TW201138786A - Therapeutic 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

201138786 VI. Description of the Invention: [Technical Field] The present invention relates to novel compounds suitable for use as antiviral agents, in particular hepatitis C virus (HCV) inhibitors, pharmaceutical compositions comprising the same, and The use of a compound to treat or prevent a viral infection such as Hcv infection and a disease associated with such infection. [Prior Art] HCV infection is a major cause of human liver disease throughout the world. 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. In 1997, it was estimated that the cost of treatment for the United States 11 (: ¥ infection was 5.46 billion US dollars. It is estimated that more than 200 million people worldwide are chronically infected. HCV infection is 4〇_6〇% of all chronic liver diseases and 30% of all liver transplants. In the United States, chronic Hcv infection accounts for 30% of all liver cirrhosis, end-stage liver disease, and liver cancer. According to CDC estimates, the number of deaths due to HCV will increase at least until the end of 2001. Up to 38 〇〇〇/year. Due to the high degree of variability of viral surface antigens, the presence of multiple viral genotypes and the display of immunospecificity, it is unlikely that a successful vaccine will be developed in the near future. Alpha-interferon has been widely used. (alone or in combination with ribavirin) because it is approved for the treatment of chronic HCV infection. However, this treatment usually produces adverse side effects: flu-like symptoms, leukopenia, thrombocytopenia, interferon-induced Depression, and ribavirin-induced anemia (Lindsay, KL (1997) Hepat〇l〇gy 26 (suppl. 1): 71S_ 77S). This treatment is caused by infection of the HCV genotype (the composition has been developed 1540) 05.doc 201138786 About 75% of all HCV infections in the market) are less effective than infections caused by the other five major HCV genotypes. Unfortunately, only about 5〇_8〇% of patients are treated for this. Reacts (measured by decreased serum HCV RNA levels and normalization of liver enzymes)' and in the treatment, 50-70% relapse within 6 months of discontinuation of treatment. Recently, by introducing pegylated interferon, initial The response rate and sustained response rate have been substantially improved, and the combination therapy of peg_IFN and ribavirin constitutes the gold standard. However, the side effects associated with combination therapy and the weak response of patients with genotype 1 are Improvements in disease management have provided opportunities. In 1989 (Choo, QL et al. (1989) Science 244: 359-362), the first identification of hepatitis C virus (HCV) by molecular selection is now widely recognized as a transfusion The most common pathogen of A non-B hepatitis (NANBH) (Kuo, G et al. (1989) Science 244: 362-364). HCV is an enveloped virus containing a single-stranded RNA molecule with a positive polarity. In this, the RNA is directly transferred Translated into a polypeptide having about 3 amino acids constituting a structural viral protein and a non-structural viral protein. This large polypeptide is then processed into a combination of individual structural proteins and non-structural proteins by a combination of a host and a protease encoded by a virus (Rice, c M. (1996), BN·Fields, DMKnipe and PM Howley (ed.) Virology, 2nd edition 'pp. 931-960; Raven Press, Ν·Υ·). 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 contains other RNA viral polymerases. A typical primitive that exists in it. The necessity of HCV NS5B RdRp activity for the production of infectious progeny virions 154005.doc 201138786 has been officially confirmed in chimpanzees (AAK〇lykhal〇v et al. (2000) J0urnai 〇f Virol〇gy 74(4) 2〇46 2〇 Page 51 “Therefore, it is predicted that inhibition of NS5B RdRp activity (inhibition of rna replication) will cure HCV infection. Based on the above, there is a significant need to identify the ability of synthetic compounds or biological compounds to inhibit the replication of genotype ia and genotype 11 of HCV. SUMMARY OF THE INVENTION The present invention provides benzofuran compounds substituted with a boron-containing moiety at the 6 position, pharmaceutical compositions comprising the compounds, methods of synthesizing the compounds, and the compounds for treating and/or preventing viral infections (such as Use of a flavivirus infection, such as an HCV infection. [Embodiment] The present invention provides a compound of formula (I):

Wherein: R1 is one or more substituents independently selected from the group consisting of halogen, C..6 alkyl, alkoxy, _CN, -CF3, optionally substituted by halogen-C6-1 ( An aryl group and, optionally, a heteroaryl group, R is hydrogen, hydroxy, C, .6 alkyl or C3.6 cycloalkyl, of which 6 alkyl or 154005.doc 201138786 C3·6 ring The alkyl group may be optionally substituted by a hydroxyl group; R3*CN6 alkyl, C3-6 cycloalkyl or CN6 alkoxy; R4 is -S(0)2R5, P(0)(0R5)R5 or P(0)(〇 H) R5; R5 is Cw alkyl or c3.6 cycloalkyl; X is Ci-6 alkyl optionally substituted by c!.6 alkyl, hydroxy, amine or c3.6 cycloalkyl; And (a) a heteroaryl group which is substituted by B(OR7)(OR8) and optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-6 alkoxy, -CF3 , Ci_6 alkyl, hydroxy, S02R5, S02NH2, -CN, -OCF3 and C3·6 cycloalkyl; or R7 and R8 together with the oxygen atom to which they are attached form a 5 to 8 membered carbocyclic or heterocyclic ring which may be a single Ring or bicyclic and optionally substituted with one or more pendant oxy (0X0) or Cu alkyl; or (b) C6. An aryl group, which is substituted by b(OR7)(〇r8) and optionally substituted with one or more substituents selected from the group consisting of halogen, Cl.6 alkoxy, -CF3, C. .6 alkyl, hydroxy, S〇2R5, s〇2NH2, CN, -OCF3, and CM cycloalkyl; or 尺 7 and Han 8 together with the oxygen atom to which they are attached form a 5 to 8 membered carbocyclic or heterocyclic ring, It may be monocyclic or bicyclic and optionally substituted with one or more pendant oxy or ci 6 alkyl; R and R8 are hydrogen or C16 alkyl; or a pharmaceutically acceptable salt thereof. The term "hospital" refers to a straight or branched chain of tobacco chains containing a specified number of carbon atoms. For example, c "6 alkyl" means a straight or branched alkyl group containing at least ! and up to 6 carbon atoms. As used herein, "alkyl" is 154005.doc 201138786 includes, but is not limited to, Mercapto, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, tert-butyl and 1,1·didecylpropyl. The term "alkylene" as used herein, unless otherwise specified, means a straight or branched chain divalent hydrocarbon group preferably having from 1 to 10 carbon atoms. Examples of "alkylene" as used herein include, but are not limited to, anthracenylene, ethylidene, n-propyl, n-butyl and the like. The term "homoxyloxy" means a straight or branched alkoxy group containing a specified number of carbon atoms. For example, Cl_6 alkoxy means a straight or branched alkoxy group containing at least 1 and up to 6 carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, decyloxy, ethoxy, propyl-hydrazine, propyl-2-oxide, butoxy, butoxy, 2_ Methyl propylene oxide

C1), Mo (Mosquito, Br) or Iodine (Moth, 1} atom. "Zhao Ji" refers to a group or substituent of the formula 。H (unless otherwise specified). Examples include cyclopropyl The term "ring-based" means a saturated cyclic group having 3 to 6 carbon ring atoms, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

: a number of carbon atoms, especially 6-10 such as phenyl or naphthyl). Examples of the aryl group include a fluorenyl group, a base group, a fluorenyl group, a fluorenyl group, a phenanthrene group, and the like. Unless otherwise included, each of the aromatic hydrocarbon groups is used unless otherwise possible 154005.doc 201138786 Positional isomers such as "naphthyl, 2-naphthylnaphthyl, ..., ... tetrahydrogangan η 疋丞, 4- Examples of phenidinyl, 7-morphine; =, =^, = listening and ^1 groups include) a base group, a thiol group, a benzyl group, a base group, a thiol group, a tetrachlorocaline group, a dicarbon = two "Aryl" means a group containing 5 to 2 ° carbon atoms, more than a stomach, 6 members, 8 members, 9 members or 10 members of the carbocyclic or bicyclic aromatic monocyclic ring:: group 'where - or more Preferably, each of the m ring carbons is replaced by a hetero atom such as P. Preferred heteroaryl groups include 5-6 membered monocyclic heterocycles: earth and 8_1G membered bicyclic heteroaryl groups. The term material also includes a group containing a non-aromatic ring containing a hetero atom fused to one or more aromatic rings such as a morpholinic morphine or a tetrahydroindenyl group, wherein the linking group Or the point of attachment is on a non-aromatic ring containing heteroatoms. Heteroaryl moieties include, but are not limited to, acridine, pyrazine, thiazole, thiophene, oxadiazole, oxazole, pyrimidine, pyridazine, tri"i, hour, stupid and dioxane, benzo, benzene And dioxetane, anthracene, benzimidazole, benzofuran, anthracene, oxazole, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, Benzopyrene Saliva, benzotriazine " Than the bite " set,. Fu 幷 幷 嗪 、,. Fu 幷 幷 Μ幷 Μ幷 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦Thiophenoxazine, thiophene D-pyrazine, thiophene triazine, thiazolium pyridinium, carcinoxine, thiazosin, oxazolidine, pyridazine, oxazolidine, oxazolidine Pyrimidine, oxazole, oxazole, oxazine, oxazolidine, imidazolium, imidazolium 154005.doc -9· 201138786 bite, taste, sputum, sputum, taste, taste. Triazine, compared to salidine, pyridoxine, pyrithione, pyridinopyrazine, pyridoxine three: three saliva. than bite, three saliva (four) 'three saliva Oxazine, three... material, (four) lin, (four) lin, dissipate, material, _ 幷 嗔 嗔 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比(4) (4). Set the taste and sell the saliva (4). All of the above heteroaryls are in the mouth of the present invention. Each of the heteroaryl groups can be attached at any ring carbon, or when the nitrogen is 5 Member ring - °p is the time, each heteroaryl can be Nitrogen connection. "Hetero atom" means nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen such as Ν(0){Ν+·〇-}; and any oxidized form of sulfur, such as s(0) And S(0)2; and any quaternary ammonium form of basic nitrogen. The invention relates to compounds of formula (I), wherein R1 is - or two elements. The present invention relates to a compound of formula (I) wherein 112 is (:|6 alkyl. The present invention relates to a compound of formula (I) wherein R34C3' is alkyl. The present invention relates to a compound of formula (1) 'wherein 丨.aryl The aryl group is substituted by b(〇r7)(or8), which is hydrogen and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -cf3. (1) A compound, wherein R6Aheteroaryl, which is substituted by B(OR7)(0R8), wherein r^r8 are all hydrogen, and optionally, one or more selected from the group consisting of dentate and _CF3 Substituted by a substituent of the group. The present invention relates to a compound of the formula (1), wherein R1 is a ruthenium; R2 is a Ci 6 alkyl group; R3 is a Cw cycloalkyl group; and R6 is an aryl group, and the C6 | aryl group is 154005. -10-201138786 B(OR7)(〇R8)substituted, wherein R7 and R8 are both argon and, as the case may be, substituted by one or more substituents independently selected from the group consisting of halogen and -cf3. a compound of formula (I), wherein R1 is halogen; R2 is Cl-6 alkyl; R3 is C3-6 cycloalkyl; and R6 is heteroaryl, which is substituted by B(OR7)(〇R8), Wherein the ruler 7 and the ruler 8 are both hydrogen and, as the case may be, substituted by one or more substituents independently selected from the group consisting of halogen and -CF3. The invention relates to compounds of the formula (1), wherein Ri is halogen; R2 is CN6 Alkyl; R3 is C3-6 cycloalkyl; r^_s(〇)2r5; and Rule 6 is heteroaryl, the heteroaryl is substituted by B(〇R7)(OR8), wherein both the ruler 7 and the ruler 8 Is hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF3. The present invention relates to a compound of formula (1) as described above, wherein R4 is _s(o)2R5. The invention also provides a formula (1), a compound:

Wherein: c, .6 alkyl, alkoxy, _CN, R are one or more substituents independently selected from the group consisting of halo-CF3, optionally substituted by halogen, 0 C6.10 aryl a heteroaryl group substituted by a halogen; optionally a hydrogen hydroxy group, a C 1-6 alkyl group or a C 3.6 cycloalkyl group, wherein the Ci6 alkyl group or the 154005.doc 201138786 C3-6 cycloalkyl group may be optionally substituted by a hydroxyl group. R3 is Cw alkyl, c3.6 cycloalkyl or c!.6 alkoxy; R4 is hydrogen, -S(〇)2R5, P(〇)(〇R5)R5 or P(0)(0H) R5; R5 is c, -6 alkyl or c3-6 cycloalkyl; X is a C1-6 alkyl group optionally substituted by c6 alkyl, hydroxy, amine or c3-6 cycloalkyl; R6 is: (a a heteroaryl group which is substituted by B(OR7)(〇r8) and optionally substituted with one or more substituents selected from the group consisting of halogen, Cl6 alkoxy, -CF3, C. -6 alkyl, hydroxy, s〇2R5, S02NH2, -CN, _〇CF3 and C3.6 cycloalkyl; or R7 and R8 together with the oxygen atom to which they are attached form a 5 to 8 membered carbocyclic or heterocyclic ring, May be monocyclic or bicyclic and optionally substituted with one or more pendant oxy groups or CN6 alkyl groups; or (WChi. aryl 'the oxime 6_丨. The aryl group is substituted by B(〇R7)(〇R8) and is optionally substituted with one or more substituents selected from the group consisting of halogen Cu6 alkoxy, _Cf3, Ci 6 alkyl, hydroxy , s〇2R5, s〇2NH2, -〇CF2, _〇CF3, _c(〇)〇r7, C3 6 cycloalkyl, and N(R7)2, NH(R7), alkoxy substituted R9, or By alkoxy group, -R9〇R9; or RW forms a 5-membered carbocyclic or heterocyclic ring with the oxygen atom to which it is attached, which may be monocyclic or bicyclic and, as the case may be, a mono or alkoxy group or CN6 Alkyl-substituted; R and R8 are hydrogen or c--6-based; R9 is an alkylene group; or a pharmaceutically acceptable salt thereof. 154005.doc • 12-201138786 The present invention relates to formula (1), a compound, Wherein R1 is one or two halogens. The invention relates to a compound of formula (1)', wherein R2 is C,·6 alkyl. The invention relates to a compound of formula (1)', wherein R3 is C3_6 cycloalkyl. The compound of the formula (1) wherein R4 is -S(0)2R5 ° The present invention also relates to a compound selected from the group consisting of: (6-{[{5-cyclopropyl-2-(4-fluorobenzene) Base)··3_[(methylamino)carbonyl]_丨_ benzofuran-6- (2-([{5-cyclophenyl]-)-[(曱) Amino) carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl b 4-pyridyl) lysine; (4-{[{2-(4-fluoro) Phenyl)-3-[(methylamino)carbonyl]nonylethyl)oxy]-1 -benzofuran-6-yl}(fluorenylsulfonyl)amino]methyl}phenyl) _ acid; (3-{[{2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-5-[(l-methylethyl)oxy]-1-benzo) Furan-6-yl}(fluorenylsulfonyl)amino]methyl}phenyl)carboxylic acid; (2-{[{2-(4-fluorophenyl)-3-[(decylamino)) Carbonyl]-5·[(1-methylethyl)oxy]-benzofuran-6-yl}(fluorenylsulfonyl)amino]indenyl}phenyl)-acid; (3-{ [{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino] Methyl}phenyl)folic acid; (4-{[{5-cyclopropyl-2-(4-1phenyl)-3-[(decylamino))]- benzofuran- 6-yl}(fluorenylsulfonyl)amino]mercapto}phenyl)-acid; (2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(A) Alkyl)carbonyl ]-1-笨和154005.doc -13· 201138786 Furan-6-yl}(fluorenylsulfonyl)amino]mercapto}phenyl)g-acid; 4-((N-(5-cyclopropyl) Benzyl-2-(4-fluorophenyl)-3-(decylamine decyl)benzobenzoin-6-yl)nonylsulfonylamino)indenyl)-2-fluorophenyl broad acid; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine decyl)benzofuran-6-yl)nonylsulfonylamino) fluorenyl -2-methoxyphenyl|claric acid; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine)methyl)benzofuran- 6-yl)methylsulfonylamino)methyl)-2-mercaptophenyl phthalic acid; 4-((N-(5-cyclopropyl-2-(4-fluoro))-3·( Mercaptoamine thiol) benzo. Furan-6-yl)methylsulfonylamino)methyl)-2-(trifluoromethyl)phenyl-acid; 4-((N_(2-(4-)phenyl)-5-cyclo Propyl-3-(methylamine-mercapto)benzopyran-6-yl)nonylsulfonylamino)mercapto)-2-(trifluoromethyl)phenylg-acid; 4-( (N-((2-(4-Chlorophenyl)-5-cyclopropyl-3-(decylaminecarbazyl)benzobenzoin-6-yl)indolyl)methylsulfonylamino)曱-)-2-fluorophenyl g-p-acid; 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine)) benzo Furan-6-yl)methylsulfonylamino)ethyl)phenyl lysine; 3-(2-(N-(5-cyclopropyl-2-(4-phenylphenyl)-3-)曱醯 并 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 4-fluorophenoxy)phenyl)-3-(methylamine methyl) benzofuran-6-yl)methyl hydrazinyl)methyl)-2-phenylphosphonic acid; 4-((N-((5-cyclophenoxy)phenyl)-3-(decylamine)methyl)benzofuran-6-yl)indole ()N-(5-cyclopropyl-2-(4-fluorophenyl); 2-(5-cyclopropyl-2-(4-fluorophenyl) )-3-(methylaminoindenyl)benzo-bisting-6-yl)methyl-hydrogenated amino)methyl)-3-1 phenyl-piconic acid; 154005.doc •14· 201138786 4- ((Ν-(5-cyclopropyl-2·(4-fluorophenyl)-3-(decylamine)methyl)benzofol-6-yl)methylsulfonylamino) fluorenyl -3-oxooxyphenyl|claric acid; [4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)·ι_ stupid And furan-6-yl](methylsulfonyl)amino]methyl}-2-(trifluoromethyl)phenyl]g-p-acid; (5-{[{5-cyclopropyl-2- (4-fluorophenyl)-3-[(methylamino)carbonyl]benzofuran-6-yl}(fluorenylsulfonyl)amino]indolyl 2-fluorophenyl)carboxylic acid; 4 - ((Ν-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine decyl)benzobenzoin-6-yl)nonylsulfonylamino) fluorenyl )_3_(trifluoromethyl)phenyl phthalic acid; 5-cyclopropyl-2-(4-fluorophenyl) _methyl-6-((methyl scutellaria) {[4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-(trifluoromethyl)phenyl]methyl}amino)-1-benzofuran 3-carbamamine; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylaminecarbinyl)) stupid bite -6-yl)ethylsulfonylamino)methyl)_2.fluorophenyl-acid; 4-((#-(5-cyclopropyl-2-(4-fluorophenyl)-3-) Amidino) benzofuran-6-yl)ethylsulfonylamino)hydrazino)_2_(trifluoromethyl)phenyl-fatanoic acid; 4·((#-(5-cyclopropyl- 2-(4-Fluorophenyl)-3-(decylamine decyl)benzofuran-6-yl)methylsulfonylamino)methyl)_3_mercaptophenyl phthalic acid; (4- {[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(fluorenylamino)carbonyl]<_stupt-pyran-6-yl}(methylsulfonyl)amine (4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl) 2-(4-fluorophenyl)-1-benzophenanyl) Furan-6-yl](fluorenylsulfonyl)amino]mercaptopurine_2_fluorophenyl)folate; 5-cyclopropyl-2-(4-fluorophenyl)_6_[{[3- Fluorine_4_(4,4,5,5-tetramethyl-1,3,2·dioxoindol-2-yl)phenyl]fluorenyl}(methylsulfonyl)amino]_#· 154005.doc -15- 201138786 methyl-1-benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonate) Mercapto)({3-(trifluoromethyl)-4-[(111,211,63,811)-2,9,9-trimethyl-3,5-dioxo-4-borane tricyclo[6· 1·1· 02,6]癸-4-yl]phenyl}methyl)amino]_1_benzopyrano_3_formamide; 5-cyclopropyl-2-(4-fluorophenyl)-6- [{[3-fluoro-4-(4,4,6,6-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]methyl hydrazine (methylsulfonyl) Amino] Ν 曱 曱 -1- 1-benzofuran _ 3-carbamamine; 5-% propyl-6-[{[3-fluoro-4-(6-methyl-4,8-dioxine) Tetrahydro-4Η-1,3,6,2-dioxaborolan-2-yl)phenyl]methyl}(fluorenylsulfonyl)amino]-2-(4-fluorophenyl) ·Ν-Methyl-1-benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-6-[({3·fluoro-4-[(lR,2R) ,6S,8R) -2,9,9-trimethyl-3,5-dioxo-4-boron tricyclo[6.1.1.02,6]non-4-yl]phenyl} fluorenyl) (methyl Sulfhydryl)amino]-N-methyl-1-benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro- 4-(tetrahydro-3aH-cyclopentanyl[d][l,3,2]dioxoin-2-yl)phenyl]fluorenyl}(methylsulfonyl)amino]_N_methyl- 1-benzofuran-3-carboxamide; (3-cyano-4-{[{5-cyclopropyl-2-(4-fluorophenyl)·3-[(methylamino)carbonyl)] -1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)decanoic acid; (4-{[{5- Cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino]methyl}_2 , 3_difluorophenyl) face acid; (4-{[{5-cyclopropyl·2-(4.fluorophenyl)-3-[(decylamino)carbonyl]-1- benzofuran) -6-yl}(fluorenylsulfonyl)amino]methyl}_2,5-difluorophenyl) offic acid; 154005.doc •16·201138786 (2 - gas - 4-{[{5-ring Propyl-2-(4-fluorophenyl)-3-[(indolyl)yl] _1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl ) 醐 ;; [4-U{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl benzo benzoate-6-yl} (methylsulfonyl) Amino]mercapto}-2-fluoro-3-(trifluoromethyl)phenyl]-acid; {4-U{5-cyclopropyl-2-(4-fluorophenyl)-3-[ (Methylamino)carbonyl·benzopyranyl-6-yl}(fluorenylsulfonyl)amino]indenyl}_2_[(difluoroindolyl)oxy]phenyl}-acid; 4·( 2-(#-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminoindolyl)benzofuran-6-yl)methylsulfonylamino)B 2-fluorophenyl phthalic acid; 2-(N-(5-cyclopropyl-2-(4-disorganophenyl)-3-(decylamine oxime) Benzo 4-(2-(#-(5-cyclopropyl-2-(4-fluorophenyl)-3-) Hydrazinyl)benzofuran-6-yl)nonylsulfonylamino)ethyl)-2-(trifluoromethyl)phenylg-p-acid; [4-{[{5-cyclopropyl) 2-(4-Fluorophenyl)-3-[(decylamino)carbonyl]-1·benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-fluoro -5-(trifluoromethyl)phenyl]-acid; 4-(2-(iV-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamyl)) Stupid and inferior 11-N-6-yl) fluorenylamino)ethyl)-3- gas-based carboxylic acid, 4-(2-(N-(5-cyclopropyl-2-)4- Fluorophenyl)-3-(mercaptoaminemethanyl)benzofuran-6-yl)decylsulfonylamino)ethyl)-3-(trifluoromethyl)phenyl self-acid; {4- [({5-Cyclopropyl-2-(4-fluorophenyl)-3_[(decylamino)carbonyl]-1-benzofuran-6-yl}amino)methyl]-2-fluoro Phenyl}-acid; {4-{[{5-cyclopropyl-2-(4-fluorophenyl)_3·[(decylamino)carbonyl]-1- stupid 154005.doc -17- 201138786 and Furan-6-yl}(methylsulfonyl)amino]mercapto}-2-[(methoxy)carbonyl]phenyl}}-acid; {4-{ [{5-cyclopropyl-2- (4 -fluorophenyl)-3-[(methylamino)carbonyl]d-benzofuran-6-yl}(fluorenylsulfonyl)amino]indenyl}-2-[(trifluoromethyl) Oxy]phenyl}-acid; {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]benzofuran-6-yl} (methylsulfonyl)amino]methyl}-2-[(decyloxy)methyl;]phenyl}-acid; {4-{[{5-cyclopropyl-2-(4-fluoro) Phenyl)-3-[(methylamino)benzyl]_1-benzofuran-6-yl}(fluorenylsulfonyl)amino]methyl}-2-[(dimethylamino) Methyl]phenyl}-acid; {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3.[(methylamino)carbonyl)benzofuran-6-yl} (methylsulfonyl)amino]methyl}-2-[(decylamino)indenyl]phenyl}-acid; [4-{[{5·cyclopropyl-2-(4-fluoro) Phenyl)-3-[(methylamino)carbonyl]· _ benzofuran-6-yl}(methyl hydrazino)amino] fluorenylfluoro-6-({[(曱 曱oxy)) Methyl]oxy}methyl)phenyl]g-p-acid; (4-{[[3-(aminocarbonyl))-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran -6-yl](methylsulfonyl)amino]methyl}-2-fluorophenyl)gmin; 4-(l-(iV-(5-cyclopropyl-2-(4-fluoro) Phenyl)-3-(methylamine A Mercapto) benzofuran-6-yl)methylsulfonylamino)propan-2-yl)phenyl decanoic acid; and pharmaceutically acceptable salts thereof. Certain compounds of formula (I) and (I) 1 may be in stereoisomeric form (e.g., they may contain one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and 154005.doc • 18-201138786 diastereomers) and mixtures of such stereoisomers are included within the scope of the invention. The invention also extends to formula (1) and (1), the conformational isomerization of the compounds and any geometric (cis and/or trans) isomers of the compounds. The racemic = compound can be resolved using a preparative hplc and a column with a palmitic stationary phase or by methods known to those skilled in the art to obtain individual enantiomers. In addition, the palmitic intermediate compound can be analyzed and used to prepare the palm compound of the present invention. Diastereomeric mixtures of the compounds of formula (1) and (I) can be isolated according to methods well known in the literature, for example by preparative hunger. Alternatively, the purified HpLc can be purified by chromatography using a preparative HpLc and having a palmitic stationary phase: a column to separate the analytes into individual enantiomers by methods known to those skilled in the art. Alternatively, the palmitic intermediate compound can be resolved and used to prepare the antagonistic compounds of the present invention. The formula (I) and (1)' may be in the form of a tautomeric form other than those shown in the formula, and such forms are also included in the scope of the invention. It is also contemplated that the compounds of the invention and mixtures thereof in the form of polymorphs are within the scope of the invention. The invention also relates to a compound of formula (1) or (1), or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" means compound: not suitable for pharmaceutical use. The term "pharmaceutically acceptable" when used in connection with a component that can be included in a pharmaceutical composition for administration to a patient, is meant to mean that the knife is compatible with any other component present in the four drug composition. It is acceptable and harmless to its recipients. "Forms (1) and (1) suitable for use in medicine, the salt of the compound is a pharmaceutically acceptable salt of the relative ion 154005.doc -19- 201138786. However, the salt of the relative ion is in the material of the present invention. Accepting the formula (1) or (1)• compound and its medicinal use, for example, for the preparation of other, ie, pharmaceutically acceptable. The spoon king is buried (also prescribed as a free test or pharmaceutically acceptable) A salt, a pharmaceutically acceptable solvate or a pharmaceutically acceptable brew. The invention also includes a pharmaceutically acceptable salt complex. The present invention also encompasses compounds of formula (1) and (1). A pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein means that the salt retains the desired biological activity of the compound of the invention and exhibits minimal undesirable toxicological effects. For a review, see Berge et al, J pharm Sci, 1977, 66, 19. 19. The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable bases. Salt formation. These medicines can be connected The salt can be prepared in situ during the final isolation and purification of the compound, or separately by separately reacting the purified compound in free acid or free base form with a suitable base or acid. The salt can be precipitated from the solution and It may be collected by filtration or may be recovered by evaporation of the solvent. Thus, according to another aspect, the invention provides a pharmaceutically acceptable salt of the compound of formula (1) or (I), and examples thereof. In embodiments, the compound of formula (I) or (I) may contain an acidic functional group' and thus may be capable of forming a pharmaceutically acceptable test addition salt by treatment with a suitable base. Pharmaceutically acceptable The addition salt can be determined as follows: 154005.doc -20- 201138786 □ According to the situation in a suitable solvent such as an organic solvent, the formula (1) or (1), and the appropriate S and the appropriate reaction, to obtain the addition salt, It can be isolated, for example, by crystallization and filtration. Pharmaceutically acceptable base salts include ammonium salts (e.g., ammonium or tetraalkylammonium); metal salts such as alkali or alkaline earth metal salts (such as sodium hydroxide, hydroxide) Potassium, calcium hydroxide Magnesium hydroxide); organic amines (such as tris [also known as tr〇methamine or ginseng (amino) methane], ethanolamine, diethylamine, triethanolamine, choline, isopropylamine, Dicyclohexylamine or N-methyl-D-glucosamine); cationic amino acids (such as spermine, lysine or histidine); or insoluble salts (such as procaine ( Procaine) or benzathine. In certain embodiments, the compound of formula (1) or (I)' may contain a basic functional group, and thus may be capable of forming a pharmaceutically acceptable treatment by treatment with a suitable acid. Accepted acid addition salts. Pharmaceutically acceptable acid addition salts can be formed by reacting a compound (1) or a compound with a suitable inorganic strong acid (such as hydrogen in acid), as appropriate in a suitable solvent such as an organic solvent. , hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or perchloric acid) or react with suitable organic strong acids: for example sulfonic acids [such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethyl) Alkanesulfonic acid, naphthalenesulfonic acid (eg 2-naphthalenesulfonic acid)], carboxylic acid (such as acetic acid, propionic acid, Fumaric acid 'maleic acid, benzoic acid, salicylic acid or succinic acid), anionic amino acid (such as glutamic acid or aspartic acid), hydroxy acid (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 acids for insoluble salts (such as bis-naphthoic acid or resin acids [eg polystyrene sulfonate] ), a salt is obtained which is separated by, for example, crystallization and enthalpy. In one embodiment 154005.doc -21 · 201138786, the pharmaceutically acceptable acid addition salt of the compound of formula (i) or (i)' is a salt of a strong acid such as a hydrobromide, a hydrochloride, or a hydrogen. Iodate, sulfate, nitrate, percarbonate, phosphate, p-toluenesulfonate, besylate or decanesulfonate. Those skilled in the art will appreciate that the organic acid and/or its organic lysate may form an "ate" mis-addition salt, such as an organic borate, in the presence of a suitable nucleophilic miscible reagent. Suitable nucleophilic mismatch reagents include, but are not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; or fluorides. Examples of organoborate mis-addition salts and methods for their preparation will be readily apparent. For example, one such suitable organoborate miscide salt is a trihydroxyorgano borate alkali metal salt such as a tris-based organoborate sodium salt. By way of illustration, the trihydroxyarylboronic acid-brown and trishydroxyalkylborate sodium mis-addition salts and their preparation are described in Cammidge, A_N. et al., Org. Lett., 2006, 8, 4071-4074. . Pharmaceutically acceptable "ester" mis-addition salts as described herein are also considered to be within the scope of the invention. The present invention relates to suitable formulas (I) and (I), and pharmaceutically acceptable salts of the compounds 'including acid salts' such as sodium, potassium, calcium, magnesium, salt, and tetraalkyl; a salt and a tris or a sulphuric acid-methyl sulphate; and a similar salt with a suitable acid to form a monobasic or dibasic salt, such as an organic carboxylic acid, such as acetic acid, Lactic acid, tartaric acid, malic acid, ethyl ethanesulfonic acid, lactobionic acid and succinic acid; organic sulfonic acids such as methyl benzoic acid, phenylsulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid , sulphuric acid, phosphoric acid and amino sulfonic acid; and similar acids 154005.doc -22- 201138786 The present invention relates to a pharmaceutically acceptable test addition salt of a compound of formula (1) or (1) which is a salt of a strong base For example, a sodium salt, an isoleate, a salt, an N-methyl D-glucosamine salt, a potassium salt, a choline salt, a arginine (for example, arginine) salt or a magnesium salt. In another aspect, the salt is a sodium salt, an ammonium salt, an ammonium salt, a N methyl-D-glucosamine salt, a demineralized, a gallate salt or a arginine (eg, l-arginine) salt. . Other non-pharmaceutically acceptable salts, such as oxalates, can be used, for example, in the isolation of a compound of formula (I) or (I)' and such salts are included within the scope of the invention. The materials of the present invention include all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I) and (I). Salts of the compounds of formula (1) and (I) can be prepared by contacting an appropriate stoichiometric free acid with a suitable test in a suitable solvent. The free acid of the compound of the formula (1) or (1) may be added in a solid form, for example, in the form of a solution, or the free acid of the compound of the formula (1) or (1)' may be independently in the form of a solution with a suitable base. The solvent suitable for dissolving the free acid of the compound of the formula (1) or (1) includes, for example, an alcohol such as isopropyl alcohol such as acetone; acetonitrile; or toluene. If the base is added as a solution in a solvent, the solvent used may include acetone, or water. The salt of the compound of the formula (1) or (1)| can be obtained in a conventional manner from the above: the solution is isolated as a solid. For example, an amorphous salt can be prepared by sinking from a solution, spray drying or cooling; drying the solution in the east, evaporating the solution into a glass, or vacuum drying the oil, or making the self-release test with acid 154005.doc •23· 201138786 Reaction-obtained lysate solidification β ★ Formula (1) and (1), the salt of the compound may be crystallized directly from the salt in which the salt has a limited degree of resolution, or by wet milling of the amorphous salt or otherwise The amorphous salt is crystallized to prepare. For example, an organic solvent such as acetone, acetonitrile, butanone, butanol, ethanol, propanol or tetrahydrofuran, or a mixture of such solvents may be used. The improved salt yield can be obtained, for example, by evaporation of some or all of the solvent at various stages, or by crystallization at elevated temperatures followed by controlled cooling. Careful control of the precipitation temperature and seeding can be used to improve the reproducibility of the production process and the particle size distribution and form of the product. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which the compounds are reacted or precipitated or crystallized from such solvents. These complexes are referred to as "solvates." For example, "the complex formed by water is called "hydrate." The solvates of the formula (1) and (1), the compound of the compound, and the solvates of the salts of the compounds of the formulae (I) and (1) are included in the scope of the invention. The term "solvate" as used herein means a stoichiometrically variable complex formed by a solute (in the present invention, a compound of the formula (I) or (1), a salt thereof) and a solvent. For the purposes of the present invention, such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol, and acetic acid. Most preferably, the solvent used is water and the solvate may also be referred to as a hydrate. The solvate of the compound of the formula (1) and (1) which is suitable for use in medicine is a pharmaceutically acceptable solvate of the solvent. However, solvates having a non-pharmaceutically acceptable solvent are within the scope of the invention, for example, for the preparation of other compounds of formula (1) and pharmaceutically acceptable salts and solvates thereof 154005.doc • 24- 201138786 The intermediate of things. Further, some of the crystalline forms of the compounds of the formula (I) and (ι)' or salts and solvates thereof may be in one or more polymorphic forms, which are included in the present invention. The prodrugs of the compounds of formula (I) and (I) are included in the scope of the present invention. Those skilled in the art will appreciate that certain protected derivatives of the compounds of formula (1) or (1), which may be prepared prior to the final stage of removal of the protecting group, may not have the same pharmacological activity' but In some cases, it can be administered orally or parenterally and thereafter metabolized in the body to form a pharmacologically active compound as defined in the first aspect. Such derivatives can thus be described as "prodrugs". All protected derivatives and prodrugs of the compounds defined in the first aspect 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, pp. 499, 538 and Topics in Chemistry, Chapter 31, pages 3-6-316 and "Design of pr〇" drUgs", H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures of which are incorporated herein by reference). Those skilled in the art will further appreciate that when a suitable functional group is present in a compound of formula (1) or (1), it is known to those skilled in the art as "a precursor moiety (for example, by Η·Bundgaard," A part of the design described herein may be placed on the functional groups. Suitable prodrugs of the compounds of the invention include: esters, carbonic acid Esters, half esters, phosphates, nitroesters, sulfates, hydrazines, decylamines, urethanes, azo compounds, phosphoniumamines, glycosides, ethers, acetals, ketals, folates and Fine anhydrides. It has been found that the compounds of the invention exhibit antiviral activity, in particular HCV inhibition, 154005.doc •25-201138786, and thus may be applicable to, A, or viral infections associated with such infections, such as HCV infection. The applicability of the compound as an antiviral agent. The present invention provides a compound of the formula (1) or (1), a compound or a pharmaceutically acceptable salt thereof, which is used in medical therapy. Or (1), the compound or its pharmaceutically acceptable The use of the salt is for the manufacture of a medicament for the treatment and/or prevention of viral infections such as HCV infection and/or diseases associated with such infections. The invention provides a compound of formula (1) or (1) I or a medicament thereof An acceptable salt for use in the treatment and/or prevention of a viral sensation such as HCV infection and/or a disease associated with such infection. The invention provides a method of treating and/or preventing a viral infection such as an HCV infection or A method of treating a disease associated with such infection, the method comprising administering to a subject (e.g., a human) a therapeutically effective amount of a compound of formula (1) or (][)| or a pharmaceutically acceptable salt thereof. Therapy or treatment may include, but is not limited to, prevention, delay, prevention, and cure of the disease. The present invention provides compounds and pharmaceutical compositions for treating and preventing viral infections such as HCV infection and diseases associated with viral infections in a living host. It is to be further understood that the treatment or prevention of HCV infection as referred to herein includes the treatment or prevention of HCV-related diseases such as liver fibrosis, cirrhosis and hepatocellular carcinoma. In the context of the description, the terms used to describe the indications used herein are classified in Merck Manual of Diagnosis and Therapy, 17th Edition and/or International Classification of Diseases, 10th Edition (ICD-10) 154005.doc -26- 201138786. The various subtypes of the diseases referred to herein are contemplated as part of the present invention. The compounds of formula (I) and (I)' can be prepared by the methods described herein or by any method known to those skilled in the art. The methods of preparing the compounds of formula (I) are illustrative of other aspects of the invention.

