.485 mmol) in anhydrous DMF (15 mL). After the filtration, the residue was dissolved in EtOAc EtOAc (EtOAc)EtOAc. (2-bromo-3-phenylphenyl)-3-(t-butyldimethylmethylalkyloxy)propyl)decylsulfonylamino)-5-cyclopropyl-2-(4-fluoro Phenyl)-N-methylbenzofuran-3-indoleamine (1.4 g ' 1.83 mmol, 73%). Step 6: 6-(N-(3-(2-bromo-3-chlorophenyl)) 3-hydroxypropyl)methylsulfonylamino 5-cyclopropyl-2-(4-fluorophenylmethylbenzofuran-3·decylamine 6-(; under nitrogen atmosphere at 40C; Ν-(3·(2-Bromo-3-phenylphenyl)-3-( Dibutyl dimethyl fluorenyloxy) propyl) decyl sulfonylamino) _5_cyclopropyl·2-(4-phenylphenyl)-#-methylbenzoindole „南_3 A solution of carbamazepine (13 g, 17 mmol) and HCl (5 N in water, 12.5 mL) in anhydrous THF (30 mL) The reaction solution was cooled to room temperature and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and dried over anhydrous Na2 EtOAc. After removal of the solvent, the residue was purified by column chromatography to give 6-((3-(2-bromo-3-phenylphenyl)-3-hydroxypropyl)methylsulfonium as a brown solid. Amino)_5_cyclopropyl-2-(4-fluorophenyl)-indole-mercaptobenzofuran_3_decylamine (〇85 g, 131 mmol, 77%). 154007.doc 201221131 Step 7: 6-(N-(2-(7-Gaxo-1-hydroxy-1,3-dihydrobenzo[c][l,2]oxazacyclohexene-3- Ethyl)ethylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide at 98 ° C in a nitrogen atmosphere Heating under 6-(iV-(3-(2-bromo-3-phenyl)-3-hydroxypropyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl) Benzo-indolizine-3-decylamine (0.85 g, 1_31 mmol), bis(pinacolyl)diboron (0.665 g, 2.62 mmol), acetic acid unloading (385 mg, 3.93 mmol) and PdCl2 ( A solution of the dppf)-CH2Cl2 adduct (151 mg, 0.131 mmol) in hexanes (25 mL). The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and residue Purification by HPLC to give 6-(iV-(2-(7-a)-1-hydroxy-1,3-dihydrobenzo[cHl,2]oxacyclopentene-3- as a white solid Ethyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-iV-methylbenzofuran-3-carboxamide (55 mg, 0.092 mmol, 7 %). NMR (300 MHz, methanol-d4) δ: 7.94-7.89 (m, 2 Η), 7.72-7.69 (d, 1 Η), 7.37 -7.11 (m, 6 Η), 5.33-5.30 (m, 1 Η), 3-97-3.92 (m, 2 Η), 3.13-3.11 (d, 3 Η), 2.94 (s, 3 Η), 2.49 -2.22 (m? 2 Η), 1.89-1.76 (m, 1 Η), 1.08-1.01 (m, 3 Η), 0.91-0.69 (m, 1 H). LCMS(m/z, ES+)=597.1 ( M+H). Example 62 5-Cyclopropyl-6-[[(7-fluoro-1-hydroxy·ι,3-dihydro-2,1-benzoxoxaborole-5-yl) )methyl](methylsulfonyl)amino]_2-(4-fluorophenyl)-1_benzofuran-3-cartoamine 154007.doc -241 - 201221131

Step 1: 5-{[[3-(Aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-6-yl](methylsulfonyl) Amino]methyl}-2·bromo-3-fluorobenzoic acid vinegar vinegar heated 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1- Benzofuran-3-indolamine (1.561 g, 4.02 mmol) '2-Bromo-5-(bromoindolyl)-3-fluorobenzoate decyl ester (1.31 g, 4.02 mmol), K2CO3 (0.666 g, 4.82 Methyl) and a mixture of Nal (0.060 g, 0.402 mmol) in EtOAc (EtOAc) (EtOAc) Purified by column chromatography to give 5-{[[3-(amino)-5-cyclopropyl-2-(4-1phenyl)-1-benzene as a pale yellow oil. And furan-6-yl](nonylsulfonyl)amino]mercapto}_2-bromo-3-fluorobenzoic acid methyl ester (2.43 g ' 3.84 mmol, 95% yield). NMR (400 MHz, gas-like d) δ: 7.87-7.94 (m, 2 H), 7.46 (s, 1 H), 7.36 (s, 1 Η), 7.30 (s, 1 Η), 7.16-7.25 (m , 3 Η), 5.74 (br. s., 2 H), 4.96 (d, 1 H), 4.77 (d, 1 H), 3.90 (s, 3 H), 3.06 (s, 3 H), 2.16 ( s, 1 H), 1.01-1.12 (m, 1 H), 0.88-1.01 (m, 2 H), 0.52-0.63 (m, 1 H). Step 2: 6-[{[4-Bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- Fluorophenyl)-1-benzofuran-3-carboxamide to 5-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)- at room temperature 1-benzopyran-6-yl](methylsulfonyl)amino]methyl b-2-bromo-3-benzoic acid A 154007.doc

• 242-S 201221131 Ester (2_4 g, 3.79 mmol) in THF (12 mL) and methanol (2 mL). After the addition, the solution was stirred at room temperature until all starting materials were completely consumed. The solution was quenched with EtOAc (EtOAc)EtOAc. Fluoro-5-(hydroxymethyl)phenyl]indolyl κmethanesulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)_ι_benzofuran_3_decylamine • (1.66g'2.74mmOb 72.4% yield) βlHNMR (400 MHz, gas-c〇δ: 7.91 (dd, */-8.8, 5.3 Hz, 2 H), 7.36 (s, 1 H), 7.31 (s, 1 H), 7.16-7.24 (m, 3 Η), 7.05 (dd, "7=8.6, 1.4 Hz, 1 Η) 5.69 (br. s., 2 H), 4.93-5.02 (m, 1 H), 4.75 (d, 7=14.4 Hz 1 H), 4.71 (s, 2 H), 3.05 (s, 3 H), 2.13-2.24 (m, 1 H), 1.03- 1.13 (m, 1 H) , 0.87-1.03 (m, 2 H), 0.59 (d, 7 = 5.7 Hz, 1 H). Step 3: 6-[{[4-bromo-3-fluoro-5-({[(decyloxy)) ) 罗 ] 氧基 氧基 氧基 氧基 氧基 氧基 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3-decylamine to 6-[{[4-bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2- (4-fluorophenyl)-indole benzofuran_3_formamide (165, 2.73 mmol) in THF Add Henrigger's base (Himigs, base) (0.570 mL, 3.27 mm 〇1) to the solution in (10 mL) and DMF (1 mL) followed by gas methyl methyl ether (0.248 mL) at room temperature , 3.27 mmol) of the solution. After the addition, the solution was heated to (10) with stirring overnight. The solution was washed with water, extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography to give 6-[{[4-bromo-3-fluoro_5_({[(methyloxy)methyl)oxy)methyl)phenyl)] phenyl]} Indolesulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzoindole-3-indoleamine (139 g, 2.140 mmol, 79% yield). Step 4: 5-Cyclopropyl-6-[{[3-fluoro-5-({[(methyloxy)methyl)oxy)methyl)-4-(4,4,5,5- Tetramethyldiboron-2-yl)phenyl]methyl]methyl benzyl)amino]-2-(4-fluorophenyl)-1-benzopyrene-3-indolyl Downward to 6-[{[4-bromo-3-fluoro-5-({[(fluorenyloxy)methyl)oxy)indolyl)phenyl]methyl}(methylsulfonyl)amine ]-5-cyclopropyl-2-(4-fluorophenyl)_ι_ Bentofufu-3-carboxamide (1.35 g, 2.079 Ment), 4,4,4,,4,,5,5,5,5-octamethyl-2,2'-linked-1,3,2-dioxy odor (1.056 g, 4.16 mmol) and To a mixture of EtOAc (0.62 g, 6.24 mmol), EtOAc (EtOAc) was obtained. The mixture was heated at 80 &lt;0&gt;C overnight. The mixture was filtered over EtOAc EtOAc. The filtrate was purified by column chromatography to give 5-cyclopropyl-6-[{[3-fluoro-5-({[(fluorenyloxy)methyl)oxy)] yl) as a colorless oil. ) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]fluorenyl}(sulfonyl)amino]_ 2-( 4_Denbenji)-1_Benzobenzoate_3_carbamamine (〇·9 g, 1.292 mmol, 62.2% yield). LC-MS (m/z, ES+) = 671 (M+H). Step 5: 5-cyclopropyl-6-[[(7-fluoro-1-hydroxy-1,3-dihydro-2,1-benzoxepoxy-5-yl)methyl]( Hydrazinyl)amino]-2-(4-fluorophenyl)-1-benzofuran-I decylamine heated 5-cyclopropyl·6-[{[3-fluoro-5-({[ (methyloxy)methyl]oxy}methyl)-4-(4,4,5,5·tetramethyl-l,3,2-dioxaborin-2-yl)phenyl]- (a 201221131 sulfonyl)amino]-2-(4-fluorophenyl)-1-benzofuran-3-decylamine (0.9 g, 1.292 mmol) and 6 N HCl (2 mL, 1.292) A solution of mmol in THF (8 mL) to 60 ° C for 4 h. The solution was extracted with EtOAc and EtOAc (EtOAc m.) 2,1-benzoxene shed heterocyclopentene_5_yl)methyl](methyl aryl)amino]-2-(4-fluorophenyl)-1·benzopyran_3_曱Guanidine (0.250 g, 0.453 mmol, 35.0% yield). 4 NMR (400 MHz, OMSO-d6) δ: 9.26 (br. s., 1 H), 7.91-8.04 (m, 3 H), 7.79-7.90 (m, 1 H), 7.70 (br. s., 1 H), 7.38 (t, J=8.5 Hz, 2 H), 7.18 (br. s., 1 H), 6.96 (br. s., 2 H), 5.02 (d, "7=14.6 Hz, 1 H), 4.93 (br. s., 2 H), 4.85 (d, /=14.6 Hz, 1 H), 3.24 (br. s.,3 H), 2.29 (br. s·,1 H), 0.94 (br. s.,1 H),0.80 (br. s·,2 H), 0.22 (br. s., 1 H) 0 LC-MS (m/z, ES+)=553 (M+H) ° Example 63 5-Cyclopropyl-6-(N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo(4)),]]oxazacyclopentan-3-yl)B Base) thiol amido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-decylamine

Step 1: 1-(2-Bromo-3-fluorophenyl)prop-2-en-1-ol to 2-bromo-3-fluorobenzaldehyde (5 g, 24 at -50 ° C under nitrogen atmosphere 63 154007.doc -245· 201221131 mmol, Ouhe) A solution of (vinyl)magnesium bromide (27 mL, 1 Μ) was added to a solution of anhydrous THF (120 mL) and the reaction mixture was stirred at room temperature for 2 hr. The reaction solution was quenched with EtOAc (EtOAc EtOAc (EtOAc) The combined organic layers were washed with sat. NaHC3 (aq) and brine and dried over anhydrous Naj. Removal of the solvent gave 1-(2-&gt; odor-3-dendyl)propan-2-di-l-ol (5.68 g, 24.63 mmol * 99%) as a colorless oil. Step 2: (1 (2-Bromo-3-fluorophenyl)allyloxy)(t-butyl)dimethylcarbazine at 5C under nitrogen gas to 1-(2-indol-3-fluorophenyl) Add TBSC1 (5.56 g, 36.95 mmol) of DMF (10%) to a solution of propan-2-indole-1-ol (5.68 g '24.63 mmol) and imidazole (4.188 g, 61.58 mmol) in dry DMF (20 mL) (mL) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with EtOAc (EtOAc)EtOAc. The organic solution was washed with NaHC 3 (saturated aqueous) and brine and dried over anhydrous Naj. After the solvent is removed, the residue is purified by column chromatography to yield (1-(2-bromo-3-fluorophenyl)allyloxy) (t-butyl) dimethylbenzene as a colorless oil. Evening (8 g, 23.19 mmol, 94%). Step 3: 3-(2-Bromo-3-fluorophenyl)-3-(t-butyldimethylsilyloxy)propan-1-ol will be (1-( 2-Bromo-3-fluorophenyl)allyloxy)(t-butyl)dimethyloxane (8 g, 23.19 mmol) and 9-BBN (74.2 mL, 0.5 EtOAc in THF) The solution in 160 mL) was stirred overnight. The reaction solution was quenched with NaOH (3 N aqueous solution, 120 mL) at 0 ° C, 154007.doc • 246-201221131 followed by the addition of hydrogen peroxide (30%, 8 〇ml) n reaction solution was stirred at room temperature for 4 hours. It was then extracted with Et 〇Ac (3 x 15 mL). The combined organic layers were washed with water and brine and dried over anhydrous NaCI. After the solvent was removed, the residue was purified by column chromatography to yield 3 (br.br.). Alcohol (8 g, 22 59 mmol, 97 〇/〇) Step 4: (3-Bromo-[-(2-bromo-3-fluorophenyl)propoxy)(t-butyl)dimethyl sulphate To a calcination of 3_(2-bromo-3-fluorophenyl)_3_(t-butyldifluorenyloxy)propanol (802 g, 22.59 mmol) under a nitrogen atmosphere at 〇 ° C

To a solution of <RTI ID=0.0># </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The reaction solution was quenched with water (50 mL)EtOAc. After the solvent was removed, the residue was purified by column chromatography to yield (3-bromo-1-(2-bromo-3-fluorophenyl)propoxy) (t-butyl) Methyl stagnation (7.8 g, 18.3 mmol, 80%). Step 5: 6-(Ν-(3-(2-Bromo-3.fluorophenyl)-3-(t-butyldimethylsulfonyloxy)propyl)methylsulfonylamino)- 5_Cyclopropyl·2_(4-fluorophenyl)_N_methyl benzofuranamine was heated at 80 ° C under nitrogen atmosphere with 5_cyclopropyl_2_(4-fluorophenyl)_N曱-6-(methylsulfonylamino)benzofuran-3_carbamidamine g, 2.485 mmol), (3-bromo-1-(2-bromo-3-fluorophenyl)propoxy) a solution of (t-butyl)dimethyl decane (1.6 g ' 3.73 mmol), potassium carbonate (1_03 g, 7.455 mmol) and hydrazine (0·41 g' 2.485 mmol) in anhydrous DMF (10 mL) 154007.doc -247- 201221131 hours. The reaction bath was quenched with water (50 mL). After filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na 2 SO 4 . After removal of the solvent, the residue was purified by column chromatography to yield 6-(N-(3-(2-bromo-3-fluorophenyl)-3)-(t-butyldimethyl decane) as a brown solid. Benzyloxy)propyl)methylsulfonylamino)·5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzoc-butan-3-carboxamide (1 _7 g, 2.27 mmol, 91%). Step 6-(N-(3-(2U·Fluorophenyl)_3_hydroxypropyl)decylsulfonylamino-5-cyclopropyl-2-(4-indoleylmethyl benzofuran 6-(#-(3-(2-bromo-3-fluorophenyl)-3-(t-butyldimethyl oxalate)oxypropyl)曱 醯 醯 醯 醯 ) ) ) -5 -5 -5 -5 _ _ _ _ _ _ _ _ _ _ _ _ _ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Aqueous solution (20 mL) EtOAc (EtOAc m. After removal of the solvent, the residue was purified by column chromatography to yield 6-(N-(3-(2-bromo-3-fluorophenyl)-3-hydroxypropyl)methylsulfonamide as a brown solid. _5_cyclopropyl-2-(4-fluorophenyl)_N-mercaptobenzofuran-3-decylamine (1.2 g, 1,9 mmol, 70 〇/〇). Step 7: 5- Cyclopropyl_6_(N_(2_(7_fluorosuccinate-13-dihydroindol [c][l,2]oxaborolyl)ethyl)methylsulfonylamino)_2_ (4_Denylphenyl)-~N-methylbenzoindolocarbamide at 120 ° C in a nitrogen atmosphere Heating 6-(^(3-(2-bromo-3-fluorophenylhydroxypropyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-#-曱Stupid and furan-3-decylamine (ι·2 g, 1.9 mmol), bis(pinacolyl)diboron 154007.doc •248· 201221131 (1.93 g ' 7.6 mmol), barium fluoride (200 mg , 3.44 mmol) and a solution of PdCl2(dppf)-CH2Cl2 adduct (219 mg '0.19 mmol) in dioxane (25 mL) for 1.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 5-cyclopropyl-6-(#-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][ l,2]oxaborole-3-yl)ethyl)indolylsulfonylamino)·2·(4-fluorophenyl)-#-曱basic and 0-calling Amine (45 mg, 0.077 mmol, 4%) NMR (300 MHz, chloroform-d3) δ: 7.89-7.85 (m, 2 H), 7.50-7.44 (m, 3H)S 7.22-7.17 (m, 2H) , 7.05-6.94 (m, 2H), 5.77 (s, 1H), 5.31-5.21 (m5 1H), 4.02-3.85 (m, 2H), 3.05 (s, 3H), 2.99 (d, 3H), 2.37- 2.28 (m, 2 H), 1.77-1.74 (m, 1H), 1.07-0.94 (m, 3H) 0.71 (m, 1H). LCMS (m/z, ES+) = 581.1 (M+H). Example 64 6-[[2-(6-Gas-1-hydroxy-1,3-dihydro-2,1-benzoxoxaborole-3-yl)ethyl](methylsulfonyl) Amino] 5-cyclopropyl·2-(4-fluorophenyl)-N-methyl-I-benzo[beta]--3-armamamine

Step 1: 1-(2-Bromo-4-chlorophenyl)-2-propan-1-ol was treated with 1.0 Μbromo(vinyl)magnesium (47.7 mL, 47.7 mmol) to give 2-bromo- 154007. • 249· 201221131 4-gasaldehyde (9.1 g, 41 5 mm - solution) in tetrahydrofuran (200 mL) and maintained at fyk ^ under stirring. The mixture was poured into 10% ammonium chloride (aq) and the organic layer was separated with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure &quot;LV&quot; Purification by column chromatography to give (/ chlorophenyl)-2-propen-1-ol (ΜΙ g, 37.6 mm 〇i, 9" / 0 yield) as a clear oil. NMR (DMSO-d6) δ: 7-70 (d, J=2.〇Hz, 1H) 7 45 7 , 5 · 7-55 (m, 2H), 5.80-5.96 (m, 2H), 5.32 (t , J=4.9 Hz, 1H) 5 24 rnt τ , X24 (dt, 1=17.2, 1.6 Hz, 1H), 5.10 (dt, J=l〇.3, 1.5 Hz, 1H) 〇Step 2. {[1 -(2-Oct-4-phenyl)-2-propanyl]yl]oxy}(11-diylethyl) dimethyl sulfonate with sodium saliva (2.S6 g, 37.6 〇1) And Ding 峨 1 (5 π g, 3 γ ^ surface 〇 1) treatment 1♦ desert _4_ gas phenyl) · 2 propylene propylene alcohol (93i g, W _., N, N-dimercaptomethyl hydrazine A solution in the amine 〇〇〇mL). The mixture was maintained at room temperature for 16 hours with stirring. The mixture was diluted with diethyl ether and washed with EtOAc EtOAc EtOAc (EtOAc m. Purified by column chromatography to give {[丨气^bromo_4_acetoyl)-2-propen-1-yl]oxy}(11-dimethylethyl) as a clear oil. Dimethyl decane (9 61 layers, 26.6 mmo, 70.6% yield).丨H NMR (gas simulation_sentence δ: 7 48 7 54 (m, 2H)} 7.31 (dd, J=8.4, 2.0 Hz, 1H), 5.89 (ddd, J=17.〇, 10-3, 5.0 Hz , 1H), 5.51 (d, J=5.1 Hz, 1H), 5.31-5.39 (m, 1H), 5.10 (dt, J=l〇.2, 1.5 Hz, 1H), 0.92 (s&gt; 9H)5 0.10 (s, 3H), 0.01 (s, 3H) 0 I54007.doc - 250- 201221131 Step 3: 3((2-bromo-4-chlorophenyl)-(1)-di-l-ylethyl)(dimethyl石 烷基 alkyl]oxy}-1-propanol cooled {[1-(2-bromo-4-chlorophenyl)-2-propenyl-1-yl]oxy} (11-dimethylethyl) Dimethyl decane (4.00 g, 11_〇6 mm〇i) in THF (4 〇 卩 至 solution to 0 ° C. Add 9-BBN solution (33 2 mL, 0.5 Μ in THF) over 35 minutes &lt;» The reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0 &lt;0&gt;C and treated sequentially with sodium hydroxide solution (18 4 mL, 3 EtOAc), &lt After 30 minutes, it was allowed to warm to room temperature. After a further 30 minutes, the mixture was diluted with EtOAc (EtOAc)EtOAc. Chromatography (containing hydrazine to 100% dichloro Purification of the hexanes of the alkane to give 3-(2-bromo-4-pyrimidinylethyl)(dimethyl)nonanyl]oxy}-1-propanol (4.30 g, Quantitative yield) ιΗ NMR (gas-d) δ·· 7.49-7.56 (m, 2H), 7.33 (dd, J=8.4, 2.0

Hz, 1H), 5.25 (dd, J=7.7, 3.6 Hz, 1H), 3.71-3.81 (m, 2H), 1.93-2.09 (m, 1H), 1.74-1.89 (m, 1H), 0.91 (s, 9H), 0.09 (s, 3H), -0.12 (s, 3H). LCMS 〇/z, ES+) = 379 (M+H). Step 4: {[3-Bromo-1-(2-bromo-4-phenylphenyl)propyl]oxy}(1J·dimethylethyl &amp;) dimethyl oxime 3-(2-bromo- 4-Phenylphenyl)·3-{[(ΐ,ι_dimethylethyldidecyl)decyl]oxy}-1-propanol (2.88 g' 7.58 mmol) and triphenylphosphine (2.39 g) , 9.10 mmol) of the solution in dioxane (4 mL) was cooled to dryness and treated with NBS (1_62 g, 9_10 mm 〇i). The reaction was allowed to warm to room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. Water layer 154007.doc -251 - 201221131

DCM back extraction. The combined organic layers were washed with water (1×) and brine. Purification by gelatin chromatography (100% hexane) gave {[3-bromo-1-(2-bromo-4-phenylphenyl)propyl]oxy} (1, b. Base ethyl) dimethyl Shi Xiyuan (2.46 g, 73%). 4 NMR (chloroform-d) δ·· 7.52 (d, J=2.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 5.18 ( Dd, J = 8.7, 3.1 Hz, 1H) 3.37-3.63 (m, 2H), 1.93-2.26 (m, 2H), 0.82-0.97 (m, 9H), 0.12 (s, 3H), -0.14 (s, 3H). Step 5: 6-[(3-(2-Molychlorophenyl)-3-{[(l,l-dimethylethyl)(dimethyl)decyl]oxy}propyl) (Methanesulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenylindenyl-1-benzofuran-3-carboxamide heated 5-cyclopropyl-2-(4- Fluorophenyl)-#-methyl-6-[(anthracenyl)amino]_1-benzoxofan-3-cartoamine (1.71 g, 4.25 mmol), {[3-bromo- 1-(2-&gt;Smelly-4-chlorophenyl)propyl]oxy}(1,1-dimethylethyl) dimethyl sulfoxide (2 45 g '5.52 mmol) and carbonic acid If (1.47 a mixture of g '1 〇.62 mmol) in acetonitrile (5 mL) to 75 ° C for 22 hours. DMF (10 mL) was added to this mixture and heating was continued for another 24 hours "temperature increased to 85 ° C The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2 EtOAc). The combined organic layers were washed with water (1x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by gelatin chromatography (containing hydrazine to 1 〇〇% hexane in ethyl acetate) to give 6-[(3-(2-bromo-4-phenylphenyl)-3-) as a pale yellow bubble [(1,1-dimercaptoethyl)(dimethyl)decane ]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-iV-mercapto-1-benzofuran-3-carboxamide 2.84 g ' 87%) NMR (DMSO-d6) δ: 8.43 (br. 154007.doc • 252-201221131 s.5 1H), 7.94 (m, 2H), 7.74-7.86 (m, 1H), 7.68 ( d, J=7.9 Hz, 1H), 7.31-7.54 (m, 4H), 7.05 (s, 1H), 4.85-5.05 (m, 1H), 3.67-3.88 (m, 2H), 3.12 (s, 3H) , 2.82 (br. s., 3H), 2.20-2.39 (m, 1H), 1.68-1.93 (m, 2H), 0.85-1.10 (m, 3H), 0.71-0.85 (m, 9H), 0.30-0.59 (m,1H), 0.01 (s,3H), -0.19 (d,3H). LCMS (m/z, ES + ) = 763 (M+H). Step 6: 6-[[3-(2- Bromo-4-phenylphenyl)-3-hydroxypropyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-~N-mercapto-1-benzene Treatment of 6-[(3-(2-bromo-4-phenylphenyl)-3-{[(1,1-dimethylethyl)) with furan-3-carbamide with 5 N HCl (10 mL) (didecyl)nonyl]oxy}propyl)(indolyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-#.methyl-oxime·benzofuran _3_Metformamide (2.83 each, 3.7 〇 111111 〇 1) was solution in 1'1^ (4〇1111〇 and stirred at room temperature for 3.5 days). The reaction mixture was poured into water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine (1×) then dried over sodium sulfate. Separately, 6-[(3-(2-bromo-4-phenylphenyl)-3-{[(1,1-didecylethyl)(didecyl) sulphate]oxy}propyl Alkyl](5-cyclopropyl-2-(4-phenylene)-N-methyl-1-benzofuran-3-carboxamide (1.43 g, 1.87 mmol) The solution in THF (20 mL) was taken with 1 N EtOAc (10 mL). (: heating under 19 hours) followed by heating under reflux until the reaction was mostly completed by lc/mS. The reaction mixture was poured into water and extracted with ethyl acetate (2 EtOAc). The combined organic layer was washed with brine (1×) It is then dried over sodium sulfate and concentrated. Both of these crude products are purified by silica gel chromatography (hexane containing ethyl acetate to ethyl acetate) to yield 6-[[ 3_(2_bromo-cardiac-based)-3-propyl-propyl](anthracenyl)amino]_5_cyclopropyl_2_(4-_phenyl)_ 154007.doc •253 - 201221131 Methyl -1-benzofuran-3-carboxamide (3.47 g, 96% combined yield) NMR (DMSO-d6) δ: 8.45 (m, 1H), 7.90-8.00 (m, 2H), 7.83 (d , J=16.8 Hz, 1H), 7.64 (t, J=1.9 Hz, 1H), 7.43-7.55 (m, 2H), 7.39 (td, J=8.9, 1.6 Hz, 2H), 7.05 (d, J= 4.4 Hz, 1H), 5.66 (dd, J=13.4, 4.5 Hz, 1H), 4.70-4.85 (m, 1H), 3.76-3.92 (m, 2H), 3.14 (d, J=1.7 Hz, 3H), 2.83 (d, J=4.6 Hz, 3H), 2.23-2.38 (m, 1H), 1.52-1.96 (m, 2H), 0.79-1.03 (m, 3H), 0.39-0.60 (m, 1H). LCMS ( m/z, ES + ) = 649 (M+H). Step 7: 6-[(3-(2-bromo-4-phenylphenyl)- 3-{[(f-oxy)methyl]oxy}propyl)(nonylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl- 1-benzofuran-3-mercaptoamine was treated with DIEA (0.94 mL ' 5.38 mmol) and chloromethyl methyl ether (0.41 mL, 5.3 8 mmol) 6-[[3-(2-bromo-4- Phenyl)-3-hydroxypropyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-#·methyl-1-benzofuran_3-A a solution of the guanamine (1.75 g ' 2.69 mmol) in THF (30 mL). The reaction was heated in a 50 ° C bath for 16 h then cooled to room temperature. separately using DIEA (0.27 mL '1 - 54 mmol) and Treatment of 6-[[3-(2-bromo-4-phenylphenyl)_3_hydroxypropyl](methionine)amino]- by gas methyl ether (0-12 mL, 1.54 mmol) A solution of 5-cyclopropyl-2-(4-fluorophenylmethyl-1·benzofano-3-decylamine (500 mg, 0.769 mmol) in THF (1 mL). The reaction was heated in a 50 ° C bath for 21 hours' and then cooled to room temperature. The two reaction mixtures were combined, diluted with water and extracted with ethyl acetate (2 EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate Purified by gelatin chromatography (containing 0 to 75% ethyl acetate in hexane) to give a white foam. 154007.doc •254· 201221131 6-[(3-(2-bromo-4-phenylphenyl) -3{[(indolyloxy)methyl]oxy}propyl)(anthracene)amino]-5-3⁄4propyl- 2-(4-fluorophenyl)-7V-曱Alkyl-1-benzoquinone π-nan-3-carbamamine (1-74 g, 72% (for both reactions)). 1H NMR (DMSO-d6) δ: 8.44 (m, 1H), 7.94 (ddd, J=8_8, 5.4, 1.4 Hz, 2H), 7.84 (d, J = 6.7 Hz, 1H), 7.70 (dd, J=4.8 , 2.0 Hz, 1H), 7.33-7.52 (m, 4H), 7.05 (d, J=4.7 Hz, 1H), 4.86 (ddd, J=12.9S 8.5, 4.0 Hz, 1H), 4.53 (dd, J= 6.8, 2.2 Hz, 1H), 4.37 (dd, J=6.8, 4.1 Hz, 1H), 3.68-3.94 (m, 2H), 3.05-3.26 (m, 6H), 2.82 (d, J=4.6 Hz, 3H ), 2.22-2.40 (m, 1H), 1.72-1.95 (m, 2H), 0.78-1.05 (m, 3H), 0.36-0.62 (m, 1H). LCMS 〇/z, ES+) = 693 (M+H). Step 8: 6-[[2-(6-Chloro-1-hydroxy-1,3-dihydro-2,1-benzoxabiborolanyl)ethyl](methylsulfonyl)amine 5-[4-(2-bromo-)--5-cyclopropyl-2-(4-fluorophenylindol-1-benzofuran-3-carboxamide in a thick-walled glass pressure vessel 4-oxophenyl)-3-{[((methyloxy)indenyl]oxy}propyl)(indolyl)amino]-5-cyclopropyl-2-(4-phenylphenyl) Mercapto-1-benzo-fusin-3-anthracene (5〇〇mg, 0.72 mmol), acetic acid unloading (141 mg, 1,44 mmol), bis(pinacolyl)diboron (274 mg) , 1.08 mmol), sodium bromide (74 mg, 0.72 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 force chelates (59 mg, 0.072 mmol) in 1,4-dioxane (15 mL) Degassing, followed by heating at room temperature for 16 hours under stirring. Adding additional bis(pinacolyl)diboron (91 mg, 0.36 mmol) and PdCl2(dppf)-CH2Cl2 adduct (29 mg, 0.036) (mmol) and reheat the reaction for 24 hours. The reaction mixture was cooled to room temperature, filtered through Celite 154007.doc • 255 - 201221131 且 and concentrated by gelatin chromatography (with hydrazine to 1 〇〇% ethyl acetate) Hexane) purification , yielding 6·[(3_[4_gas-2-(4,4,5,5-tetramethyl-1,3,2-dioxos-2-yl)phenyl) as a colorless oil] -3-{[((Methoxy)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenylmethyl-1-benzene And furan-3-carboxamide (〇.58 8, purity 81% (according to 1^(:/)^8)). This residue was dissolved in THF (15 mL) with 1 N HCl (5 mL The treatment was followed by heating under reflux. After 16 hours, the reaction was taken up with EtOAc (1 mL) and then warmed for 4 hrs. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 EtOAc) The combined organic layers were washed with water (2×) and brine (1×), then dried over sodium sulfate and evaporated. Purification of 3 5 〇 / methanol dioxane) followed by lyophilization to give 6-[[2-(6-chloro-1-hydroxy-1,3-dihydro-2,1) as a fluffy white solid. _Benzooxaborolan-3-yl)ethyl](indenyl)amino]-5-cyclopropyl_2_(4_qiben) iV-mercapto-1-benzene And furan _3_formamide (0.23 g, 43% (after 2 steps)) 4 NMR (sterol-d4) δ: 7.86-7.96 (m, 2H), 7.70 (d, J = l6 8 仏 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.39 (ddd, J= 8.l 6 2 ? nt ? 1H), 7.12-7.29 (m, 4H), 5.17-5.37 (m, 1H), 3 7〇·4 ΐ7 (m 2H), 3.05-3.17 (m, 3H), 2.94 (s,3H), 2.15-2.52 (m,2H)' 1.56-1.86 (m,1H),0.84-1.14 (m,3H),〇.46_〇76 (m ih) LCMS (w/z, ES+ ) = 597 (M+H). Example 65 6-[[2-(5-Gas-1-yl-1,3-hydro-2'1-benzooxazepine)-ethyl](M) Amino]-5-cyclopropyl-2-(4-1 strepyl)methyl 154007.doc -256- 201221131 1-benzofuran-3-carboxamide

Step 1: 1-(2-Bromo-5-gasphenyl)-2-propene-I alcohol Maintained at 0C in 2-beta-5-benzoquinone (8β,