A bromide source (eg, NBS) and a free radical initiator (eg, AIBN or benzoquinone) can be used in a suitable solvent (eg, four gasified carbon) under heat (eg, 90 ° C). (X=N) Direct radical bromination is carried out to prepare a type III active aryl/heteroaryl alkylating agent (RL1, CbBr, R3=Br). Alternatively, starting materials such as 11 (i.e., R2 = CO2H, C02Alk, CH2OH) having a pre-oxidized alkyl moiety can be converted to III using standard chemistry known to those skilled in the art. For example, II (R2=CH2OH) can be converted to III (R3=Br) using a suitable bromide source (ie, bromine) and an activator (eg, triphenylphosphine) in a solvent such as dioxane. ). Alternatively, II (R2 = CH2 〇 H) can be obtained from the relevant compound (i.e., R2 = C02H, CO2Me) by treatment with a reducing agent (i.e., LAH or BH3) in a solvent (i.e., THF). Those skilled in the art will appreciate that many examples of Formulas I and II are commercially available or previously reported in the chemical literature. 154005.doc 27· 201138786

IV

R4 R4 V The chemical method described above is a stable method which allows the aryl compound (IV) to be purchased from many cottons (wherein R4 can represent H, 〇尬, ΒΓ by (1) substituents as appropriate , 1, C1, CF3, CN or a combination thereof) is a highly functionalized benzyl desert (V) for the initial makeup.

Form VIII benzofuran can be obtained via a two-step procedure comprising first performing VII under standard alkylation conditions including a burning agent (eg, isopropyl bromide) and a base (eg, potassium carbonate) in a solvent (eg, DMF). Alkylation. Second, the intermediate can be nitrated using a nitrating agent such as nitric acid in a solvent such as sulfuric acid. The phenolic VII can be prepared by adding VI to phenylhydrazine under suitable conditions including Lewis Acid (i.e., zinc chloride (hydrazine)) and a solvent (sterol). The ester VI is readily prepared by those skilled in the art by reacting potassium malonate with a suitably functionalized benzoquinone gas (e.g., r5 = F, C1). R7

154005.doc -28· 201138786 The general structure of ix (r6=alkyl/cycloalkyl) can be obtained directly from VIII using a three-step process, which involves the use of a Lewis acid (eg BC13) in a solvent such as di-methane. The removal of the alkyl group results in a free reaction and subsequent conversion of the phenol to the corresponding difluoromethyl lactate using, for example, a trifluoromethyl acidification source such as trifluorosulfonate anhydride and a base such as diisopropylethylamine. Finally, derivatized trifluorosulfonate (IX 'for R6 = 〇Tf), palladium catalyst (eg Pd (PPh3) 4), fluoride source (kf) and caudate (eg cyclopropyl carboxylic acid) are used. The Suzuki reaction is carried out to obtain IX (R6 = alkyl/cycloalkyl). Amidinoalkyl) is readily obtained by using a suitable aqueous solution (eg, sodium hydroxide) in a solvent (eg, THF) for hydrolysis, followed by a suitable indole coupling reagent (eg, HATU) and an amine. Source (HzNR7 'for example methylamine or methylamine hydrochloride). R7

The key sulfonamide X; can be prepared from X via two steps from the conversion of the nitro functional group to the corresponding xanthanamine, which comprises first using a metal catalyst (eg palladium/carbon) and a reducing agent in a solvent such as decyl alcohol. Reduction (for example, hydrogen), followed by treatment with ruthenium such as L π α #友, _ ^ -X - 4 ^ ^ β ^ //Χ> · 1 under-agent (such as sulfonate) and base (for example, two Isopropylethylamine)sulfonated MR7 〇7

A

8rxy

154005.doc

XIV • 29- 201138786 Functionalized compounds ΧΠ, ΧΠΙ and XIV can be treated directly with a base (eg potassium carbonate) by heating (eg 50 lt;t) in a suitable solvent (eg acetonitrile) The agent (including hydrazine or ¥) is prepared by direct alkylation of the phantom.

The production of aryl octanoic acids (XV, XVI, and χνΐΐ) from the corresponding aryl bromides (XH, XIII, XIV) is well known to those skilled in the art and can be tested by using a catalyst (e.g., PdCl2 (dppf)). This is achieved by direct treatment of the aryl bromide (eg, acetic acid offload), boron source (eg, dipinocol diboron), and solvent (eg, dioxo). The free acid can be released from the intermediate pinacol-acid via hydrolysis with an acid (e.g., HCl) in a solvent/water mixture (e.g., thf/h2o). R8

XVIII XIX

XX In another embodiment, a homologous alkylating agent (eg, XIX) can be produced from a corresponding aryl breaking compound via a two-step process comprising 154005.doc -30- 201138786 tin reagent in a solvent such as DMF. (eg, tributylvinyltin) and a palladium catalyst (eg, Pd(PPh:}) 4) undergo a Still coupling reaction (stme c〇UpHng reacti〇n) followed by a hydroboration/oxidation process (eg, using 9_bbN, This is followed by the use of hydrogen peroxide to give XIX (R8 = 〇H). XIX (R8 = OH) can be converted to the corresponding bromide as described above for m, followed by conversion to hydrazine using methods known to those skilled in the art and similar to those described for XV.

In another embodiment, the m-acid having a boron functional group between the phenylsulfonylsulfonamide functional group or the ortho (XXII) may be prepared directly analogously to xv, wherein the alkylating agent ( m and IV) are derived from a suitably functionalized starting material known to those skilled in the art.

In another embodiment, those skilled in the art will appreciate that a variety of functionalized oleic acid and vinegar (e.g., XXIII & XXIV) are available directly from commercial sources or as standardized 154005.doc-31-201138786. It will be appreciated that XXIII and XIV are suitable for direct use as a phantom burn-in agent to provide a functional XR functionalized structure after treatment under standard firing conditions, including, for example, carbonic acid and a solvent such as acetonitrile. The butterfly can be converted to the corresponding acid ester by treatment with an alcohol (e.g., ethanol) or a glycol (e.g., pinacol) in a suitable solvent (e.g., toluene) and a dehydrating agent (e.g., a powdered sieving sieve). The invention also includes a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The term "excipient" means a compound (e.g., diluent, carrier) suitable for use in the preparation of a pharmaceutical composition. The compounds of the present invention can be administered in a conventional dosage form prepared by combining a compound of the present invention with a standard pharmaceutical carrier or diluent according to conventional procedures well known in the art. Such procedures may include mixing, granulating, and compressing or dissolving the ingredients as appropriate. (IV) The desired formulation H form and the procedure may comprise an amorphous dispersion, a molecular dispersion, hot melt extrusion, micron sizing or wet bead milling ( Nanomilling) reduces particle size, self-emulsifying systems or complexes (eg cyclodextrin). The pharmaceutical compositions of the present invention may be formulated for administration by any route, and include pharmaceutical compositions in a form suitable for oral, topical, intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal or transmucosal administration. . For oral administration, the compounds may be formulated into any suitable dosage form, such as lozenges, capsules, powders, granules, troches, creams or liquid preparations, such as oral or sterile solutions or suspensions, syrups, elixirs and Concentrate the drops. Tablets and capsules for oral administration can be presented in unit dosage form, and 154005.doc • 32- 201138786 can contain conventional excipients such as binders such as syrup 'acacia, gelatin, sorbitol , tragacanth or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; ingot lubricants such as magnesium stearate, talc, polyethylene glycol Or cerium oxide; a disintegrant such as potato starch; or an acceptable humectant such as sodium lauryl sulfate. Tablets may be coated according to methods well known in the standard pharmaceutical practice. If 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. If the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier conventionally used in the preparation of dispersions or suspensions, such as aqueous gums, celluloses, silicates or oils, may be contemplated and incorporated Soft gelatin capsules in the outer casing. The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives such as a suspending agent such as sorbitol, thioglycolic acid, glucose syrup, gelatin, ethylcellulose, and mildening. Cellulose, hard gel or nitrided edible fat; emulsifiers such as (iv) fat, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), such as almond oil, oil! • a sputum such as glycerol, propylene glycol or ethanol; a preservative such as p-propyl benzoate or sorbic acid; and if necessary' contains conventional flavoring or coloring agents. (d) The formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier and a flavoring or coloring agent such as ethanol, peanut oil, olive oil, glycerin or 154005.doc • 33· 201138786 Main injection (parenteral administration), such as intramuscular, intravenous, intraperitoneal, subcutaneous injection, fluid unit dosage form is prepared by using a compound and a sterile vehicle, such as water, physiological saline solution, Hank Solution (Hank's s〇luti〇n) or Ringer's solution (Ringer, ss〇iuti〇n). Depending on the vehicle and concentration employed, the compound can be suspended or dissolved in the vehicle. In the preparation of the cold liquid, the compound can be dissolved in water for injection and sterilized by a filter, then filled into a suitable vial or ampoule and sealed. Alternatively, the compounds of the invention may be formulated in solid form and reconstituted or suspended prior to use. Freeze-dried forms are also produced. A typical parenteral composition consists of a solution or suspension of the compound or salt in a sterile aqueous or nonaqueous vehicle, optionally containing a parenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, or an egg. Phospholipids, peanut oil or sesame oil. For transmucosal or transdermal administration, a suitable penetrant for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, including bile salts and fusidic acid derivatives. Alternatively, a cleaning agent can be used to aid in penetration. Transmucosal administration can be, for example, nasal spray, rectal suppository or vaginal suppository. A typical tincture formulation comprises a compound of formula (I) or (1), a compound or a pharmaceutically acceptable salt thereof (which is active when administered in this manner) and a binder and/or lubricant, such as polymerized two Alcohol, gelatin, cocoa butter or other low melting vegetable wax or fat, or a synthetic analogue thereof. A typical composition for inhalation 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 a conventional non-CFC propellant such as 1,1,1,2-tetra Fluorine or 1,1,1,2,3,3,3-heptafluoropropane. 154005.doc • 34- 201138786 The topical formulation of the present invention may be presented as, for example, an ointment, cream, gel, ointment or lotion, ophthalmic ointment or eye drop or ear drop, impregnated dressing And aerosols, and may contain suitable conventional additives such as preservatives, solvents to aid in the penetration of the drug, and emollients in ointments and creams. The formulations may also contain compatible conventional carriers such as a cream or ointment base and an alcohol or oleyl alcohol for use in a lotion. The formulation may be suitably formulated to control/delay release of the active compound. The amount of each compound to be administered can be determined by standard procedures, such as compound potency (IC5〇), efficacy tendon, and (compound) biological half-life, patient age, body size, and body weight, and patient-related a disease or condition. The importance of these and other factors considered is known to those of ordinary skill in the art. The amount administered will also depend on the route of administration and the extent of oral bioavailability. For example, for compounds with lower oral bioavailability, relatively high doses will have to be administered. Oral administration is a preferred method of administering a compound of the present invention. A σ is preferably in unit dosage form. For oral administration, for example, an ingot: or a capsule may be administered; for nasal administration, a metered aerosol may be administered; for lining administration, a topical formulation or patch may be administered; and for transmucosal delivery Skill and cheek patch. In each case, the administration can be carried out in such a manner that the patient can be administered a single dose. - For 舨, the dosage suitable for each of the above conditions will be in the range of 1 mg to 25 mg per kilogram per day (for example, human), preferably in the mother's kilogram weight 〇. Within the range of 1 〇〇 mg, and optimally in the range of 0.5 mg to 30 mg per kg of body weight per 154005.doc • 35· 201138786 days, and especially in the range of 1.0 mg to 20 mg per kg of body weight per day. Unless otherwise indicated, all weights of the active ingredient are calculated as the parent compound of formula (1) or (1); for its salt or ester, the weight will increase proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. "In some cases, the desired dose may be separated. Available on a daily basis or on other appropriate schedules, such as weekly or monthly. Such sub-doses may be administered in unit dosage form, for example, from 5 to 100 mg, from 5 to 1 mg, or from 5 to 500 mg, or from 2 to 5 mg, or from 50 to 400 per unit dosage form. The active ingredient of mg. It will be understood by those skilled in the art that the optimal amount and spacing of the individual doses of the compounds of the present invention will be determined by the nature and extent of the condition being treated, the form of administration, the route and location, and the particular mammal being treated, and such The optimum value can be determined by conventional techniques. Those skilled in the art will also appreciate that the optimal course of treatment, i.e., the number of doses of the compound of the invention provided daily for a specified number of days, can be determined by those skilled in the art using conventional treatment determination tests. The compound of the formula (I) or (I)' or a pharmaceutically acceptable salt thereof can also be used in combination with other therapeutic agents. Thus, in another aspect, the invention provides a combination comprising a compound of formula (I) or (I), a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. The compounds of the invention may be administered in combination with other therapeutic agents, for example, immunotherapeutic agents (e.g., interferons); therapeutic vaccines; anti-fibrotic agents; anti-inflammatory agents such as corticosteroids or NSAIDs; bronchodilators, such as beta -2 adrenergic agonist and jaundice (eg tea); mucus 154005.doc • 36- 201138786 Solvent, anti-muscarinic agent; anti-leucotriene agent; cell adhesion inhibitor (eg ICAM antagonism) Antioxidant (eg N_ethylcysteine); cytokine agonist; cytokine antagonist; pulmonary surfactant and/or antimicrobial and antiviral (eg ribavirin and amantadine) (amantic^ne)). 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 interferons; ribavirins; protease inhibitors such as phililibrevir; polymerase inhibitors, For example, compounds disclosed in boceprevir, teUprevir or PCT/US2010/046782; small interfering RNA compounds, antisense compounds; nucleotide analogs; nucleoside analogs; immunoglobulins Protein; immunomodulator; hepatoprotectant; anti-inflammatory agent; antibiotic; antiviral agent, and anti-infective compound. For example, a combination therapy can comprise providing a compound of formula (I) or (la) or a pharmaceutically acceptable salt thereof with other antiviral agents such as acyclovir, famciclovir, and more / valganciclovir and related compounds, viral sputum and related compounds, amantadine and related compounds, various interferons (such as interferon-α, interferon-β, interferon γ and their analogues) and interferon Alternative form (such as pegylated interferon). When the compound of the formula (I) or (I)' or a pharmaceutically acceptable salt thereof is used in combination with the second therapeutic agent, the dose of each compound may be different from the dose when the compound is used alone. The appropriate dosage will be readily understood by those skilled in the art. 154005.doc •37· 201138786 It will be appreciated that the amount of the compound of the invention required for use in therapy 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. Combinations as mentioned above are preferably presented in the form of a pharmaceutical composition for use, and thus, a pharmaceutical combination comprising a combination as defined above and at least one pharmaceutically acceptable carrier and/or excipient The object constitutes another aspect of the invention. The individual components of the combination, such as the combination of β, and the like, may be administered in a form of a pharmaceutical composition, either separately or in combination, by any convenient route, either sequentially or simultaneously. When administered sequentially, the HCV inhibitor or the second therapeutic agent can be administered first. When administered simultaneously, the combination can be administered in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same formulation, it will be appreciated that the two compounds must be stable and compatible with each other and with the other components of the formulation. Each of the eight fields is formulated in a manner that is known in the art for use in the form of such compounds in any convenient formulation. The following non-limiting examples illustrate the invention. EXAMPLES It is desirable to use, as is known in the art of nitrogen or those skilled in the art, to use an anhydrous solvent when a solvent is used in the reaction. When appropriate, it is more desirable to carry out the reaction under an inert atmosphere, for example, under argon. 154005.doc •38· 201138786 Abbreviation PS-BBA = polymer supported benzene acid aq. = aqueous solution μΜ = microliter = micromolar concentration NMR = nuclear magnetic resonance boc = third butoxycarbonyl br = broad peak Cbz - Benzyloxycarbonyl d δ = doublet = chemical shift °C = degrees Celsius DCM = dioxane dd = double doublet DMEM = Dulbeco's Modified Eagle's Medium DMF = N, N-dimethylformamide DMSO = diterpene hard EtOAc = ethyl acetate g = g or h - hour HCV = hepatitis C virus HPLC - HPLC Hz = Hertz IU = International unit IC50 = 50 Inhibition concentration under % inhibition J = coupling constant (in Hz unless otherwise indicated) m = multiple peak M = molar concentration M+H+ = parent nuclear mass peak + H + mg = milligram mL = ml mM = milli Molar concentration mmol = millimolar MS = mass spectrum run = nanomolar concentration ppm = parts per million qs = sufficient s = single peak sat. = saturated t = triplet TFA = trifluoroacetic acid 154005.doc -39- 201138786 Intermediate 1 2-(4-fluorophenyl)-5-pyridyl-1-benzo Call _3- acid methyl ester

An oven-dried glass was used and the anhydrous zinc sulfide (25 g, 183 mmol) was stirred in anhydrous decyl alcohol (60 mL) under a nitrogen atmosphere, followed by heating to an internal temperature of 75 °C. 4-Fluorobenzylideneacetic acid (39.6 g '202 mmol) was added in a single portion. Then a solution of p-benzene (丨9 g '183 mmol) in anhydrous diethyl ether (500 mL) was added dropwise over 4 hours. . At the same time, diethyl ether was distilled from the reaction mixture so that the reaction volume remained substantially constant (the bath temperature at 140 ° C maintained the internal temperature initially at 75 t, and then gradually rose to the highest temperature of 115 ° C). 2.5 hours after the start of the addition of phenylhydrazine, additional methanol (20 mL) was added to aid in the mixing. After the addition of benzene was completed, the reaction mixture was further heated under 丨〇〇〇c (internal) for 1 hour. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate (8 mL). The insoluble solids were removed from the two-phase solution, then the organic layer was separated and dried (NaJO4) 'Filter and evaporate under vacuum. The brown residue was slurried in warm air (about 225 mL) and the mixture was allowed to stand in the refrigerator for one hour. The resulting solid was filtered from a dark brown solution, washed with a small volume of di-methane and then dried in vacuo to give 2-(4-fluorophenyl)-5-hydroxy-l-benzofuran-3-carboxylic acid Ester "LCMS (/n/z, ES+) = 285 (M-1). Intermediate 2 2-(4.Fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzopyrene _3_carboxylic acid methylase 154005.doc -40- 201138786

iPrO

F 2-(4-Fluorophenyl)-5-hydroxy-indole-benzofuran_3_carboxylic acid methyl ester (18.86 §, 65.9 111111〇1), isopropyl bromide (24.7411^) under nitrogen at 60 ° C , 264 mmol) and a mixture of carbonic acid (42. 9 g, 132 mmol) in anhydrous N-methyl-2-pyrrolidine (1 91 mL) were stirred for 20 hours. The resulting thick suspension was cooled to room temperature and then a 7% aqueous ammonia solution (2 mL) was added under rapid mixing. The mixture was extracted with heptane (700 mL) and then the aqueous phase was separated. Ethyl acetate (about 100 mL) was added to the organic phase, and the resulting mixture was shaken, then dried over Na.sub.2SO.sub.4 and evaporated. This material was recrystallized from hot methanol, and the solid was collected by filtration, washed with methanol, and finally dried under vacuum to give 2-(4-fluorophenyl)-5-[(1-methylethyl) Oxy]·ι_ benzofuran_3_carboxylic acid methyl ester. Lcms (m/z, ES+)=329 (M+1). The mother liquor from the first recrystallization is secondarily crystallized to obtain another batch of 2-(4-fluorophenyl)·5_[(didecylethyl)oxy]_丨_benzofuran-3-decanoate . Intermediate 3 2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]_6-nitro 4benzofuran-3_carboxylic acid methyl ester

To a solution of methyl 2-(4-fluorophenyl)-5-[(1-decylethyl)oxydoprene benzofuran-3-carboxylate (6.16 g, 18.76 mmol) at -15 °C A solution of 70% nitric acid (11 mL, 172 mmol) in a solution (22 mL) was added dropwise to a solution of 154005.doc •41·201138786 in a mixture of 22 mL. After stirring for 1 hour at 〇t:, the reaction mixture was washed with water (50 mL). The solid was wet-milled in methyl tert-butyl ether (25 mL), and the obtained pale yellow powder was filtered, washed with heptane and dried under vacuo to give 2-(4-fluorophenyl)-5-[ (1-Methylethyl)oxy]_6-nitro benzofuran-3-carboxylic acid oxime ester. LCMS (w/z, ES+) = 764 (2M+NH4). Intermediate 4 6-Amino-2-(4-fluorophenyl)-5.[(1-methylethyl)oxy]benzofuran_3_carboxylic acid methyl ester