A solution of &lt;5 mmol&gt; in furan (200 mL) was taken from &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The mixture was poured into saturated aqueous ammonium chloride (aq) and the organic layer was diluted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the residue was evaporated to dryness, and purified by column column chromatography to give the product of s. g, 2〇16 _〇i, w 3 rate) of dilute phenol (4). NMR (DMS0_d6) δ: 7 61 (d, J=8 6 (d, J=2.7 Hz, 1H), 7.29 (dd, J=8.5, 2.6 Hz, 1H), 5.83-5 99 (m, 2H), 5.20-5.36 (m, 2H), 5.12 (dt, J=l〇.3, 1&gt;5 Hz, lH) ' Armor Step 2: m-(2-Molychlorophenyl)_2_Propylene·Base] Oxyethylethyl)dithiol oxime is maintained at room temperature under the conditions of mixing to maintain H2-bromo-5-chlorophenyl)_2-propanol.ol (5 g ·2〇mm〇l) (2.75 g, 40·4 mmol) and TBSC1 (3.35 g, 22.22 mmol) in N,N-dimethylformamide (5 () Xenopus solution "hours. The mixture was poured into ether and used 5% Lia (aqueous solution) was washed 3 times. The organic layer was separated, dried over sodium sulfate, filtered, and then evaporated to the residue under reduced pressure and purified by column chromatography to yield a crude oil. -MoM-5- 154007.doc -257- 201221131 Phenyl phenyl)·2-propenyl yl]oxy}(11•dimethylethyl) bismuth sulphate (6.23 g, 17.22 mmol, 85% yield) Rate) lH NMR (chloroform... 7.53 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 8 4 Hz, ih), 7 Q9 (4), J = 8.5, 2.6 Hz, 1H), 5.89 (ddd , j=17.〇, 1〇3, 4 9 Hz, 1H), 5.49 (d, J=4.9 Hz, 1H), 5.37 (d, (d) ❽ Hz, ih), $ u (4) J = 10.3 Hz, 1H), 0.85-0.99 (m, 9H), 〇.i〇(s, 3H), (0.01 (s, 3H). Step 3 : 3-(2-Mo-5-Phenylphenyl)-3-{[(U-dimethylethyl)(dimethyl)-male-alkyl]oxy}-l-propanol cold part{[1 -(2-bromo-5-phenylphenyl)-2-propenyl-yl]oxy}(11-didecylethyl)dimethylhydrazine (3.00 g ' 8.29 mmol) in THF (30 mL a solution of 9-BBN (24 9 mL·, 0.5 Μ in THF) was added dropwise over 25 minutes. The reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0 ° C. Treated with sodium hydroxide solution (13 8 mL, 3.0 Μ), 30% hydrogen peroxide (8.5 mL) in turn. After stirring for an hour, the reaction mixture was diluted with water and allowed to warm to room temperature and then with ethyl acetate Ester (2χ) extraction. The combined organic layers were washed with brine, dried over sodium sulfate Purified by silica gel chromatography (0 to 20% ethyl acetate in hexanes) to give 3-(2-bromo-5-phenylphenyl)-3-{[(1,1-di) as a colorless oil. Methylethyl)(dimethyl)anthracene]oxy}-1-propanol (2.97 g, 94% yield). NMR (chloroform-d) δ: 7.56 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 5.22 (dd, J=7.9, 3.5 Hz, 1H), 3.66-3.89 (m, 2H), 1.72-2.16 (m, 3H), 0.86-0.96 (m, 9H), 0.04-0.15 (m, 3H), -0.16-- 0.06 (m, 3H). LCMS (m/z, ES+) = 379 154007.doc 201221131 (M+H). Step 4 ··{[3-Bromo-1-(2-bromo-5-chlorophenyl)propyl]oxy}(υ_dimethylethyl) γ 矽 矽 冷却 冷却 3-(2-bromo) -5-gas phenyl)-3-{[(1,1-didecylethyl)(dimethyl) oxalate]oxy}-1-propanol (2.94 g, 7.74 mmol) and three A solution of phosphine (2.44 g, 9.49 mmol) in di-methane (40 mL) to hydrazine. It was treated with NBS (1.65 g, 9_29 mmol). After 1 hour, the reaction was allowed to warm to room temperature. After another 3 hours, the reaction mixture was diluted with a two-air-burning and washed with water. The aqueous layer was back extracted with DCM. The combined organic layers were washed with water (1×) and brine. Purification by gelatin chromatography (100% hexahydrate) to give {[3-bromo-i-(2-bromo-5-phenylphenyl)propyl]oxy} (1, 1-di) as a colorless oil. Mercaptoethyl) Diterpenoid Shi Xiyuan (2 89 g, 840/.). 4 NMR (gas-d) δ: 7.52 (d, J = 2.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 5.16 ( Dd, J=8.8, 2.9 Hz, 1H), 3.38-3.65 (m, 2H), 1.95-2.29 (m, 2H), 0.87-0.94 (m, 9H), 0.03-0.20 (m, 3H), -0.19 -0.06 (m, 3H). Step 5: 6-[(3-(2-Mo-5-chlorophenyldimethylethyl)(dimethyl)sulfonyl]oxy}propyl)(alkyl)amino]- 5-cyclopropyl-2-(4-fluorophenyl)-~N-methyl-1-benzoquinone °v-3-cartoamine heating 5-cyclopropyl-2-(4-fluorophenyl -Methyl-6_[(oxasulfonyl)aminopyr 1-benzofuran-3-carbamidamine (2.00 g, 4.97 mmol), {[3-bromo-1-(2-bromo-5) - gas phenyl) propyl]oxy} (1,1-dimercaptoethyl) dimethyl decane (2.86 g, 6.46 mmol) and potassium carbonate (1.72 g, 12.42 mmol) in acetonitrile (50 154007.doc Mix the mixture in -259- 201221131 mL) to 75 ° C for 16 hours. DMF (10 mL) was added to this mixture and heating was continued for another 24 hours. The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2 EtOAc). The combined organic layers were washed with water (1×;) and brine (1×) and then dried and concentrated. Purification by gas chromatography (containing hydrazine to loo% ethyl acetate in hexane) gave 6-[(3-(2-indol-5-chlorophenyl)-3) as a pale yellow bubble. -{[(1,1-didecylethyl)(dimethyl)decyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluoro Phenyl)-#-mercapto-1-benzofuran-3-carboxamide (3.67 g, 97%). 4 NMR (DMSO-d6) δ: 8.43 (m, 1H), 7.94 (m, 2H), 7.74-7.87 (m, 1H), 7.56 (dd, J = 10.3, 8.5 Hz, 1H), 7.33-7.46 ( m, 3H), 7.27 (m, 1H), 7.05 (s, 1H), 4.84-5.02 (m, 1H), 3.67-3.91 (m, 2H), 3.13 (d, J=4.2 Hz, 3H), 2.82 (d, J=4.6 Hz, 3H), 2.17-2.40 (m, 1H), 1.71-1.94 (m, 2H), 0.86-1.06 (m, 3H), 0.69-0.86 (m, 9H), 0.33-0.61 (m, 1H), 0.01 (d, J = 4.4 Hz, 3H), -0.18 (d, J = 5.2 Hz, 3H). LCMS (w/z, ES+) = 763 (M+H). Step 6 : 6-[[3-(2-Bromo-5-phenylphenyl)-3-hydroxypropyl](methylsulfonyl)amino]_ 5-cyclopropyl-2-(4-fluorobenzene Methyl-I-benzobenzoin-3-carboxamide 6-[(3-(2-bromo-5.chlorophenyl)-3-{[(1,1-dimethylethyl)) Dimethyl) decyl]oxy}propyl)(methylsulfonyl)amino]_5·cyclopropyl-2-(4-fluorophenyl)-methyl-1-benzofuran-3-A A solution of the amine (3.65 g, 4.78 mmol) in THF (50 mL) was taken eluted with 5 N EtOAc (15 mL) and EtOAc After room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (2×). 154007.doc. 260·201221131 The organic layer was washed with 10% aqueous sodium carbonate (1×) and brine (1 χ) and dried over sodium sulfate. And concentrating. The resulting viscous yellow foam was wet-milled in a mixture of dioxane and 2 alkane to give 6-[[3 (2 = 2''''''''曱 醯 ) ) ) ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( δ: 8.44 (m, 1H), 7.94 (dd, J=7.7, 5.5 Hz) , 2H) 7.83 (d5 1=14.1 Hz, 1H), 7.51 (ddd, 1=19.2, 8.1, 2.2 Hz, # 2H)^ 7.39 (td, J=8.9, 1.3 Hz, 2H), 7.19-7.29 (m5 1H), 7.05 (d, J=4.4 Hz, 1H), 5.60-5.85 (m, 1H), 4.75 (m, 1H), 3.74. 3.93 (m, 2H), 3.15 (s, 3H), 2.82 (m , 3H), 2.20-2.39 (m, 1H), 1.50-1.99 (m, 2H), 0.76-1.06 (m5 3H), 0.39-0.63 (m, 1H). LCMS (m/z, ES+)=649 ( M+H) 0 Step 7: 6-[(3-(2-Bromo-5-chlorophenyl)-3_{[(methyloxy)methyl]oxy)propyl)(sulfonyl) Amino]-5-cyclopropyl-2-(4-fluorophenylindenyl-1-benzofuran-3-carboxamide is claimed as DIEA (1.28 mL, 7.35 mmol) and gas decyl decyl ether ( 〇.56 mL, 7.35 mmol) of 6-[[3-(2-bromo-5-phenylphenyl)-3-hydroxypropyl](methyl)amino]-5-cyclopropyl-2 -(4-Phenylphenyl)--/V~decyl-1-benzon-n-y-3-methanamine (2.81 g, 4.32 mmol) in THF (35 mL). The reaction was heated in a 50 ° C bath for 16 h at which time additional DIEA (1.28 mL, 7. The bath temperature was increased to 55 ° C for 24 hours. The reaction was cooled to room temperature and diluted with water then ethyl acetate (2 EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate Purification by gelatin chromatography (containing hydrazine to 75% acetic acid 154007.doc -261 - 201221131 ethyl acetate) gave 6-[(3_(2-bromo-5- phenyl)-3) as a white solid. -{[(Methoxy)methyl]oxy}propyl)(methylsulfonyl)amino]_5_cyclopropyl-2-(4-fluorophenyl)-7V-methyl-1-benzene And furan_3-decylamine (2 15 g, 72%). *H NMR (DMSO-d6) δ: 8.44 (m, 1H), 7.94 (m, 2H), 7.84 (d, J = 5.1 Hz, 1H), 7.58 (dd, J = 8.5, 6.2 Hz, 1H), 7.34-7.44 (m, 3H), 7.29 (ddd, J=8.5, 4.7, 2.7 Hz, 1H), 7.05 (d, J=4.7 Hz, 1H), 4.77-4.93 (m, 1H), 4.56 (dd, J=6.9, 2.5 Hz, 1H), 4.35-4.47 (m, 1H), 3.73-3.94 (m, 2H), 3 18-3 25 (m, 3H), 3.07-3.18 (m, 3H), 2.82 ( m, 3H), 2.22-2.42 (m, 1H), 1.80-1.96 (m, 2H), 0.81-1.05 (m, 3H), 0.38-0.63 (m, 1H). LCMS (m/z, ES+) = 693 (M+H). Step 8: 6-[[2-(5-Gas-1-hydroxy-1,3-dihydro-2,1-benzoxaborolan-3-yl)ethyl] 6-[(amino)-5-cyclopropyl-2-(4-1phenyl)_N-methyl-1-benzofuran-3-indoleamine in a thick-walled glass pressure vessel 6-[( 3-(2-Bromo-5-gasphenyl)_3_{[(methyloxy)methyl]oxy}propyl)(aminocarbyl)amino]-5-cyclopropyl-2-( 4-fluorophenyl)-W-mercapto-1-benzocypan-3-carbamoin (1.15 g, 1.66 mmol), potassium acetate (0.33 g, 3.31 mmol), bis (pinacol) Ershipeng (0.63 g' 2.49 mmol), sodium bromide (170 mg, 1.66 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (135 mg, 0.166 mmol) in 1,4-dioxane (20 mL) The mixture was degassed and then heated at 85 ° C for 64 hours with stirring. The reaction mixture was cooled to room temperature and transitioned and concentrated through a pad of celite. Purification by gelatin chromatography (containing 0 to 100% ethyl acetate in hexanes) to give 6-[(3-[5- gas-2-(4,4,5,5-four) as a light green oil. Methyl·1,3,2-di 154007.doc -262· 201221131 Oxystan oxime-2-yl)phenyl]-3-{[(methyloxy)methyl]oxy}propyl) (A Sulfhydryl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-indenyl-i-benzofuran_3_decylamine (1.22 g, purity 56% (according to LC/MS )). The residue was taken up in EtOAc (30 mL)EtOAc. The reaction was treated with 5N EtOAc (1 mL) and EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water (2x) and brine (1 EtOAc) then dried over sodium sulfate and concentrated. Purified by Shihic acid chromatography (containing 0 to 100 〇 / 〇 ethyl acetate in dichloromethane, followed by hydrazine to 3 5% methanol), followed by; Donggan, resulting in a fluffy white solid 6-[[2-(5-Gas-i-hydroxy-丨'3·dihydro-2,1-benzothiaborole-3-yl)ethyl](sulfonyl) Amino]_5_cyclopropyl_2_(4-fluorophenyl)_沁methyl-1-benzofuran-3-carboxamide (0·35 g, 35〇/〇 (after 2 steps) 4 NMR (methanol-d4) δ: 7.86-7.97 (m, 2H), 7.70 (m, 1H), 7.56 (d J = 7.8 Hz, 1H), 7.20-7.35 (m, 4H), 7.16 (s, 1H) ),5.15.5.37 • (m, 1H), 3.69-4.19 (m, 2H), 3.03-3.17 (m, 3H), 2.87-3.0l (m, 3H), 2.15-2.54 (m, 2H), 1.53 -1.87 (m} 1H), 0.82-1.13 (m, 3H), 0.46-0.75 (m, 1H). LCMS (w/z, ES+) = 5q7 (M+H). Example 66 6-[[2- (4-Gas-1-hydroxy-i,3_dihydro-2,1-benzooxaborole-3-yl)ethyl 1(methylsulfonyl)amino]-5-cyclopropane Base_2_(4_fluorophenyl)_Nmethyl-1-benzotrim-3 -cartoamine 154007.doc -263- 201221131

Step 1: 1-(2-Bromo-6-glyphenyl)-2-propenyl i-anol was cooled 2-bromo-6-gasbenzaldehyde (7 g, 31 9 mm 〇1) (synthesis described in / Voceu (2008) I], page 1293) a solution in tetrahydrofuran (150 mL) to (TC and drip with THF (39.9 mL, 39.9 mm〇i) containing gasification of (vinyl) magnesium The mixture was stirred for 2 hours and then quenched by the slow addition of 丨〇% ammonium sulphate (aq). The mixture was diluted with ethyl acetate and the organic layer was washed with water, dried, dried over sodium sulfate, filtered, Concentrate to a residue and purify by EtOAc (EtOAc) eluted to elute 〇乂 yield). 4 NMR (DMSO-d6) δ: 7.60 (dd, J=8.0, 1.2 Hz, 1H), 7.45 (dd, J=8.0, 1.0 Hz, 1H)s 7.21 (t, 1=8 .! Hz, 1H), 6.18 (ddd! 17.3, 10.4, 5.1 Hz, 1H), 5.80-5.87 (m, 1H), 5.73 (d, J=4.7

Hz, 1H), 5.09-5.22 (m, 2H). Step 2 '{[1~(2冬6_气笨基)·2 Propylene Small Group]oxy•dimethylethyl) dimethyl oxime with human azole (4.20 g, 61.7 mmol), TBSC1 (4.84 g, 32.1 〇1) treatment of H2,-6-phenylphenyl)-2-propanol (6.ug, 24.69; hydrazine, hydrazine monomethylcarbamide (1 〇〇mL) The solution was maintained at room temperature for half an hour. The mixture was poured into ether and 5% LiCl (water 154007.doc)

• 264 - S 201221131 solution) Wash 3 times and wash the times with saturated sodium chloride (aqueous solution). The organic layer was separated, dried over sodium sulfate, filtered and evaporated tolululululululululululululululululululu -propen-1-yl]oxy...salt-f-ylethyl)dimethyl decane (different g ' 22.06 mmo 〇 89 〇 /. yield). NMR (DMSO-d6) δ: 7.63 (d, J = 8.0 Ηζ, 1 Η), 7.48 (d, J = 8.0 Hz, 1 Η), 7.23 (t, j = 8 1