2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1·benzofuran_3·carboxylate (391) under a hydrogen atmosphere at 21 C , a solution of 〇47 mmol) in ethyl acetate (15 mL) was stirred with 1% palladium / carbon (ni mg, 0. 105 mmol) for 16 hours. The reaction mixture was filtered through celite, and evaporated to give a white solid. This material was redissolved in a smaller volume of diethyl ether and evaporated to give 6-amino-2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1- Furan_3_carboxylic acid decyl ester. LCMS (w/z, ES+) = 344 (M+1). Intermediate 5 6- [Bis(methylsulfonyl)amino]-2-(4-phenylphenyl)_5•indole (1-methylethyl)oxy]-1-benzofuran-3- Methyl Formate 154005.doc •42· 201138786 C〇2Me

iPrO

(MeS02)2N to 6-amino-2_(4-fluorophenyl)5[(1mercaptoethyl)oxy]-l-benzopyrene 3. carboxylic acid hydrazine under 〇 °c, under nitrogen Add diisopropylethylamine (1.895 mL ' 10.85 mmol) to a stirred mixture of anhydrous dichloromethane (25 mL), then add a sulphur 744 mL, 9.55 mmol). The reaction mixture was stirred for 1 hour and warmed to room temperature, washed with water and evaporated in vacuo to give <RTIgt;"""""""""""" _Mercaptoethyl)oxy]methyl benzofuran-3-carboxylate. LCMS (m/z, ES+) = 517 (M+NH4). Intermediate 6 2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]_6_[(methylsulfonyl)aminol-1- benzofuran-3-carboxylic acid co2h

'6-[Bis(methylsulfonyl)amino]_2_(4.fluorophenyl)-5-[(1-methylethyl)oxy]·benzofuran at 80 ° C 3_Methyl decanoate (2 199 g, 4.40 mmol) was heated in a mixture of methanol (20 mL), THF (20.00 mL) and 2 EtOAc (20 mL, 40.0 mmol). The solvent was partially evaporated under vacuum, and the reaction mixture was partitioned between dilute aqueous hydrochloric acid and dioxane. The organic phase is separated by a hydrophobic filter and evaporated to dryness to give 2-(4-fluorophenyl)-5.[(1-methylethyl)oxy]-6-[(methyl) Base]·1_benzofuran-3·formic acid. LCMS (m/z, 154005.doc -43 - 201138786 ES+) = 406 (M_H). Intermediate 7 2-(4-Fluorophenyl)-fluorene-methyl-5-indole (1-methyl & yl)oxy]·6_[(methylsulfonic acid)amino]-1-benzene Cough-3-carboxamine

iPrO MeS02NH

F 2-(4-Fluorophenylindolyl)oxy]_6_[(fluorenylsulfonyl)amino]-1-benzofuran·3·carboxylic acid (1.738 g, 4.27) at 21 °C Methyl) was stirred with diisopropylethylamine (1.639 mL, 9.39 mmol) in anhydrous N,N-dimethylformamide (2 mL). HATU (1.946 g, 5 12 mmol) was added, and after 1 min, a 2 M solution of methylamine in THF (1 〇 66 mL, 21.3 3 mmol) was added. The reaction mixture was stirred for 18 hours then evaporated under vacuum. The residue was partitioned between digas methane and water. The organic phase was separated, passed through a hydrophobic filter and evaporated under vacuum. The residue was purified by ISC 〇 Companion automated flash chromatography </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The appropriate fractions are combined and evaporated in vacuo to give 2-(4-fluorophenyl)-#-methyl·5·[(1-mercaptoethyl)oxy]_6-[(mercaptosulfonyl)amine ]-1-benzofuran_3-decylamine. Lcms 0? ES+)=421 (M+H). t-Intermediate 9 2-(4-Phenylphenyl)-5-carboxyl-6-decyl-1-benzopyrene _3_ decanoic acid

154005.doc • 44· 201138786 In a nitrogen atmosphere, using a syringe pump for 30 minutes to 2_(4-fluorophenyl)-5-[(1-mercaptoethyl)decyl nitrobenzofuran 3_Methyl decanoate (5.237 g, 14_03 mmol) in a stirred solution of anhydrous dichloromethane (7 〇 mL) was added 三M solution of boron trichloride in dichloromethane (23 85 , 23 · 85 mmol). The dark brown-red reaction mixture was poured onto ice (about 25 〇 mL). The ice was thawed and the mixture was extracted with di-methane (about 45 mL). The organic phase was separated from a hydrophobic filter and evaporated in vacuo 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} qbenzofuran-3-carboxylic acid methyl ester CF3S〇3r^vJ〇 2M® 〇2Nx^k&gt;f to methyl 2-(4-fluorophenyl)-5-hydroxy-6-nitro-benzofuran-3-indole (4.915 g, 14.84 mmol) under nitrogen And 4-(didecylamino)pyridine (0·181 g' 1.484 mmol) was added triethylamine (3 1 mL, 22.26 mmol) to ice-cold mixture in anhydrous methane (130 mL). Then, tri-Itananesulfonic anhydride (3.76 mL, 22.26 mmol) was added. After 50 minutes, it was quenched by the addition of water. (: The reactant in the ice bath. The reaction mixture was partitioned between dichloromethane and water, and the organics were separated. The aqueous phase was extracted with di-methane and the combined organics were washed sequentially with 2 M HCl and water.疏154005.doc -45· 201138786 Aqueous filter tube dries the organics and evaporates to give 2_(4-fluorophenyl)_6_nitro_5_{[(trifluoromethyl)methane]oxybenzophenoline Methyl furan_3_carboxylate LCMS (w/z, ES+) = 481 (M+NH4) + Intermediate 11 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1 _ benzofurancarboxylic acid methyl ester

'2-(4-Fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylic acid oxime ester under air gas (7 12 g, 15 37 mmol), cyclopropyl-folic acid (2-19 g, 25.5 mmol), potassium fluoride (3.26 g, 56.1 mmol), sodium bromide (175 g '1.01 mmol) and hydrazine (triphenyl) a mixture of (0) (0.85 g '0.736 mmol) in toluene (90 mL) and water (2.25 mL)

The mixture was stirred together and heated at 1 Torr (rc for 18 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried from a hydrophobic filter and evaporated in vacuo. C〇mpanion automated flash chromatography's purification of the residue by gradient elution with 〇_5% ethyl acetate in cyclohexane. The product-containing fractions were evaporated in vacuo to give 5-cyclopropyl- Methyl 2-(4-oxophenyl)-6-nitro-i-benzofuran·3-carboxylate [CMS (w/z, ES + ) = 728 (2 Μ + ΝΗ 4) +. Intermediate 12 6- Amino-5-cyclopropyl_2·(4-fluorophenyl)_1_benzofuran_3_decanoate

154005.doc •46- 201138786 '5-Cyclopropyl-2-(4-fluorophenyl)_6-; ε-Schothyl-1-benzofuran-3-indole methyl ester under 21C, hydrogen gas atmosphere A solution of (3.175 g, 8.94 mmol) in EtOAc (EtOAc) (EtOAc) The reaction mixture was filtered through celite, and the filtrate evaporated in vacuo to give a dark green solid. The solid was dissolved in a gas-fired gas, washed with sodium bicarbonate solution, separated by a hydrophobic frit, then evaporated to dryness, and autoclaved by ISCO Companion to pass the gelatin to contain 0-3. Purification was carried out by gradient elution of 〇% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give 6-amino-5-cyclopropylphenyl)-p-benzopyran-3-carboxylate. LCMS (m/z, ES+) = 326 (M+H). T-intermediate 13 6-[bis(methylsulfonic acid)amino]-5-cyclopropyl-2-(4-fluorophenyl)_;!_benzofuran-3-carboxylic acid methyl ester

Methyl 6-amino-5-cyclopropyl-2-(4-tert-phenyl)-1-benzofuran-3-indole (1.96 g, 6.02 mmol) and triethylamine (2.52 mL, A solution of 18.07 mmol) in dry methylene chloride (40 mL) was cooled (EtOAc) to EtOAc (EtOAc) Here. The reaction was stirred for 2 hours under hydrazine (ice bath). TLC (1:1 ethyl acetate / cyclohexane) showed no significant residue of &lt;EMI ID&gt; Water (100 mL) was added, and the organics were extracted three times with di-methane, dried using a hydrophobic frit 154005.doc -47·201138786 and evaporated to dryness to give 6_[bis(methylsulfonyl)amino] _5_Cyclopropyl _ 2 · (4-fluorophenyl) small benzofuran _3 - methyl formate. LCMS (w/z, ES+) = 482 (M+H). Intermediate 14 5-cyclopropyl-2·(4-fluorophenyl)_6_[(methylsulfonyl)amino]benzofuran-3-carboxylic acid

Treatment of 6-[bis(indolylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran with potassium hydroxide (6.71 g, 12 〇mm〇l) A suspension of _3_methyl decanoate (2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was then warmed to reflux for one hour (after heating, the suspension became a solution). The reaction was concentrated under vacuum, water (100 mL) was then evaporated and evaporated. The resulting precipitate was filtered, washed with 〇·5 M HCl, and then dissolved in methanol. This solution was evaporated to dryness and azeotroped twice with toluene to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]_ι_benzene.咦 曱-3-decanoic acid. LCMS (w/z, ES+) = 390 (M+H). Intermediate 15 5-cyclopropyl-2-(4-fluorophenyl)-; V-methyl-6-[(methyl-indenyl)aminodi 1benzofuran-3-carboxamide

154005.doc •48· 201138786 '5-Cyclopropyl-2-(4-fluorophenyl)-6-[(decyl-decyl)amino]-1-benzoxofan at room temperature -3 -carboxylic acid (2.52 g, 6.47 mmol), HATU (2.95 g ' 7.77 mmol) and triethylamine (1.984 mL, 14.24 mmol) in anhydrous di-methane (100 mL). The amine was treated with q6.18 mL, 32.4 mmol). The solution was stirred at room temperature under nitrogen for 4 hours during which time a precipitate formed. The reaction was diluted with dioxins (300 mL) and sodium bicarbonate solution (200 mL) and stirred for 1 min. The layers were separated and the aqueous layer was extracted with dichloromethane (150 mL). The combined organics were washed with brine (200 mL), dried and evaporated to dryness The crude product was slurried in dichloromethane and applied to the top of a pre-filled gelatin cartridge (Biotage SNAP, 100 g), followed by an ISC〇companion automated flash chromatography apparatus to (Μ 〇〇 % acetic acid B) The vinegar/cyclohexane is dissolved to dissolve. Some products are dissolved in the range of 40-60% ethyl acetate' but recovered from the column to a lower quality. The column is washed with 10% methanol/two gas. However, Some of the white solid remained on top of the bismuth hydride cylinder. The dissolved product, the decyl alcohol/two gas rinsing rinse solution and the residual white solid at the top of the column were combined in a single flask and evaporated to dryness. The material was dissolved in hot methanol-chloroform (10% ν/ν) (some insoluble solids still present) and the loose tannin was added. The mixture was evaporated and the resulting solid extract was loaded onto the top of a 2 x 100 g Biotage SNAP prefilled rubber column. Without pre-equilibration of the column in the initial dissolution solvent, the ffiisc〇Companion is automatically flash chromatographed and purified by dissolving 〇_1〇% methanol/di-decane. The product-containing fractions are combined and evaporated. , get 5_ ring Base 2_(4_fluorophenyl)-JV-methyl-6-[(fluorenylsulfonyl)amino]-b benzofuran 154005.doc •49· 201138786 Amine.LCMS (w/z, ES+)=403 (M+H). Example 1 Cyclopropyl-2·(4·fluorophenyl)_3_[(Methylamino)yl]Phenylbenzopyrano-6-yl}(Methylsulfonate) Mercapto)amino]methyl}_3_pyridyl)-acid

〇. * Step 1: 5-Bromo-2-(bromomethyl)pyridin

And maintained at reflux for 6 hours. Will dissolve

A solution of 0.310 g, 1.282 0 of pyridine (4.41 g, 25.6 mmol) and NBS (5. C of carbon chloride (150 mL) was used, and concentrated in deciduous earth and refluxed in reflux. Purification by column chromatography gave 5-bromo-2-(bromomethyl)pyridine as a dark semi-solid (2.25 g, 8 97 mm, yield 35.0%) 〇'H NMR (DMSO- D6) δ: 8.71 (d5 J=2.l Hz, 1H) 810 (dd, J=8.3, 2.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.70 (s, 2H). 2 : 6-[[(5-bromo-2-n-pyridyl)indolyl](methylsulfonyl)amino]_5_cyclopropyl-2-(4-fluorophenyl)-N-methyl -1-benzofurancarbamamine 5-cyclopropyl-2-(4-fluorophenyl)-N-mercapto-6-[(indolyl)indolyl]-1-benzofuran _3·Carbamine (25〇mg, 0.621 mmol), 5-bromo-2-(bromoindolyl)n ratio bite (195 mg, 0.777 mmol) and potassium carbonate (172 mg, 1.242 154005.doc -50- A solution of 201138786 mmol) in acetonitrile (10 mL) was maintained at 8 〇 &lt;t for 3 hrs. Residue was obtained under reduced pressure and purified by column chromatography , 6-[[(5-bromo-2-β ratio)) methyl](methyl fluorenyl)amino]-5-cyclopropyl-2-(4-fluorobenzene) Base) Ν-methyl-hydrazine-benzofuran_3-cartoamine (297 mg, 0.519 mmol, yield 84%). LCMS (w/z, ES+) = 574 (M+H). Propyl-2-(4-fluorophenyl)_3_[(methylamino)methyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}_3•pyridyl 6-[[(5-Bromo-2"pyridyl)methyl](methylsulfonyl)amino]-5-cyclofluorophenyl)_N_A Small benzophenone, % acetaminophen (55 mg, 〇._ mm〇1), potassium acetate (37 7 , such as _ called bis (pinacol)) (6). 〇mg, 〇24 〇mm〇1) and pdci2(dppf) CH2Cl2 adduct (7.85 y, 9.61 μ — ) The solution in W ward (15 mL) was maintained in a thick-walled glass pressure vessel for a few hours under the air. When the solution is at room temperature, the algae is diluted, concentrated, and passed through a gelatin plug containing acetic acid. The filtrate is concentrated and purified by reverse phase hpk to obtain a white solid (6_{[{5-cyclopropyl) Base_2·(4_fluorophenyl)_3_[(methylamino) Base]_卜 Ben and. Furan-6.yl}(Methylmercapto)amino]methyl b 3" is fluorenyl (18 mg, 〇.033 _〇1' yield 34 9%).咕ν jobs (methanol ^ 8.58 (br. S., 1H), 8.38 (br.s., lH), 8.03-8.17 (m, 1H), 7.79_7·95 (m, 2H), 7.58 (s, 1H), 7.53 (br. s., 1H), 7.15-7.30 (m, 2H), 7.05 (S, 1H), 5.06 (s, 2H), 3.24 (s, 3H), 2.92 (br. S., 154005.doc 51. 201138786 3H), 2.28 (br. s., 1H), l.〇〇(br. s., 1H), 0.83 (d, J=3.3 Hz, 2H), 0.38 (br. s. , 1H) LCMS (m/z, ES + ) = 538 (M+H). Example 2 (2-{[{5-cyclopropyl-2_(4-fluorophenyl)-3-[(methyl) Amino)carbonyl]-l-benzofuran-6-yl}(methylsulfonyl)amino]methylpyridyl)carboxylic acid

Step 1: 4 -Bromo-2-(bromomethyl) σ was treated with 4-bromo-2-methyl using benzoquinone peroxide (0.472 g, 1.947 mmol). A solution of pyridine (6.7 g, 38·9 mmol) and NBS (7.28 g, 40.9 mmol) in carbon tetrachloride (200 mL) was maintained at reflux for 16 h. The solution was concentrated on celite and purified by EtOAc EtOAc (EtOAc) NMR (DMSO-d6) d: 8.45 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 5.4, 1.9 Hz, 1H), 4.67 (s, 2H). Step 2: 6-[[(4.bromo-2-0-pyridyl)fyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N -methyl-1-benzofuran-3-carboxamide treated with potassium carbonate (258 mg, 1.864 mmol) 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[ (methylsulfonyl)amino]-1-benzofuran_3_formamide 154005.doc •52· 201138786 (250 mg, 0.621 mmol) and 4-bromo-2-(bromoindenyl)pyridine ( A solution of 234 mg, 0.932 mmol) in acetonitrile (10 mL) was maintained for 3 h. The solution was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzo-acetonide (303 mg, 0.529 mmo yield: 85%). LCMS (m/z, ES+) = 574 (M+H). Step 3: (2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino))]-1-benzofuran-6-yl} (曱Alkylsulfonyl)amino]methyl"_4_ than a butyl group) is characterized by 6-[[(4-bromo-2-»pyridyl)indolyl](nonylsulfonyl)amino]_5 _cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carbamide (285 mg, 0.498 mmol), potassium acetate (195 mg, 1.991 mmol), double a solution of (pinacoholyl) diboron (316 mg, 1.245 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (40·7 mg, 0.050 mmol) in 1,4-dioxane (1 mL) It was maintained in a sealed pressure flask at 9 ° C for 16 hours. The mixture was cooled, and the mixture was eluted on Shishizao soil, and the residue was purified by reverse phase hplc to give (2-{[{5-cyclopropyl·2-( 4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl b 4_pyridyl) Mg, 0·〇33 mmol, yield 6.73%). A NMR (f'-d4)d: 8.32-8.45 (m, 2H), 7.81-7.94 (m, 2H), 7.68 (br. s., 2H), 7.61 (s, lH), 7.16-7.33 (m) , 2H), 7.04 (s, lH), 5. 〇 4-5.19 (m, 2H), 3.24 (s, 3H), 2.90 (s, 3H), 2.15-2.36 (m, 1H), 154005.doc - 53· 201138786 0.93-1.03 (m, 1H), 0.76-0.91 (m, 2H), 0.35 (br· s·, 1H). LCMS (m/z, ES+) = 538 (M+H) &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&& -methylethyl)oxy]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)decanoic acid

To 2-(4-phenylphenyl)-7V-indolyl-5-[(l-methylethyl)oxy]_6-[(methylc-bromo)amino]-1-benzo. Add [4-(bromoindolyl)phenyl]carboxylic acid to a solution of N,N-dimethylformamide (2.5 mL) in a solution of N-N-dimethylformamide (1 mg, 0.24 mmol) (102 mg, 0.48 mmol) and carbonic acid (99 mg, 0.71 mmol). The reaction was heated in a microwave at 120 ° C and 300 W for 15 minutes. The reaction seems to be completed by 30%. In the microwave at 120. (: and reheat the reaction at 300 W for 30 minutes "no change" so add 1 equivalent of each of potassium carbonate (33 mg '0.24 mmol) and [4-(bromomethyl)phenyl]zinc acid (51 mg, 〇24 mmol) 'and the reaction was heated in a microwave at 12 (rc and 3 〇〇w for 2 。w. The reaction was evaporated in vacuo and purified by MDAP. The appropriate fractions were combined and evaporated in vacuo. Freeze-drying using hydrazine, 4~ dioxane to give (4·{[{2-(4-fluorophenyl)-3-[(decylamino)carbonyl)-5·[(1) -mercaptoethyl)oxy]_ι_benzofuran_6-ylindole (fluorenylsulfonyl)amino]indenyl}phenyl)-acid. 1H NMR (DMSO-d6) δ: 8.37-8.47 I54005 .doc -54 - 201138786 (m, 1H), 7.99 (s, 2H), 7.88 (dd, J=8.8, 5.6 Hz, 2H), 7.67 (d, J=7.8 Hz, 2H), 7.30-7.42 (m , 3H), 7.24 (d, J=7.8 Hz, 2H), 7.11 (s, 1H), 4.90-5.12 (m, 1H), 4.75-4.89 (m, 1H), 4.52-4.74 (m, 1H), 3.14 (s, 3H), 2.80 (d, J=4.5 Hz, 3H), 1.40 (d, 6H). LCMS (m/z, ES+)=555 (M+H). Example 4 (3-{[{ 2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]_5_[(1-methylethyl)oxy -1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)decanoic acid

Similar to for (4-{[{2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-5-[(1-methylethyl)oxy]-1-benzene) And 吱嗔-6-yl}(methyl fluorenyl)amino]methyl}phenyl) lysine as described in the 'Using [3-(bromoindolyl)phenyl] face acid (3-{ [{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(l-methylethyl)oxy]-1-benzofuran-6-yl}( Methylsulfonyl)amino]indenyl}phenyl)-acid. 1H NMR (DMSO-d6) δ: 8.36-8.51 (m, 1H), 8.12 (s, 2H), 7.81-7.96 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.29-7.43 (m, 4H), 7.18-7.29 (m, 1H), 7.10 (s, 1H), 4.90-5.08 (m, 1H), 4.76-4.91 (m, 1H), 4.54-4.72 ( m, 1H), 3.13 (s, 3H), 2.80 (d, J=4.5 Hz, 3H), 1.40 (d, J=5.8 Hz, 6H). LCMS (/w/z, ES+) = 555 (M+H). 154005.doc ·55· 201138786 Example 5 (2-(1)2-(44 phenyl)-methylamino post group]_s](i-methylethyl)oxy]1benzo-benzo- 6-yl} Methyl hydrazide) amino group] methyl}phenyl)

To 2 (4Fluorophenyl)_jv-methyl·5_[(1methylethyl)oxy]_6-heptamethylphenyl)amino]-1-benzophenone bite _3 mercaptoamine (10) 〇 Call, 〇Μ 〇 1)

In THF (5 mL), the solution φ $丄μ, A is added with 〇(bromomethyl)phenyl]zinc acid (307 mg' L43 〇1) and sodium butoxide (91 〇, 〇95 noodles) 〇 1). The reaction was stirred overnight. Then it was evaporated to dryness in vacuo. Use 2 Μ sinking to talk about the crude product, pick up the organic matter with two gas smoldering, separate from the water phase, use hydrophobic! · Raw frit dry and concentrate in vacuum. By purifying the crude product. Appropriate fractions were combined and evaporated in vacuo, followed by lyophilization with <RTIgt; dioxane</RTI> to afford (2_{[{2_(4-fluorophenyl)~3 [(methylamino)carbonyl]-5-[(l -Methylethyl)oxy]benzofuran-6-ylsulfonylsulfonyl)amino]methyl}phenyl)gminic acid. iH NMR (DMSO-d6) δ: 8.37-8.44 (m, 1H), 8.08 (s, 2H), 7.84-7.92 (m, 2H), 7.60 (d, J = 7.8 Hz, IH), 7.41 (S, IH), 7.29-7.39 (m, 4H), 7.10-7.17 (m, 1H), 7.09 (s, 1H), 5.06 (br. s., 2H), 4.70-4.86 (m5 1H), 3.07 (s, 3H), 2.80 (d, J = 4'5 Hz, 3H), 1_40 (d, 6H). LCMS (w/z, ES+) = 555 (M+H). 154005.doc -56- 201138786 Example 6 (3-{[{5-cyclopropyl-2-(4-fluorophenyl)_3.[(methylamino)carbonyl)benzofuran-6-yl} (methyl) aryl group] methyl} phenyl) carboxylic acid

Add 5-cyclopropyl-2-(4-fluorophenyl)·#-fluorenyl-6-[(methyl aryl)amino]-1-benzofuran-3- to the flask for drying in a box Indoleamine (201 mg, mmol) [3~(&gt;odormethyl)phenyl]-acid (322 mg, 1.5 mmol, CombiBlocks), potassium butoxide (112 mg, 1 mmol) and THF (5 mL). The mixture was stirred at ambient temperature for 2 days. 2 N HCl (5 mL) was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude residue which can be purified by preparative hplc (3-{[{5~~~~~~~~ ))-3-[(methylamino)carbonyl]-1-phenyl'yl)(methyl scutane)amino]indenyl}phenyl)-acid (55 mg, yield 2%) . H NMR (300 MHz, CD30D) δ: 7.89 (t, 2H), 7.47 (m, 3H), 7·24 (m, 4H), 7.01 (s, 1H), 4.60 (s, 2H), 3.14 ( s' 3H), 2.9i (s, 3H), 2.21 (m, 1H), 0.93 (m, 1H), 0.77 (m, 2H), 0.37 (m, 1H) e LCMS (/w/z, es+) =537 (M+l). Example 7 (4_U{5-cyclo)_2_(4-fluorophenyl)3[(methylamino)carbonyl]4benzofuran-6-yl}(fluorenylsulfonyl)amino] A Base phenyl) oleic acid 154005.doc -57- 201138786

Add 5 • cyclopropyl phenyl) winter formazan to the Ua-dried flask [(methyl succinyl) amino]-1-benzopyran-3-yl sylamine (201 mg, 〇.5 mm 〇1), [4-(filled methyl)phenyl]folic acid (322 mg, 1.5 mmol, CombiBlocks), tributy tributol clock (112 mg, i claws) and thf (5 mL). The mixture was stirred at ambient temperature for 2 days. 2 n mL) was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered and evaporated tolulululululululululululululululululululululululululu (Mercapto-amino)carbonyl hydrazone benzocyt-6-yl}(methylsulfonyl)amino]methyl}phenyl)carboxylic acid (13%, yield 49%). 4 NMR (300 MHz, CD30D) δ: 7.89 (t, 2H) 7.55 (m, 3H), 7.24 (m, 4H), 7.02 (s, 1H), 4.59 (s, 2H), 3·14 (s, 3H), 2·92 (s, 3H), 2.21 (m, 1H), 0.94 (m, 1H), 0.78 (m, 2H), 0.34 (m, 1H). LCMS (m/z, ES+) = 537 (M+l). Example 8 (2-{[{S-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-i-benzofuran-6-yl} (methyl Sulfhydryl)amino]methyl}phenyl)-acid

-58 - 154005.doc 201138786 Add 5-cyclopropyl_2_(4-fluorophenyl)-iV-mercapto-6-[(methylsulfonyl)amino]_ι-benzene to an oven-dried flask And furan_3_formamide (2〇1 mg, 0.5 mmol), [2-(bromoindolyl)]-acid (322 mg, 15 mm〇1, CombiBlocks), potassium t-butoxide ( 112, 1 mmol) and THF (5 mL). The mixture was stirred at room temperature for 1 day. 2 n HCl (5 mL) was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 3-[(decylamino)carbonyl]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino]mercapto}phenyl)carboxylic acid (32 mg, yield 14%). 4 NMR (300 MHz, gas-d-d) δ: 8.39 (m, 1H), 8.05 (s, 1H), 7.91 (t, 2H), 7.62 (s, 1H), 7.34 (m, 5H), 6.92 ( s, 1H), 5.14 (s, 2H), 3.18 (s, 3H), 2.80 (m, 3H), 2.22 (m, 1H), 0.83 (m, 3H), 0.35 (m, 1H). LCMS (w/z, ES+) = 537 (M+l) </RTI> Example 9 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine) Benzofuran-6-yl)methylsulfonylamino)methyl)-2-fluorophenyl-fat

Step 1: 1-Bromo-4-(bromomethyl)-2-fluorobenzene to (4-di-3-oxo)methanol (500 mg, 2.45 mmol) in 10 mL EtOAc. A solution of phosphorus tribromide (460 mg, i 72 mm 〇 1) in M 2 mL diethyl ether was added to the stirred solution of the 201138786 ether. Once the addition was complete, the mixture was stirred at room temperature for 30 minutes and then heated to reflux for an hour. The cooled reaction mixture was poured into ice water (1 mL) and organic layer was evaporated. The combined organic layers were washed with aq. NaH.sub.3 (1 mL) and brine (1 mL) and dried over Naj. 593 mg, yield 91%) which was used in the next step without further purification. Step 2: 6-(N-(4-Bromo-3-fluorobenzyl)methylsulfonylamino-5-cyclopropyl-2-(4-1phenyl)---methyl stupid Treatment of 5-cyclopropyl-2-(4-fluorophenyl)-N-indenyl with 1-di-4-(indimeth)-2-fluorobenzene (532 mg '2.0 mmol) 6-(Indolylsulfonylamino)benzofuran_3_carbamidine (400 mg, 1.0 mm〇l), KI (166 mg, 1.0 „1„1〇1) and K2C〇3 (414 mg, 3 - 0 mmol), EtOAc (30 mL EtOAc) (EtOAc) The combined organic layer was dried over anhydrous Naq.sub.4 and evaporated. 6-(N-(2-(phenyloxyindolyl)-propyl)methyl-hydroxylamino)-5-cyclopropyl-2-(4-fluorophenyl)benzofol-3 - methotrexate (464 mg, yield 79%) Step 3: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetra-l-yl-1) 3,2-dioxaborin-2-yl)benzylmethyl)methyl-decylamino)-2-(4-fluorophenyl)-indole-methylbenzene And furan-3-carboxamide 154005.doc •60· 201138786 ι,ι,_bis(diphenylphosphino)ferrocene_di-palladium(II) dichlorohydrazine composite in a nitrogen atmosphere (51 mg '0.044 mm〇l) and N-(2-(benzophenoxy)ethyl)-6-(N-(2-(benzoyloxymethyl)allyl)decylsulfonate Amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran_3_decylamine (256 mg &gt; 0.44 mmol) was dissolved in dioxane (1 mL). (pinacoldin) diboron (224 mg, 〇·88 mmol) and potassium acetate (129 mg, 1.32 mmol), and the mixture was stirred overnight at 100 ° C. The cooled reaction mixture was poured into water (20 mL) The residue was extracted with EtOAc (30 mL EtOAc) (EtOAc (EtOAcjjjjj To give 5_cyclopropyl_6_(N_(3_fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzyl) Mercaptosulfonylamino)-2-(4-fluorophenyl)-N-methylbenzofuran_3_decylamine (220 mg, yield 81%). Step 4: 4-((N- (5-cyclopropyl-2-(4-fluorophenyl) )-3-(methylamine-mercapto)benzofuran-6-yl)methylsulfonylamino)hydrazino)_2_fluorophenyl-tertanoic acid 5-cyclopropyl-6-(N-( 3-fluoro-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)benzyl)methylsulfonylamino)_2_(4-fluoro Phenyl)-N-mercaptobenzopyran-3-carboxamide (200 mg 'crude, i_9l _〇1) was dissolved in THF (10 mL) and 5 N HCl (10 mL). Continue to 60 ° C overnight. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine) Benzofuran-6-yl)nonylsulfonylamino)hydrazino)_2_fluorophenyl-acid (52 mg 'yield 30%). 4 NMR (300 MHz, CD3OD) δ=7.95 (m, 2H), 7.63 (s, 1H), 7.30 (q, 3H), 7.08 (q, 3H), 154005.doc -61 - 201138786 4.97 (m} 2H ), 3.38 (s, 3H), 2.95 (s, 3H), 2.04 (m, 1H), 1.03 (m, 1H), 0.83 (m, 2H), 0.39 (m, 1H). LCMS (m/z) ES+=555 (M+l) 〇 Example 10 4-((N-(5-cyclopropyl_2_(4-fluorophenyl)_3_(methylaminemethanyl)benzofuran Miso-6-yl)methylsulfonylamino)methyl)_2-methoxyphenyl-fat

〆〇OH Step 1: 1-Bromo-4-(bromomethyl)-2-methoxybenzene to (4-oxa-3-methoxyphenyl)methanol (5 〇〇 mg, 2.32 mm 〇 1) A solution of phosphorus tribromide (435 mg, 1.62 mmol) in 2 mL of diethyl ether was added dropwise to a stirred solution of EtOAc. Once the addition was complete, the mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice water (1 mL) and organic layer was evaporated. The combined organic layers were washed with aq. sat. NaH.sub.3 solution (1 mL) and brine (10 mL). -2-decyloxybenzene (574 mg, yield 8.5) was used in the next step without further purification. Step 2: 6-(N-(4-Bromo-3-f-oxybenzyl)sulfonylamino)_5_cyclopropyl-2-(4-fluorophenyl)-indole·methylbenzene And furan_3_formamide treated with 1-bromo-4-(bromomethyl)-2-methoxybenzene (556 mg, 2 〇mm〇i) 154005.doc -62 · 201138786 5-cyclopropyl -2-(4-Phenylphenyl)-N-methyl-6-(fluorenylamino)benzophenone °-3--3-decylamine (400 mg '1.0 mmol), KI (166 mg, A suspension of 1.0 mmol) and K2C03 (414 mg '3.0 mmol) in dry DMF (10 mL). The reaction was cooled, diluted with EtOAc (EtOAc) The combined organic layers were dried over anhydrous Na.sub.4 and evaporated. The crude product was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to give 6-(n-(4-bromo-3-indolylphenyl)methyl) gf amine)_5- Cyclopropyl-2-(4.fluorophenyl)-indole-indenylbenzo D-propan-3-cartoamine (5 12 mg, yield 85%). Step 3. 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methoxy-4-(4,4,5,5-tetradecyl-1,3, 2-Dioxaboron p-Et-2-yl)benzyl)methylsulfonylamino-decyl benzofuran-3-indole amine 1,1'-bis(diphenyl) under nitrogen atmosphere Phosphinyl)ferrocene-palladium(II) dioxane complex (37 mg, 0.032 mmol) and 6-(N-(4-,; odor-3-methoxybenzyl) Hydrazinylamino)_5_cyclopropyl_2_(4-fluorophenyl)·Ν_methylbenzofuran-3-carboxamide (192 mg '0.32 mmol) dissolved in dioxane (10 mL) Add bis(pinacolyl)diboron (163 mg, 〇64 mmol), acetonitrile (94 mg, 0.96 mmol), and stir the mixture overnight at 1 Torr. The cooled reaction mixture was poured over The mixture was extracted with EtOAc (30 mL EtOAc) (EtOAc) Purification of the residue by petroleum to give 5-cyclopropyl·2·(4-fluorophenyl)-6-(N-(3-methoxy-4-(4,4,5,5-tetramethyl) _1,3,2_dioxaboron-2-yl)phenylhydrazinyl sulfhydryl -Ν·Methylbenzofuran·3_Protonamine (17〇mg, yield 83〇/〇' 154005.doc •63· 201138786 Crude material). Step 4 ·· 4-((N-(5_ Cyclopropyl winter (4_Fluorophenyl)_3_(methylamine-mercapto)benzoyl--6-yl)methyl-hydrogenated amino)-yl)- 2-methoxyphenyl taric acid will be 5- Cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methoxy winter (4,4,5,5-tetramethyl-1'3'2-dioxaboride shouting _ 2·yl)phenylhydrazinyl)methylsulfonylamino)_N_methylbenzotrile-3-cartoamine (150 mg, crude material, 〇23 _〇1) dissolved in THF (1 mL) And a solution of 5NHC1 (10 mL), and the obtained reaction mixture was heated to 60 t overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 4·((Ν_(5•cyclopropyl_2_) (4-fluorophenyl)-3-(decylamine-methylhydrazino)benzofuran-6-yl)methylsulfonylamino)indenyl 2-methoxyphenyl-fatanoic acid (40 mg, yield 31%). 1h NMR (300 MHz, CD3OD-^) 5=7.94 (m, 2H), 7.50 (s, 1H), 7.30 (q, 3H), 7.07 (d, 2H), 6.86 (d, 1H) , 4.91 (m, 2H), 3.78 (s, 3H), 3.16 (s, 3H), 2.95 (s, 3H), 2.04 (m, 1H), 1.03 (m, 1H), 0 .83 (m, 2H), 0.39 (m, 1H). LCMS (m/z) ES+ = 567 (M+l). Example 11 4_((N-(5-Cyclopropyl-2-(4-fluorophenyl)·3_(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonylamino)methyl Methylphenyl-carboxylic acid

154005.doc • 64 - 201138786 Step 1: In(Methyl)_2•methyl stupid (4/odor _3_mercaptophenyl) decyl alcohol (400 mg, 2 mmol) in 10 mL of hexyl ether Add phosphorus tribromide to the stirred solution (375 is called, i4 is called in 2 mL of the solution in the yoke... Once the addition is complete, the mixture is allowed to fall off at room temperature for 30 minutes, then heated to reflux for 1 hour. It will be cooled. The reaction mixture was poured into ice water (丨〇mL), the organic layer was separated, and the aqueous phase was extracted with diethyl ether (5 mL×2). The combined organic layer was washed with saturated NaHC〇3 solution (mL) and brine ((7) mL). , dried and concentrated under reduced pressure to give 1-bromo-4-(bromomethyl)-2-methylbenzene (488 mg, yield 93%) . Step 2: 6-(N-(4-Bromo-3-methylbenzyl)methylsulfonylamino)·5_cyclopropyl-2-(4-fluorophenyl)-N-nonylbenzene And furancarboxamide was treated with 1_indol-4-(bromomethyl)-2-methylbenzene (488 mg, 1.86 mmol). 5·Cyclopropyl-2-(4-fluorophenyl)-N- -6-(methylsulfonylamino)benzofuran-3-carboxamide (400 mg, 1.0 mmol), KI (166 mg, 1.0 111111〇1) and K2C03 (414 mg, 3.0 mmol) in anhydrous The suspension in DMF (10 mL) was maintained for half an hour after heating the reaction under nitrogen to reflux. The reaction was cooled, diluted with water (15 mL) andEtOAc. The combined organic layers were dried over anhydrous Na.sub.SO.sub.4 and evaporated. The crude product was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to afford 6·((-bromo-3-(phenyl)methyl)methylsulfonylamino) 5-5-Cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-decylamine (480 mg, yield 82%). Step 3 ··· 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl·4~(4,4,5,5-tetramethyl) Dioxaboron-2-yl)benzyl)sulfonylsulfonamide 154005.doc -65· 201138786 base) benzopyramine-3·anthracene amine under nitrogen atmosphere '1,1,_ double (diphenylphosphino)ferrocene-dipleated palladium(II)-chloranthroate complex (40 mg, 0.035 mmol) and 6-(Ν-(4-,; odor-3-mercaptobenzoic acid) Ethylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-indole-methylbenzofuran-3-carboxamide (205 mg, 0.35 mmol) dissolved in dioxins In the alkane (1 〇 mL). Bis(pinacolyl)diboron (178 mg, 7 〇 mmol), potassium acetate (103 mg '1·〇5 mmol) was added, and the mixture was stirred overnight at 10 °C. The cooled reaction mixture was poured into water (2 mL) andEtOAcEtOAc The combined organic layers were dried with EtOAc EtOAc. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc N-(3-Methyl-4-(4,4,5,5-tetradecyl·1,3,2-dioxaborin-2-yl)phenylhydrazinyl) fluorenyl hydrazino)benzene And furan-3·decylamine (156 mg, yield 72%). Step 4: 4-((N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl) benzofuran-6-yl)decylsulfonylamino )methyl)-2.methylphenyl-acid 5-cyclopropyl-2-(4-phenylphenyl)-N-methyl-6-(N-(3-methyl-4-(4) ,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzyl)methyl arylamino)benzofuran-3-carboxamide (120 The crude material was dissolved in THF (10 mL) and 5N EtOAc (10 mL). The reaction mixture was concentrated in vacuo and the residue was purified mjjjjjjjjjjjjjjjjjjjjj Benzyl fluoroindolyl-6-yl)methyl hydrazinyl) fluorenyl) 2 - methylphenyl sunbaic acid (20 mg, yield 19%). 4 NMR (300 MHz, CD3OD-^) 5=7.94 (m, 2H), 7.57 (s, 1H), 7.27 (t, 2H), 7.16 154005.doc -66 - 201138786 (t,2H),7.05 (d , 2H), 4.95 (m, 2H), 3.16 (s, 3H), 2.94 (s, 3H), 2.26 (s, 4H), 0.98 (m, 1H), 〇·83 (m, 2H), 0.30 ( m, 1H). LCMS (m/z) ES+ = 551 (M+l) 〇. Benzopyran-6-yl)methylsulfonylamino)methyl)-2-(trifluoromethyl)phenyl decanoic acid

Step 1: 1-Bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene 1-bromo-4-methyl-2-(trifluoromethyl)benzene (1 g, 4 2 mm 〇1), benzamidine peroxide (0.1 g, 0.42 mmol) and N-bromosuccinimide (〇75 g, 4.2 mmol) were dissolved in 50 mL of CCU and heated to reflux for 2 hours. The reaction mixture was filtered and the filtrate was cooled and concentrated in vacuo. The residue was purified by column chromatography (solvent eluting with petroleum) to afford bromobromo-2-(bromomethyl)-2-(trifluoromethyl)benzene (1. lg, yield 86 〇 / 。). Step 2: 6-(N-(4-Bromo-3·(trifluoromethyl)benzyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenylindenyl) And furan_3_formamide treated with 1-bromo-4-(bromomethyl)_2-(trifluoromethyl)benzene (1丨g, 3 5 111111〇1) 5-cyclopropyl-2·(4· Fluorophenyl)_N-indenyl-6-(methylsulfonylamino) benzofuran-3-indole amine (1 g, 2.5 mmol), κΐ (0·415 g, 2.5 mmol) and K2CO3 (1.04) g, 7.5 mmol) suspended 154005.doc -67 - 201138786 in anhydrous DMF (1 () mL), and the reaction was heated to reflux for half an hour under nitrogen. The reaction was cooled and diluted with water (15 mL) 'And extracted with EtOAc (30 mL > &lt; 3). The combined organic layer was dried over anhydrous NazSO4 and evaporated. The crude product was purified by column chromatography eluting with 0-50% ethyl acetate. 6_(n_(4_Bromo-3-(trifluoromethyl)benzoinyl)methylsulfonylamino)_5_cyclopropyl_2_(4fluorophenyl)-N-methylbenzofuran·3 _ decylamine (1.1 g, yield 69%). Step 3. 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(Ν-(4-(4,4) ,5,5·Tetramethyl-1,3,2-dioxodus-2-yl)-3-(trifluoromethyl)benzene Methyl)methyl hydrazino)benzofuran-3-carboxamide 1,1,·bis(diphenylphosphino)ferrocene-palladium dichloride (H) II under nitrogen atmosphere Gas-fired complex (185 mg, 0.16 mmol) and 6-(N-(4-(3-methyl-3-methylbenzyl) fluorenyl)- 5-cyclopropyl-2-(4-fluoro Phenyl)-N-methyl benzofuran-3-carboxamide (1 g, 1.6 mmol) was dissolved in dioxane (1 〇 mL). Add bis(pinadol) diboron (0.8 g, 3.2 mmol), potassium acetate (0.47 g ' 4.8 mmol), and the mixture was stirred at EtOAc overnight. The cooled reaction mixture was poured into water (20 mL) The combined organic layers were dried over Na 2 EtOAc (EtOAc) elute EtOAc (EtOAc) Phenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl 4,3,2-dioxaborin-2-yl)-3-(trifluoro) Methyl)phenylhydrazinyl)methyl succinylamino)benzo ou-flavor _3-inosine (420 mg, yield 3 9%) 〇Step 4: 4-((N-(5-cyclopropyl) Keto-2-(4-fluorophenyl)-3-(methylaminecarbamyl) and. Furan-6-yl)methylsulfonylamino)methyl)-2-(trifluoromethyl)phenyl 154005.doc -68 - 201138786 5-cyclopropyl-2-(4-fluorobenzene -N-methyl_6-(N-(3-methyl-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)benzene Methyl)methylsulfonamide)benzofuran-3-carboxamide (300 mg, crude material, 〇43 mm〇1) was dissolved in THF (10 mL) and 5 N HCl (10 mL) And the reaction mixture was heated to 60 ° C overnight. The reaction mixture was concentrated in vacuo and the residue was purified mjjjjjjjjjjjjjjjjjjjjjj Benzofuran-6-yl) fluorenylamino) fluorenyl) 2_methylphenyl phthalic acid (125 mg 'yield 47./〇). NMR (300 MHz, CD3OD-d4) 5=7.94 (m, 2H), 7.65 (d, 2H), 7.47 (d, 1H), 7.36 (t, 2H), 7.03 (s, 1H), 6.86 (d, 1H), 5.12 (m, 2H), 3.21 (s, 3H), 2.94 (s, 3H), 2.25 (m, 1H), 0.98 (m, 1H), 0.83 (m, 2H), 0.30 (m, 1H) ). LCMS (m/z) ES+ = 605 (M+l). Example 13 4-((N-(2-(4-Phenylphenyl)-5-cyclopropyl-3-(methylaminemethanyl)benzofuran-6-yl)decylsulfonylamino) Methyl)-2-(trifluoromethyl)phenylhydrazine

Step 1 : 3-(4-chlorophenyl-oxo-propionic acid B to 4-chlorobenzoic acid (3〇_〇g' 〇·192 mol) in DCM (250 mL) 154005.doc -69- Ethanol (25 mL, 0.288 mol) was added to the solution, then DMF (0.5 mL) was added dropwise. The reaction mixture was refluxed for 2 hours. The obtained clear yellow solution was concentrated in vacuo. Add TEA (67 mL) to a solution of ethyl malonate (41 g, 0.241 mol) in acetonitrile (537 mL), and cool in ice brine, add MgCl2 (27 4 g, 0.288) Mol) 'and the resulting mixture was stirred at this temperature for 3 hours. The acid sulphate prepared above was added and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. After completion of the reaction (as monitored by TLC), in an ice bath The mixture was cooled and the intermediates were stripped by careful addition of 2 N HCl (600 mL). The mixture was stirred in an ice bath for 1.5 hours, then transferred to a sep. funnel and ethyl acetate (3×2) 〇〇mL) extraction. Wash the combined organic layer with saturated sodium bicarbonate (450 mL), brine (250 mL) Drying over sodium sulphate, EtOAc (EtOAc m.) Step 2: 2-(4-Chlorophenyl>-5-hydroxybenzofuran_3_carboxylic acid ethyl acetonate under a nitrogen atmosphere, using an oven-dried glassware, gasification words (28.3 g, 0.2 〇7 mol) was stirred in absolute ethanol (45 mL), then heated to 95 C (reflux). Add 4-[p-phenylphenyl phenylacetate (44, 0.194 mol) in a single portion, followed by 2 hours. A solution of phenylhydrazine (22 6 g, 〇21 ❶丨) in anhydrous MTBE (500 mL) was added dropwise. At the same time, MTBE was steamed from the reaction mixture to keep the reaction volume large. For most of the entire addition process, the bath temperature was maintained at 145_155 and the internal temperature was C 〇 in the middle of the addition. 'Because the reaction mixture thickened and suspected 154005.doc •70- 201138786 The original volume of ethanol in the distillation process has some loss, so Add anhydrous ethanol (45 mL). After the addition is completed, 'continue to heat for 3 minutes. Cool the reaction mixture until Warmly partitioned between water (1 mL) and EtOAc (250 mL). The insoluble solid was removed by filtration of the two-phase solution, then the organic layer was separated, washed with water, dried and evaporated in vacuo. The solid was slurried in warm dichloromethane and the mixture was cooled to room temperature and further cooled by refrigeration. The tan solid was filtered from a dark brown solution and washed with a small volume of DCM and dried in vacuo to give &lt;RTIgt;&quot;&quot;&quot;&quot;&quot;&quot; g, 43.9%). Step 3: 2-(4-Chlorophenyl)-5-isopropoxybenzofuran·3-formic acid ethyl acetate to 2-(4-phenylphenyl)-5-hydroxybenzofuran_3•decanoic acid Isopropyl (Μ mL) was added to the solution of ethyl ester (26 g, 0·051 mol) in NMP (160 mL), and niacin was added (33 g' 0.101 mol). The reaction mixture was stirred in a 6 ° C oil bath for 20 hours' and then cooled to ambient temperature. The reaction mixture was treated with a 5% EtOAc solution and stirred for 15 min. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> (4-Acetyl)_5-Isopropoxybenzofuran-3-furoate ethyl ester (15 g, 82%). Step 4 · 2-(4-Chlorobenzyl)-5-isopropoxy-based benzo-afu „南_^_carboxylic acid ethyl acetate 2-(4-chlorophenyl)-5-isopropoxy Stupid and furan-3-formic acid ethyl ester 4 (3〇g ' 0.084 mol) / glutamic solution in chloroform (75 mL), and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in the gas ( 75 mL), and cooled in an ice bath. Add the acid solution dropwise to 2-(4-phenylphenyl)-5-iso 154005.doc •71 · 201138786 Propyloxy stupid and n. The reaction mixture was stirred for 1.5 hours under 〇〇c. The reaction mixture was diluted with water (60 mL) and the layers were separated and dried over anhydrous sodium sulfate. Concentrated to give a brown oil which was purified by column chromatography (PE/ea=5/i) to afford 2-(4··················· Oxy-6-nitrobenzo-cing-3-carboxylic acid ethyl vinegar (11 g, 32.4%) Step 5: 2-(4-Chlorophenyl)-5-carbyl-6-bowlylbenzoa 2-(4-Chlorophenyl)-5-isopropoxy-6-nitrobenzopyrano_3_decanoic acid ethyl vinegar (11 g, 27.2 mmol) Dissolved in anhydrous DCM (150 mL) and cooled in an ice bath under nitrogen atmosphere. Add boron trioxide (41 mL, 41.0 mmol) over about 20 minutes. After completion of the reaction, by pouring into ice/water mixture The reaction mixture was quenched with EtOAc (EtOAc m.) Ethyl furan-3-carboxylate (10.2 g, 84%). Step 6: 2-(4-Phenylphenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzophene Ethyl-3-carboxylic acid ethylacetate to 2-(4-phenylphenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid ethyl ester (10.2 g, 22.9 mmol) And a solution of DMAP (0.289 g, 2.3 mmol) in anhydrous DCM (300 mL) EtOAc (EtOAc) The reaction mixture was stirred for 30 min, then quenched with water (200 mL) EtOAc (EtOAc) elute The combined organic layers were washed, dried over anhydrous sodium sulfate and filtered Concentration under reduced pressure gave 154005.doc-72-201138786 2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzopyrene as a yellow solid. Ethyl 3-formate ethyl ester (10 g, 80%). It was used without further purification. Step 7: 2-(4-Chlorophenyl)-5-cyclopropyl-6-nitrobenzofurancarboxylic acid ethyl acetate to 2-(4-chlorophenyl)-6-nitro-5-(trifluoro Methylsulfonyloxy)benzofuran-3-carboxylic acid vinegar (10 g '18 mmol), KF (4 64 g, 79 9 _〇1), NaBr (2.48 g, 24 mmol), cyclopropyl lysine Toluene (13 〇 mL) and water (2.8 mL) were added to a mixture of (3.2 g, 37 mm 〇1) and Pd(Ph3P)4 (l.33 g' 1.15 mmol). The reaction flask was evacuated for about 3 minutes and then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hours and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography (EtOAc /EtOAcEtOAcEtOAc Ethyl benzofuran-3-carboxylate (7.9 g, 99%). Step 8: 6-Amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran_3•carboxylic acid B to 2-(4-indolyl)-5-cyclopropyl-6 Add ι 〇 % palladium / carbon (1.83 g), 1 N HCl solution to a solution of ethyl nitrobenzofuran _3_ decanoate (8 g, 18.2 mmol) in ethyl acetate (45 mL) 2.5 mL), and stirred at room temperature under 〇.4 MPa of hydrogen for 8 hours. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) , 990/.). Step 9. 2-(4-Chlorophenyl)-5-cyclopropyl-6-(N-(methyl decylmethyl) 154005.doc -73· 201138786 Methyl sulfonate Ethyl)benzofurancarboxylic acid ethyl acetonate at 6 ° C under N2 atmosphere to 6-amino-2_(4-hydrophenyl)-5-cyclopropyl stupid Add anhydrous TEA (6 73 red, 45.15 mmol) to a solution of the ester (7.4 g, 18.06 mmol) in anhydrous methane (170 mL). Then add sputum (4% mL, 63.2 mmol) The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (1 mL) and extracted with DCM (3×l··········· Evaporation to give ethyl 2-(4-hydroxyphenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonylamino)benzofuran-3-carboxylate ( 9.2 g, 99%) Step 10: 5-Cyclopropyl_2_(4-_phenylphenyl)_6(f-sulfonylamino)benzophenant-3-indole Potassium bismuth oxide (15.1 g, 270 mmol) was added to 2-(4-phenylphenyl)-5-cyclopropyl-6-(N-(methylsulfonylhydrazino)methylsulfonate under nitrogen atmosphere Ethylamino)benzofuran-3-carboxylic acid ethyl ester in a bath of ethanol (64 mL) and water (32 mL). The reaction was refluxed for one hour and then concentrated in vacuo. And acidified the solution with 1 N HCl (250 mL) until a precipitate formed. The solid was filtered and then dried to give 5-cyclopropyl-2-(4-phenylphenyl)-6-(methylsulfonylamino)benzene. Furan-3-decanoic acid (8.7 g, quantitative yield). Step 11 · 5-cyclopropyl-2-(4-phenylene)-N-methyl (methylsulfonylamino) benzopyrene Benzylamine at 5C to 5-cyclopropyl-2-(4-hydrophenyl)-6-(methylsulfonylamino)benzofuran·3·carboxylic acid (5 g, U.52 mmol DIPEA (3.3 g ' 25.34 mmol), HATU (5.15 g, 13.5 mmol) was added to a solution of 154005.doc 201138786 in anhydrous DMF (30 mL). After 15 min, 2 m of guanamine in THF was added dropwise. 23.04 mL, 46.08 mmol) 'and the mixture was stirred for an additional 2 hours, then water (60 mL) was added. EA (3x200) (M)) Extract the mixture, wash with water (2χ2〇〇m L), dry and dry; attenuate to a standard solid 5 _ cyclopropyl-2-(4-phenylphenyl)-N-曱Base-6-(indolylsulfonylamino)benzofuran-3_ an amine (4.7 g, 97%). Step 12: I-Bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene 1-Bromo-4-methyl-2-(trifluoromethyl)benzene (2 g, 8.4 mmol) Benzoyl peroxide (0.20 g '0.84 mmol) and N-bromosuccinimide (1.5 〇g, 8.4 mmol) were dissolved in 50 mL CCU and heated to reflux for 2 hours. The reaction mixture was filtered and the filtrate was cooled and concentrated in vacuo. The residue was purified by column chromatography (solvent eluted with petroleum) to afford &lt;RTIgt;&lt;/RTI&gt;&gt; Step 13: 6-(N-(4-Bromo-3-(trifluoromethyl)benzyl)methylamino)-2-(4-chlorophenyl)-5-cyclopropyl-N -methylbenzopyran-3-carbamide treatment of 2-(4-chlorobenzene) with 1-di-4-(bromomethyl)-2·(trifluoromethyl)benzene (758 mg, 2.40 mmol) ))-5-3⁄4 propyl-N-fluorenyl-6-(fluorenylamine-based amine)benzox-f--3-anthracene (500 mg ' 1.20 mmol), KI (199 mg, 1.20 mmol) And a suspension of K2C03 (497 mg '3·60 mmol) in dry DMF (10 mL). The reaction was cooled, diluted with water (20 mL) andEtOAcEtOAc. The combined organic layers were dried over anhydrous Na.sub.2.sub.4 and evaporated. The crude product was purified by column chromatography (solvent eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Phenylmethyl)methylsulfonylamino)-2-(4-phenylphenyl)-5-cyclopropyl-N-mercaptobenzopyran-3-amine (535 mg, 68%) . Step 14: 2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2) -Bornomyl-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonylamino)benzofuran-3-decylamine 1,1'- under nitrogen atmosphere Bis(diphenylphosphino)ferrocene-di-palladium(II) digas methane complex (95 mg, 0.082 mmol) and 6-(N-(4-bromo-3-(trifluoromethyl)) Benzoyl)methylsulfonylamino)-2-(4-chlorophenyl)-5-cyclopropyl-N-mercaptobenzofuran-3-decylamine (535 mg, 0.82 mmol) was dissolved in In dioxane (20 mL). Bis(pinacolyl)diboron (41 7 mg, 1.64 mmol) and potassium acetate (241 mg, 2.46 mmol) were added at 100. (The temperature was stirred overnight. The cooled reaction mixture was poured into water (2 mL). Column chromatography (purification of petroleum containing 〇_5〇% ethyl acetate) to purify the residue 'to give 2_(4-hydrophenyl)_5_cyclopropyl_N_methyl-6-(N-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonylamino) Furan-3-3-decylamine (423 mg, 73%) Step 15: 4-((N-(2-(4-Phenylphenyl)·5-cyclopropyl-3-(methylamine) Benzofuran-6-yl)methylsulfonylamino)mercapto(trimethyl)phenyl-tert-acid 2-(4-phenylphenyl)-5-cyclopropyl-N-methyl 6-(Ν-(4·(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-3-(trifluoromethyl)benzoinyl)anthracene Sulphonamide 154005.doc -76- 201138786 basal) and ketone-3-amine (423 mg, 0.60 mmol) dissolved in THF (10 mL) and used 5 N HCl (1.5 mL) Treatment with PS-benzene-tanning acid (1.16 g, 3.0 mmol). The suspension was stirred for 6 h, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-((2-(4-chlorophenyl)-5-cyclopropyl-3-(decylamine) benzo) benzoate.曱 确 确 胺 曱 曱 曱 曱 ) ) ) ) ) no no no no no no no no no no no no no no no no no no no no no no no ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( , 2H), 7.64-7.35 (m, 6H), 7.02 (s, 1H), 5.11-4.84 (m, 2H), 3.19 (s, 3H), 2.93 (s, 3H), 2.24-2.18 (m, 1H ), 0.97-0.96 (m, 1H), 0.80-0.71 (m, 2H), 0.29-0.28 (m, 1H) LCMS (m/z) ES+=621 (M+l). Example 14 4-((N -((2-(4-Phenylphenyl)-5-cyclopropyl-3-(methylaminemethane)benzofuran-6-yl)methyl)methylsulfonylamino)) _2_fluorophenyl decanoic acid