Hz, 1H), 6.15 (ddd, J=17.1, 10.4, 5.1 Hz, 1H), 5..93 (d, J=4.9 Hz, 1H), 5.29 (dt, J=17.0, 1.5 Hz, 1H), 5.19 (dt, J = 10.3, 1.6 Hz, 1H), 0.86 (s, 9H), 0.06 (s, 3H), -0.12 (s, 3H) 〇' Step 3: 3-(2-Bromo-6-gas Phenyl)-3-{[(l,l-dimethylethyl)(dimethyl)zetanyl]oxy}-1-propanol cooled {[1-(2-bromo-6-chloro) A solution of phenyl)-2-propenyl]oxy}indole-1-dimethylethyl)dioxanane (4.00 g, 11.06 mm 〇1) in THF (4 mL) was taken to 0. A solution of 9-BBN (33.5 mL·, 0.5 Μ in THF) was added dropwise over 35 minutes. The reaction was allowed to warm to room temperature overnight. The reaction was cooled to o ° c and treated sequentially with a solution of sodium hydroxide (18 4 mL, 3 〇 Μ), 30% hydrogen peroxide (11.3 mL). After stirring for 5 hours, the reaction mixture was diluted with water and allowed to warm to room temperature then extracted with ethyl acetate (2 EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate Purification by chromatography on silica gel (0 to 25% ethyl acetate) afforded 3-(2-bromo-6-chlorophenyl)-3.{[(1,1) _Dimercaptoethyl)(dimethyl)decyl]oxy}-1-propanol (4.02 g, 96% yield). iH NMR (chloroform_d) δ: 7.42-7.56 (m,1H), 7.29-7.38 (m,1H), 7.04 (t,1H),5.55- 154007.doc •265· 201221131 5.78 (m,1H), 3.73-3.94 (m, 2H), 2.39-2.71 (m, 1Η), 2·16 (br. s·, 1H), 1.73-1.97 (m, 1H), 0.91 and 0.90 (s, 9H, rotational isomerism (), 0.09 and 0.08 (s, 3H, rotamer), -0.19 and -0.20 (s, 3H, rotamer). LCMS (m/z, ES+) = 379 (M+H). Step 4: {[3-Bromo-1-(2-bromo-6-chlorophenyl)propyl]oxy}(1,1-dimethylethyl)dimethylhydrazine is said to cool 3-(2- Bromo-6·gasphenyl)-3-{[(1,1-dimethylethyl)(diindenyl)oxalyl]oxy}-1-propanol (4.00 g, 10.53 mmol) and A solution of triphenylphosphine (3.31 g, 12.64 mmol) in hexanes (50 mL) was taken to EtOAc (EtOAc) After 30 minutes, the reaction was allowed to warm to room temperature. After another hour, the reaction mixture was diluted with dioxane and washed with water. The aqueous layer was back extracted with DCM. The combined organic layers were washed with water (1×) and brine (1×) Purification by gelatin chromatography (100% hexanes) afforded [[3-bromo-1-(2-bromo-6-phenylphenyl)propyl]oxy} (1, 1- Methyl ethyl) dimethyl decane (4.23 g '91%). 4 NMR (DMSO-d6, 85°) S: 7.62 (dd, 1H), 7.47 (d, 1H), 7.23 (t, 1H), 5.47-5.76 (m, 1H), 3.47-3.76 (m, 2H) , 2.66-2.93 (m, 1H), 2.00-2.18 (m, 1H), 0.87 (s, 9H), 0.11 (s, 3H), -0.17 (s, 3H). Step 5: 6-[(3-(2-Bromo-6-gasphenyl)-3-{[(1,1-dimethylethyl)(dimethyl)decyl]oxy}propyl) (Methanesulfonyl)amino]cyclopropyl-2-(4-cepphenylmethyl-1-benzofuran-3-decylamine heated 5-cyclopropyl-2-(4-fluorophenyl) )·#-曱基·6_[(methylsulfonyl)amino]- 1-benzox-fol-3-carboxamide (2.95 g, 7.33 mmol), {[3-漠154007.doc -266 - 201221131 bromo-6-chlorophenyl)propyl]oxy}oxime, ;!-dimethylethyl)dimethyl decane (4 ug, 9.53 mmol) and potassium carbonate (2_53 g, 18 33 〇1 ) A mixture of 5: ι 乙 / DMF (90 mL) to 75 t ' for 16 hours. The temperature was increased to 85 ° C for 6 hours. The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2 EtOAc). The combined organic layers were washed with water (1 EtOAc) and brine (EtOAc). Purification by gelatin chromatography (hexane containing 1% by weight of ethyl acetate) afforded 6_[(3_(2_ • bromochlorophenyldidecylethyl) (dimethyl) as a yellow foam.矽alkyl]oxy} propyl)(methyl aryl)amino]-5-cyclopropyl-2-(4-fluorophenyl)·#-methyl-1-benzofuran-3-A Guanamine (5.08 g, 91 〇 / 0). A NMR (DMSO-d6) δ: 8.38-8.50 (m, 1H)S 7.94 (m, 2H), 7.80-7.89 (m, 1H), 7.53-7.66 (m, 1H), 7.32-7.52 (m, 3H ), 7.13-7.27 (m, 1H), 7.06 (s, 1H), 5.21-5.55 (m, 1H), 3.81-3.98 (m, 1H), 3.56-3.78 (m, 1H), 3.04-3.20 (m , 3H), 2.74-2.89 (m, 3H), 2.23-2.54 (m, 2H), 1.56-1.95 (m, 1H), 0.86-1.06 (m, 3H), 0.66-0.86 瘫(m, 9H), 0.35-0.59 (m, 1H), -0.06-0.11 (m, 3H), -0.38--0.20 (m, 3H) » LCMS (w/2, ES+) = 763 (M+H). Step 6: 6-[[3-(2-Bromo-6-chlorophenyl)-3-hydroxypropyl](nonylsulfonyl)amine; 5·Cyclopropyl-2-(4-fluorophenyl) Treatment of 6-[(3-(2-bromo-6-phenylphenyl)-3-{[(1,1-) with methyl N-benzofuran-3-carbamide with 5 N HCl (20 mL) Dimercaptoethyl)(dimethyl)decyl]oxy}propyl)(methylsulfonyl)amine group μ5_cyclopropyl-2-(4-fluorophenylindenyl-1-benzofuran- a solution of 3-nonylamine (5.06 g ' 6.62 mmol) in THF (EtOAc) (EtOAc) (EtOAc) 267- 201221131 The mixture was diluted with ethyl acetate and washed with water (1 χ), 10% aqueous sodium carbonate (1×) and brine (IX), then dried over sodium sulfate and concentrated. Purification to 100% ethyl acetate in hexanes to give 6-[[3-(2-bromo-6-phenylphenyl)-3-hydroxypropyl](methylsulfonyl)amine as an off-white foam 5-(cyclopropyl-2-(4-fluorophenyl)-#-methyl-1-benzofuran-3-cartoamine (4.13 g, 96%). NMR (DMSO-d6) δ : 8.39-8.52 (m, 1H), 7.95 (dd, 2H), 7.85 (d, 1H), 7.56 (td, 1H), 7.32- 7.46 (m, 3H), 7.16 (td, 1H), 7.06 (d, 1H), 5.47-5.70 (m, φ 1H), 5.13-5.38 (m, 1H), 3.77-3.99 (m, 1H) , 3.57-3.77 (m, 1H), 3.06-3.22 (m, 3H), 2.82 (m, 3H), 2.18-2.44 (m, 2H), 1.58-1.95 (m,1H), 0.77-1.08 (m, 3H), 0.37-0.63 (m, 1H). LCMS ES+) = 649 (M+H). Step 7: 6-[(3-(2-bromo-6-chlorophenyl)-3-{[( Benzyl)methyl]oxy}propyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenylmethyl-l-benzo-indolyl-3- Treatment of 6-[[3-(2-bromo-6-chlorophenyl)-3-hydroxypropanol with DIEA (1.89 mL ' 10.8 mmol) and gas methyl decyl ether (0.82 · mL, 10.8 mmol) (methanesulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-#-methyl-1-benzofuran-3-carboxamide (4.13 g ' 6.35 mmol A solution in THF (60 mL). The reaction was heated to an internal temperature of 45 ° C for 16 hours, at which time additional DIEA (1.89 mL, 10.8 mmol) and gas methyl ether (0.82 mL, 10.8 mmoip temperature increased to 53 ° C for 24 hours) The reaction was cooled to room temperature and diluted with EtOAc EtOAc (EtOAc) (EtOAc)

Purification of 201221131 (containing 0 to 75% ethyl acetate in hexanes) afforded 6-[(3-(2.bromo-6- phenylphenyl)-3-{[(decyloxy) as a white foam.曱 ] 丨 丨 丨 ) ) ) ) ) ) ) ) ) ) 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- Indoleamine (3.30 g, 75%). 4 NMR (DMSO-d6) δ: 8.44 (m, lH), 7.95 (m, 2H), 7.87 (d, lH), 7.55-7.65 (m, lH), 7.33 - 7.51 (m, 3H), 7.21 ( m, 1H), 7.05 (d, 1H)S 5.15-5.41 (m, 1H), 4.54 (t, J=6.8 Hz, 1H), 4.35 (d, J=6.8 Hz, 1H), 3.59. 3.99 (m , 2H), 3.06-3.20 (m, 6H), 2.82 (m, 3H), 2.42-2.58 (m, 1H), 2.27-2.41 (m, 1H), 1.73-1.97 (m, 1H), 0.79-1.06 (m, 3H), 0.41-0.58 (m, 1H). LCMS (m/z, ES+) = 693 (M+H). Step 8. 6-[[2-(4-Chloro-1-trans-yl-1,3-dihydro-2,1-benzothiazepine-1-yl)ethyl](methane) 6-[indenyl]amino]-5-cyclopropyl_2·(4-fluorophenyl)-methyl-1-benzo-α-propan-3-carboxamide in a thick-walled glass pressure vessel (3-(2·Bromo-6-indolyl)-3-{[(indolyloxy)indolyl]oxy}propyl)(methylsulfonyl)amino]]_5_cyclopropyl_2_ (4_fluorophenyl)·#·methyl-1-benzofuran-3-carboxamide (1.57 g, 2.26 mmol), potassium acetate (0.44 g '4.52 mmol), bis(pinacol) diboron a mixture of (0.86 g, 3.39 mmol), sodium bromide (233 mg, 2.26 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (185 mg, 0.226 mmol) in 1,4-dioxane (20 mL) After degassing, it was heated at 85 ° C for 64 hours under stirring. The reaction mixture was cooled to room temperature and passed through a pad of Celite. Purification by gelatin chromatography (containing 0 to 100% ethyl acetate in hexane) gave 6-[(3-[2- gas-6-(4,4,5,5-) as a light green foam. Tetramethyl·154007.doc •269· 201221131 1,3,2-dioxos-2-(yl)phenyl]-3-{[(methyloxy)methyl]oxy}propyl) Further hydrazino)amino]-5-cyclopropyl-2-(4-phenylphenylmethyl_ι-benzofuran-3-carboxamide (1.38 g, purity 76% (according to LC/MS) This residue was dissolved in THF (30 mL) and taken with 1 N HCl (1 mL)

The mixture was then heated under reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with H~~~ The combined organic layers were washed with water (2 EtOAc) and brine. Purified by Shiki gum chromatography (dialdehyde methane containing 0 to 100% ethyl acetate followed by methane methane containing hydrazine to 35% methanol) followed by lyophilization to give a fluffy tan solid -[[2-(4-Ga-1-hydroxy-1,3-dihydro-2,1-benzooxaborole-3-yl)ethyl](methylsulfonyl)amine 5_cyclopropyl_2·(4_fluorophenylindenyl-1-benzofuran·3-decylamine (0.67 g, 50% (after 2 steps). lH NMR (sterol-d4) δ : 7.91 (m, 2Η), 7.62-7.78 (m, 1Η), 754 (m, 1H), 7.28-7.41 (m, 2H), 7.24 (t, 2H), 7.15 (d, 1H) 5.23-5.44 ( m, 1H), 3.68-4.14 (m, 2H), 3.02-3.22 (m, 3H) 2.87-3.02 (m, 3H), 2.56-2.79 (m, 1H), 2.26-2.54 (m, iH), 1.61 -1.83 (m, 1H), 0.81-1.15 (m, 3H), 0.44-0.74 (m, ih). LCMS (m/z, ES+) = 597 (M+H). 2-(4-Fluorophenyl)-6-(N-(2-(l-hydroxy-3,4-dihydro·1H•benzo[c][l,2]oxaborane] 3_yl)ethyl)methylsulfonylamino)N-methylbenzofuran-3-carboxamide 154007.doc •270· 201221131

Step 1: 2-(2-Phenylphenyl)acetic acid methyl acetate to a solution of 2-(2-bromophenyl)acetic acid (20.0 g, 〇·〇9 mol, BeiJing〇uHe) in MeOH (100 mL) H2S〇4 (2 mL) was added and the separator was heated under reflux. The reaction solution was concentrated under reduced pressure. The residue was taken up in EtOAc (EtOAc)EtOAc. The solvent was removed under reduced pressure to give (yield: 21.0 g, 〇. 〇 9 mol, 98.0% yield) as a colorless oil. Step 2: 2-(2-Molybdyl)ethanol was added dropwise to a solution of LiAlH4 (1. g, 26 mmol) in THF (80 mL) at EtOAc. Base acetate (5.0 g, 22 mm 〇 1) in THF. The mixture was stirred at 〇 C: the resulting mixture was stirred for 3 min and then EtOAc (1 mL) and water (20 mL). The solid was filtered off and the filtrate was dried over anhydrous Na. After the solvent was removed, the residue was purified by column chromatography to afford 2-(2-di-phenyl)ethanol (3.7 g, 18.4 mm, 84% yield). LC-MS fm/z, ES+)=202 (M+H) Step 3: 2-(2-bromophenyl) hexanes EtOAc EtOAc EtOAc A solution of 2-(2-bromophenyl)ethanol (3.7 g, 18 mm 〇1) in dcm (2 〇 mL) was added to the suspension to cause a slight exothermic reaction while forming a black reaction mixture 'in the chamber Stir for 15 hours while warming. Next, add B 154007.doc -271 - 201221131 (150 mL) and the mixture was filtered through a silica gel on a diatomaceous earth pad. The residue was washed with EtOAc (EtOAc) (EtOAc) Yield). LCMS (m/z, ES+) = 199 (M+H) Step 4: 1-(2.bromophenyl)but-3-en-2-ol at -60 ° C under nitrogen atmosphere to 2-( To the solution of 2-bromophenyl)acetaldehyde (3.4 g, 17 mmol) in 100 mL THF was added dropwise EtOAc EtOAc. The resulting reaction mixture was stirred at room temperature for additional 1 hour. Chlorinated acid (saturated aqueous solution, 50 mL) was added and the organic layer was separated. The combined organic layers were washed with brine (1 mL) and dried over anhydrous Na Na. After the solvent was removed, the residue was purified with EtOAc EtOAc EtOAc EtOAc. ). LCMS (m/z, ES+) = 227 (M+H) Step 5: (1-(2-bromophenyl)but-3-en-2-yloxy)(t-butyl)difluorenyl To the solution of 1-(2-bromophenyl)but-3-en-2-ol (2.3 g, 10 mm〇i) in DMF (30 mL) was added imidazole (1 g, μ mm 〇 1) &amp; TBSC1 (2.3 g, 15 mmol). The resulting reaction mixture was stirred at room temperature for an hour. Water (50 ml) was added and EtOAc (3×30 mL) The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na? After removal of the solvent, the residue was purified by column chromatography to give (1 _ (2-bromophenyl)but-3-en-2-yloxy) (t-butyl) as a colorless oil. Dimethyldecane (2 9 g '8.5 mmol, 85. / oxime yield). LCMS (m/z, ES+) = 341 (M+H) Step 6 ··· 4-(2-bromophenyl)-3-(t-butyldimethylmethylsulfanyl)butyl - 154007.doc • 272- 201221131 1-Alcohol under nitrogen atmosphere to (1-(2-bromophenyl)but-3-en-2-yloxy)(t-butyl)dimethyl Shi Xiyuan (2.9 g, 8.5 Addition of 9-BBN (0.5 Μ in THF, 26 mL, 13 mmol) in THF (30 mL). The reaction mixture was cooled to dryness and Na~H (2N aqueous solution, 15 mL) was then applied. After stirring for 1 hour, hydrogen peroxide (15 mL) was added and the resulting reaction mixture was stirred at room temperature for 2 hours. The separated organic layer was washed with brine (100 mL) and dried over anhydrous Na. After the removal of the solvent, the residue was purified by column chromatography (EtOAc eluting with EtOAc EtOAc EtOAc) to afford 4-(2-bromophenyl)-3- Tributyldimethylmercaptooxy)butan-1-ol (1.6 g, 4.5 mmol, 53% yield). LCMS (m/z, ES+) = 359 (M+H). Step 7: (4-Bromo-1-(2-bromophenyl)butan-2-yloxy)(t-butyl)dimethyl sulphur was stirred at room temperature for 4-(2-bromobenzene) 3-(t-butyldimethylmethylalkyloxy)butan-1-ol (1.6 g, 4.5 mmol), PPh3 (18 g, 6 7 _〇1) and NBS (1.2 g, 6·) 7 mmol) of the solution in DCM (100 mL) for 1 hour. The reaction solution was concentrated under reduced pressure. Base stone simmering (1.72 g, 4.0 mmol, 91% yield). Step 8: 6-(N-(4-(2-Bromophenyl)-3-(t-butyldimethylsilyloxy)butyl)methylsulfonylamino)-5-cyclopropyl 2-(4-Fluorophenyl)-N-mercaptobenzofuran-3-carboxamide was heated at 120 ° C. 5-cyclopropyl-2·(4-fluorophenyl)-halylidene 6_[(Methanesulfonate 154007.doc -273-201221131) Amino]-1-benzox-fol-3-carboxamide (1.0 g, 2.5 mmol), (4-bromo-1-(2-) Bromophenyl)butan-2-yloxy)(t-butyl)dimethyloxane (1.7 g, 4.0 mmol), potassium carbonate (ι·〇g, 7.5 mmol) and potassium iodide (400 mg, 2.5 mmol) The solution in DMF (50 mL) was for 4 hours. The solution was cooled to room temperature and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous Na.sub.4. After removal of the solvent, the crude product was purified by column chromatography to yield 6-(N-(4-(2-bromophenyl)-3-(t-butyl-2-methyl hydrazide) as a white solid. Butyl)methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-N-methylbenzol-3-cartoamine (ι·2 g, 1.6 mmol, 63 %Yield). LCMS (w/z, ES+) = 742 (M+H). Step 9: 6-(N-(3-(Tertiary butyldimethylmethylalkyloxy)_4_(2_(4,4,5,5-tetramethyl-1,3,2-dioxaborane) -2-yl)phenyl)butyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofurancarboxamide 6-(N- (4-(2-bromophenyl)-3-(t-butyldimethylsilyloxy)butyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluoro Base)_N-methylbenzofuran-3-cartoamine (1.2 g, 1.6 _〇1), potassium carbonate (221 mg, i 6 awake 1), bis (pinacol) base (4 g,i 6 mm(&gt;i)Apdci2 (dPPf)-CH2Cl2 adduct (58 mg, us with degassed solution in Essence (ι〇〇mL) and refilled with nitrogen 3 The mixture was heated overnight. After cooling the reaction mixture to room temperature, water (1 mL) was added and the solution was extracted with Et EtOAc (3×8G mL). After the removal of the solvent, the residue was purified by column riding to give a white solid 6_(N_(3_(: base: methyl 7 alkyloxy) (4'4'5'5·4 ke-H2·dioxosole·2•yl)phenyl)butyl)醯 154007.doc • 274· 201221131 Amino)-5-cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran_3_ anthraquinone (710 mg, 0.90 mmobu 55 % yield) LCMS 〇/z, ES+)=791 (M+H) Step 10. 5_Cyclopropyl-2·(4-fluorophenyl)_6_(Ν_(2_(ι_基基二氢_ 1H-benzo[c][l,2]oxaborofenyl)ethyl)methylsulfonylamino)-N-mercaptobenzofuran-3-carboxamide at room temperature 6-(N-(3-(Tertiary butyl fluorenyl decyloxy) _4_(2_ # (4'4'5,5_tetramethyl-1,3,2_di-n-boron-2 -yl)phenyl)butyl)sulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-amine (700 mg, The crude product, 〇 〇 〇 〇 ) ) ) ) HC 〇 〇 〇 〇 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 5_cyclopropyl-2-(4-fluorophenyl)·6-(Ν-(2-(1-)-based-3,4-dihydro-1H-benzo[c][l] , 2] oxaborolan-3-yl)ethyl) fluorenylamino)-N-methylbenzox-am--3-carboxamide (260 mg, 51% yield). NMR (曱-d4) δ: • 7·94 (4) 2Η), 7.89 (d, 1Η), 7.58 (d, 1Η), 7.35 (m, 6Η), 4.36 (m, 1H), 4.12 (m, 1H), 3.98 ( m, 1H), 3.12 (s, 3H), 2.94 (s, 3H), 2.83 (m, 2H), 2.42 (m, 1H), 1.89 (m, 2H), 1.04 (m, 3H),, 0.59 ( m, 1H). LCMS (m/z, ES+) = 577 (M+H). Example 68 5-Cyclopropyl-6-(N-(2-(4-fluoro-1-hydroxy-l,3-dihydrobenzoxoxalin-3-yl)ethyl)methyl Amidoxime)_2_(4·fluorophenyl)_N-methylbenzofuran-3-decylamine 154007.doc •275· 201221131

Add brominated (vinyl) magnesium to a solution of 2-di-6-fluorobenzate (5 g, 24 6 _〇1) in anhydrous THF (100 mL) at -40 C (27^ mL, 27·1 mmol, i M/L). After stirring at this temperature for 3 minutes, the reaction mixture was warmed to room temperature and poured into ice/water (15 mL). The aqueous layer was extracted with EtOAc (3 mL EtOAc)EtOAc. After removal of the solvent, it gave 1-(2-bromo-6-fluorophenyl)propan-2-diol (5 2 g, 22 5 mm 〇1, 94% crude yield) as a pale yellow oil. . LCMS (m/z, ES+) = 232 (M+H) Step 2: (1-(2-bromo-6-fluorophenyl)-propenyl) (t-butyl) dimethyl sulphur To a solution of 1-(2-bromo-6-fluorophenyl)propan-2-low-1-ol (5.2 g, 22.5 mmol) in DCM (100 mL) EtOAc. 24.7 mmol) and imidazole (2.3 g, 33.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hr. The reaction mixture was poured into water (丨 5 mL). The aqueous layer was extracted with DCM (3×1 mL) and the combined organic layer dried over anhydrous Na? After removal of the solvent, it yielded (2-(bromo-6-fluorophenyl)allyloxy)(t-butyl)didecyldecane as a yellow oil (6 5 g, 18.8 mmob 84 % crude product). LCMS ES ES+) = 346 (M+H) Step 3: 3-(2-Bromo-6-fluorophenyl)-3-(t-butyldimethylmethylalkyloxy) 154007.doc •276· 201221131 Propan-1-ol to (1-(2-di-6-danophenyl)-dipropoxy)(t-butyl)dimethyl sulphur (6.5 g' 18.8 mmol) at room temperature 9-BBN (4.64 g, 20-7 mmol) was added to the solution in THF (118 mL) and the reaction solution was stirred at room temperature for 4 hr. After the reaction solution was cooled to 〇 ° C, NaOH (54 mL, 3 N/L) and H 2 〇 2 (54 mL, 30%) were added dropwise and stirred at room temperature for 2 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAcEtOAc The combined organic layer was washed with H2〇 (3x 100 mL). After removal of the solvent, it gave 3-(2-bromo-6-fluorophenyl)-3-(t-butyldifluorenyloxy)propan-1-ol (6.2) as a colorless liquid. g, 17.1 mmol, 91% yield). Step 4: (3-Bromo-1-(2-bromo-6-fluorophenyl)propoxy)(t-butyl)dimethyl sulphate to 3-(2--6- under nitrogen) 1 phenyl)-3-(t-butyldidecyl fluorenyloxy)propan-1-ol (6.2 g, 17.1 mmol) and NBS (6.09 g, 34.2 mmol) in DCM (100 mL) A solution of pph3 (8.9 g, • 34.2 mmol) in DCM (10 mL) was then evaporated. The reaction mixture was poured into ice/water (100 mL) andEtOAc. The combined organic layers were dried over anhydrous NaiSO4. After removing the solvent, the crude product was purified by column chromatography to yield (3-bromo-1-(2-bromo-6-fluorophenyl)propoxy)(t-butyl)didecyldecane (5.1) g, 12 mmol, 70% yield). Step 5: 6-(N-(3-(2-Bromo-6-fluorophenyl)-3-(t-butyldimethyl fluorenyloxy)propyl)methylsulfonylamino)· 5-Cyclopropyl-2-(4-fluorophenyl) benzofuran-3-carboxamide was heated at 80 ° C under nitrogen atmosphere (3-bromo-1 -(2-bromo-6-fluoro) Stupid) propoxy 154007.doc • 277- 201221131 base) (t-butyl) dimethyl decane (1·26 g, 2_97 mm〇l), 5-cyclopropyl -2-(4-fluorophenyl) -N-methyl_6_(nonylsulfonylamino)benzofuran_3_decylamine (1 g, 2.48 mmol), K2CO3 (0.68 g, 4.96 mmol) and oxime (0.41 g, 2.48 mmol) a solution in DMF (20 mL) for 2 hours. After cooling the mixture to room temperature, water was added and extracted with EtO Ac. The combined organic layers were dried over anhydrous NazSO4. Purification to give 6-(JV-(3-(2-bromo-6-fluorophenyl)-3·(t-butyldimethylsilyloxy)propyl)methylsulfonate as a white solid醯 ) ) 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC ES+) = 737 (M+H) Step 6: 6-(N-(3-(2-Bromo-6-) Phenyl)-3-hydroxypropyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-~N-methylbenzofuran-3-carboxamide at 45 Stir 6-(Ν-(3-(2-bromo-6-fluorophenyl)-3-(t-butyldidecylfluorenyloxy)propyl)methylsulfonylamino)- 5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1.5 g, 2.03 mmol) and HCl (5 N aqueous solution '15 mL, 75 mmol) The solution was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. -(#-(3-(2-Bromo-6-fluorophenyl)-3-hydroxypropyl)decylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-indole -methylbenzofuran-3.carboxamide (1.1 g, 1.72 mmol, 85% yield) Step 7: 5-cyclopropyl-6-(N-(2-(4-fluoro-1-hydroxy) -1,3-dihydrobenzo[c][l,2]oxaborol-3-yl)ethyl)indolylsulfonylamino)-2-(4-indolyl-indole Benzo benzoin-3-cartoamine 154007.doc •278- 201221131 Heating 6-(#-(3-(2-bromo-6-fluorophenyl)-3) at 90 ° C under nitrogen atmosphere - Propyl)methylsulfonylamino)_5·cyclopropyl-2-(4-fluorophenyl)-iV-methylbenzofuran-3-decylamine (1.1 g, 1.72 mmol), PdCl 2 ( Dppf) (36 mg, 0.05 mmol), dppf (27 mg, 〇·〇 5 mmol), KOAc (237 mg, 1.72 mmol) and Pin2B2 (655 mg, 2.58 mmol) in dioxane (50 mL) 1 hour. The mixture was poured into ice/water (5 〇 mL). The aqueous layer was extracted with EtOAc (3×50 mL). After removal of the solvent, the crude material was purified by reverse phase HPLC to yield 5---propyl-propyl-6-(N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzene) as a white solid. And [d[l,2]oxaborol-3-yl)ethyl)methylsulfonylamino)_2_(4-fluorophenyl)-N-indenylbenzofuran-3-3- Guanidine (2 mg, 0.34 mmol, 20% yield). 4 NMR (300 MHz, methanol-d4) δ: 7.94 (m, 2 H), 7.73-7.68 (d, 1 H), 7.43-7.32 (m, 2 H), 7.27-7.07 (m, 4 H), 5.48-5.40 (m, 1 H), 4.12-3.78 (m, 2 H), 3.14 (d, 3 H), 2.94 (s, 3 H), 2.46-2.35 (m, 2 H), 1.81-1.68 ( m, 1 H), 1.07-0.90 (m, 3 H), 0.69-0.57 (m, 1 H); LCMS (m/z ES+)=581 (M+1)° Example 69 5-cyclopropyl-6 -(Ν-(2-(5.fluoro-lhydroxy·1&gt;3_dihydrobenzo[c][i,2]oxaborol-3-yl)ethyl)methylsulfonate Amino)_2_(4-fluorophenyl)_N_methylbenzotrile-3. Alanine 154007.doc -279- 201221131

Step 1: 1-(2-Bromo-5-fluorophenyl)prop-2-en-1-ol to 2-bromo-5-fluorobenzaldehyde (5 g, 24.6 mmol) at -40 C under nitrogen atmosphere Bromine (vinyl) magnesium (27.1 mL ' 27.1 mmol ' 1 M) was added dropwise to a solution of anhydrous THF (100 mL). The reaction mixture was stirred at this temperature for 30 minutes and then warmed to room temperature. The reaction mixture was poured into ice/water (150 mL)EtOAc. The organic layer was washed with brine (50 mL) and dried over anhydrous Nad. After removal of the solvent, it yielded 1-(2-bromo-5-fluorophenyl)propan-2-ene-1-ol (5.9 L, 25.5 111111 〇1, 98°/. Yield). Step 2: (1-(2-Bromo-5-fluorophenyl)allyloxy)(t-butyl)dimethyl zexi pit at 0 C to 1-(2-bromo-5-fluorobenzene A solution of propyl-2-ene-1-alcohol (5.9 g, 25.5 mmol) in DCM (100 mL) EtOAc (t. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hr. The reaction mixture was poured into water (15 mL) and extracted with DCM (3.times. The combined organic layers were dried over anhydrous Na.sub.2.sub.4. The solvent was removed under reduced pressure to give (y-(2-bromo-5-fluorophenyl)allyloxy) (t-butyl) dimethyl decane 2 g, 18 mm 〇1, as a colorless liquid. 72% crude yield). Step 3: 3-(2-Bromo-5-fluorophenyl)-3-(t-butyldimethylmethylalkyloxy) 154007.doc 280· 201221131 Propan-1-ol at room temperature (1 Add (2-bromo-5-fluorophenyl)allyloxy) (t-butyl) dimethyl oxime (6.2 g, 18 mm 〇i) in THF (100 mL) ΒΒΝ (4·2 g, 18.8 mmol). After stirring at room temperature for 4 hours, the reaction was cooled to 0 ° C then slowly Na Na H (54 mL, 3 N/L) and EtOAc 2 (54 mL, 30%) and then at room temperature Stirring was maintained for another 2 hours. The reaction mixture was quenched with EtOAc (EtOAc) The combined organic layers were washed with H.sub.2 (3.times.s. After the solvent was removed, the crude product was purified by column chromatography (Pe: ea = 1:1) to yield 3-(2-bromo-5 fluorophenyl) _3 as a colorless oil. Methylglycolyloxy)propan-1-ol (5 g, 13.8 mmol, 77% yield). Step 4: (3-Bromo-1-(2-bromo-5-fluorophenyl)propoxy)(t-butyl)dimethyl zexi pit to 3-(2-bromo-5) under nitrogen atmosphere -fluorophenyl)-3-(t-butyldidecylfluorenyloxy)propan-1-ol (5 g, 13.8 mmol) and NBS (4.9 g, 27 ό mmol) in DCM (100 mL) A solution of pph3 (72 g, 27.6 mmol) in DCM (1 mL) was added dropwise and stirred at room temperature for hrs. The reaction solution was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried over anhydrous Naj. After removal of the solvent, the crude product was purified by column chromatography (PE: EA = 1 : 100) to yield (3 bromo 5-fluorophenyl)propoxy) (t-butyl) dimethyl decane ( 5 2 g, 12 2 mm 〇 1, yield). Step 5: 6-(N-(3-(2-Bromofluorophenyl)·3_(t-butyldimethylsulfonyloxy)propyl)methylsulfonylamino)_5_cyclopropyl _2_(4_Fluorophenylmethyl 154007.doc -281 - 201221131 Benthofuran-3-carboxamide was heated at 80 ° C under nitrogen atmosphere (3-bromine_ι·(2_bromo_5_) Fluorophenyl)propoxy)(t-butyl)-indenyl sulphate (1.26 g, 2.97 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl- 6- Benzene bites „南_3_carbamamine (1 g, 2.48 mmol), K2CO3 (0.68 g, 4.96 mmol) and KI (〇.41 g ' 2.48 mmol) in DMF (50 The solution was stirred for 2 hours. The reaction mixture was poured with EtOAc EtOAc (EtOAc (EtOAc) Purification by column chromatography to give 6-(N-(3-(2-bromo-5-fluorophenyl)-3-(t-butyl-didecyl fluorenyloxy)propyl)methyl decylamine Base)_5_cyclopropyl_2_(4-amino)-N-methylbenzo.Funan_3_decylamine (1.5 g, 2 mmol, 80% yield). LCMS (w/z , ES+)=737 (M+H) Step 6: 6-(N-(3-(2-Bromo-5-fluorophenyl) 3-Hydroxypropyl)methyl hydrazinyl) 5-cyclopropyl-2-(4-fluorophenylmercaptobenzofuran-3-carboxamide) heated at 80 C 6-(N- (3 - (2- &gt; Omega-5-phenyl)-3-(t-butyldimethylsilyloxy)propyl)methylsulfonylamino)-5-cyclopropyl-2 -(4-Fluorophenyl)-N-methylbenzopyrene _3-carbamidine (1.5 g, 2 mmol) and HC 1 (15 mL '75 mmol, 5 Μ) in THF (30 mL) The solution was extracted with EtOAc (3×50 mL). The combined organic layer was dried over anhydrous Na.j. -Bromo-5-fluorophenyl)-3-hydroxypropyl)methylsulfonylamino)-5-cyclopropyl-2- 2-(4-fluorophenylmercaptobenzofuran-3-carboxamide) 1.1 g, 175 mmol, 85% yield). Step 7: 5-cyclopropyl-6-(n-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo 154007.doc 201221131) [C][1 '2]oxachocyclopentene_3_yl)ethyl)methylsulfonylamino)_2_(4_dendylphenyl)-N-methylbenzofuran_3 formazan The amine is heated under nitrogen at 90 C 6_(#_(3_(2_bromo-5-fluorophenyl)_3_hydroxypropyl)methyl hydrazide))5·cyclopropyl_2_(4 _Fluorophenylmethylbenzofuran 3-formamide (1.1 g 'i_75 mm〇i), pdci2 (dppf) (36.5 mg '0.05 mmol), KOAc (724 mg, 5.25 mmol) and Pin2B2 (889 mg ' 3.5 mmol) of the solution in dioxane (5 mL) for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase hplc to give 5-cyclopropyl-6-(-(2-(5-fluoro-1-hydroxy-1,3-dihydro)[c][ 1,2]oxaborol-3-yl)ethyl)indolylsulfonylamino)-2-(4-fluorophenyl)-#-methylbenzofuran-3-decylamine (1 〇〇 mg, 0.17 mmol, 12% yield). NMR (300 MHz, sterol _44) 3: 7.94 · 7.89 (m, 2 Η), 7.72-7.59 (m, 2 Η), 7.27-6.94 (m, 5 Η), 5.30-5.22 (m, 1 Η ), 4.11-3.82 (m, 2 Η), 3.13-3.11 (d, 3 Η), 2.94 (s, 1 Η), 2.45-2.28 (m, 2 Η), 1.82-1.67 (m, 1 Η), 1.07-0.92 (m, 3 H), 0.68-0.60 (m, 1 H). LCMS (m/z, ES+) = 581 (M+1). Example 70 5-Cyclopropyl-6-(Ν·(2-(6-fluoro-1-alkyl-1,3-dihydrobenzo[c][i,2]oxaster heterocyclopentene- 3-yl)ethyl)methylsulfonylamino)-2-(4-fluorophenyl)-N-mercaptobenzopyran-f-___-------