Step 1: 6-(Ν·(4-bromo-3-fluorobenzyl)methylsulfonylamino chlorophenyl)-5-cyclopropyl-indole-methylbenzo. Potassium citrate (494 mg, 3.58 mmol), KI (198 mg ' 1.19 mmol) and 1-bromo-4-(bromomethyl)_2_fluorobenzene (640 mg ' 2.39) under nitrogen atmosphere 154005.doc -77- 201138786 mmol)Addition to 2-(4-Phenylphenyl)_5_cyclopropyl·Ν_曱yl_6_(methylsulfonylamino)benzoquinone-3-cartoamine (0.5 g, j 194 〇 1) in a solution of anhydrous dmf (8 mL). The reaction mixture was stirred at room temperature for 3 min then diluted with water (30 mL) and filtered. The filtered residue was taken up in EtOAc EtOAc (EtOAc m. 6_(N_(4_bromo-3-ylfluoromethyl)methylsulfonylamino)-2-(4-phenylphenyl)_5-cyclopropylmethylbenzo-°f°nan-3-formazan Amine (536 mg, 74%). Step 2: 2-(4-Phenylphenyl)-5-cyclopropyl·6-(small (3_fluoro_4_(4&gt;4&gt;55•tetramethyl-1,3,2-dioxaboronium) 2-(N-(4-bromo-3-fluorobenzyl)-2-yl)benzyl)methylsulfonylamino)-N-methylbenzofuran-3-mercaptoamine under nitrogen atmosphere Methylsulfonylamino)-2-(4-phenylphenyl)-5-cyclopropyl-N-methylbenzofuran_3-formamide (536 mg, 0.885 mmol), dipinacol Root diboron (449 mg '177 mmol) and KOAc (260 mg, 2.655 mmol) were added to 1,4-dioxin (20 mL). Pd(dppf)2Cl2 (204 mg, 0.177 mmol) was added and the mixture was stirred for 24 hours. The solvent was removed under reduced pressure, and the crude residue was purified by column chromatography (EA/PE = 1: 5 s then EA/PE = 1:2) to give 2-(4- chlorophenyl)-5- Cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzyl) fluorenyl Sulfonamide)·Ν-methylbenzofuran_3_formamide (0.412 g, 72%). Step 3: 4-((Ν-((2)-(4-chlorophenyl)-5-cyclopropyl-3-(methylaminecarbamimidyl) benzofuran-6-yl)methyl)methyl Sulfhydrylamino)methyl)_2_fluorophenyl-acid 2-(4-phenylphenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5) ,5-四甲154005.doc -78- 201138786 yl-1,3,2-dioxaboron-2-yl)benzyl)methylsulfonylamino)-N-methylbenzofuran-3 - Methotrexate (0.412 g, 0.631 mmol) was dissolved in THF (15 mL) eluting with &lt The suspension was stirred overnight, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to afford 4-((2-(4-)-phenyl)-5-cyclopropyl-3-(decylamine decyl)benzene as a white solid. And furan-6-yl)hydrazino)nonylsulfonylamino)methyl)-2-fluorophenyl lysine (11 mg, 30.5%). lH NMR (300 MHz, CDC13) 6=7.88-7.83 (d, 2H), 7.62-7.50 (m, 3H), 7.30-7.26 (t, 1H), 7.07-6.98 (m, 3H), 5.00-4.80 ( m, 2H), 3.17 (s, 3H), 2.93 (s5 3H), 2.27-2.22 (m, 1H), 0.98 (m, 1H), 0.84-0.80 (m, 2H), 0.35-0.34 (m, 1H) ° LCMS (m/z) ES+ = 571.1 (M+l) 〇 Example 15 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)_3_(methylamine formazan) Benzofuran-6-yl)methylsulfonylamino)phenyl)carboxylic acid

Step 1 · 1-Bromo-4-(2-bromoethyl) was added to 2-(4-bromophenyl)ethanol (丨g, 三3, tribromide minus g, 0.005 mmol) Add 15 mL of diethyl ether in a solution of 15 mL· diethyl ether (0.94 g, 0.0035 mmo丨) at 1〇&quot; Once the addition was completed, the mixture was stirred at room temperature and then heated to reflux for 1 hour. The solution will be cooled; 5 geese in diethyl ether. Once the addition was for 30 minutes, the reaction was cooled 154005.doc •79- 201138786 The mixture was poured into ice water (20 mL), the organic layer was separated, and acetonitrile (20 mL &lt;&lt;2&gt; The combined organic layers were washed with aq. NaH.sub.3 (aq) (25 mL) and brine (25 mL). Benzene (1.1 g, 84%) was used in the next step without further purification. Step 2: 6-(N-(4-Bromophenethyl)methylsulfonylamino)_5·cyclopropyl-2-(4-1phenyl)-N-mercaptobenzopyran-3- Treatment of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- with 1-carb-4-(2-diethyl)benzene (650 mg, 2.48 mmol) Methyl hydrazide) benzofuran _3_ anthraquinone (500 mg ' 1.24 mmol), KI (208 mg, 1.24 mmol) and K2C 〇 3 (5 13 mg, 3.72 mmol) in anhydrous DMF ( The suspension in 15 mL) was maintained at reflux for half an hour after heating the reaction under nitrogen. The reaction was cooled, diluted with water (20 mL) The combined organic layers were dried over anhydrous NaJCU and evaporated. The crude product was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to afford 6-(ν-(4·bromophenethyl)methylsulfonylamino)-5-cyclopropyl- 2-(4-Fluorophenyl)-indole-mercaptobenzox-m-carbamimid (336 mg, 46%). Step 3: 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetradecyl-1,3,2) -Bismomyl bromide-2-yl)phenethyl)methylsulfonylamino)benzoxyl-3-carboxamide A 1, fluorene-bis(diphenylphosphino)di Ferrocene-palladium dichloride (ruthenium dichloride) gas-fired complex (66 mg, 0.057 mmol) and 6-(anthracene-(4-phenyleneethyl)methylsulfonylamino)-5-cyclopropyl 2-(4-Fluorophenyl)-indole-methylbenzofuran-3-carboxamide (330 mg '0.57 mmol) was dissolved in two chews (2 mL) 154005.doc -80-201138786. Bis(pinacolyl)diboron (287 mg, 1.13 mmol) and potassium acetate (168 mg, 1.71 mmol) were added at 1 Torr. The mixture was stirred overnight under the arm. The cooled reaction mixture was poured with EtOAc EtOAc m. The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenethyl)methylsulfonylamino)phenylhydrazine-β-propan-3 - Methionamine (256 mg, 71%). Step 4: 4-(2·(Ν-(5-cyclopropyl-2·(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonate Amino)ethyl)ethylidene acid 5-cyclopropyl-2-(4-phenylphenyl)-N-mercapto-6-(N-(4-(4,4,5,5 -4) Mercapto-1,3,2-dioxy shed p-branche-2-yl)phenethyl)methyl hydrazinyl)benzoquinone-3-carboxamide (25 0 mg '0.40 mmol) was dissolved in A solution of THF (10 mL) and 5N HCl (1. 5 mL) was evaporated. The reaction mixture was concentrated in vacuo <RTI ID=0.0> Mercapto)benzofuran-6-yl)nonylsulfonylamino)ethyl)phenyl-p-piconic acid (59 mg, 27%).咕NMR (300 MHz, CD3OD) δ=7·97 (m, 2H), 7.61 (m, 3H), 7.31 (m, 5H), 4.02 (q, 2H), 3.05 (s, 3H), 2.97 (s , 3H), 2.93 (m, 2H), 2.04 (m, 1H), 1.07 (m, 1H), 0.93 (m, 2H), 0.83 (m, 1H). LC-MS (m/z) ES+ = 551 (M+l). Example 16 3-(2-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(decylamine)methyl)benzofuran-6-yl)methylsulfonamide Ethyl)phenyl phthalic acid 154005.doc -81 - 201138786

One. Step 1: 1-Bromo-3-(2-bromoethyl)benzene to 2-(3·bromophenyl)ethanol (1 g, 〇〇〇5 „^〇1) in a stirred solution of 15 mL of 6 ether A solution of phosphorus tribromide (〇94 g, 〇〇〇35 mm〇丨) in 1 mL of diethyl ether was added dropwise. Once the addition was completed, the mixture was stirred at room temperature for 30 minutes, and then heated to reflux to maintain 1 The cooled reaction mixture was poured into ice water (20 mL), the organic layer was separated, and the aqueous phase was extracted with diethyl ether (2 〇mL×2) washed with saturated NaHC 3 solution (25 mL) and brine (25 mL) The combined organic layers were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Step 2: 6-(N-(3-Bromophenethyl)nonylsulfonylamino)_5_cyclopropyl-2-(4-fluorophenylmethylbenzopyran-3) Treatment of 5-Hydroxy-2-(4-fluorophenyl)-N-methyl-6-(methyl) with 1-Methyl-3-(2-diethyl)benzene (500 mg ' 1.90 mmol) Sulfonamide) benzofuran _3_decylamine (400 mg '1.00 mmol), KI (166 mg, 1·〇〇mmol) and K2C03 (414 mg, 3.0 0 mmol) A suspension of EtOAc (15 mL EtOAc). The combined organic layer was dried over anhydrous Na.sub.2.sub.sub.sub.sub.sub.sub.sub.sub. Aminoamino)-5-cyclopropyl-2-(4-fluorophenyl)_N-methylbenzene 154005.doc -82 - 201138786 and furan-3-carbamide (200 mg, 34%). Step 3 : 5-cyclopropyl-2-(4-fluorophenyl)-N--yl-6-(N-(3-(4,4,5,5-tetramethyl-1,3,2-di Boron-2-yl)phenethyl)fluorenyl hydrazide-based benzofuran_3·carbamamine 1, bis-bis(diphenylphosphino)ferrocene under nitrogen atmosphere ·Palladium (II) dioxazole complex (39 mg, 0.034 mmol) and 6-(Ν-(3-bromophenethyl)methylsulfonyl)-5-cyclopropyl-2 -(4-Fluorophenyl)-indole-mercaptobenzofuran-3-carboxamide (200 mg '0.34 mmol) was dissolved in two. Ethylene (15 mL). Add bis (pinacol) Boron (174 mg, 0.69 mmo l) and potassium acetate (100 mg, 1.02 mmol)' and the mixture was stirred at 100 ° C overnight. The cooled reaction mixture was poured into water (15 mL)EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-indolyl-6- (&gt ; 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenethyl)methylsulfonylamino)benzopyran -3 - an amine (196 mg, 910/〇). Step 4: 3-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzopyran-6-yl)methylsulfonate醯Amino)ethyl)phenyl-flutonic acid 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4,4,5,5-) Tetramethyl-1,3,2-dioxaboran-2-yl) phenylethyl) decylamino)benzofuran-3-decylamine (190 mg, crude material, 0.30 mmol) dissolved In a solution of THF (10 mL) and 5 N HCl (1. 5 mL), and the obtained mixture was heated to 154 005.doc. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;5&lt;5&gt;5-cyclopropyl-2-(4-fluorophenyl)-3-(mercaptoamine) Benzofuran-6-yl)methylsulfonylamino)ethyl)phenyl decanoic acid (50 mg, 30%). 4 NMR (300 MHz, CD3OD) δ=7.97-7.92 (m, 2H), 7.62 (s, 1H), 7.46-7.41 (t, 2H), 7.30 (m, 5H), 4.04 (m, 2H), 3.03 (s, 3H), 2.96 (s, 3H), 2.88 (m, 2H), 2.34 (m, 1H), 1.06 (d, 2H), 0.90 (m, 1H), 0.70 (m, 1H). LCMS (m/z) ES+ = 551 (M+l) &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&&& Aminomethyl benzo) benzofuran-6-yl)methylsulfonylamino)methyl)_2_fluorophenyl decanoic acid

Step 1 : Add ethyl bromide to a solution of 4-bromobenzoic acid (40.0 g, 0.199 mol) in DCM (300 mL) (27 mL, 0.311 mol) followed by DMF (0.5 mL). The reaction mixture was refluxed for 2 hours. The resulting clear solution was concentrated in vacuo. An acid gasification in the form of a yellow liquid is obtained. Add TEA (76 mL) to a solution of ethyl sulphate (38 g, 0.222 mol) in MeCN (550 mL) and cool in an ice salt bath to add MgCl2 (28.4 g, 0.299 mol) The resulting mixture was allowed to admix for 3 hours at this temperature. Add the above acid chloride prepared by 154005.doc • 84 · 201138786 and allow the reaction mixture to warm to ambient temperature and stir overnight. After completion of the reaction (as monitored by TLC), the mixture was cooled in an ice bath and the intermediate of the intermediate was removed by careful addition of 2 N HCl (600 mL). The mixture was stirred for 1.5 hours in an ice bath, then transferred to a sep. funnel and extracted with EA (3x200 mL). The combined organic layers were washed with EtOAc EtOAc EtOAc (EtOAc m. Ethyl propionate (48.4 g, 89%). Step 2: 2-(4-Molyphenyl)-5-p-benzotrile-taste 3-carboxylic acid ethyl acetonate Under a nitrogen atmosphere, use an oven-dried glassware m to vaporize zinc (26_8 g, 〇_ 197 mol) was stirred in absolute ethanol (75 mL) and then heated to 95 ° C (reflux). 4-bromobenzylidene ethyl acetate (5 〇g, 0.184 mol) was added in a single portion, followed by dropwise addition of phenylhydrazine (215 g, 〇.199 mol) in anhydrous MTBE (550 mL) over 2 hours. Solution. At the same time, MTBE' was distilled from the reaction mixture so that the reaction volume remained substantially constant. The bath temperature was maintained at l45_155t for most of the entire addition process and the internal temperature was 75-95 °C. In the middle of the addition, no water ethanol (75 mL) was added because the reaction mixture became thick and there was some loss of the original volume of ethanol during the 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) and Et.sub. The insoluble solid was removed by filtration of the two phase solution, followed by separation of the organic layer, washed with water, dried and evaporated in vacuo. The residual brown solid was slurried in warm di-methane methane and the mixture was cooled to room temperature and further cooled overnight by refrigeration. The tan solid was filtered from a dark brown solution, 154005.doc * 85 - 201138786 and washed with a smaller volume of DCM and dried under vacuum to give 2-(4-bromophenyl)-5- thiophene Ethyl acetate-3-acetate (26.5 g, 39%). Step 3. 2-(4-Bromophenyl)-5-isopropoxybenzopyrene a South_3·ethyl acetate to 2-(4-bromophenyl)-5-hydroxybenzofuran_3_ Add ethyl 2-iodopropane (22 mL) to a solution of ethyl formate (26 5 g, 0.073 mol) in NMP (300 mL). Then add carbonic acid (47·8 g, 0·147 m〇1). The reaction mixture was stirred in a (9) force oil bath for 4 hours and then cooled to ambient temperature. The reaction mixture was treated with a 5% ammonium solution and stirred for 15 min. The mixture was then diluted with water and extracted with hexane. The organic layer was washed with EtOAcqqqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2%). Step 4. 2-(4-Bromophenyl)-5-isopropoxy-6-decylbenzofuran·3·carboxylic acid ethyl acetate 2-(4-bromophenyl)-5-isopropoxybenzene And furan_3•ethyl formate (3〇g, 0.073 mol) was dissolved in gas (6〇mL), and the solution was cooled in an ice bath. Nitric acid (49 mL) was also dissolved in gas (6〇mL). ) and cooled in an ice bath. The acid solution was added dropwise to the compound 2 -(4-bromophenyl)-5-isopropoxy oxo-pyrano- 3 - decanoic acid ethyl ester solution over 0.5 hours, followed by mixing the reaction mixture for 5 hours. . The reaction mixture was then diluted with water (1 mL) and the layers were separated. The organic layer was dried over anhydrous sodium This oil was slurried in 15 m]L mtbe then filtered to give 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3- as an orange solid. Ethyl formate (14.5 g, 44.6%). Step 5. 2-(4-(4-Fluorophenoxy)phenyl b-5-isopropoxy-6 nitrobenzo 154005.doc -86- 201138786 Bite urethane-3-acetate vinegar 2- (4-Bromophenyl)-5-isopropoxy-6-nitrobenzopyrano-3·carboxylic acid ethyl ester (13.2 g, 29.45 mmol) was dissolved in hydrazine (80 mL). Tributyl(2,4',6'-diisopropylidene-2-yl)phosphine (2 g, 4.712 mmol), potassium silicate (12.5 g '58.9 mmol) and palladium diacetate (529 mg) , 2.356 mmol). The resulting solution was stirred overnight at 1 ° C, N2. The reaction was cooled to room temperature and washed with water (3×50 mL). The combined solution was dried and concentrated and evaporated Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a solid (in g, 78.7%) ° Step 6: 2 -(4-(4-Fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzo. Furuine formic acid ethyl acetate 2-(4-(4-fluorophenoxy)phenyl)- 5-Isopropoxy-6-nitrobenzoin. Dissolved in a dry DCM (150 mL) and cooled in an ice bath under a nitrogen atmosphere. 2 minutes Tri-vaporized boron (35 mL, 34.7 mmol). After completion of the reaction, the reaction mixture was quenched by pouring into ice/water mixture. The reaction mixture was poured into ice/water mixed with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl ester (10.4 g, quantitative yield) Step 7: 2-(4-(4-Fluorophenoxy)phenyl)-6-nitro-5-(trifluoromethyl decyloxy)benzene And furan-3-carboxylic acid ethyl vinegar under nitrogen, in an ice bath, to the vast 茗 154005.doc -87- 201138786 base - (5-media name table #哒诘-3-f splashing 锴 (10.4 g, 23.15 Methyl ester (36. The reaction mixture was stirred under nitrogen for 30 min then quenched with EtOAc EtOAc (EtOAc) (EtOAc) Washing the combined organic layer 'with anhydrous sulfuric acid Sulfate, filtered and concentrated under reduced pressure. Ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-(trifluorodecylsulfonyloxy)benzofuran-3-carboxylate as a yellow solid 13.25 g, 100%) » Step 8: 5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzo. Ethyl 3-acetate to ethyl 2-(4-(4-fluorophenoxy)phenyl)-6.nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (13.25 g, 23.27 mmol), KF (4.73 g '81.45 mmol), NaBr (2.54 g, 24.67 mmol), cyclopropyl g-p-acid (3.0 g, 34.91 mmol) and Pd(Ph3P)4 (1.34 g, 1.16) To a mixture of mmol) was added toluene (130 mL) and water (3 mL). The reaction flask was evacuated for about 3 minutes' and then filled with nitrogen. The reaction mixture was refluxed for 2 Torr under nitrogen and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc EtOAc EtOAc. By column chromatography (first PE/EA = 4/1, followed by purification of the residue to give 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_6_ Benzylfuran-3-furic acid ethyl ethane (8.4 g, 78%). Step 9: 6-Amino-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl) Benzo-cough 154005.doc • 88 - 201138786 Ethyl ethanoacetate to 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_6-nitrobenzofuran_3_ A solution of ethyl formate (8.4 g, 18.2 mmol) in ethyl acetate (4 mL) was added 10% palladium / carbon (1. The mixture was stirred for 8 hours under MeOH. The mixture was filtered over EtOAc EtOAc (EtOAc) (4_Fluorophenoxy)phenyl)_6_(Ν(methyl decyl-f-yl)methylsulfonylamino)benzofuran-3-carboxylic acid ethyl acetonate in a -bC, A atmosphere, to 6_ Amino _5_cyclopropyl·2(4-(4-fluorophenoxy)phenyl)benzo. Ethyl fluoro-3-carboxylate (8 g, 18 54 mm 〇1) in anhydrous dichloromethane ( Solution in 180 mL) Anhydrous TEA (6.91 mL·, 46.35 mmol) was added. Then methanesulfonate (5 〇 5 mL, 64 9 paws (1)) was added dropwise. The stirred solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc (EtOAc m. -Fluorophenoxy)phenyl)_6_(Ν_(methylsulfonylhydrazinyl)decylsulfonylamino)benzofuran_3_carboxylic acid ethyl ester 5 g, 87 〇/〇). Step U: 5-cyclopropyl·2·(4-(4-fluorophenoxy)phenyl)·6-(methylsulfonylamino) Benbital. Toluic acid potassium hydroxide (13.6 g, 243 mmol) was added to 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_6_(N_(nonylsulfonyl) under nitrogen atmosphere Ethylmethyl) decylsulfonylamino)benzofuran-3-furic acid ethyl ester in ethanol (70 mL) and water (35 mL). The reaction was refluxed for a few hours and then concentrated in vacuo 154005.doc. The remaining solid was dissolved in water, and 2 N HCl (i4i acidified solution was formed until the formation of the slab. The solid was dried and then dried to give 5-cyclopropyl-2-(4-(4-phenoxy)) as a white solid. Phenyl)_6_(methyl arylamino)benzofuran-3-decanoic acid (9 g, quantitative yield) Step 12: 5-cyclopropyl·2_(4_(renfluorophenoxy)phenyl N•methyl_6_(methylsulfonylamino) benzofuranamine I2VCT, sentence 5-cyclopropyl_2_(4_(4-fluorophenoxy)phenyl)6 (mercaptosulfonate)蜃羞”茗#Poor _3_严躞(9 9 g, 2〇56 mm〇1) Add DIpEA to a solution of anhydrous DMF (50 mL) (5 g, 45 23匪〇1)

And HATU (9.42 g ' 24.67 mmol). After 15 minutes, a 2 M solution of methylamine in THF (41.12 mL, 82.24 mmol) was added dropwise, and the mixture was stirred for a further 2 s, then water (2 〇〇 mi). The mixture was extracted with EtOAc (3 mL) (EtOAc) (EtOAcjjjjjjj Phenoxy)phenyl)_N_methyl-6-(methylsulfonylamino)benzofuran-3-indoleamine (1 〇g, 98%). Step 13: 1-Bromo-4-(bromomethyl)-2-fluorobenzene to (4·glyle-3-fluorophenyl)methanol 5 g, 〇〇74 m〇i) in 4 mL of diethyl ether A solution of phosphorus tribromide (14 g, 0.052 mol) in 10 mL of ethyl bond was added to the stirred solution. Once the addition was complete, the mixture was stirred at room temperature for 3 Torr and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice water (50 mL). The combined organic layers were washed with EtOAc EtOAc (EtOAc) 62%), which was used in the next step without further purification 154005.doc -90- 201138786. Step 14: 6-(N-(4-Bromo-3-fluorophenyl)methylsulfonylamino)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl) -N-methylbenzofuran-3-carbamide treatment of 5-cyclopropyl-2-(4-) with 1-di-4-(indimeth)-2-fluorobenzene (537 mg, 2.02 mmol) (4-fluorophenoxy)phenyl)-N-mercapto-6-(methylsulfonylamino) benzofuran-3-carboxamide (500 mg, 1.01 mmol), KI (168 mg , 1.01 mmol) and a suspension of K2C03 (418 mg, 3.03 mmol) in anhydrous DMF (10 mL). The reaction was cooled with EtOAc EtOAc (EtOAc) The crude product was purified by column chromatography (solvent eluting with 0-50% ethyl acetate) to afford 6-(N-(4-bromo-3-fluorobenzyl)sulfonylamino)- 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide (5 11 mg, 74%) 〇Step 15:5- Cyclopropyl-6-(]^-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzyl) 1,5'-bis (by sulfonylamino)-2-(4-(4-fluorophenoxy)phenyl)-N-mercaptobenzofuran-3-decylamine under nitrogen atmosphere Diphenylphosphino)ferrocene-dipleated palladium(Π)dioxane complex (87 mg, 0.075 mmol) and 6-(N-(4-bromo-3-fluorophenylindenyl)methyl Sulfonamide)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-mercaptobenzofuran-3-decylamine (5 11 mg, 0.75 mmol) Dissolved in dioxane (20 mL). Bis(pinacoldyl)diboron (382 mg, 1.50 mmol) and potassium acetate (221 mg, 2.25 mmol) were added, and the mixture was stirred at 100 ° C overnight. The cooled reaction mixture was poured into water (30 mL) EtOAc EtOAc (EtOAc (EtOAc) The combined organic layers were dried over Na 2 S 〇 4 and concentrated in vacuo. By column chromatography (with 〇_5〇% acetic acid)

Purification of the residue by petroleum to give 5-cyclopropyl_6_(N-(3-fluoro I (4,4,5,5-tetradecyl·1,3,2-dioxaboron-2-yl) Phenylhydrazino)nonylsulfonylamino)-2-(4-(4-fluorophenoxy)phenyl)indole_methylbenzofuran_3_formamide (387 mg, 71%) » Step 16: 4-((N-(5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylaminemethylindenyl)benzofuran-6-yl) Methylsulfonylamino)methyl)_2-fluorophenyls-succinic acid 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5·tetradecyl) _1,3,2-dioxaboron-2-yl)benzyl)methylsulfonylamino)-2-(4-(4-fluorophenoxy)phenyl)-indole-methylbenzene The furan-3-carbamide (380 mg, crude material, 0.52 mmol) was dissolved in THF (10 mL) and treated with 5 N EtOAc (1. . The suspension was stirred for 4 hours, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford 4-((N-(5-cyclopropyl </RTI> </RTI> <RTIgt; Benzofuran-6-yl)nonylsulfonylamino)methyl)-2-fluorophenyl-tanning acid (140 mg, 42%). 4 NMR (300 MHz, CD3OD) 5 = 7.87 (d, 2H), 7.58 (s, 1H), 7.31 (m, 10H), 5.00 (m, 2H), 3.17 (m, 3H), 2.93 (s, 3H) ), 2.24 (m, 1H), 1.07 (m, 1H), 0.81 (m, 2H), 0.68 (m, 1H). LCMS (m/z) ES+ = 647 (M+l). Example 18 4-((N-((5-Cyclophenoxy)phenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl )methyl)methylsulfonylamino)methyl)-2-(trifluoromethyl)phenyl decanoic acid 154005.doc -92- 0, 0,201138786

NH

Step 1: 6-(N-(4-Bromo-3-(trifluoromethyl)benzyl)methylsulfonylamino)-5-cyclopropyl-2-(4-(4-氤 alum) Phenyl)-N-methyl benzofuran 3-carboxamide A potassium carbonate (418 mg, 3.03 mmol), KI (168 mg '1.01 mmol) and 1-bromo-4-( under nitrogen) Bromomethyl)-2-(trifluoromethyl)benzene (642 mg, 2.02 mmol) was added to 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-fluorenyl A solution of -6-(mercaptosulfonylamino) benzofuran _3_ decylamine (0.5 g, 1.01 mmol) in anhydrous DMF (8 mL). The reaction mixture was stirred at 60 ° C for 30 minutes, then diluted with water (30 mL) and filtered. The filtrate was dissolved in ethyl acetate, dried and concentrated in vacuo and purified by column chromatography (EtOAc/EtOAc: EtOAc: 6-(N-(4-Bromo-3-(trifluoromethyl) adenyl) decylsulfonylamino)_5 cyclopropyl-2-(4-(4-indolyl)phenyl )-N-曱-based stupid and astringent amine (350 mg, 47%). Step 2: 5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl (4·(4,4,5,5·tetramethyl-1,3,2-dioxaboronium) -2-yl)·3·(trifluorofyl)benzyl)methylsulfonylamino) benzofuranamine 6-(N-(4-bromo-3-) under nitrogen atmosphere Trifluoromethyl)benzyl)methylsulfonylamino)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)_N-mercaptobenzo 154005.doc -93 · 201138786 bite ° South-3-formamide (350 mg, 0.478 mmol), bis-propylacoyl bromide (243 mg '0.957 mmol) and acetic acid clock (141 mg, 1.434 mmol) added to 1,4-two ° in a bad burn (20 mL). Pd(dppf)2Cl2 (55.2 mg, 0.048 mmol) was added and the mixture was stirred for 48 hours. The solvent was removed in vacuo and the crude residue was purified by column chromatography (EtOAc/EtOAc: EtOAc: (4-fluorophenoxy)phenyl)·Ν_ fluorenyl-6_(Ν-(4-(4,4,5,5-tetradecyl·1,3,2-dioxaborin-2-yl) - -3-(tri-II fluorenyl) fluorenyl) benzyl hydrazino) benzonaphthyl- 3 - decylamine (0.379 g, quantitative yield). Step 3 · ' 4-((Ν·((5-cyclopropyl)2-(4-(4.fluorophenoxy)phenyl)) (f-aminomethylcarbazyl)benzofuran-6-yl Methyl)methylsulfonylamino)methyl(trifluoromethyl)phenyl-hydroxy acid 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-f -6·(Ν-(4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)-3-(trifluoromethyl)benzyl)曱 sulfamoylamino)benzofuranylcarbamide 0/ΙΊ9 %, 0Λ% η mmol) was dissolved in THF (10 mL) with 5 N HCl (0.68 mL) and ps benzene acid (0.84 g) , 2.435 mmol) treatment. The suspension was stirred overnight, then dried and concentrated in vacuo. The crude product was purified by preparative HPL to afford 4-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylamine) as a white solid. Mercapto) benzofuran-6-yl)methyl)methyl-branched amino)methyl)-2-(difluoromethyl)phenyl-acid (78 mg '23%). 4 NMR (300 MHz, CDC13) 5=7.87-7.84 (d, 2H), 7.61-7.59 (d, 2H), 7.48-7.45 (d, 1H), 7.37-7.35 (d, 1H), 7.20-7.01 ( m, 7H), 5.10-4.95 (m, 2H), 3.19 (s, 3H), 2.92 (s, 3H), 2.20 (m, 1H), 0.98 154005.doc •94- 201138786 (m,1H),0.92 -0.85 (m, 2H), 0.35-0.33 (m, 1H). LCMS (m/z) ES+ = 697.1 (M + 1) 0 </ RTI> 19 (4-N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminocarbamoyl) Benzofuran·6-yl)methylsulfonylamino)methylfluorophenyl decanoic acid

Step 1: (4-Bromo-2-fluorophenyl)methanol 4-decrom-2-fluorobenzoate decyl ester (ίο g, 4.3 mmol) was dissolved in THF (25 mL) and then cooled to n. -15 ° C, and LiBH4 (327 mg, 8.6 mmol) was added. The solution was stirred for 15 minutes. The mixture was poured into water (1 5 ml), filtered and evaporated with Et.sub.2 (3×20 mL), dried and concentrated under reduced pressure to give 4-bromo-2-fluorobenzoic acid ethyl ester as a yellow oil (900 mg) , 102 ° /.) 'It was used in the next step without further purification. Step 2: 4-bromo-1-(bromomethyl)-2-fluorobenzene was added dropwise to a solution of Er2(3 mL) in two deserts (825 mg, 3.08 mmol) under nitrogen atmosphere. _Bromo-2-fluorobenzoquinone methyl ester (9 〇〇 mg '4.4 mmol) in Et20 (15 mL). The mixture was stirred at room temperature for 30 minutes. Pour the mixture into ice/water (15 ml) and use