Step 1: 1-(2-Bromo-4-fluorophenyl)prop-2-en-1-ol to 2-bromo-4-fluorobenzaldehyde (1〇2 g, under a nitrogen atmosphere at 〇 ° C 5 〇mm〇l) (BeihUa) bromo(vinyl)magnesium (5 〇mL, 5 〇mmol, 1 M) was added dropwise to a solution of anhydrous THF (丨〇〇 mL). The reaction mixture was stirred at this temperature for 1 hour and then warmed to room temperature for an hour. The reaction mixture was poured into aq. EtOAc (3 mL). The organic layer was washed with water (200 mL), brine (200 mL) and dried

NaaSO4 is dry. After removal of the solvent, it gave bromo-4-fluorophenyl)prop-2-y-1-ol (11.9 g, quantitative) as a yellow oil. Step 2: (1-(2-Bromo-4-fluorophenyl)allyloxy)(t-butyl)-rhologine Xikeng under 〇C to 1·(2-di-4 fluorophenyl) To a solution of propyl-2-di-1-ol (5.9 g, 25.5 mmol) in DCM (100 mL), TBSC1 (9.33 g, 61.8 mmol) and imidazole (7.00 g, i 〇 3 mm 〇i) were added. The reaction mixture was warmed to room temperature and maintained under a tax mixture for 2 hours. The reaction mixture was poured into water (5 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.sub.sub.sub. Butyl) dimethyl decane (14.45 g, 82% yield). Step 3: 3-(2-Bromo-4-fluorophenyl)-3-(t-butyldimethylmethylalkyloxy) 154007.doc -284· 201221131 Propyl alcohol at room temperature (1- (2-Bromo-4-fluorophenyl)allyloxy) (t-butyl) dimethyl sulphur (6.9 g, 20 mmol) in THF (100 mL) was added 9 ΒΒΝ (2) · 93 g, 12 mmol). After stirring at room temperature for 7 hours, the reaction was cooled to (TC, then Na.sub.2H (90 mL, 1 N/L) and EtOAc 2 (230 mL, 30%) was slowly added and then stirred at room temperature The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. After the solvent was removed, the crude product was purified by column chromatography to yield 3-(2-bromo- 4-fluorophenyl)_3_(t-butyl-methyl- s. 1-propanol (4.4 g, 60 〇/〇 yield) Step 4: (3-Bromo-1-(2-bromo-4-fluorophenyl)propoxy)(t-butyl)dimethyl Shi Xizhuo to 3-(2-bromo-4-fluorophenyl)·3-(t-butyldimethylmethylalkyloxy)propan-1-ol (4.4 g, 12.1 mmol) under nitrogen atmosphere NPC (4.3 g, 24.2 rummol) was added dropwise EtOAc (EtOAc) (EtOAc) (100 mL) was quenched and extracted with DCM (3×1 mL). After removal of the solvent, the crude product was purified by column chromatography to yield (3-bromo-bromo-bromo-4-phenylphenyl)propoxy) (t-butyl)-methyl- 3.3 g, 64% yield). Step 5: 6-(N-(3-(2-Bromo-4-fluorophenyl)-3-(t-butyldimethylphenyl phenyloxy)propyl)methylsulfonylamino)- 5-cyclopropyl_2·(4-fluorophenyl)_N_methyl benzofuran-3-methyl decylamine 154007.doc •285· 201221131 Heating at 8 〇C under gas and gas ( 3-&gt;Smelly-1-(2-&gt; Odor-4-Phenylphenyl)propoxy)(t-butyl) dimethyl sulfoxide (1.28 g, 3 mmol), 5-cyclopropyl- 2-(4-Fluorophenyl)-N-methyl-6-(indolylsulfonylamino)benzofuran-3-indoleamine (1 g '2.5 mmol), K2CO3 (1.03 g, 7.5 mmol) And a solution of KI (0.415 g, 2.5 mmol) in DMF (50 mL) for 2 h. The reaction mixture was poured into ice/water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL) andEtOAc. After removal of the solvent, the crude product was purified by column chromatography to give 6-(N-(3-(2-bromo-4-fluorophenyl)-3-(tert-butyldifluorenyl)oxyl Propyl) decylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran_3·cartoamine (1.72 g, 92% yield) . LCMS (w/z, ES+) = 747.0 (M+H). Step 6: 6-(Ν·(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)methylsulfonylamino)_ 5-cyclopropyl-2-(4-fluorobenzene -N-Mercaptobenzofuran_3_formamide to 6-(N-(3-(2-bromo-4-fluorophenyl)_3_(t-butyldidecyldecane) at room temperature氧基oxy)propyl)methylsulfonylamino)_5_cyclopropyl_2_(4-fluorophenyl)_N-mercaptobenzopyrene_3·carbamidamine 5 g, 2 with. HC) HCbX solution (5 N, 15 mL, 75 mm 〇i) was added dropwise to the solution in thF (15 °) and then heated at 8 ° C for 15 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous and concentrated in vacuo to give a white solid. </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; _ gas phenyl) nasal methyl benzofuran-3 methamine (1.1 g, 85%). Step 7: 5-cyclopropyl-6-(Ν·(2_(6-fluorosm-m-)-dihydrobenzo[c][L2]oxaborol-3,ethyl)f-based Continued hydrazine-based) Winter (heart 154007.doc 201221131 Stupid thiol and furan_3_carbamamine 6-(Ν-(3·(2-bromo-4-fluorophenyl)-3-hydroxypropyl) Methylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)_N-methylbenzofuran_3_decylamine (1"g, J 72 mmol), PdCl2 (dppf) (36.5 mg, 0.05 mmol), KOAc (724

A solution of mg, 5.25 mm 〇l) and Pin2B2 (889 mg '3 5 mm 〇1) in dioxane (5 〇 mL) was degassed and refilled with nitrogen three times and then at 9 Torr. The underarm was heated under nitrogen and oxygen for 1 hour. The cadaver was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give 5-cyclopropyl-6-((-(2-(6-fluoro-1-hydroxy-1,3-dihydro)). Cyclopenten-3-yl)ethyl)decylsulfonylamino)2-(4-fluorophenyl)-indole-tauylbenzofuran-3-decylamine (180 mg '21%). 4 NMR (300 ΜΗζ, Methanol·^) 5=7.94-7.89 (111,2 11), 7,72-7.59 (01,211), 7.27- 6*94 (m5 5 Η), 5.30-5.22 (m, 1 Η ), 4.11-3.82 (m, 2 Η), 3.13-3·Π (d, 3 Η), 2.94 (s, 1 Η), 2.45-2.28 (m, 2 Η), 1.82-1.67

(m,1 Η), 1.07-0.92 (m,3 Η), 0.68-0.60 (m,1 Η). LCMS (w/z, ES+) = 581 (Μ + Η). Example 71 5_Cyclopropyl-2-(4-fluorophenyl)-6-[{[(4R)-2-hydroxy-1,2-oxo boron-flavor] 4-methyl}(methylsulfonate) Amino]-indole-methyl-1-benzofuran-3-carboxamide: an alternative synthetic scheme for Example 8

Ν, Ό 154007.doc •287· 201221131 Stage 1: (4R,5S)-4-methyl-5-phenyl-3-[3_(44,55_tetramethyl_1&gt;32_ diborate _ 2_base) propyl alcohol stagnation _2 ketone stirred at a temperature to the third sodium butoxide (〇 419 g, 4 36 DPEPhos (0.783 g ' 1.453 mmol) and copper chloride (1) (0144 g, 1.453 mmol The suspension in THF (50 mL) was cooled to hydrazine, and treated with bis(pinadol) diboron (12.91 g, 50.9 mm 〇l) (in 50 mL THF). Stir for 45 minutes and then add (4R,5S)_3_propenyl _4_methyl_5•phenyl d,% oxazolidine-2-one (li2 g, Μ.# mmol) (in THF) , 50 mL) and the solution was warmed to room temperature and maintained for 3 hours under mixing. The mixture was passed through a glass filter paper, diluted with diatomaceous earth, concentrated, and purified by column chromatography to give a white solid (4R , 5S)_4_methyl-5-phenyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)propanyl] - 1,3- ° ° ° sit ketone (8.13 g ' 22.63 mmol, 47% yield). ijj NMR (methanol-d4) d: 7.30-7.47 (m, 5H), 5.78 (d, J=7 4 Hz, 1H), 4.77 (t, J=6. 9 Hz, 1H), 2.88-3.14 (m, 2H), l, 16-1.3〇 (m, 12H), 0.95 (q, J—6.5 Hz, 2H), 0.83 (d, J=6.6 Hz, 3H) Stage 2: (2R)-3-[(Benzyl)oxy]-2-[(4,4,55 tetramethyl-132•dioxoxan-2-yl)methyl]-1- Propyl alcohol cooling (4R,5S)-4-methyl-5-phenyl-3-[3-(4,4,5,5-tetramethyl-1,3 2 dioxane-2-yl) A solution of propylidene-2-yl ketone (5. 〇g, 丨3 % mmol) in DCM (69.6 ml) and then DCM with 1 M Tic (16.70 ml) ' 16.70 mmol). Stir the yellow reaction for 1 ' ' then add DIEA (3.04 m s 17.40 mmol) to the reaction. After stirring at 0 ° C, with MeOH (. 154007.doc • 288-201221131 mmol) The reddish reaction was treated. The mixture was slowly warmed to room temperature with stirring for 2 hours. The reaction was treated with DCM, saturated aqueous ammonium sulfate and water. The layers were separated and the combined organic layer was washed with sat. The crude residue was dissolved in THF (41.5 ml) and MeOH (0.43 (6), EtOAc (EtOAc: EtOAc) The solution was treated with EtOAc (aq. EtOAc EtOAc (EtOAc m. Purification by column chromatography (4 〇g), elution with 〇_3〇% Et〇Ac/hexane, yielding (2R)_3_[(m-methyl)oxy]_2_[( 4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)methyl]propanol. ιΗ &gt;JMR (sterol-(14)〇1:7_22-7.38 (111, 511), 4.48 (3, 211), 3.51 - 3.59 (m, 1H), 3.41-3.51 (m, 2H), 3.33-3.41 (m, 1H), 3.26-3.33 (m, 1H), 2.02 -2.11 (m, 1H), 1.20 (d, J = 2.9 Hz, 12H), 0.75. (dd, J = 7.2, 2.9 Hz, 2H) Stage 3: 5-cyclopropyl-2-(4-fluorobenzene Methyl-6-((methylsulfonyl){(2R)-3-[(benzyl)oxy]-2-[(4,4,5,5-tetramethyl-1,3, 2-Bisboroin-2-yl)methyl]propyl}amino)_ι_benzoxazone A. in 〇°C Maintenance of 5-cyclopropyl-2-(4-fluorophenyl)-indole-yl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (175) with stirring Mg, 0.435 mmol), (2R)-3-[(phenylhydrazino)oxy]-2·[(4,4,5,5-tetradecyl-1,3,2·dioxaborene-2 a solution of hydrazino]-1-propanol (233 mg, 0.761 mmol) and triphenylphosphine (257 mg '0.978 mmol) in tetrahydrofuran (5 mL) with 154007.doc -289· 201221131 DIAD (0.169 The mixture was warmed to room temperature, maintained under stirring for 16 hours, diluted with diatomaceous earth, concentrated, and the residue was adsorbed on diatomaceous earth and chromatographed by column chromatography (20 to Purification of 50% EtOAc / hexanes to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl as a white foam of NMR/LCMS. 6-((Methanesulfonyl) {(2R)-3-[(phenylhydrazino)oxy]-2-[(4,4,5,5-tetradecyl-1,3,2-dioxo) Benzene-2-yl)methyl]propyl}amino)·ι_benzofuran_3_decylamine (235 mg '0.340 mmol, 78% yield). Stage 4: 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[(4R)-2-hydroxy-1,2·oxaborin-4-yl]methyl} (methane)醯-)Amino]_N_methyl·benzafuran_3_formamide maintained 5_cyclopropyl_2_(4-fluorophenyl)-N- under rapid stirring at 40 psig of hydrogen Methyl-6-((methyl hydrazino) {3-[(phenylhydrazino)oxy]_2_[(4,4,5,5-tetramethyl-i,3,2-dioxaborazole- 2-yl)methyl]propyl}amino)-benzo-3-folly-3-carboxamide (.600 g '0.869 mmol) and l〇〇/0 Pd/C (Degussa type (wet () 300 mg, 0.869 mmol) in tetrahydrofuran (1 () mL). The mixture was filtered through celite, concentrated under reduced pressure and dissolved in tetrahydrofuran (10 mL / 5.0 N HCl (aq) (1.216 mL ' 6 〇 8 mmol), and ps-benzene g-p-acid (2.6 668 g, 4 34 mmol). The mixture was stirred at room temperature for 2 hours, filtered over celite, concentrated, and partitioned between di-methane and HCI (pH &lt;3). 'Concentrate to a residue under reduced pressure, and purified by column chromatography to give a white foam as a purity of &lt;95% and ee%&gt; 95% as determined by palm chromatography. 5_cyclopropyl_2·(4_gasphenyl)_6_ 154007.doc 201221131 [{[(4R)-2_hydroxy_ι,2_oxaborin-4-yl]methyl}(sulfonium sulfonate) Amino]]N-methyl-1-indole oxime. South 3-mercaptoamine (297 mg '0.5 94 mmol, 68.3% yield). NMR spectral properties and retention time using palmitic HPLC and The nmr spectral properties and residence time were consistent from the earlier dissolving enantiomers of Example 8. The residue was dissolved in acetonitrile/water, chilled, and stored on a / dry sump for 16 hours to yield a liquid white solid. . The absolute configuration is specified as 4r based on VCD spectroscopy; the theoretical energy level: # 〇ΝΙ〇Μ method, b3pw 91/6-311+g (2df) is applied to S〇2, and Β3ίγρ/ 6 3 11 G (d, p) applied to the rest of the molecule. The designation is consistent with the expected non-stereo induction from the alcohol brewing step of Example 1. Example 72 2-(4-Phenylphenyl)_5_cyclopropyl_6•[丨2_(6 • Fluorohydroxy 13-dihydro 21 benzoxaborole-3-enyl)ethyl](methylsulfonyl)amino]_N-methyl-^benzofuran-3-carboxamide

Can be directly analogous to the manner of preparation as described in Example 69

]54007.doc •291 - 201221131 -1-benzofuran-3-carboxamide. Example 73 2-(4·Phenylphenyl)-5-cyclopropyl-6-indole [2-(1-hydroxy·ι,3-dihydro-2, iota-benzoxanthene)- 3-yl)ethyl](methyl aryl)amino]_ν_methyl_ι_benzofuran-3-carboxamide