Et2O (3 x 20 mL) was extracted. Wash the organic layer of 154005.doc -95· 201138786 with NaHC03 (3〇mL) and brine (30 mL), dry over anhydrous NazSO4 and evaporate to give 4········ (650 mg, 55%) was used in the next step without further purification. Step 3: 6-(N-(4-Diethyl-2-fluorobenzyl)methylsulfonylamino)_$_cyclopropyl-2-(4-oxaphenyl)-N-methylbenzo Treatment of 5-cyclopropyl-2-(4-fluorophenyl) with 4-bromo-1-(bromoindolyl)-2-fluorobenzene (402 mg, 1.5 mmol) N-methyl-6-(methyl-nonylamino)benzofuran_3_ decylamine (300 mg '0.75 mmol), KI (6 mg, 0.04 mmol) and K2CO3 (310 mg, 2.25 mmol) in anhydrous The suspension in DMF (15 mL) was taken and the reaction was stirred at room temperature under nitrogen for 1 hour. The reaction was diluted with water (3 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with water (5 mL) and brine (50 mL). The crude product was purified by column chromatography (EtOAc: EtOAc: EtOAc) _5_cyclopropyl-2-(4-fluorophenyl)-N-methyl benzofuran_3_decylamine (278, 62%). Step 4: 5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl) stupid Methyl)methyl benzylamino) 2_(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide 6-(N-(4-bromo-2-fluorobenzene) under nitrogen atmosphere Methyl)nonylsulfonylamino)-5-1⁄4propyl-2-(4-fluorophenyl)_N-mercaptobenzofuran_3_decylamine (275 mg, 0.47 mmol) dissolved in dioxins Alkane (15 mL)*. Add bis(pinacolyl)diboron (239 mg '〇·94 mmol), potassium acetate (138 mg, 1.41 mmol) and 1, bismuth-bis(diphenylphosphino)ferrocene palladium dichloride ( π) (54, I54003.doc • 96. 201138786 0.05 mmol), and the mixture was stirred at 100 ° C overnight. The cooled reaction mixture was poured into water (20 mL)EtOAc. The combined organic layers were dried over NazSCU and concentrated under reduced pressure. The residue was purified by column chromatography eluting EtOAc EtOAc EtOAc 4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)phenylhydrazinyl)methylsulfonylamino)_2-(4.fluorophenyl)-N- Mercaptobenzofuran-3-carboxamide (250 mg, 83%). Step 5. 4-((1(5-Cyclopropyl-2-(4-phenyl)-3-(indolyl)yl)benzofuran-6-yl)indolylsulfonylamino) Methyl)-3-fluorophenyl-acid 5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetradecyl-1,3,2-di) Boronium-2-yl)phenylhydrazinyl)methylsulfonylamino)-2-(4-fluorophenyl)-indole-indolylbenzofuran-3-cartoamine (250 mg, 0.4 Methyl acetate was dissolved in THF (15 mL) and treated with 5 N EtOAc (0.56 mL) and &lt The reaction mixture was stirred at 30 ° C overnight. The reaction mixture was filtered and concentrated in vacuo and purified title title title title title Mercapto)benzofuran-6-yl)nonylsulfonylamino)methyl)-3-fluorophenyl facestock (90 mg, 40%). LCMS (m/z) ES+ = 555.1 (M+1). 4 NMR (300 MHz, CD3OD) = 7.93-7.88 (m, 2H), 7.56 (s, 1H), 7.28-7.22 (m, 5H), 7.03 (s, 1H), 5.8-4.91 (m, 2H), 3.19 (s, 3H), 2.93 (S, 3H), 2.27-2.22 (m, 1H), 0.99-0.76 (m, 3H), 0.35-0.30 (m, 1H). Example 20 4-((N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonylamino) Mercapto)-3-methoxyphenyl-acid 154005.doc -97- 201138786

Step 1: (4-Bromo-2-methoxyphenyl)methanol LiBH4 (4 ml '2 N/mol ' 8.04 mmol) was slowly added to 4-bromo-2-methoxy group maintained at 〇 ° C Methyl benzoate (1 g, 4 〇 4 mm 〇 1) in THF (75 ml). The solution was stirred at room temperature for 45 min, poured over EtOAc EtOAc (EtOAc (EtOAc) (Et〇Ac: hexane = 1:10) was purified to give (4-di-2-phenyloxyphenyl) decyl alcohol (850 mg, yield 96%) as a colorless oil. Step 2: 4-Bromo-1-(bromomethyl)-2-methoxybenzene to (4-bromo-2-methoxyphenyl)methanol (850 mg, 3.93 mmol) in DCM (100 mL) Pph3 (2. 〇 6 g, 8 mmol) and NBS (1.36 g '8 mmol) were added to the solution and mixed for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with DCM (3 X 100 mL). The combined organic layer was dried with EtOAc EtOAc (EtOAc) Decyloxybenzene (950 mg, 87%) » Step 3: 6-(N-(4-bromo-2-methoxybenzyl)methylindenylcyclopropyl-2-(4- Fluorophenyl)-N-mercaptobenzopyran-3-cartoamine 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(nonylsulfonylamino) Stupid and keto-3-carbamide (578 mg ' 1.42 mmol), 4-bromo-1-(bromomethyl)·2- 154005.doc •98- 201138786 methoxybenzene (400 mg, 1.42) Methyl acetate (100 mg) was added to acetonitrile (50 ml). Diluted, EtOAc (3 mL EtOAc) (EtOAc (EtOAcjMeOH (Ν-(4-bromo-2-methoxyphenylindenyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzox 3-carbamidine (670 mg, 78%). Step 4. 5-ring 2-(4-oxophenyl)-6-(N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron- 2-(yl)benzylidene)methyl hydrazinyl)·Ν-mercaptobenzofuran-3-carboxamide 6-(Ν-(4-bromo-2-indolylbenzene) under nitrogen Indenylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-indole-methylbenzofuran-3-formamide (670 mg, 1.1 mmol), bicyclo Hexylphosphinobiphenyl (77 mg, 0.22 mmol), HBPin (3.7 g, 33 mmol), triethylamine (224 mg, 2.2 mmol) was added to dioxane (50 ml) and immersed in a 100eC oil bath. Quickly add

PdOAc2 (24.6 mg '0.11 mol). The mixture was stirred until the reaction was completed by LCMS. The residue was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -(2-methoxy-4-(4,4,5,5-tetradecyl-i,3,2-dioxobutan-2-yl)phenylhydrazino)methyl-nonylamino)- N-methylbenzoate bites. South _3 - an amine (560 mg, 76%). Step 5: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1-trans-yl-1)-diaminobenzo[c][1,2] °oxabungyl) Methyl)methyl 醯 醯 醯 甲基 甲基 154 154 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 005 Cyclopropyl-2-(4-fluorophenyl)_6^n-(2-methoxy-4-(4,4,5,5-tetradecyl-1,3,2-dioxaboron- A solution of 2-yl)benzyl)mercaptosulfonylamino)-;--mercaptobenzofuran-3-carboxamide (300 mg, 0.46 mmol) in THF (20 mL). After stirring for 15 minutes, the mixture was poured into EtOAc EtOAc (EtOAc) The combined organic layer was washed with EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -(Ν-((1-hydroxy-1,3-dihydrobenzo[c][ 1,2]oxabor-5-yl)indolyl)methylsulfonylamino)·Ν-mercaptobenzoene Furan-3-decylamine (580 mg, 31%). LCMS (w/z, ES+) = 567 (M+1). W-NMR (300 MHz, CDC13) 7.83 (m, 2H), 7.62-7.55 (m, 2H), 7.25-7.11 (m, 5H), 5.74 (br, 1H), 5.07-4.91 (m, 2H), 3.81 (s, 2H), 3.75 (s, 1H), 3.10 (s, 3H), 3.00 (m, 3H), 2.21-2.16 (m, 1H), 1.01-0.90 (m, 3H), 0.53-0.50 ( m, 1H). Example 21 [4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6-yl](methylsulfonate) Mercapto)amino]methyl}-2-(trifluoromethyl)phenyl]-acid

154005.doc .100· 201138786 Step 1: 6-[{[4-Bromo-3-(trifluoromethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl- Ethyl-2-(4-fluorophenyl)-1-benzofuran-3-carbamide with 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)- 6-[(decylsulfonyl)amino]·1_benzofuran·3·decylamine (750 mg, 1.801 mmol), 1-bromo-4·(bromomethyl)·2_(trifluoromethyl) A solution of benzene (954 mg, 2.251 mmol) and carbonic acid (498 mg, 3.60 mmol) in acetonitrile (25 mL) was maintained at 80 °C for 3 hours. The mixture was cooled and poured into water and diluted with acetic acid. The organic layer was separated, dried over sodium sulfate, filtered,jjjjjjjjjjjjjjjjjjjjjj Phenyl]fluorenyl}(methylsulfonyl)amino]·5·cyclopropyl-N-ethyl-2-(4-fluorophenyl)-1-benzofuran-3-indole Amine (1.05 g ' 1.607 mm〇i, yield 89%). LCMS (m/z, ES+) = 654 (M+H). Step 2: [4-{[[5-Cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenylbenzofuran-6-yl](nonylsulfonyl) Amino]methyl}_2·(trifluoromethyl)phenyl]S-acid 6-[{[4·bromo-3-(trifluoromethyl)phenyl]methyl}(methylsulfonyl) Amino]cyclopropyl-indole·ethyl-2·(4-fluorophenyl)-1-benzofuran-3-carboxamide (5 11 mg '0.782 mmol), potassium acetate (3〇7 mg) , 3.13 mmol), bis(pinacolyl)diboron (496 mg, 1.955 mmol) and PdCl2(dppf)-CH2Cl2 adduct (63.9 mg '〇·〇78 mmol) in 1,4-dioxaldehyde The solution in (7 mL) was maintained at 90 C for 20 hours. The mixture was cooled, filtered over celite and washed with dichloromethane. The filtrate was concentrated and suspended in tetrahydrofuran (15 mL). Sun acid (15〇5 mg, 3.91 mmol) and 154005.doc 201138786 HC1 (5.0 N) (7.82 mL, 39 hours. Cool the solution to room temperature, solidify the solid. Separate the organic layer, EtOAc, 39.1 mmol) Maintaining 5 I room temperature at 70 ° C 'filtered through diatomaceous earth, washed with ethyl acetate' dried over sodium sulfate, filtered, and the residue was obtained under reduced pressure. Purification by column chromatography gave [4-{[[5-cyclopropyl-3-[(ethylamino))yl]_2-(4.fluorophenyl)benzobenzene as a white foam. And furan-6-yl](methylsulfonyl)amino]methyl}_2-(trifluoromethyl)phenyl]carboxylic acid (200 mg, 0.323 mmo yield: 41.4%). DMSO-d6); 80 ° C; δ: 8.20 (br. s., 1H), 7.86-7.99 (m, 3H), 7.71 (S} 1H), 7.58 (br. s., 1H), 7.44 (s , 1H), 7.46 (s, 1H), 7.34 (t, J=8.9 Hz, 2H), 6.99 (d, J=3.3 Hz, 1H), 4.96 (br. s., 2H), 3.26-3.39 (m , 2H), 3.04 (s, 3H), 2.15-2.31 (m, 1H), 1.14 (t, J=7.2 Hz, 3H), 0.91 (d, J=17.2 Hz, 2H), 0.67-0.85 (m, 1H), 0.19-0.36 (m, 1H). LCMS (m/z, ES+) = 619 (M+H). Example 22 (5-{[{5·cyclopropyl-2-(4-fluorophenyl) )-3-[(Methylamino)carbonyl]-1-benzonyridin-6-yl}(methylsulfonyl)amino]methyl}_2·fluorophenyl)-acid

Step kicking, (3-bromo-4-fluorophenyl) methyl acetonate (3-bromo-4-fluorophenyl)methanol (500 mg, 2.439 mmol) was dissolved in four 154005.doc -102· 201138786 Hydrogen oxime (5 mL) and cooled in an ice bath. Add NaH (107 mg ' 2.68 mmol) to this solution and add methane sulfonium chloride (〇285 mL, 3.66 mmoip to maintain the mixture under stirring for 1 hour. Remove ice) and pour the reaction into water and ether. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give an oil. The oil was loaded on the silica stone column and dissolved in 0 to 80% EtO Ac. Methanesulfonic acid (3-bromo-4-fluorophenyl)methyl ester (51 mg, 1.801 mmol, yield 73.9%) was obtained as a mixture. The residue was used in the next step without further purification. iH NMR (400 MHz, gas-d-d) δ: 7.60 (dd, J=2.05, 6.35 Hz, 1H), 7.32 (ddd, 7=2.15, 4.54, 8.35 Hz, IH), 7.12 (t, /=8.40 Hz, 1H), 5.14 (s, 2H), 2.97 (s, 3H). Today's Ί \ 6·[[(3-bromo-4-fluorophenyl)methyl](methyl fluorenyl)amino] 5_cyclopropyl-2-(4-fluorophenyl)-indole-methyl-1-benzofuran-3-carboxamide 5- 5-cyclopropyl-2-(4-phenylene)-indole -Methyl-6-[(indolyl)amino]-1-benzophene-11 Nan-3-decylamine (350 mg, 0.870 mmol), a hospital (3-bromo-4) -fluorine Phenyl)methyl ester (492 mg, 1.739 mmol), K:2C〇3 (120 mg '0.870 mmol) and KI (144 mg, 0.870 mmol) in combination with N,N-dimethylformamide (2 mL) And the mixture was heated to 60 ° C until the reaction was completed. The reaction mixture was poured into water, and the solid was filtered. The solid was purified eluted with EtOAc and hexane to afford 6-[[ 3-bromo-4-fluorophenyl)indenyl](fluorenylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-indenyl-1-benzofuran -3-carboxamide (412.3 mg, 0.699 mmol, yield 80%). <H NMR (400 MHz, chloroform-d) δ: 7.73 (dd, 7=5.27, 8.79 Hz, 2H), 7.42 (dd, 7=2.05, 6.54 Hz, 1H), 154005.doc -103- 201138786 7.21 (s,1H), 7.12 (s,1H), 7.01-7.10 (m,3H),6.88-6.97 (m, 1H), 6.15 (d, 7=4.69 Hz, 1H), 4.61-4.81 (m, 2H), 2.97 (s, 3H), 2.87 (d, /=4.88 Hz, 3H), 2.05-2.16 (m, 1H), 0.90- 1.00

(m, 1H), 0.75-0.88 (m, 2H), 0.35-0.47 (m, 1H). LCMS (m/Z, ES + ) = 589 (M+H) ° Step exposure 3 ·. (5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methyl) Amino)-1-yl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl-2-fluorophenyl)-acid 6-[[(3-bromo-4-) Fluorophenyl) fluorenyl](methylsulfonyl)amino]_5_cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide 412 mg, 0.699 mmol), potassium acetate (274 mg, 2.80 mmol), bis(pinadol) two sides (311 mg' 1.223 mmol) and PdCl2(dppf)-CH2Cl2 adduct (42.8 mg, 0.052 mmol) Combined in a sealed tube containing 1,4-dioxane (8 mL), the reaction vessel was purged with A and stirred overnight. The reaction was filtered and the residue was partitioned between water andEtOAc. The organic layer was dried over sodium sulfate and dried to give a residue. The residue was dissolved in Thf and 5 equivalents of polymer supported benzene acid was added. The mixture was stirred for 2 hours and LCMS indicated the reaction was completed. The reaction was filtered and evaporated to give a residue. The residue was purified by reverse-phase HPLC to give (5-{[{5-cyclopropyl-2-(4-fluorophenyl)·3_[(decylamino)carbonyl) as a dark brown solid. Benzofuran-6-yl}(methylsulfonyl)amino]methyl-2-hydroxyphenyl)g-acid (97, 0.170 mmo yield 24.28%). NMR (400 MHz, DMSCM6) δ: 8.29-8.50 (m, 1 Η), 7.75-7.84 (m, 1H), 7.65-7.98 (m, 3H), 7.29-7.53 (m, 2H), 7.13-7.29 (m , 1H), 6.77-7.04 (m, 2H) 154005.doc 201138786 4.91 (d, /=14.06 Hz, 1H), 4.76 (d, 7=14.26 Hz, 1H), 3.20 (d, /=3.91 Hz, 3H )S 2.73-2.85 (m, 3H), 2.15-2.34 (m, 1H), 0.61-0.98 (m, 3H), 0.18 (d, */=5.08 Hz, 1H). LCMS (m/Z, ES+) = 555 (M+H). Example 23 4-((N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(indolylcarbamoyl)benzofuran-6-yl)methylsulfonylamino) A Benzyl-3-(trifluoromethyl)phenyl decanoic acid

B octa OH Step 1: 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene 4-bromo-1-methyl-2-(trifluoromethyl) stupid (460 mg, A solution of 1.92 mmol), NBS (379 mg, 2.13 mmol) and phenylhydrazine benzoate (47 mg, hydrazine 19 mmol) in tetra-carbonated carbon (10 mL) was heated under reflux for 24 hours. The reaction solution was extracted with DCM (60 mL) and organic layer was washed with brine and dried over anhydrous NazSO4. After removal of the solvent, the crude product was purified by column chromatography to afford 4-bromo-1·(bromomethyl)-2-(trifluoromethyl)benzene as a colorless oil (500 mg, 1.57 mm. %). GCMS 〇/z, ES+) = 317 (M+H). Step 2: 6-(N-(4-Bromo-2-(trifluoromethyl) benzyl)methanesulfonylamino)-5-cyclopropyl-2-(4-phenylene)-1 ^-Methyl stupid and biting _3-carbamamine 5·cyclopropyl-2-(4-fluorophenylindolyl-6-[(fluorenylsulfonyl)amino] 154005.doc •105 - 201138786 -1·benzofuran-3-carboxamide (632 mg ' 1.57 mmol), 4-bromo-1-(molyl)-2-(trifluoromethyl)benzene (500 mg, 1.57 mmol) And a solution of the carbonic acid (65 1 mg, 4.71 mmol) in EtOAc (20 mL). The dried NajCU was dried. After the solvent was removed, the crude product was purified by column chromatography to afford 6-(N-(4-di-2-(trimethyl)phenyl)methyl) as a white solid. Amidino)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (300 mg '0.47 mmol, yield 30 〇/〇). (m/z, ES+)=639 (M+H) Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-indole methyl-6-(N-(4-(4,4) ,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2-(trifluoromethyl)benzyl)methyl anthranyl) Furan-3-decylamine will be 虏-2-(trifluoromethyl)benzyl) fluorenyl hydrazino)_5_cyclopropyl-2-(4-fluorophenyl)-iV-methylbenzene And furan-3-decylamine (3〇〇mg, 0.47 mmol), acetic acid unloading (138 mg, 1.41 mmol), bis(pinaquinolyl) two sides (180 mg '0.71 mmol) and PdCl2 (dppf) ( A solution of 17 mg, 0.023 mmol) in 1,4-dioxane (10 mL) was heated at 95 ° C for 16 h. The reaction solution was cooled to room temperature and extracted with EtOAc EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO. After the solvent was removed, the crude product was purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-#-mercapto-6-(N-(4-( 4,4,5,5-tetradecyl·1,3,2-dioxaboron-2-yl)-2-(trifluoromethyl)benzyl)f-sulfonylamino)benzofuran _3-carbamamine (280 mg, 0.41 mmo yield 87%). LCMS (w/z, ES+)=687 (M+H) 154005.doc •106- 201138786 Step 4 ·· 4-((N-(5_cyclopropyl_2_(4·fluorophenyl)_3•( Methylamine-mercapto) benzofuran-6-yl)methylsulfonylamino)methyl)_3_(trifluoromethyl)phenyl self-clarified acid 5_cyclopropyl-2-(4-fluoro ))-Ν-mercapto-6-(Ν-(4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)_2-(trifluoroanthracene) Benzyl)methylsulfonylamino)benzofuran-3-decylamine (280 mg, 0.41 mmol), PS-BBA (707 mg, 2.05 mmol) and HCl (5 N in water, 0.25 mL) The solution in THF (10 mL) was stirred at room temperature for 12 h. Dilute the reaction solution with water and Et0Ac. The organic layer was separated and washed with brine and dried over anhydrous EtOAc EtOAc. After removal of the solvent, the crude product was purified by reverse phase HPLC to afford 4-((--- 5--propyl-propyl-2-(4-fluorophenyl)-3-(methylamine oxime) as a white solid. Benzofuran-6-yl)methylsulfonylamino)hydrazino)-3-(trifluoromethyl)phenyl facial acid (90 mg '0.15 mmo yield 36%). 4 NMR (methanol_heart) δ: 7.80-7.97 (m, 5 Η), 7.65 (s, 1 Η), 7.20-7.27 (m, 2 Η), 7.02 (s, 1H), 5.20-5.28 (m, 1H), 5.06-5.13 (m,1H),3.20 (s 3H), 2.92 (s,3H),2.24-2.29 (m,1H),0.97-1.03 (m, 〇75.0.90 (m,2H),0.32 ( Br. s·,1H). LCMS (w/z, es+)=6〇5 (M+H). Example 24 5-cyclopropyl-2-(4-fluorophenyl)-indole-methyl-6 -((Methyl aryl) {[4-(4,4,5,5-tetramethyl-1 '3,2-dioxo-p-phenyl-2-yl)-3-(tri-methyl) Phenyl]methyl}amino)-1-benzofuran-3-carboxamide 154005.doc •107- 201138786

Treatment of [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-) with pinacol (30.5 mg '〇·25 8 mmol) and powdered 4 A molecular sieve (100 mg, 0.215 mmol) 3-[(decylamino)carbonyl]-1-benzofuran-6-yl}(methylglycosyl)amino]indenyl}-2-(trimethylsulfonyl)phenyl]bornic acid A solution of (130 mg, 0.215 mmol) in toluene (5 mL) was maintained at <RTI ID=0.0></RTI> </RTI> <RTIgt; The solution was cooled, mixed with diatomaceous earth and concentrated to give a residue, which was purified by column chromatography to give 5-cyclopropyl-2-(4-fluorophenyl)-N-A as a white solid. -6-((methylsulfonyl) {[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-3-(trifluoroanthracene) Phenyl]methyl}amino)-1-benzofuran-3-carboxamide (106 mg, 0.154 mmol, yield 71.8%) » 4 NMR (methanol-d4) δ: 7.89 (dd, J =8.8, 5.3 Hz, 2H), 7.52-7.67 (m, 3H), 7.42 (d, J=7.6 Hz, 1H), 7.23 (t, J=8.8 Hz, 2H), 6.99 (s, 1H), 5.07 (d, J=14.2 Hz, 1H), 4.85 (d, J=14.2 Hz, 1H), 3.16 (s, 3H), 2.90 (s, 3H), 2.13-2.27 (m, 1H), 1.32 (s, 12H), 0.89-1.04 (m, 1H), 0.62-0.84 (m, 2H), 0.17-0.35 (m, 1H). LCMS (m/2, ES+) = 687 (M+H). I54005.doc -108- 201138786 Example 25 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine)) stupid and cough-6-yl Ethylsulfonylamino)methyl)-2-fluorophenylnonanoic acid

Step 1: 6-(N-(4-di-3)-ethyl-ethyl-ethylamino)-5-cyclohexyl-2-(4-fluorophenyl)-1methylbenzofuran Methionine 5-cyclopropyl-6-(ethylsulfonylamino)-2-(4-fluorophenyl)-N-indolylbenzofuran-3-carboxamide (1.5 g ' 3.6 mmol) , 1-bromo-4-(bromomethyl)-2-fluoroindole (0.965 g, 3.6 mmol, U25285/119/1), KI (598 mg, 3.6 mmol) and K2CO3 (1.50 g' 10.8 mmol) The solution in anhydrous DMF (8 mL) was heated at 50 °C for 30 min. The reaction solution was quenched with water (20 mL). After filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous NaaSO4. After the solvent was removed, the residue was purified to purified crystals eluted eluted eluted eluted 2-(4-Fluorophenyl)-N-methylbenzofuran-3-indoleamine (1.72 g, 2.85 mmol, 79%). Step 2 · ' 5-Cyclopropyl-6·(Ν_(3•Fluoro_4_(4,4 5 5-tetramethyl_13 2•dioxobic-2-yl)benzyl)ethylsulfonate醯()-(4_fluorophenyl)_N_mercaptobenzofuran-3-cartoamine 6_(#_(4_bromo-3_fluorobenzyl)B under nitrogen atmosphere Sulfosamine 154005.doc -109- 201138786 base)-5-cyclopropyl-2-(4-fluorophenyl)-//-mercaptobenzofuran-3-decylamine (1.72 g, 2.85 mmol ), PdCl2(dppf)-CH2Cl2 adduct (289 mg, 0.285 mmol), bis(pinacolyl)diboron (L09 g, 4.275 mmol) and acetic acid clock (838 mg, 8.55 mmol) in dioxane ( The solution in 20 mL) was at 1 Torr. Heat under 24 for 24 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified to purified purified crystals eluted eluted 5-tetramethyl-1,3,2-dioxaboron-2-yl)phenylhydrazinyl)ethylsulfonylamino)-2-(4-fluorophenyl)-N-methylbenzofuran 3-Methylguanamine (2.2 g, 3.38 mmol, 119%, crude material). Step 4: 4-((N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(decylamine)methyl)benzofuran-6-yl)ethylsulfonylamino曱-)-2-fluorophenyl-folic acid 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Boron-2-yl)phenylhydrazinyl)ethylsulfonylamino)-2-(4-fluorophenyl)-N-methylbenzofuran-3-decylamine (0.925 g, 1.42 mmol A solution of HCl (5 N in water, 2 mL) and EtOAc (yield: EtOAc, EtOAc) The reaction solution was filtered. After removal of the solvent, the residue was purified by reverse phase HPLC to afford 4-((--- 5-(4-propylpropyl-2-(4-fluorophenyl)-3-(methylaminomethyl)methyl) benzofuran -6-yl)ethylsulfonylamino)methyl)-2_fluorophenyl-folic acid (270 mg, 0.475 mmo, 33%). 4 NMR (300 MHz, sterol-(14)5:7.92-7.88 (111,2 11), 7.54 (3,111), 7.28-7.22 (m, 3 Η), 7.03 (m, 3 Η), 4.94 -4.89 (m, 2 Η), 3.36-3.31 (m, 2 Η), 2.93 (s, 3 Η), 2.05 (m, 1 Η), 1.47-1.43 (m, 3 Η), 1.05-0.47 (m , 4 H). LCMS (m/z, ES+) = 569.1 (M+H). 154005.doc -110· 201138786 Example 26 4-((iV-(5-cyclopropyl-2·(4-fluorobenzene) 3-(methylamine-mercapto)benzofuran-6-yl)ethylsulfonylamino)methyltrifluoromethyl)phenyl-acid

Step 1: 1-Bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene to 1-bromo-4-methyl_2-(trifluoromethyl)benzene (3.〇g, 12 61 mm〇1,

To a solution of Alfa) and NBS (2.24 g, 12.61 mmol) in carbon tetrachloride (45 mL), benzammonium peroxide (0.305 g, 丨.26 mmol) was added, and the reaction solution was heated under reflux for 2 hours. After the solvent was removed, the residue was purified mjjjjjjjjjjjjj %). Step 2 ···6-(N-(4-Bromo-3-(trifluoromethyl)benzenef-yl)ethylsulfonylamino)-5-cyclopropyl-2-(4-fluorobenzene Methylbenzofuran-3·carbenamide 5-cyclopropyl_6_(ethylsulfonylamino)_2_(4-fluorophenyl)·Ν_τ-based benzofuran 0 South_3· Amine (1.5 g, 3.6 mmol), 1-divir-4-(molyl)_2-(trifluoromethyl) stupid (1.5 g, 4.75 mmol), KI (598 mg, 3.6 mmol) and K2C03 (1.5 〇) A solution of g, i 〇 8 mmol) in anhydrous DMF (8 mL) was warmed for 50 hrs at 50 C. The reaction was cooled to room temperature and quenched with water (5 mL). Et~Ac. Dry the solution with anhydrous Na2S 〇4. After removing the solvent, the residue was purified by column chromatography to yield 154005.doc • 111 - 201138786 6-(N-(4-bromo) -3-(Trifluoromethyl)phenylmethyl)ethyl hydrazinyl)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzopyrene _3 formamide (2 2 g, 3.366 mm Ol, 93%). Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl·6-(ν_(4_(4&gt;4&gt;55_tetramethyl-1'3, 2-Dioxol-2-yl)-3-(trifluoromethyl)benzyl)ethylglycosylamino)benzofuran-3-carboxamide in a nitrogen atmosphere '6-(N -(4-bromo-3-(trifluoromethyl) benzyl)ethylsulfonylamino)-5-cyclopropyl-2·(4-fluorophenyl)-N-methylbenzofuran _ 3_Metformamide (2.2 g, 3.37 mmol), PdCl2(dppf)-CH2Cl2 adduct (342 mg, 0_34 mm〇l), bis(pinacolyl)diboron (1 28 g, 5 〇 6 mmol) And a solution of potassium acetate (989 mg, 10.11 mmol) in dioxane (25 mL) was heated at 100 ° C for 24 hours. The reaction was cooled and filtered. The solvent was removed and purified by column chromatography. The residue gave 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl·6_(n_(4_(4 4 5 5 tetradecyl-1'3,2-di) as a brown solid. Boron bromide-2-yl)_3_(trifluoromethyl)benzyl)ethylsulfonylamino)benzoquinone-3-carboxamide (2.1 g, 3.00 mm (1, 89%)). Step 4: 4-((N-(5-cyclopropyl_2·(4_phenylphenyl)_3_(methylamine-branyl)benzofuran-6-yl) Ethylsulfonylamino)methyl)_2(trifluoromethyl)phenylphosphoric acid 5-cyclopropyl-2-(4-fluorophenyl)_Ν_曱yl_6 (Ν·(4_(4) ,4,5,5 tetramethyl-1,3,2-dioxaboron-2-yl)_3_(trifluoromethyl)benzyl)ethylsulfonylamino)benzofuran-3·A Indoleamine (1·05 g,! 5 mm〇1), 5 N HC1 (2” mL) and? 8-Benzene-acid (2.5 g, 75 _〇1) was dissolved in THF (I5 solution was smashed under room fox overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC. 4_((Ν_(5_环154005.doc •112· 201138786 propyl-2-(4-fluorophenyl)-3-(decylamine fluorenyl)benzofuran-6-yl) Ethylsulfonylamino)hydrazino)-2-(trifluoromethyl)phenyl-fatanoic acid (345 mg, 0.558 mmol, 37%). <H NMR (300 MHz, methanol-d4) δ: 7.93- 7.90 (m, 2 Η), 7.88-7.56 (m, 2 Η), 7.38-7.23 (m, 4 Η), 7.02 (s, 1 Η), 5.04-4.94 (m, 2 Η), 3.39-3.33 ( m, 2 Η), 2.93 (s, 3 Η), 2.05 (m,1 Η), 1.49-1.44 (m,3 Η), 1.05-0.41 (m,4 Η). LCMS (w/z,ES+) =619.0 (Μ+Η). Example 27 4-((7-(5-cyclopropyl-2-(4-)phenyl)-3-(methylamine-methyl)-benzofuran-6 -yl)methylsulfonylamino)methyl)-3-methylphenyl-acid

Step 1: (4-Bromo-2-methylphenyl)methanol to 4-bromo-2-methylbenzoic acid (2. g, 9.3 mmol) in anhydrous THF BH3 (1 Μ in THF, 10.2 mL, 10.2 mmol) was added to a solution in 12 mL). The resulting mixture was stirred at room temperature for 1 hour, then the reaction mixture was cooled to 0 &lt;&gt; and quenched with &lt;RTI ID=0.0&gt;&gt; The mixture was extracted with ethyl acetate (3 x 20 mL). use

The combined organic layers were washed with NaHCO3 (10% aqueous solution, 30 mL), water (30 mL) and brine (3 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (4-bromo-2-mercaptophenyl)methanol (193 154 005. doc - 113 · 201138786 g, 9.6 mmol, quantitative). Step 2: 4-Bromo-1-(bromoindolyl)-2-mercaptobenzene (4-(bromo-2-indenylphenyl) decyl alcohol (1.93 g, 9.6 mmol), PPh3 (under nitrogen) A solution of 5.03 g, 19.2 mmol) and NBS (3.42 g, 19.2 mmol) in DCM (50 mL) The reaction mixture was poured into ice water (30 mL) and then extracted with CH2C12 (3×30 mL). The combined organic layers were washed with aq. NaH.sub.3 (30 mL) and brine (30 mL). After concentrating under reduced pressure, the crude product was purified by column chromatography to afford 4-bromo-1 -(bromomethyl)-2-methylbenzene as a white solid (1.7 g, 6.5 mmol, yield 67 %). Step 3: 6-(N-(4-Bromo-2-methylbenzyl)methylsulfonylamino)-5-cyclopropyl-2-(4-1phenyl)-N-nonylbenzene And n-fusin-S·cartoamine at room temperature under nitrogen, 5-cyclopropyl-2-(4-fluorophenyl)-#-mercapto-6-(indolyl) And cumin-3-carbamide (600 mg, 1.5 mmol), KI (12 mg '0.08 mm〇l), k2C03 (621 mg, 4.5 mmol) and 4-bromo-1-(bromomethyl)-2 A solution of methylbenzene (792 mg, 2 mmol) in dry DMF (20 mL) The reaction solution was diluted with water (4 mL EtOAc) The combined organic layers were washed with EtOAc (EtOAc)EtOAc. After removing the solvent, the crude product was purified by column chromatography to give 6-(#-(4-bromo-2-methylphenylmethyl)methylsulfonylamino)_5_ ring as a color solid. Propyl-2-(4-fluorophenyl)-#-methylbenzofuran-3-carboxamide (8〇6 mg, i 37 mmol, yield 920/〇). Step 4: 5-cyclopropyl_2_(4-fluorophenyl-methyl_6·(Ν·(2_methyl-4-(4,4,5,5-tetramethyl-oxime, 2·) Boron bromide-2·yl)benzyl)methylsulfonamide 154005.doc •114- 201138786 base) stupid and furan-methane amine 6-(iV-(4-bromo-2-mercaptobenzene) Mercapto)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzopyran-3-carboxamide (800 mg, 1.36 mmol), double (pinacol root) two sheds (693 mg, 2.73 mmol), potassium acetate (392 mg, 4.10 mmol) and PdCl2(dppf)-CH2Cl2 adduct (161 mg '0.14 mmol) in dioxane (25 mL) The solution was degassed and refilled with nitrogen three times, then the reaction was stirred at rt over night. &lt;RTI ID=0.0&gt;&gt;&gt; The organic layer was dried over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. 2-mercapto-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)phenylhydrazinyl)methylsulfonylamino)benzofuran- 3 - Brewed Amine (750 mg' 1.2 mmol , yield 86%). Step 5: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminemethanyl)benzofuran-6-yl) Methylsulfonylamino)methyl)nonylphenyl-acid 5-cyclopropyl-2-(4-fluorophenyl)_#_methyl_6_(#_(2_mercapto-4) -(4,4'5,5-tetradecyl-1,3,2-dioxaborin-2-yl)phenylhydrazino)nonylsulfonylamino)benzofuran-3-carboxamide 4〇〇mg, 〇63 mm〇1), HC1 (5 Ν水/谷液 '0.9 mL) and PS-BBA (1.2 g, 315 mm〇1) in THF (15 mL) in 30 C The mixture was stirred overnight. The reaction mixture was evaporated and evaporated,jjjjjjjjjjjjjjjjj )········································································ Buffer yield 40%). Towel NMR (methanol_d4) &amp; 7 μ 9〇(10), 154005.doc •115· 201138786 2H), 7.74 (S,1H), 7.35-7.19 (m,4H),7.04- 1.00 (m, 2H) 5.19-4.76 (m, 2H), 3.19 (s, 3H), 2.94 (S, 3H), 2.32 (S, 3H), 2.23-2.17 (m, 1H), 0.94-0 .63 (m, 3H), 0.19-0.09 (m, 1H). LCMS (w/z, ES+) = 551.0 (M+H). Example 28 (4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]benzofuran-6-yl} (methyl) Amino]methyl oxadiphenyl)

Step exposure\·. 6-[[(4-bromo-1-naphthyl)methyl](fluorenylsulfonyl)amino]% cyclopropyl-2-(4-fluorophenyl)·Ν-曱Benzyl-1 benzofuran_3_carbamamine 5-cyclopropyl-2-(4-fluorophenylmethyl-6-[(methylsulfonyl)amino]-1- Furan-3-carboxamide (400 mg, 0.994 mmol), 1-bromo-4-(bromomethyl)cai (298 mg, 0.994 mmol) AK2C03 (137 mg, 0.994 mmol) in acetonitrile and heated to 6 〇〇c until the starting material is consumed. The reaction is partitioned between water and 〇1 ,, the organic layer is dried over MgSO 4 and evaporated to give a residue. The residue was purified to give 6-[[(4-bromo-1-naphthalenyl)methyl](indolyl)amino]-5-cyclopropyl-2-(4-1) as a solid. Phenyl)-N-fluorenyl benzofuranium amide (5 〇 9 mg, 0.819 mmol, yield 82%). NMR (4 〇 0 MHz, hexane) δ: 8.63-8.71 (m, 1H) , 8.19-8.26 (m, 154005.doc •116- 201138786 1H), 7.99-8.08 (m, 2H), 7.96 (s, 1H), 7.64-7.72 (m, 2H), 7.53 (d, J=7.62 Hz , 2H), 7.23-7.32 (m, 2H), 7.02 (d, 7=7.62 Hz, 1H), 6.89 (s, 1H), 5.80 (d, 7=1 3.68 Hz, 1H), 5.07 (d, J=13.48 Hz, 1H), 3.28 (s, 3H), 2.89 (d5 7=4.69 Hz, 3H), 2.04 (dt, /=2.17, 4.45 Hz, 1H), 0.53-0.66 (m, 2H), -0.48 (dd, J=4.49, 6.64 Hz, 1H), -0.66--0.57 (m, 1H). LCMS (m/Z, ES+)=621 (M+H) Step 2 ·. (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(rhoylamino))l-l-benzofuran-6-yl }(Methylsulfonyl)amino]methyl}-1-naphthyl)-acid 6-[[(4-bromo-1-naphthalenyl)methyl](fluorenylsulfonyl)amino] -5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1·benzofuran-3-carboxamide (500 mg, 0.804 mmol), potassium acetate (3 16 mg, 3· 22 mmol), bis(pinacolyl)diboron (358 mg, 1,408 mmol) and PdCl2(dppf)-CH2Cl2 adduct (49.3 mg '0.060 mmol) in combination with 1,4-dioxane (8 mL) And degas. In a sealed container at 70. (The reaction mixture was heated overnight. The reaction was filtered through celite and evaporated to a small volume. The residue was stirred in &lt;RTI ID=0.0&gt; Obtained as a brown solid (4-{[{5-cyclopropyl-2_(4-fluorophenyl)·3_[(methylamino)carbonyl]-1-benzofuran-6-yl} (曱Alkylsulfonyl)amino]methyl}-1-naphthyl)-acid (30.1 mg, 0.051 mm〇i, yield 6.38%) 〇!H NMR (400 MHz, DMSO-d6) δ: 8.54 (d , J=8.4〇Hz, 1H), 8.35-8.45 (m, 2H), 8.14 (s, 1H), 7.83-7.97 (m, 2H), 7.46-7.61 (m, 2H), 7.32-7.46 (m, 3H), 7.08 (d, J=7.03

Hz' 1H), 6.71 (s, 1H), 5.65 (d, "7=13.28 Hz, 1H), 5-05 (d, 154005.doc •117· 201138786 7=13.47 Hz, 1H), 3.29 (s, 3H), 2.75 (d, J=4.49 Hz, 3H), 1.94-2.05 (m, 1H), 0.47-0.68 (m, 2H), -0.50-0.35 (m, 1H), -0.71--0.58 (m , 1H). LCMS (m/Z, ES+) = 495 (M+H). Example 29 (4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6-yl] (methylsulfonate) Mercapto)aminomethyl-2-fluorophenyl)-acid

Step 1: 6-[[(4-Bromo-3-fluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-N-ethyl (4-1 phenyl)- 1-Benzene ketone-3-cartoamine 5-cyclopropyl-fluorene-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1- Benzophene-Nan-3 -cartoamine (1.00 g, 2.40 mmol), 1-divin-4-(molybdenum)-2-d-benzene (0.97 g ' 3.60 mmol), iodinated needle (〇. 4〇g, 2.40 mmol) and a mixture of potassium bromate (1.00 g, 7.20 mmol) in DMF (10 mL) were heated to 60 ° C for 1 hour. Cool the mixture to room temperature and pour in water (400 mL) in. This material was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by gas chromatography (containing 0 to 75% ethyl acetate in hexane) gave 6-[[(4-bromo-3-fluorophenyl)indolyl] Sulfhydryl)amino]_5_cyclopropyl_#_ethyl-2-(4-fluorophenyl)-1-benzofuran-3 - an amine (1415 g, 98%). NMR NMR (DMSO-^6) δ: 8.52 (t5 1=5.5 Hz, 1H), 7.93 (dd, 154005.doc •118· 201138786 J=8.7, 5.5 Hz, 2H), 7.84 (s, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.27 (dd, J=9.7, 1.3 Hz, 1H), 7.04 (dd, J=8.2, 1.0 Hz, 1H) , 6.91 (s, 1H), 4.95 (d, J = 14.5 Hz, 1H), 4.78 (d, J = 14.5 Hz, 1H), 3.18-3.34 (m, 5H), 2.15-2.29 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H), 0.88-0.99 (m, 1H), 0.66-0.83 (m, 2H), 0.13-0.24 (m, 1H). Step 3: (4-{[[5-Cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenylhi-benzofuran-6-yl Kmethylsulfonyl) Amino]methyl}-1-indolyl)-acid 6-[[(4-bromo-3-fluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropane -iV-ethyl-2-(4-fluorophenyl)-1- benzofuran-3-indolamine (1.41 g, 2.34 mmol), potassium acetate (0.92 g, 9.3 5 mmol), double (frequency) a mixture of diboron (1.48 g ' 5.84 mmol) and bis(tricyclohexylphosphine)palladium dichloride (11) (0.172 g '0.234 mmol) in 1,4-dioxane (30 mL) Degassing in a thick-walled glass pressure vessel' followed by heating at 95 ° C for 24 hours with stirring. The reaction mixture was cooled to room temperature and passed through a pad of celite and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), taken up in EtOAc EtOAc (EtOAc) The reaction was cooled to room rt, filtered and concentrated to EtOAc EtOAc. The organic layer was washed with water (2 mL) and brine (1x) The residue was re-treated with THF (50 mL), 6N EtOAc (50 mL) and EtOAc (EtOAc) The reaction was cooled to room temperature, filtered and concentrated to remove THF and diluted with ethyl acetate. The organic layer was washed with water (2 Torr) and brine (1×), then dried and concentrated over sodium sulfate 154005.doc - 119 · 201138786. By gelatin chromatography (containing hydrazine to 1% acetonitrile)

2-(4-fluorophenyl)-1-benzofuran-6(yl)(fluorenylsulfonyl)amino]methyl}-2-fluorophenyl)-acid (563 mg, 42 %). NMR (methanol-t/4) δ: 7.91 (dd, J=8.6, 5.3 Hz, 2H), 7.60 (s, 1H), 7.19-7.31 (m, 3H), 6.93-7.09 (m, 3H), 4.93 -5.01 (m, 1H), 4.77-4.85 (m, 1H), 3.37-3.47 (m, 2H), 3.16 (s, 3H), 2.24 (quin, J=6.8 Hz, 1H), 1.11-1.26 (m , 3H), 0.91-1.07 (m, 1H), 0.79 (t, J = 5.8 Hz, 2H), 0.25-0.40 (m, 1H). LCMS (m/z, ES+) = 569 (M+H). Example 30 5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Boron-2-yl)phenyl]methyl}(fluorenylsulfonyl)aminomethylbenzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,5,5-tetra-1fyl-1,3,2-dioxaboronium) -2-yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-decylamine 154005.doc • 120· 201138786 with pinacol ( Treatment with 45 mg, 0.38 mm 〇l) (4_{[{5-cyclopropyl-2(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl) A solution of the sulfonyl)amino]methyl}-2-random base) acid (2 〇〇 mg, 0.36 mmol) in toluene (10 mL) and maintained at 9 ° C for 5 min. . The reaction mixture was cooled to room temperature and concentrated, then purified by silica gel chromatography eluting with EtOAc EtOAc. The obtained foam was wet-milled in hexane (3×) and dried to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-) as a white solid. (4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)phenyl]fluorenyl}(methylsulfonic acid)amino]-JV-fluorenyl- 1- benzofuran-3-decylamine (153 mg, 67%). 4 NMR (sterol 〇 δ: 7.91 (dd, J = 8.6, 5.4 Hz, 2H), 7.50-7.62 (m, 2H), 7.24 (t, J = 8.7 Hz, 2H), 6.92-7.10 (m, 3H) ), 4.93-5.00 (m, 1H), 4.80-4.86 (m, 1H), 3.16 (s, 3H), 2.92 (s, 3H), 2.25 (quin, J=6.8 Hz, 1H), 1.32 (s, 12H), 0.73-1.07 (m, 4H), 0.27-0.46 (m, 1H). LCMS (w/z, ES+) = 637 (M+H). Example 31 5-cyclopropyl-2-(4- Fluorophenyl)-N-methyl·6-[(methylsulfonyl)({3-(trifluoromethyl)-4-[(111,:211,68,811)_2,9,9-trimethyl 3-,5-dioxo-4_boron tricyclo[6.1.1.〇2,61癸-4-yl]phenyl}methyl)amino]-1-benzofuran-3-carboxamide Ο Η

154005.doc 201138786 5-Cyclopropyl-2-(4-fluorophenyl)-N-f-based _6_[(methylsulfonyl) (p (trifluoromethyl) 4-[(111'2 厌, 68,8&amp;)-2,9,9-trimethyl-3,5-dioxo-4-borane tricyclo[6·1·1.02,6]decyl]phenyl}fluorenyl)amine hl_ Benzofuran_3^ decylamine was added to (18,28,311,53)-2,6,6-trimercaptobicyclo[311]heptane-2,3-diol (42'3 mg, 0.248 mmol) to [4_{[{5_cyclopropyl_2_(4 fluorophenyl)-3-[(methylamino)carbonyl]_ι· benzofuran-6-yl}(methylsulfonyl)amino] a suspension of mercapto}-2-(difluoroindolyl)phenyl]g-acid (15 mg, 〇248 in toluene (2.5 mL). Heat the reaction to 9 (rc until all the material is dissolved) The molecular sieve is then added to the reaction and the reaction is stirred overnight. The molecular sieves are filtered off and the filtrate is evaporated to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[ (methylsulfonyl) ({3_(trifluoromethyl)_heart [(lR, 2R, 6S, 8R)-2,9,9-tridecyl_3,5-dioxo-4-flap three Ring [6.1.1.02,6]Indol-4-yl]phenyl}methyl)amino]_ι_benzofuran-3-amine (90.7 mg, 0.117 mmol, yield 47.0%). NMR (Acetone) δ: 7.98-8.08 (m, 2H), 7.68-7.77 (m, 3H), 7.50-7.60 (m, 2H), 7.28 (t, J=8.9 Hz, 2H), 7.09 (s, 1H) ), 5.10-5.20 (m, 1H), 4.96-5.05 (m, 1H), 4.53 (dd, J=8.9, 1.9 Hz, 1H), 3.22 (s, 3H), 2.92 (d, J=4.7 Hz, 3H), 2.38-2.48 (m, 1H), 2.32 (ddd, J-8.5, 5.2, 3.1 Hz, 1H), 2.21-2.29 (m, 1H), 2.08 (t, J=5.6

Hz, 1H), 1.85-1.95 (m, 2H), 1.44 (s, 3H), 1.30 (s, 3H), 1.18-1.23 (m, 1H), 0.91-1.00 (m, 1H), 0.89 (s, 3H), 0.66-0.87 (m, 2H), 0.24 (dd, J=9, l, 4.4 Hz, 1H). LCMS (m/Z, ES+) = 739 (M+H): 154005.doc -122-201138786 Example 32 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro- 4-(4,4,6,6·tetramethyldiboroborolan-2-yl)phenyl]methyl}(methylsulfonyl)amino]_Ν_methyl 4benzofuran-3- Amine

5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,6,6-tetramethylboryl-2-yl)phenyl) Methyl}(methylsulfonyl)amino]_ν_decyl-1-benzofurancarboxamide 2,4-monodecyl-2,4-pentanol (47.7 mg, 0.361 mmol) was added to (4_{[{5-cyclopropyl-2-(4-fluorophenyl)·3-[(decylamino)carbonyl]_丨_benzofuran_6_yl}(fluorenylsulfonyl) A suspension of the amine [methyl] 2 -fluorophenyl) ruthenic acid (2 〇〇 mg, 0.361 mmol) in toluene (2.5 mL). The reaction was heated to 90 C until all the materials were dissolved, then the molecular sieve was added to the reaction, and the reactants were mixed for 1 hour to remove the molecular sieves, and the liquid was evaporated. The residue was dissolved in DCM and purified by silica gel chromatography eluting with 0 to 30. Dissolve EtOAc in DCM to give 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,6,6-tetradecyl-i,3,2 -dioxaboron·2_yl)phenyl]fluorenyl}(methyl-glycosyl)amino]methyl-indole_stupyl-pyrene-3_carbamamine (189.3 mg' 0.276 mmo yield 77 %). iH NMR (400 ΜΗζ, 154005.doc -123· 201138786 chloroform-d) δ: 7.84-7.93 (m, 2H), 7.62 (t, ·7=6·94 Hz, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 7.15-7.22 (m, 2H), 6.98-7.04 (m, 1H), 6.90 (d, /=9.97 Hz, 1H), 5.76 (d, 7=4.49 Hz, 1H), 5.04 (d, «7=14.46 Hz, 1H), 4.65 (d, /=14.46 Hz, 1H), 2.93-3.04 (m, 6H), 2.24 (tt, J=5.25, 8.33 Hz, 1H), 1.94 (s , 2H), 1.43 (s, 12H), 0.98-1.11 (m, 2H), 0.93 (dd, ./=4.10, 8.99 Hz, 1H), 0.54-0.65 (m, 1H). LCMS (m/Z, ES+) = 651 (M+H). Example 33 5-Cyclopropyl-6-[{[3-fluoro-4-(6-methyl- 4,8-di-oxo-tetrahydro-4H-1,3,6,2-dioxazoboron)啐-2-yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)-indole·methyl-1-benzofuran-3-carboxamide

5-cyclopropyl-6-[{[3-fluoro-4-(6-methyl-4, 8-di-oxytetracycline•4H-1,3,6,2-dioxaborazolium- 2-yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-1phenyl)methyl-1-benzo. husband. South-3-carbamamine will be 4-([{5-cyclopropyl-2-(4-fluorophenyl)_3.[(fluorenylamino)carbonyl)]-furan-6-yl}(methyl Sulfhydryl)amino]methyl b-2-fluorophenyl) citric acid (2 〇〇 mg, 0.361 mmol) suspended in toluene (5 mL), dimethyl sulfoxide (1 mL) and 2,2 '-(Methylimido)diacetic acid (53 1 mg, 0.361 154005.doc • 124·201138786 mmol). The reaction was heated with a Dean Stark trap (Dean_Stark) until reflux for 4 hours. Evaporate the solvent to a smaller volume&apos; and pour into water. The precipitate formed was filtered and dried under vacuum to give 5-cyclopropyl- 6·[{[3-fluoro-4-(6-fluorenyl)- 4,8-di- oxy-tetra. Hydrogen-4H-1,3,6,2-dioxaborolan 4-2-yl)phenyl]methyloctamethylsulfonyl)amino]-2-(4-fluorophenyl)-N- Methyl-1-benzofuran_3_decylamine (234.4 mg, 0.335 mmo yield 93%). 1h NMR (400 MHz, acetone) δ: 7.98-8.06 (m, 2H), 7.65 (s, 1H), 7.53 (d, J=3.71 Hz, 1H), 7.48 (t, 7 = 7.23 Hz, 1H), 7.28 (t, /=8.89 Hz, 2H), 7.14 (d, *7=7.62 Hz, 1H), 7.10 (s,1H), 7.06 (d, /=10.75 Hz,1H), 4.88-5.06 (m, 2H), 4.38 (d, 7=17.78 Hz, 2H), 4.13 (d, /=17.00 Hz, 2H), 3.19 (s, 3H), 2.92 (d, J=4.69 Hz, 3H), 2.82 (s, 3H), 2.28-2.37 (m, 7=5.42, 5.67, 8.23, 8.23 Hz, 1H), 0.90-1.00 (m, 1H)} 0.76-0.85 (m, 2H), 0.25-0.35 (m, 1H). LCMS (m/Z, ES+) = 666 (M+H) &lt;&quot;&quot;&gt;&gt;&gt;&lt;&gt;&gt;&gt; 5-cyclopropyl-2-(4-fluorophenyl)-6-[({3-fluoro-4-[(lR,2R) ,6S,8R)-2,9,9-trimethyl-3,5-dioxo-4-borane tricyclo[6·1·1·02,6]癸-4-yl]phenyl}methyl )(methylsulfonyl)amino]-fluorenyl-mercapto-1-benzofuran-3-cartoamine Ο Η

154005.doc -125 - 201138786 5-Cyclopropyl-2-(4-fluorophenyl)-6-[({3_fluoro-4-[(11^21(,63,811) -2,9,9- Dimethyl-3,5-dioxo-4-decanetricyclo[6.1.1.〇2,6]indol-4-yl]phenyl}methyl)(methyl-decyl)amino]methyl -1-Benzo-follycanthamide (18,28,311,58)-2,6,6-trimercaptobicyclo[3.1.1]heptane-2,3-diol (61.4 mg, 0.361 mmol Add to (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl} (fluorenyl) Sulfhydryl)amino]mercapto} _2-gas base) a suspension of p-acid (2 〇〇 mg '0.361 mmol) in toluene (2.5 mL). Heat the reaction to 9 〇 ° C until all the substances are dissolved. Then molecular sieves are added to the reactants, and the reactants are scrambled for 1 hour. The molecular sieves are filtered off and the filtrate is evaporated to give 5-cyclopropyl-2-(4-fluorophenyl). -6-[({3-Fluoro-4-[(111,211,65,811)-2,9,9-trimethyl-3,5-dioxo-4-borane tricyclo[6.1.1.02,6]癸-4-yl]phenyl}methyl)(fluorenylsulfonyl)amino]-N-mercapto-1-benzofuran_3-formamide (223 mg, 0.324 mmol' yield 90% » 4 NMR (400 MHz, chloroform-d) : 7.86 (dd, /=5.37, 8.49 Hz, 2H), 7.66 (t, J=6.83 Hz, 1H), 7.27 (s, 2H), 7.18 (t, 7=8.59 Hz, 2H), 7.05 (d, J=7.61 Hz, 1H), 6.97 (d, J=9.76 Hz, 1H), 5.76 (d, /=4.29 Hz, 1H), 4.97-5.06 (m, 1H), 4.71 (d, 7=14.44 Hz, 1H), 4.47 (d, 7=8.00 Hz, 1H), 3.02 (s, 3H), 2.99 (d, 7=4.88 Hz, 3H), 2.35-2.46 (m, 1H), 2.18-2.30 (m, 2H) ), 2.16 (t, J=5.46 Hz, 1H), 1.90-2.02 (m, 2H), 1.49 (s, 3H), 1.31 (s, 3H), 1.20 (d, /=10.93 Hz, 1H), 1.05 (d, 7=4.10 Hz, 1H), 0.90-1.02 (m, 2H), 0.88 (s, 3H), 0.58 (d, "7=3.32 Hz, 1H). LCMS (m/Z, ES+) = 689 (M+H). 154005.doc -126- 201138786 Example 35 5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(tetrahydro-3aH-cyclopentanyl[6][1 ,3,2] Dioxane 1»Eth-2-yl)phenyl]methyl}(methyl fluorenyl)amine]_&amp;methyl-1-benzo-β-pentan-3-cartoamine

5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(tetrahydro-3αΗ-cyclopentanyl[d][l,3,2]dioxaboron -2-yl)phenyl]methyl}(methylsulfonyl)amino hN-methyl-1-benzo. Fumon-3-carboamine added 1,2-cyclopentanediol (44.2 mg '0.433 mmol) to (4-{[{5-cyclopropyl-2·(4-fluorophenyl)-3- [(Methylamino)carbonyldipyridyl-benzofuran·6_yl}(methyl hydrazino)amino]methyl}-2-fluorophenyl)carboxylic acid (2〇〇mg, 0.361 mmol) In a suspension in toluene (2.5 mL). The reaction was heated to 90 C until all the material was dissolved, then the molecular sieve was added to the mixture &lt; The molecular sieves were filtered off and the filtrate was evaporated. The residue was taken up in EtOAc (EtOAc) elute elut elut elut elut elut Fluoro-4-(tetrahydro-3aH-cyclopentanyl[d][13 2]dioxaboron-2-yl)phenyl]methyl}(methylsulfonyl)amino]indolyl „南_3_甲154005.doc •127- 201138786 decylamine (214 mg, 0-338 mmol, yield 94%). 4 NMR (400 MHz, gas-d-d) δ: 7.73 (dd, *7=5.28, 8·79 Hz, 2H), 7.53-7.59 (m, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.06 (t, J=8.60 Hz, 2H), 6.97 (d, 7=7.62 Hz, 1H), 6.91 (d, J=9.97 Hz, 1H), 6.15 (q, 7=4.36 Hz, 1H), 4.92 (br. s., 2H), 4.89 (d, 7=14.66 Hz, 1H) , 4.66 (d, 7=14.46 Hz, 1H), 2.96 (s5 3H), 2.87 (d, 7=4.89 Hz, 3H), 2.09-2.18 (m, 1H), 1.90-1.96 (m, 2H), 1.58 (s, 2H), 0.92-1.00 (m, 1H), 0.78-0.92 (m, 2H), 0.41-0.50 (m, 1H). Example 36 (3-cyano-4-{{{5-cyclopropyl 2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonic acid)amino]methyl}phenyl) Tannic acid

Step 1: bromo-2-cyanophenyl)methyl](methylsulfonyl)amino] -5-$propyl propyl-2-(4-phenylphenyl)-'^-methyl-1 - Stupid and. Fuming-3-cartoamine will be 5-cyclopropyl-2-(4-phenylene)-N-methyl-6-[(indolyl)-ylamino]-1-benzof曱醯-3-decylamine (500 mg, 1.242 mmol), 5-bromo-2-(bromomethyl)benzonitrile (342 mg ' 1.242 mmol), K2C03 (172 mg, 1.242 mmol) and KI ( 206 mg, 1.242 mmol) was suspended in N,N-dimethylamine (2 mL) and heated to 60 °C until LCMS indicated complete consumption of starting material. The reaction was poured into water and extracted with EtOAc. I54005.doc -128- 201138786 The organic layer was dried over sodium sulfate and evaporated to give a residue. The crude product was purified by dissolving in EtOAc (EtOAc) EtOAc (EtOAc) Amino]_5-cyclopropyl-2-(4-fluorophenyl)-N-mercapto-1-benzofuran-3-carboxamide (719.2 mg, 1.206 mmol yield 97%). A NMR (400 MHz, chloroform-d) δ 7.73 (dd, J = 5.28, 8.79 Hz, 2H), 7.59-7.64 (m, 1H)S 7.57 (d, /=1.95 Hz, 1H), 7.50 (d, /=8.40 Hz, 1H), 7.32 (s, 1H), 7.03-7.11 (m, 3H), 6.15 (q, /=4.43 Hz, 1H), 4.97 (d, J=〇.98