Can be directly analogous to the preparation described in Example 69 by using 5-cyclopropyl-2-(4-phenylphenyl)-7V-methyl-6-[(methylsulfonyl)amino]-b Benzofuran-3-indoleamine (synthesis described in Example 34) instead of 5-cyclopropyl-2_(4-fluorophenylmethyl**6-[(oxasulfonyl)amino]-1- And furan-3-decylamine to prepare 2♦ gas phenyl)·5·cyclopropyl-6·[[2-(1-pyridyl-1,3-dihydro-2,1-benzene^oxa Shi Peng heterocyclic pentacene _3-yl) ethyl hydrazine hydrazine) amino group] good methyl + Benxifufu-3 - ugly amine. Example 74 6·[[2_(6-Gas-1---l-1,3-dihydro-2,1-benzooxaborole-3-yl)ethyl] Amino group]·2·(4·gasphenyl)-5-cyclopropyl-indole-methyl·1-benzofurancarboxamide

CI

154007.doc •292-201221131 can be directly analogous to the preparation described in Example 69 by using 5-cyclopropyl-2-(4-chlorophenyl)-^/~methyl-6-[( Amidino)amino]_1_stupid and cough&quot;South-3-carbamamine (synthesis described in Example 34) instead of 5_cyclopropyl-2·(4·gasphenyl)-#-methyl- Preparation of ό-[[2-(6-Ga-1-yl-l-1,3-dihydro-2,1) by 6-[(methylsulfonyl)amine oxime benzofuran_3_formamide -benzoxoxaborolide-3-yl)ethyl](methylsulfonyl)amino]_2_(4_acetoyl)_5_cyclopropylmethyl-1-benzoxofan -3 - Alanine. Bioassay Transfers 150 μί 1 mM of each test compound in DMSO to the first row of a 96-well V-bottom microplate based on the Replico n Lucifer as e cell assay method. To produce a concentration that is 200 times the highest concentration of the desired dilution series. An aliquot of 50 was added to each of the remaining rows containing 100 g of LDMSO to produce a 1:3 dilution series over 1 point. Lines 11 and 12 contained only DMSO for positive and negative controls, respectively. Transfer 10 pL of each well to 90 μί supplemented with 5% v/v fetal bovine serum, 1% ν/ν non-essential amino acid solution, 100 units/ml penicillin (penicillin), 100 pg/ml streptomycin (strept) 〇myCin) and 2 mM L-glutamic acid in DMEM medium (Invitrogen #41965-039) to produce a concentration 20 times the highest concentration of the desired dilution series. For replicon detection, the lb genotype linked to the firefly luciferase reporter gene is used (by Pietschmann, T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter). , G., Strand, D. and

Bartenschlager, R., Journal of Virology, 2002, 76, 4008-154007.doc -293 - 201221131 4021 described ET cell line), la genotype (self-constructed sub-cell line 1.19) or lb C316N genotype (self Construction of the subgenomic hCv NS3_NS5B replicon stably transfected Huh-7 cells. The nearly confluent monolayer cells were stripped from the growth flask with EDTA versene-trypsin solution and the cells were resuspended in assay medium containing DMEM. Or prepare a frozen cell stock and verify that its function is comparable to fresh cells. The frozen cells from the liquid nitrogen tank were quickly dissociated in a 37 ° C water bath and transferred to a large conical tube, and complete medium was added dropwise to the conical tube. The cells were centrifuged at 1 K rpm for 5 minutes and resuspended in complete medium. The trypsin-treated cells or resuspended cold-bed cells are counted and diluted to the appropriate concentration for testing purposes. Add 95 pL of a suspension containing 15,000 cells (ib genotype luciferase replicon) or 20,000 cells (la genotype luciferase replicon) to all wells of a 96-well plate (Perkin Elmer, #6005686) Medium, except for the medium control in the 12th row of the test plate. The 5 compound solution was added to the cell suspension and the assay plate was incubated at 37 t: in a 5% CO 2 atmosphere for 48 hours. When testing for toxicity, cells from one assay plate were treated with Cell Titer Glo (Promega ' #G7573). A solution of Cell Titer Glo was prepared according to the manufacturer's instructions and 1 〇〇 pL was added to each well. The fluorescence of the assay plate is then read on Envision. A solution of Steady Glo (Promega ' #E2550) was prepared for potency according to the manufacturer's instructions and loo pL was added to each well. After 20 minutes of incubation, the plate was then read on Envision for fluorescence. Data analysis 154007.doc -294· 201221131 Human poisoning. The average absorbance of the control wells from the two wells is expressed as the percentage of the average absorbance of the control wells to determine relative cell viability. ♦ (eeU viability). The cytotoxicity of the compound is expressed as the observed viability, the lowest concentration or the 50% toxic concentration (CCID5G), which is the percentage of cytotoxicity relative to the compound concentration by using ActivityBase (IDBS software). Plotting and curve fitting via XC5(R) module to determine beta potency: averaging fluorescence values from all wells containing cells containing no cells to obtain positive control values. Holes containing no compounds from unreceived cells The mean fluorescence value is used to provide a negative (background) control value. The readings for each well are subtracted from the background value and all values are expressed as a percentage of the positive control signal. The luciferase is present in the presence of the drug. The quantifiable and specific reduction of the signal is a direct measure of replicon inhibition. BioAssay Enterprise (CamebridgeSoft) with XC50 module for curve fitting is used to plot the percent inhibition versus compound concentration and derive the 50% inhibitory concentration of the compound. (ICso). Average the EC5 enthalpy obtained from duplicate plates. The results are shown in Table 1. Most test combinations Proven to combat NS5B-3 16Ν activity and wild type

NS5B-316C is dedicated or close. NS5B-316N is a polymorphic change on residue 3 16 that occurs in approximately 40% of HCV 1 b genotype patients and thus the compound exhibits activity against NS5B-316N. 154007.doc •295- 201221131 Table 1 Example number la wild type (nM) lb wild type (nM) lb316N(nM) 1 ** 氺2 氺氺本氺氺3 ♦ * 4 **冰5 丰氺氺幸氺氺6 本** * 7 Η(氺氺8 本本本氺氺* 9 *♦本氺丰伞本* 10 *氺氺氺氺氺氺氺氺11 本本*幸12 *本幸氺幸承13 氺氺* ND 14 Fortunately φ 15 氺 φ φφ This 16 氺氺 φ * This 17 氺氺 氺 18 ♦ ♦ 氺 本 19 19 ** 20 孝氺幸氺氺氺氺* 21 ** ** 22 氺氺23 φ氺本氺♦♦ 氺本24 氺氺氺&gt;1500 25 * Umbrella&gt;1500 26 * * &gt;1500 27 ♦氺氺28 Fortunately*Ψ 29 ** ♦丰* 氺* 30 Fortunately, fortunately, φ

154007.doc -296- s 201221131

31 氺氺* 32 氺氺氺氺33 氺氺*** 氺氺34 **氺氺本氺35 氺*本36 氺本♦氺* 37 氺氺幸*本氺*氺38 氺伞氺本氺39 *氺氺本氺氺40 本φ氺氺幸φ氺41 本本φ 42 Ψ氺氺氺氺43 氺氺氺44 ***本本_ 氺幸氺45 氺Φ氺*丰氺氺氺46 ** 氺氺本47 氺氺丰氺幸氺氺48 *** ** 49 丰幸氺氺幸氺氺氺50 本氺*♦* ** 51 ** Fortunately, Cheng Hao 52 氺 umbrella umbrella *** * Fortunately本53 氺氺幸丰氺* 氺氺本54 ** 氺氺孝氺氺55 氺氺木氺氺氺氺本56 氺* * 57 氺氺氺本本 ND 58 He* umbrella*** 59 *氺氺丰水木氺60 氺氺 Umbrella 氺 氺氺 61 氺 氺氺 Umbrella 氺氺 62 * 氺氺氺本 63 氺氺氺φ氺氺♦氺64 氺氺幸氺154007.doc -297 - 201221131 65 氺♦氺** 66氺氺67 氺氺孝φφ伞** 68 本*伞幸氺69 本氺幸70 本氺丰*氺

* 100-1500 nM ** 10-100 ηΜ *** &lt;10 ηΜ ND=not detected 154007.doc •298-

s

Claims (1)

201221131 VII. Patent application scope: 1. A compound of formula (1) X where: R1 is one or more substituents independently selected from the group consisting of dentate, Cb6 alkyl, alkoxy, _CN, _cf^〇r10, wherein R10 is an aryl group optionally substituted by ii; Is hydrogen, hydroxy, Cw alkyl or (: 3.6 cycloalkyl, wherein cN6 alkyl or C3. 6 cycloalkyl may be optionally substituted by hydroxy; ... is alkyl, C3.6 cycloalkyl or Cl-6 Alkoxy; R4 is -S(0)2R5, -C(〇)〇R5 or _C(0)NR6R7; ^ is 匚!.6 alkyl or (:3_6 cycloalkyl; R6 is hydrogen; R7 is Hydrogen or Cw alkyl; X is a C 1-6 alkyl group optionally substituted by Cw alkyl, hydroxy, amine or C 3 6 cycloalkyl; R 8 is (a) optionally selected by one or more A heterocyclic ring system (Het) substituted with a substituent of the following group consisting of: Cl_6 alkyl group, hydroxy 'fungel, aristolooxyl group, aryl group, -CF3 and -〇CF3; (b) OR9B (ORa) (〇Rb); or I54007.doc 201221131 (c) N(R5)R9B(〇Ra)(〇Rb); Ra and Rb are hydrogen or Cw alkyl, or when (^.6 alkyl, Ra and Rb, together with the oxygen atom to which it is attached, forms a 5 to 8 membered ring; R9 is an alkylene group substituted with a CN6 alkyl group as appropriate; A pharmaceutically acceptable salt. The compound of formula (I) according to claim 1, wherein: R1 is one or more substituents independently selected from the group consisting of halogen, Cu alkyl, alkoxy, _cn and -CF3; R2 is hydrogen, hydroxy, CN6 alkyl or C3_6 cycloalkyl, wherein C -6 alkyl or C 3 6 cycloalkyl may be optionally substituted by hydroxy; R is 匚!·6 alkyl, c3 .6 Cycloalkyl or (: 1.6 alkoxy; 尺 4 is _8(0)2115, -C(〇)〇R5 or -C(0)NR6R7; R is Cw alkyl or c3.6 cycloalkyl R is a gas; R7 is hydrogen or cU6 alkyl; X is a Cn6 alkyl group substituted by c, 6 alkyl, hydroxy, amine or c3-6 cycloalkyl, as appropriate; R8 is (a) as appropriate a heterocyclic ring substituted with one or more substituents independently selected from the group consisting of Cw alkyl and hydroxy; (b) 〇R9B(ORa)(〇Rb); or (c) N(R5)R9B (ORa)(〇Rb); Ra&amp;Rb is hydrogen; R9 is an alkylene group substituted by CN6 alkyl group as appropriate; I54007.doc 201221131 or a pharmaceutically acceptable salt thereof. (I) a compound, wherein: R1 is one or more independently selected from the following, and Substituents: halogen, -CF3 and -OR10, wherein Ri 〇 is an aryl group substituted by means of a conditional condition; R 2 is a C. 6 alkyl group optionally substituted by a hydroxyl group; R 3 is &lt;: 3-6 Cycloalkyl; R4 is -S(〇)2r5; "is 匚^alkyl; X is a C-alkyl group substituted by Cw alkyl as appropriate; R8 is (a) optionally selected from one or more selected from the group consisting of a substituent substituted heterocyclic ring: C1_6 alkyl, hydroxy, dentate, oxyalkyl, hydroxyalkyl, _cf3 and -ocf3; or (b) OR9B(〇Ra)(〇Rb); Ra&amp;Rb And a pharmaceutically acceptable salt thereof. The compound of the formula (1) according to any one of claims 1 to 3, wherein R1 is one or two. A compound of the formula (1), wherein R 2 is a Ci 6 alkane. 6. A compound of the formula (1) according to any one of items 1 to 3, wherein the compound of the formula (1) is any one of the above items 1 to 3. Wherein R3 is q俨alkyl. 6 &amp; 154007.doc 201221131 7. A compound of formula (I) according to claim 1 or 2, wherein r^_s(〇)2r5. 8. as claimed in claims 1 to 3. A compound of the formula (I), wherein X is a Cl-6 group. 9. A compound of the formula (la) Wherein: the ruler 3 is (^.6 alkyl, C3.6 cycloalkyl or CN6 alkoxy; R is (^_6 alkyl or C3-6 cycloalkyl; X is optionally C!·6 alkyl) a hydroxyl group, an amine group or a C3·6 cycloalkyl substituted Cl-6 alkylene group; R8 is U) a heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: Cl .6 alkyl, hydroxy, dentate, calcined carbonyl, hydroxyalkyl, -CF3 and -ocf3; (b) 〇R9B(〇Ra)(〇Rb); or (c) N(R5)R9B(〇Ra (〇Rb); R and Rb are hydrogen or Cl.6 alkyl, or when Ci δ alkyl, ... and hydrazine together with the oxygen atom to which they are attached form a 5 to 8 membered ring; R9 is optionally A C,6 alkyl-substituted alkylene group; or a pharmaceutically acceptable salt thereof. 10. A compound of the formula (Ia) according to claim 9 wherein: 154007.doc 201221131 R is 匚!·6 alkyl, (: 3_6 cycloalkyl or C!_6 alkoxy; r5 is cN6 alkyl or c3.6 cycloalkyl; X is optionally substituted by Cw alkyl, hydroxy, amine or C3-6 cycloalkyl -6 alkylene; R8 is (a) optionally heterocyclic ring substituted with one or more substituents independently selected from the group consisting of: Cl-6 alkyl and hydroxy; (b) 〇R9B(〇Ra)(〇Rb); or (c) N(R5)R9B(〇Ra)(〇Rb); Ra&amp;Rb is hydrogen; R9 is optionally substituted by Cu alkyl group Base; or a pharmaceutically acceptable salt thereof. 11. The compound of formula (1) or formula (Ia) according to any one of claims 1 to 3, 9 and 1 wherein R is optionally selected from one or more of Ci 6 alkyl, via, _ A heterocyclic ring substituted with a substituent of a group consisting of a hydrazine, an alkoxycarbonyl group, a hydroxyalkyl group, and an eh and a fluorene CF3 group. 12. A compound of formula (la) according to claim 9 or 10 wherein R3 is C3.6 cycloalkyl. The compound of any one of claims 1 to 3, 9 and 10, wherein r8 is a heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of Cw alkyl and hydroxy. 14. The compound of any one of clauses 1 to 3, 9 and 1 wherein the rule 8 is 〇R9B(〇Ra)(ORb). The compound of any one of items 1 to 3, 9 and 10, wherein R8 is N(R5)R9B(〇Ra)(ORb) 〇154007.doc 201221131 16 A compound selected from the group consisting of Group: [U2-[{2-(4-Fluorophenyl)-3-[(decylamino)carbonyl]_5_[(ι_methylethyl)oxy]-1-benzofuran_6•yl丨(Methanesulfonyl)amino]ethyl methoxy)indenyl]-acid; 5 %: propyl·2-(4-fluorophenyl)_6-[[(1-hydroxy-i,3- Dihydro-2,1_benzoxoxaborole-6-yl)indolyl](indolyl)amino]7-indolyl benzofuran-3-carboxamide; ring Propyl 2-(4-fluorophenyl)_6_[[(1•hydroxy-丨,3 dihydro-2, indolobenzooxaborolan-4-yl)methyl](methylsulfonyl) ) Amino]_N_methyl 4~ and. Furan-3·decylamine; stupid 5-cyclopropyl-2-(4-fluorophenyl)-6-[[(1-hydroxy-1,3-dihydro-^- stupid,--... Heterocyclic pentene-5-yl) fluorenyl](methylsulfonyl)amino]]N-methyl-opening 2-(4-hydroxy)(4)(1)hydroxy],3-dihydromyrene-4-yl Methyl](methylsulfonyl)amino]-N-methyl_5_[(1,methyl)oxy]-1-indolofuran_3.carbamamine; Ethyl 2-(4-fluorophenyl)_6·[[(1_hydroxy·), 3_dihydro-2, 丨_笨和oxahetyl)methyl](methylsulfonyl)amine ]-Ν-methyl_5_[(1 yl)oxy]-1-benzofuran_3•carbamamine; 5-cyclopropyl-2·(4·fluorophenyl)_6_[[(2_ Hydroxy-indole, oxoboryl](nonylsulfonyl)amino]_N_methylbenzofuran_3_carbammine)methyl, yl), ())-5-cyclopropyl- 2_(4_fluorophenyl)_6_[[(2·hydroxyj, 夂 硼 y y ] ] ] ] ] ] ] 胺 _ _ _ _ 苯 苯 苯 苯 苯 ( ( ( ( ( ( ( ( ( ( _)_5_cyclopropyl-2-(4-fluorophenyl)-6-[[(2-hydroxy·1,2-oxo boron μ 154007.doc 201221131 methyl] (methyl sulfhydryl) amine group ]-N-Methyl-1·Benzobenzoquinone_3-carbamamine; [({3-[{5-Cyclopropylidene] 2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-1. benzofuran-6-yl}(nonylsulfonyl)amino]propyl}oxy)indolyl朋Phenic acid; [3-({2-[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl} (Methanesulfonyl)amino]ethyl}oxy)propyl]carboxylic acid; [({2-[ {5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamine) ))carbonyl]_ι_benzofuran-6-yl}(indolyl)amino]ethyl}oxy)indenyl]tanoic acid; # P-[{2-[{2-(4-fluoro Phenyl)-3-[(decyl)carbonyl]-5-[(l-decylethyl)oxy]-1-benzofuran-6-yl}(methylsulfonyl)amino] }}(fluorenyl)amino]propyl}-acid; 5·ethyl-2-(4-fluorophenyl·)-6-[[(2-hydroxy-1,2-oxoboron-4- (曱)](methylsulfonyl)amino]-#·methyl-1-benzofuran-3-decylamine; 2-(4-fluorophenyl)-6-[[(2-hydroxyl) -1,2-oxo boron-4-yl)indenyl](indolyl)amino]-iV-methyl- 5-(1-mercaptoethyl)-1-benzof-β- 3--branched amine; 2-(4-fluorophenyl)-6-[[(2-hydroxy-1,2-oxaboron-4-yl)indolyl](sulfonyl)-amino] 5_dimercapto-1-benzocypan-3-anthracene 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-1,2-oxoboroin-4-yl)indolyl)nonylsulfonylamino)- N-mercaptobenzofuran-3-decylamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-)-based-1,2-oxygen shed Methyl-4-yl)ethyl)mercaptosulfonylamino)-N-mercaptobenzofuran-3-indolylamine; 5-cyclopropyl-2-(4-phenylene)-6-[ [(2 - thiol-1,2-oxygen shed p-5-yl) fluorenyl] (anhydrous) amino]methyl_1_benzofuran-3 - an amine; 5 -cyclopropyl-2-(4-fluorophenyl)-6-[[2-(2-hydroxy-1,2-oxaboramid-5-yl)ethyl](methyl aryl)amino] - eight &quot; mercapto benzene and bite taste-3-cartoamine; 154007.doc 201221131 [({(2Λ)-3-[{5-cyclopropyl-2-(4-fluorophenyl)_3_[( Amidino)carbonyl]-1-benzofuran-6-yl}(nonylsulfonyl)amino]_2-mercaptopropyl}oxy)methyl]-acid; [({(2·5)) -3-[{5-cyclopropyl-2-(4-fluorophenyl)_3_[(amido)carbonyl]-benzofuran-6-yl}(sulfonyl)amino]_2- Mercaptopropyl}oxy)methyl]-acid; 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((2-hydroxy-l, 2-oxoboron-5) -based) sulfhydryl Amino)-N-methylbenzofuran_3_decylamine; | 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)_6-(N-((2-)-based -1,2-oxoboro-4-yl)indenyl)methyl-nonylamino)benzobenzoin_3_cartoamine; 5-cyclopropyl-2-(4-fluorophenyl)- 6-(N-((2-hydroxy-i,2-oxoboroindole-4-yl)indolyl)ethyl arylamino)-N-mercaptobenzopyran- 3_cartoamine; 5-cyclopropyl-: 2-(4-fluorophenyl)-6-[[(2-hydroxy-2,5-dihydro-l,2-oxaborolan-4-yl) Methyl](methyl hydrazino)amino]_octa-methyl-hydrazinofuran-3-indoleamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-(Ν- ((2-hydroxy- hydrazine, 2 oxonium 咮 4 yl) fluorenyl) propan-2-ylsulfonylamino)-hydrazine-methylbenzofurancarboxamide; hydrazine, 5-bicyclic Propyl-2-(4-fluorophenyl)-6-(anthracene-((2-hydroxy-L2-oxaboron-4-yl)methyl)indolyl] arylamino)benzopyrene _3 -carbamidine; 5-cyclopropyl-2-(4-fluorophenyl)-6-(anthracene-((2-hydroxy-indole, 2 o-boron) 4-yl) fluorenyl)醯Amino)benzophenan-3-decylamine; 5-cyclopropyl-6-(Ν-((2-hydroxy-1,2-oxaboron-4-yl)methyl)methyl Sulfur Amino)-indole-methyl-2-(4-(trifluoromethyl)phenyl)benzofuran_3•carbenamide; 154007.doc S 201221131 2-(4-Phenylphenyl)-5- Cyclopropyl-6-(N-((2-hydroxy-1,2-oxoboroin-4-yl)methyl)methylsulfonylamino)-N-mercaptobenzofuran·3_曱醯Amine; 5-cyclopropyl-2-(3-fluorophenyl)·6·(ν·((2-hydroxy-1,2-oxaboron-4)yl) fluorenylmethyl )-Ν-mercaptobenzofuran_3_carbamamine; 5-cyclopropyl-2-(3-fluorophenyl)·6_(Ν_((1_hydroxy·丨, 3_ dihydro cumin [ c] [l, 2] oxaborole-5-yl) fluorenyl) fluorenyl sulfonylamino benzo benzofuran-3 - acetaminophen; 2_(4_gasphenyl)_5_cyclopropyl_6_(#_((1hydroxy-13dihydrobenzo M[i,2]oxaborol-5-yl)indolyl) Phytosulphonylamino)_team methylbenzopyran-3-carbamimid; - soil--2_(3,4·difluorophenyl)-6-(Ν·((1-hydroxy-1, 3· Dihydro benzo[c][l,2]oxazacyclopentane _5_yl)methyl)methylsulfonylamino) thizone methylbenzofuran-3-decylamine; Propyl-6-(Ν-((1-carbyl), 3-dihydrobenzo (4) [u]oxaborolenyl) 5-yl) fluorenyl) fluorenylaminomethyl (4) Tri-i-methyl)phenyl)benzofuran·3·carbamamine; ...:yl 2(4-(4-fluorophenoxy)phenyl)6_(n_((hydroxy hydroxy oxime) .][1,2]oxazepine heterocycle pentyl-5-yl)methyl)methyl contig))-N-methyl stupid.喃 _3_ 曱 胺 amine; = bicyclo = yl-2_(4·fluorophenyl)_6_[[(1_经基_3·methyl-], 3_二气_戊妇_5_基) methyl K 甲 酿 ) )) aminomethyl-1- stupid bite. South-3-mercaptoamine; cyclopropylcyclopentanyl)methyl)methylglycine-yl)_2_(tetra)phenyl)_N boron heterocycle 11..., ri-1,3-dihydrobenzene And (4) [1,2] oxa 154007.doc 201221131 methyl benzofuran-3-carbamamine; 5·% propyl-6-(M-((4-|ti·hydroxy·13_dihydrobenzene) And [c][12]oxo-hetero% oxime-5-yl)methyl)methylsulfonylamino)_2_(4.fluorophenyl)_N_methylbenzofuran-3-decylamine; 5_cyclopropyl-2-(4-formylphenyl)-6-[{[(36&gt;1-hydroxy-3-methyl-1,3-diox 2,1-benzoxazepine, heterocyclic ring) Pentene-5-yl]methyl}(methylsulfonyl)amino]chunmethyl small benzofuran_3_formamide; propyl-2_(4·I stupid)-6-[{ [(3i〇-l-hydroxy-3-methyl-1,3-dihydro 2'1-benzothiaborole-5-yl]methyl}(methylsulfonyl)amino] I methyl-1- benzofuran·3·carbamamine; f propyl-2-(4-fluorophenyl x wO G hydroxy-U-dihydrobenzo[^[human oxacyclopentane Alkyl^ethyl^methylsulfonamide-based hydrazino-furan-3-carboxamide; 5% propyl-2-(4-(4-fluoro)phenyl)-6- (N-((2-amino-1,2-oxygen side) 4·yl) ruthenium methyl hydrazide fluorenyl)-N-mercaptobenzopyran-3-carbamide; 5 king propyl-6-(#-((6_气小经基-13) Diazo benzo (4) [12] oxo side pentyl pentyl _5·yl) methyl) fluorenyl aryl amino)-2-(4-fluorophenyl)-N-methylbenzofuran-3 -carbamamine; 5 cyclopropyl-2_(4_fluorophenyl)_6lu (2-(1-hydroxy-1,3-dihydrobenzo-2)oxazacyclopenta-5) Ethyl)methyl aryl amine) good methylbenzofuran _3_ decylamine; {[{5 cyclopropyl-2-(4' fluorophenyl)-3-[(amidino)) ]]-1-benzopyrene flooded 6 bases 曱 ) )) 胺 曱 } } · · · · -1 -1 -1 -1 -1 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 Methyl penten-7-carboxylate; 5-cyclopropyl_2_(4.fluorophenyl)6 [{[1_hydroxy_7_(hydroxymethyl)13 dihydro_ 2,1-benzoxabium boron Heterocyclic pentene _5-yl] fluorenyl}(methylsulfonyl)aminopyridylmethyl-1- benzofuran·3_decylamine; 6·(ΛΓ-((7-气-1- Hydroxy-I,3-dihydrobenzo MU, 2]oxaborolyl)methyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenylmethyl) Benzofuran-3-carboxamide; 5_cyclopropyl '2_(4.fluorophenyl)-6-[[(1-hydroxy-3,4-dihydro-indene//·2, κ stupid and deuterated boron heterocyclohexene-6- (yl) fluorenyl](sulfonyl)amino]mercapto, 1_benzofuran-3-carboxamide; 5_cyclopropylethyl·6-[[(7-fluoro-1-hydroxy-) I,3·dihydro 2,1-benzo-gas shed heterocyclic pentyl H-methyl)methyl](anthracenyl)amino]·2_(4·^ phenyl)·1-benzofuran- 3-carbalamine; propyl 2-(4- 4 stylyl)_6-(7V-(2-(l-trans-yl-1,3-di- oxo[CH1'2]oxaborofene) 3-yl)ethyl)methylsulfonylamino)-bromo-benzofuran-3-carboxamide; propyl 2 (4-oxophenyl)-6-(ΛΓ-((1- -1,3-dihydrobenzo[c][l'2]oxacyclopentanyl _3-yl)indolyl)methylsulfonylaminomethylbenzofuran-3-carboxamide ; 5 % propyl + yl-2·(4-fluorophenyl)·6(#_((I hydroxy _7(trifluoromethyl benzobenzopyrene [7,2] oxapyrene oxime _5 _ yl)methyl)methyl sulphonate) U-based benzo. Fu-flavor _3_ guanamine; 5-cyclopropyl-2 · (4-gas cage ι, gas-based)-6-[ {2-[(3·5)-1-hydroxy-1,3-dihydro-2, ι. benzooxaborolane]-3-yl] Yue sulfo group acyl) amino] - Suwa A 154007.doc • 11 · 201221131 • A Amides; -(N-(2-(7-hydroxyl_i,3·didihydrobenzo[c][l,2]oxalinocyclopentyl-1·benzofuran-3-a, although 5- Cyclopropyl-2-(4-fluorophenylbenzooxaborolan-1-benzofuran_3_methylene 3-yl)ethyl)methyl-branched amine)·5· Cyclopropyl 2 - ( 4 - gas phenyl ) heptamethylbenzofuran · 3 · formamide; 5-cyclopropyl-6-[[(7-fluoro-1-hydroxy) Benzooxaborole-5-yl)methyl;](methylsulfonyl)amino]_2_(4-fluorophenylbenzofuran-3-formamide; 5-cyclopropyl- 6-(ΛΚ2-(7-Fluoro-1·hydroxy-1,3-dihydrobenzo[c][1,2]oxaindole-5-yl)ethyl)methyl decylamine 2-(4-fluorophenyl)n-mercaptobenzofuran-3-carboxamide; 6-[[2-(6-gas-1-hydroxy-1,3-dihydro-2,1) -benzoxoxaborolecyclopentyl)ethyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl-1-pyranfuran-3-indole Indoleamine; 6-[[2-(5_gas_1-trans-yl-1,3-dihydro-2,1-benzooxaborolan-3-yl)ethyl](methane) Amidino)amino]_5_cyclopropyl-2_(4-fluorophenylindol-1-benzofuran-3-cartoamine; 6_[[2-(4 -Gas-1-hydroxy-1,3-dihydro-2,1-benzooxaborole-3-yl)ethyl](methyl hydrazino)amino]cyclopropyl_2_(4 -Fluorophenyl 154007.doc -12· 201221131 -1-benzofuran-3-carboxamide; 5_cyclopropyl-2_(4-fluorophenyl) 6 Lu (2_〇_经基_ 3, cardiac dichloro-tatabenzo [.] [1,2] oxazacyclohexanylmethylbenzofuran-3-carboxamide; propyl-6-(N-(2-(4- Fluorine small hydroxy-1,3·dihydro benzo[c][l,2]oxaside heterocyclopenten-3-yl)methanomethyl hydrazino)_2_(4·gas phenyl)_ N-methyl benzofuran _3_formamide; 5 % propyl _6_(Ν·(2-(5-Den)-trans-yl-1,3-dihydrobenzene·[c][1,2]oxazeto-3-enyl) Ethyl)methyl arylamino)_2(4-fluorophenyl)_N_decyl benzofuran-3-amine; 5% propyl-6-(N-(2-(6-fluoro) -1-yl-based '3-dihydro benzo[[]][1,2]oxazacyclopentan-3-yl)ethyl)methyl hydrazinyl)_2_(4-fluorophenyl) N_mercaptobenzofuran-3-decylamine; propyl propyl-2-(4-fluorophenyl)_6_[{[(4R)_2_hydroxy-1] oxyborate _ heart group] methyl }(Methanesulfonyl)amino]_N_methylbenzofurazan_3_decylamine; and a pharmaceutically acceptable salt thereof. a compound selected from the group consisting of: 5 tolupanyl-6-(Ν·((7-a-1-1-yl), 3-dihydrobenzo[c][borane Dilute-5-yl) fluorenyl) fluorenyl hydrazino) _2_(4_ oxo phenyl ν·methylbenzofuran-3-f decylamine; ^ (Brigade ((7-gas small hydroxy-丨) ,% dihydrobenzo[c][7,2]oxaborolan-5-yl)methyl)methyl-branched amine)_5_cyclopropyl_2_(4-fluorophenylmethyl And furan-3-carboxamide; 154007.doc •13· 201221131 5_cyclopropyl·2_(4_1 stupid)-6-[{2-[(3 phantom-1-yl-1,3-) Hydrogen·2,1-exido-oxo-heterocyclopenten-3-yl]ethyl}(indolyl)amino]-mercapto-1-benzofuran-3-decylamine; -% propyl-6-(Ν-(2-(6-fluoro_ι_hydroxy·13_dihydrobenzo[4][12]oxaside heterocyclopentanium-3'-yl)ethyl)methyl Amidino)-2-(4-phenylphenyl)-N-methylbenzofuran-3-decylamine; and pharmaceutically acceptable salts thereof 18. 19. 20. 21. 22. 23 A compound selected from the group consisting of: (1) cyclopropyl '2 · (4 j phenyl)-6-[[(2-pyridyl-1,2-oxaborimidin-4-yl) fluorenyl ](methylsulfonyl)amino]_N_曱_丨_benzofuran_3_carbamamine; 5-cyclopropyl-2-(4-fluorophenyl)·6·(Ν_(2_(2_hydroxy-丨, 2_氧硼咪_4• Ethyl)methylsulfonylamino)·Ν_methylbenzofuran_3_formamide; and pharmaceutically acceptable salts thereof. Species [({2-[{5-cyclopropyl) · 2-(4-Fluorophenylmethylamino)carbonyl]-p-benzofuran-6-yl}(methylsulfonyl)amino]ethyloxy)methyl]-acid or its medicinal A pharmaceutically acceptable salt of a compound according to any one of claims 19 to 19. A pharmaceutical composition comprising a compound according to any one of claims 19 to 19 and at least one A pharmaceutically acceptable excipient. The compound 'is used in therapy as claimed in claims 1 to 3, 9, and the formula "1" or (1) of the term "to 9". Any of the formula (1) or formula (1), the use of a compound for the manufacture of a medicament for treating or preventing a viral infection or a disease associated with the infection 154007.doc S •14· 201221131. Use of the item 23, wherein the virus infection is HCV infection 25. The formula (1) or the formula delta according to any one of claims, 9, 1 and 16 to 19, for use in the treatment or prevention of a viral infection or a disease associated with the infection. A compound of formula (1) or formula (Ia), wherein the viral infection is an HCV infection. # 27. A compound of formula (1) or formula (Ia) according to any one of claims 1 to 3, 9, 10 and 16 to 19 in combination with one or more active antiviral agents. 154007.doc -15· 201221131 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 154007.doc