Hz, 2H), 3.08 (s, 3H), 2.87 (d, 7=4.89 Hz, 3H), 2.04-2.13 (m, 1H), 0.91-1.01 (m, 1H), 0.77-0.90 (m, 2H) , 0.42 (d, J=5.08 Hz, 1H) 〇Step 2: (3-Cyano-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamine) M)]-1-benzopyran-6-yl}(indolyl)amino]methyl} stupyl)Sponic acid in the A atmosphere, 6_[[(4_bromo- 2-(cyanophenyl)indenyl](methylsulfonyl)amino]-5-cyclopropyl-2_(4-fluorophenyl)·#-methyl-1-benzofuran·3·A Indoleamine (500 mg, 〇·838 mm〇1), 44,4,,4,5,55,,5,octamethyl-2,2'-linked-1,3,2-dioxaboron (426 mg, 1.677 mmcH), dioxane (tricyclohexylphosphine) (11) (30.9 mg, 0.042 mmol) and acetic acid unloaded (247 mg, 2.51 mmol) in 1,4-dioxane (3 mL) The solution is at 80. (The mixture was maintained overnight. The mixture was filtered over celite, and the filtrate was partitioned between EtOAc and EtOAc (EtOAc). Treated with PS- succinic acid (1.6 g, 419 mmol) (2.6-3.2 mmol/g) and stirred for 3 hours at 5 ° C. The solid was removed by filtration from 154005.doc -129 - 201138786 and EtOAc The filtrate was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. Fluoryl)-3-[(methylamino)methyl]-1-benzoxanthene-5 _6_yl}(methyl aryl)amino]methyl}phenyl) lysine (160 Mg, 0.285 mmol, yield 33.97%). NMR (400 MHz, chloroform δ: 8.28 (s, 1 H), 7.89-7.96 (m, 1 Η), 7.77-7.85 (m, 2 Η), 7.66 ( d, &gt;7.8 Ηζ, 1 Η), 7.34-7.41 (m, 1 Η), 7.17 (t, J=7.5 Hz, 3 Η), 5.83 (d, 7=4.5 Hz, 1 H), 5.13 (s , 2 H), 3.17 (s, 3 H), 2.97 (d, 3 H), 2.09-2.23 (m, 1 H), 0.96-1.09 (m, 1 H), 0.82-0.96 (m, 2 H) , 0.42-0.55 (m 1 H). Example 37 (4-{[{5-cyclopropyl-2-(4-fluorophenyl)_3·[(methylamino)carbonyl)benzofuran-6-yl} (methylsulfonate) Mercapto)amino}methyl}_2,3-difluorophenyl)carboxylic acid

Stepping Λ '· 2,3-Difluoro·4-(4,4,5,5-tetramethyldioxaborin-2-yl)benzoquinone (2,3-difluoro-4-carboxamidine) Phenyl phenyl)-acid (2 〇〇g, 1 〇 76 was suspended in toluene (20 mL), and pinacol 〇 271 g, ι〇% mmol) was added. The reaction was heated to 9 (rc until all the material was dissolved, then I54005.doc • 130·201138786, the molecular sieve was added to the reaction mixture' and the reaction was stirred overnight. The molecular sieves were filtered off and the filtrate was evaporated to give a white solid. 2 3 _Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxocone-2-yl) benzyl chain (2.79 g, 10.41 mmol, yield 97 %), containing a small amount of pinacol contaminant. Η NMR (400 MHz, DMSO-d6) δ: 10.22 (s, 1 Η), 7.61-7.69 (m, 1 Η), 7.53-7.60 (m, 1 Η), 1.32 ( s,12Η). 2'.[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3&gt;2-dioxopyran-2-yl)phenyl ]Methanol will be 2,3-dioxa-4-(4,4,5,5-tetramethyl-i,3,2-dioxaboro-p--2-yl)benzaldehyde (1.00 g, 3-73 mmol) Dissolved in methanol (3.7 mL) and added NaBH4 (0.141 g, 3.73 mmol). The residue was purified to give [2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo-p-indol-2-yl)phenyl]methanol (488.7) Mg, 1.809 mmol, yield 48.5%). 4 NMR (400 MHz, DMSO-d6) δ: 7.37-7.46 (m, 1 Η), 7.29 (t, J = 6.64 Hz, 1H), 5.47 (t, 1H), 4.59 (d, "7=5.47 Hz, 2H), 1.29 (s, 12H). Special m3 'methanesulfonic acid [2,3·difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron- 2-(2,4-difluoro-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborin-2-yl)phenyl Methanol (480 mg, 1.777 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled in an ice bath. To this solution was added TEA (0.297 mL, 2.133 mmol), followed by the addition of hydrazine (0.152 mL, 1.955 mmol), and the resulting mixture was stirred for 1 hr. The EtOAc was evaporated. EtOAcjjjjjjjjj Chromatography on ruthenium with 80% ethyl acetate and hexane to chromatize the impure oil to give methanesulfonic acid [2,3-difluoro-4-(4,4,5,5-tetramethyl) Base-1,3,2-dioxaborin-2-yl)phenyl]methyl ester (526.4 mg, 1.512 mmol, yield 85%). ]H NMR (400 MHz, chloroform-(1)5:7.48-7.54 (m, 1H), 7.20 (t, /=6.74 Hz, 1H), 5.26-5.37 (m, 2H), 3.01 (s, 3H) , 1.36 (s, 12H). Step: (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino))]-1-benzofuran -6-yl}(fluorenylsulfonyl)amino]methyl}-2}3-difluorophenyl)S-minic acid 5-cyclopropyl-2-(4-fluorophenyl)-N- Methyl-6-[(decylsulfonyl)amino]-1-benzoxoff-3-decylamine (500 mg, 1.242 mmol) was dissolved in N,N-dimercaptocarboxamide ( 2 mL) with methanesulfonic acid [2,3-difluoro-4-(4,4,5,5-tetradecyl-1,3,2-dioxaboroin-2-yl)phenyl Methyl ester (433 mg, 1.242 mmol), K2C03 (258 mg, 1.864 mmol) and KI (206 mg, 1.242 mmol) to the reaction. The reaction was heated to 60 ° C until the starting material was consumed. The mixture was poured with EtOAc (EtOAc)EtOAc. The oil was treated with a solution of ' 1.242 mmol) in THF overnight to give a brown solid. (4-{ [{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl} (methyl decyl) Amino] fluorenyl}-2,3-diphenyl)carboxylic acid (51.8 mg '0.086 mmol, yield 6.92%). NMR (400 MHz, methanol-d4) δ: 7.82-7.91 (m, 154005.doc •132- 201138786 2H), 7.60 (Sj 1H), 7.21 (t, J=8.79 Hz, 2H), 6.95-7.04 (m, 3H), 5.08 (d, /=13.87 Hz, 1H), 4.83 -4.95 (m, 1H), 3.16 (s, 3H), 2.84-2.91 (m, 3H), 2.13-2.29 (m, 1H), 0.87-0.99 (m, 1H), 0.63-0.85 (m, 2H) , 0.23 (d, ·7=4·69 Hz, 1H). LCMS (m/Z, ES+) = 573 (M+H). Example 38 (4-{[{5-cyclopropyl-2-(4) -fluorophenyl)_3_[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl b 2,5-difluorophenyl)carboxylic acid

Step 1: 6-[[(4-Bromo-2,5-difluorophenyl)methyl](methyl aryl)amino]-5-cyclopropyl-2-(4- disordered phenyl) -1^-Methyl-1-benzofluorenyl-3--3-cartoamine 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonate) Amidino)amino-1-pyrenein-3-carbamide (436 mg, 1.08 mmol), 1-bromo-4-(bromomethyl)-2,5-difluorobenzene (310 mg, A solution of 1.08 mmol) and carbonic acid (3 mg, 2.17 mmol) in DMF (15 mL) was maintained at 65 °C for 3 h.

The solution was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, evaporated, evaporated, evaporated. Ottomidine) (methyl ketone) (methyl ketone) amino]-5-cyclopropyl-2-(4-fluorophenylmethyl_ι-benzopyran-3-amine (570 mg, 0.938 mmol 'yield 87 〇/〇). LCMS 154005.doc •133· 201138786 (m/z, ES+)=607 (M+H) Step 2 ·· (4-{[{5_cyclopropyl_2) ·(4-fluorophenyl)_3_[(methylamino)methyl]-1-benzobenzoin-6-yl}(fluorenylsulfonyl)amino]indenyl}-2,5-di Fluoride-based acid is mixed with '6-[[(4-bromo-2,5-difluorophenyl)methyl](fluorenylsulfonyl)amino]-5-cyclopropyl- 2-(4-Fluorophenyl)-N-mercapto-1-benzofuran-3-cartoamine (570 mg '0.938 mmol), acetic acid unloaded (184 mg, 1.87 mmol), bis (pinacol) Diboron (286 mg, 1.12 mmol) and ?&lt;^12(3卩卩£')-(1!112(^12 force. Compound (69.3 111 L, 0.094 111111〇1) in 1,4-two ° The solution in the smoldering (5 mL) was maintained in a thick-walled glass pressure vessel at 9 Torr for 16 hours. Cool the solution to room temperature and add thf:NH4OAc. (0.1 Μ aqueous solution) 6.4 (50 mL), followed by sodium molybdate (2007 mg, 9.38 mmol), and the mixture was allowed to fall for 6 hours at the temperature. The reaction was filtered and purified on cerium oxide to give Product as an off-white powder (4_{[{5_cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl)benzofuran_6_yl}(mercaptosulfonic acid) Amino]methyl}_2,5-difluorophenyl)-acid (8 〇mg, yield 15%). 4 NMR (DMSO-d6) δ: 8.45 (m, 1H), 8.32 (br. s ·, 2H), 7.93 (m, 2H), 7, 84 (s, 1H), 7.39 (m, 2H), 7.18 (m, 1H), 7.03 (m, 1H), 6.94 (s, 1H), 4.91 (m, 2H), 3.24 (s, 3H), 2.79 (s, 3H), 2.24 (m, 1H), 0.91 (m, ih), 0·77 (m, 2H), 0.19 (m, 1H). LCMS (m/z, ES+) = 573 (M + H). Example 39 (2- -4- -4-{[{5-cyclopropyl-2-(4-fluorophenyl)- 3-[(methylamine) ))carbonyl jj·benzofuran-6-yl}(methylsulfonyl)amino]methyl)phenyl)decanoic acid 154005.doc •134· 201138786

Step 1: 6-[[(4-Bromo-3-phenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)_N-A 5-1,4-benzofurancarbamide with 5-cyclopropyl-2-(4-fluorophenyl)·Ν-methyl-6-[(fluorenylsulfonyl)amino]- 1- Stupid. Fu _3_ 甲-handling amine (850 mg ' 2.112 mmol), 1-bromo-4-(bromomethyl) 2 benzene benzene (6 〇 1 mg ' 2.112 mmol) and potassium carbonate (584 mg, 4.22 mmol) The solution in N,N-dimethylformamide (5 mL) was maintained at 80 °C for 3 hours. The cooled mixture was poured into ethyl acetate and washed with water and 5% LiCl (aq). The organic layer was separated and dried with sodium sulfate, filtered, and then purified,jjjjjjjjjj Methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-d-phenyl)-N-indenyl-1-benzof-oxo-3-carboxamide (1.07 g, 1.766 mmol, yield 84%). LCMS (w/z, ES+) = 605 (M+H) Step 2: (2-chloro-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methyl) Amino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)decanoic acid 6-[[(4-bromo-3) with stirring -oxyphenyl)indenyl](fluorenylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1·benzofuran-3-indole Amine (150 mg, 0.248 mmol), acetic acid (97 mg, 0.990 mmol), double 154005.doc -135- 201138786 (pinacol root) diboron (UGmg' 0.495 mmol) and PdCl2 (dppf) -CH2CI2 addition A solution of the compound (20.22 mg '0.025 mmol) in 1,4 deg. (5 mL) was maintained at 90 for 24 hours. The mixture was cooled to room temperature, filtered through a glass filter paper, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (150 mL) eluting with EtOAc (EtOAc) The mixture was maintained under stirring, filtered over celite, and diluted with water and ethyl acetate. The organic layer was separated, concentrated and resuspended in tetrahydrofuran (15 mL), treated with 5.0 N HCl (aq) (i s) and &lt;RTI ID=0.0&gt; It was maintained for another 5 hours with stirring. The mixture was filtered over EtOAc (EtOAc)EtOAc. (2-Chloro-4_{[{5_cyclopropyl_2_(4-fluorophenyl)-3-[(decylamino)carbonyl]_1_benzofuran_6-yl)(fluorenylsulfonate) Hydrazinylamino)phenyl)benzic acid (52 mg, 0.091 mm〇i, yield 36.8%) 〇*H NMR (f S|-d4) δ: 7.89 (dd, J=8.7, 5.4 Hz, 2H), 7.60 (s, 1H), 7.10-7.30 (m, 5H), 7.01 (s, 1H), 4.96 (d, J = 14.0 Hz, 1H), 4.76 (d, J = 14.0 Hz, 1H), 3.16 (s, 3H), 2.91 (s, 3H), 2.17-2.28 (m, 1H), 0.90-1.02 (m, 1H), 0.71-0.84 (m, 2H), 0.24-0.35 (m, 1H). LCMS (m/z, ES+) = 568 (M+H). Example 40 [4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-indole (methylamino)carbonyl]benzofuran-6-yl} (methylsulfonic acid) Amino] methyl b 2 · fluoro_3_(trifluoromethyl)phenyl]imin 154005.doc -136- 201138786

Step 1: 6-Bromo-2-fluoro-3-(trifluoromethyl)phenylamine 2-fluoro-3-(trifluoroanthracene) was treated dropwise with NBS (4.45 g '25.00 mmol) in 8 mL of DMF over 2 hours. A solution of aniline (4.48 g, 25 mmol) in DMF (5 mL). The solution was diluted with water and quenched with aq. The organic layer was dried over Na2SO4, filtered, evaporated,lululululululululululululululu M, yield 88%). NMR (400 MHz, gas δ: 7.23-7.30 (m, 1 H), 6.79 (t, *7 = 8.6 Hz, 1 H), 3.93 (br. s·, 2 H). Step 2: 4-amine 3-Butyl-2-(trifluoromethyl)benzoic acid methyl vinegar 6-bromo-2-fluoro-3-(trifluoromethyl) under stirring in a CO atmosphere (about 7 psi) Aniline (5.6 g, 21.70 mmol), hydrazine (2·416 g, 23.87 mmol), acetic acid (0.974 g, 4.34 mmol) and dppf (3.61 g, 6.51 mmol) in DMSO (20 mL) and decyl alcohol (20) The solution in mL) was heated to 80 ° C overnight. The solution was filtered over EtOAc (EtOAc) (EtOAc) eluting The mixture was purified to give 4-amino-3-fluorotrimethylmethyl)benzoic acid in the form of a purple liquid (4.5 g, 18.98 mmol, yield: 154,005.doc, 137, 201138786, 87%). NMR (400 MHz, gas-like j) δ: 7.24-7.33 (m, i H) 6.90 (t, */=8.3 Hz, 1 H), 4.12 (br. s., 2 H), 3.88 (s, 3) H) 〇Step 3: 4-bromo-3-fluoro-2-(trifluoromethyl)benzoic acid methyl acetonate 4-amino-3-fluoro-2-(trifluoromethyl)benzoate oxime ester (4.5 The solution of g, 1898 mmol) in acetonitrile (30 mL) was cooled to EtOAc &lt Aqueous hydrobromide solution (21.47 mL, 190 mmol). A solution of sodium nitrite (1.440 g, 20.87 mmol) in 10 mL of water was added dropwise over 30 min. After the addition, the mixture was stirred at 0 ° C for 30 minutes, and copper bromide (3" 9 g, 2 丨 82 mmol) was added portionwise over 1 Torr. After the addition, the solution was heated to reflux (about 85 ° C) for 2 Torr. The solution was diluted with EtOAc (EtOAc) EtOAc (EtOAc m. Methyl benzoate (3.2 g, i〇63 mmol' yield 56.0%). NMR (400 MHz, gas-J) δ: 7 82 (dd, 7=8.0, 6.3 Hz, 1 Η), 7.23-7.29 (m, 1 Η), 3.94 (s, 3 H). Step 4: [4-Bromo-3-fluoro-2-(trifluoromethyl)phenyl]fol was stirred at room temperature for 4-bromo-3-fluoro-2-(trifluoromethyl)benzoic acid A solution of the ester (3.2 g, 10.63 mmol) and lithium borohydride (26 mL, 51.8 mmol) (2. EtOAc) in THF (10 mL). The solution was quenched with water, neutralized with EtOAc EtOAc EtOAc. The organic layer was dried with EtOAcjjjjjjjjjjjjjj The yield was 41.3%). H NMR (400 154005.doc -138- 201138786 MHz, gas δ: 7 54 (m, 1 h), 7.13 (m, 1 H), 4.90 (s, 2 H). 'Step 5: Methanesulfonic acid [4. Bromo_3_fluoro-2_(trifluoromethyl)phenyl] methyl vinegar was treated dropwise with ruthenium chloride (0.376 mL, 4.83 mmol) [4 · desert _3_ fluoro-2·(trifluoro a solution of methyl) phenyl]methanol (1.2 g, 4.40 mmol) and TEA (〇.673 mL, 4.83 mmol) in DCM (10 mL). The solution was stirred at room temperature for 1 hour, followed by water and Washed with brine, dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> Phenyl]methyl ester (1 3, 3.70 mmol' yield 84%). iH NMR (4 〇〇 MHz, gas imitation... &amp; 7-57-7.64 (m, 1 Η), 7.44 (d, 1 Η) , 5.41 (d, J = 1.4 Hz, 2 H), 3.06 (s, 3 H). Step 6: 6-[{[4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]- }} (f-based fluorenyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)_N-mercaptobenzofuran-% decylamine 5-cyclopropyl-2-(4) -fluorophenyl)-沁methyl-6-[(methylsulfonyl)amino] 1 benzofuran-3 -decylamine (1.248 g, 3.1 mmol), A hospital acid [4_ 'gas 2 (-fluoromethyl) base] A 6 (1.3 g, 3.70 mmol), potassium carbonate (0·471 g, 3.41 mm〇l) in DMF The mixture was heated to m °c for 1 h. The solution was diluted with Et0Ac and water. The organic layer was dried over Na.sub.2, filtered, concentrated, and purified by column chromatography. 6-[{[4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]methyl Kmethylsulfonyl)amino]-5-cyclopropyl_2_(4) ·Fluorophenyl)·Ν_曱Basic and Fennan-3-carboamine (2.6 g, 2.434 mmol, yield 790/〇). LC- 154005.doc -139· 201138786 MS (w/z, ES+) = 657 (659). Step 7: [4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(f-amino)yl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]methyl-2-fluoro-3-(trimethylmethyl)phenyl: IS-Acetic acid 6-[{[4-bromo- 3-fluoro-2-(trifluoromethyl)phenyl]fluorenyl}(methyl-glycosyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1^-methyl -1-benzofuran-3-carboxamide (0.3 g, 0.456 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked -1,3,2-two Butterfly p East (〇·232 g, 0.913 mmol), dioxane (tricyclohexylphosphine) palladium (^) (0 〇17 g, 〇〇23 mmol) and acetic acid clock (0.134 g' 1.369 mmol) at 1,4 The solution in the 2° cautery (5 mL) was maintained at 80 ° C for 2 hours. The solution was filtered through celite, and the filtrate was partitioned between water and EtOAc. The organic layer was collected and concentrated to give a residue. The residue was dissolved in THF (5.00 mL) and 3 mL of 6 M EtOAc. &lt;RTI ID=0.0&gt;&gt; 1 hour. The solid was removed via filtration and washed with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC to afford [4-{[{5-cyclopropyl-2-(4-fluorophenyl)_3_[(methylamino)) ]]] benzofuran-6-yl}(methylsulfonyl)amino]methyl-2-fluoro-3-(trifluoromethyl)phenyl]g-acid (47 mg, 0.076 mmol, Yield 16-55%). Η NMR (400 MHz, DMSO-^6) δ: 8.42 (br. s., 2 H), 7.95 (br. s·, 3 H), 7.73 (br. s., 1 H), 7.23-7.59 (m, 3 H), 6.91 (br. s., 1 H), 4.90-5.40 (m, 2 H), 3.24 (br. s., 3 H), 2.80 (br. s., 3 H), 2.24 (br. s.,1 H), 2.07 (br. s·,1 H), 0.84 (br. s·,3 H), 0.23 (br. s., 1 H) 〇LC-MS (m/ z, ES+)=623 (M+H) &lt;&gt; 154005.doc •140· 201138786 Example 41 (4-{[{S-cyclopropyl_2_(4-fluorophenyl)_3_丨 (methyl) Amino)carbonyl]^•benzofuran-6-yl}(methylsulfonyl)amino}methyl}_2_[(difluoromethyl)indolyl]phenyl}fondic acid

Step 1: 4-Bromo-3-[(difluoromethyl)oxy]benzoic acid methyl ketone treated with stone acid reflux (7.62 g, 23.3 7 mmol) and sodium difluoroacetate (3 56 , 23.37 mmol) a solution of methyl 4-bromo-3,hydroxybenzoate (2 7 g, mmol of u) in N,N-dimercaptocaramine (4 mL) with stirring at 80 ° C Maintain for 5 hours. The mixture was cooled, poured into ethyl acetate and washed three times with 5% LiCI (aq). The organic layer was separated, dried (MgSO4) eluted eluting Oxime ester (2 36 g, 8.40 mmo yield 71.9%). iH NMR (gas _d) δ: 7 86 (s, 1H), 7.78 (dd, J=8.3, 1.7 Hz, 1H)S 7.72 (d, J=8.4 Hz, 1H), 6_60 (t, J= 72 Hz, 1H), 3_94 (s, 3H). Step 2: {4-Bromo-3-[(difluoromethyl)oxy]phenyl}methanol 4-methyl-3-[(difluoromethyl)oxy]benzoic acid methyl ester (2.3 g, 818 Ment) The solution in tetrahydrofuran (100 mL) was cooled to 〇〇c and treated with a solution of 154005.doc -141 - 201138786 DIBALH (32.7 mL '32.7mm〇i) in toluene and warmed to room temperature, then continue Sandalwood mix for 5 hours. The solution was quenched by the slow addition of (10) R〇chelle's salt and further diluted with ethyl acetate. The mixture was maintained under constant stirring for 6 hours and separated by a layer, washed with brine, dried over sodium sulfate, and dried under reduced pressure to give a crude oil. Methyl)oxy]phenyl}methanol (23 8.18 mm 〇1). iH NMR (gas _d) &amp; 7 6 〇(4) j=8 2 edge, called, 7.25 (s, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.55 (t, J=72 Hz, 1H), 4.68 (br. s., 2H), 1.92 (br. s" 1H) Step 3: 1-Bromo-4-(bromomethyl)·2_[(difluoromethyl)oxy]benzene Phosphorus bromide (0.744 mL, 7.88 mmol) was treated dropwise with {4_bromo-3-([(2)-)-] The solution was maintained at room temperature for 2 hours with stirring. The mixture was poured into ice water, and the organic layer was washed with brine, dried, dried over sodium sulfate, filtered and evaporated. Purification by column chromatography gave 1-bromo-4-(bromofluorenyl)_2-[(difluoroindenyl)oxy]benzene as a clear oil (475 mg, yield: 20%, 1.503 mm). A NMR (gas-d) δ: 7.60 (d, J=8.2 Hz, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.16 (dd, J-8.3, 2.1 Hz, 1H), 6.56 (t, J=72 Hz, 1H), 4.43 (s, 2H) Step 4: 6-[({4-Bromo-3-[(difluoromethyl)oxy]phenyl}methylmethyl)-yl)amine 5-ylcyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3- ψmm 5-cyclopropyl- 2-(4-Fluorophenyl)-N-methyl-6-[(indolyl)amino]-1-benzofuran-3-decylamine (550 mg, 1.367 mmol), 1- Bromo-4-(bromomethyl 154005.doc • 142· 201138786 base) 2 [(-fluoromethyl)oxy]benzene (475 i 5〇3 ^^〇1) and potassium carbonate (378 mg, 2.73 mmol) The solution in N,N-dimethylformamide (5 mL) was maintained at C for 4 hours. The mixture was cooled, poured into water and diluted with acetonitrile. The organic layer was washed with 5 ° /. LiCl (aqueous) , separated, dried and filtered over EtOAc (EtOAc). Fluoromethyl)oxy]phenylindolemethyl)(fluorenylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-indenyl-bubenzofuran 3-carbalamine (8〇5 ^, 1 263 mmol, yield 92%). LCMS (W/z, ES+) = 639 (M+H) 〇 Step 5. {4-{[{5-Cyclopropyl Benzyl-2-(4-fluorophenyl)-3.[(f-amino)yl]-1-benzofuran_6_based methylsulfonyl)amino]methyl b 2_ Difluoromethyl)oxy] phenyl] sun-acid in a sealed pressure tube, 6-[({4-bromo-3-[(2) Methyl)oxy]phenyl}indenyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)·Ν_methylbenzf - anthraquinone (225 mg '0.353 mmol), acetic acid unloading (139 m§ '1.412 mmol), bis(pinacolyl)diboron (179 mg, 0.706 mmol) and dioxobis(tricyclohexylphosphine)palladium (π) (26 〇 mg, 〇〇 35 mm Qi) The solution in 1,4-dioxane (5 mL) was cooled with stirring at 9 ° C for 16 hours and filtered through a glass filter. The broth was concentrated, dissolved in tetrahydrofuran (150 mL) and treated with &lt;RTI ID=0.0&gt;&gt; The mixture was maintained under stirring for 4 hours, filtered through celite, washed with ethyl acetate and diluted with water. The organic layer was separated, concentrated, diluted with tetrahydroindole (15 mL), and treated with 5 〇n HCl (aq) (100 mL) and polymer supported 154005.doc - 143 - 201138786. The mixture was washed with EtOAc (br.), EtOAc (EtOAc EtOAc (EtOAc) The residue was obtained and purified by reverse phase hplc, lyophilized to give a white foamy <4-{[{5-cyclopropyl-2-(4-d-phenylphenyl). Alkyl]· benzofuran-6-yl}(amino)alkyl]mercapto}-2·[(difluoroindolyl)oxy]phenyl}-acid (87 mg' 0.144 Methyl' yield 40.9%) NMR (methanol-d4) δ: 8.39 (d, J=4.1 Hz, 1H), 7.88 (dd, J=8.9, 5.4 Hz, 2H), 7.57 (s, 1H), 7.17 -7.30 (m, 3H), 6.98-7.12 (m, 3H), 6.67 (t, J=72 Hz, 1H), 4.95 (d, J=14.0 Hz, 1H), 4.83 (d, J=14.2 Hz, 1H), 3.15 (s, 3H), 2.91 (d, J=4.7 Hz, 3H), 2.14-2.27 (m, 1H), 0.90-1.03 (m, 1H), 0.70-0.84 (m, 2H), 0.28 -0.41 (m, 1H). LCMS (w/z, ES+)=603 (M+H Example 42 4-(2-(iV-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonate) Amidino)ethyl)-2-fluorophenyl-folate

Step 1: 4-Phenyl-1-bromo-2-pyrogen at room temperature, to bromo-2-fluoro-4-iodobenzene (10 g '33.2 mmol) and 154005.doc • 144· 201138786

Pd(PPh3)4 (2.3 g '3 mmol) was added to a solution of DMF (100 mL), tris-butyltin (11.9 g, 36 mmol) and heated at 1 ° C for 12 hours. The reaction mixture was poured into ice/water (500 mL) and used

The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were washed with aq. EtOAc (EtOAc (EtOAc) After concentration under reduced pressure, the crude product was purified by column chromatography to afford 4-(4-propyl-dichloro-2-fluorobenzene (6.5 g, 30.3 mmol, yield: 91.5%). Step 2: 2- (4-Bromo-3-fluorophenyl)ethanol 4-Allyl-1-bromo-2-fluorobenzene (6.5 g, 30.3 mmol) was added to DCM/MeOH (MeOH) at -78. Solution in mL/100 mL). The reaction mixture was searched for 30 minutes until the solution turned blue. After purging with n2 for 30 minutes, NaBH4 (5.7 g, 0.15 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The solution was poured into ice/water and the aqueous layer was extracted with DCM (3×l 〇〇 mL). The combined organic layers were dried over anhydrous NazSCU. After concentrating under reduced pressure, the crude product was purified by column chromatography to afford 2-(4-&gt; odor-3- phenylphenyl)ethanol (3.5 g, 16 mmol, yield 53%) 〇Step 3: 1-Bromo-4-(2-bromoethyl)-2-fluorobenzene to NBS (5.6 g, 32 mmol) and 2-(4-/odor A solution of PPh3 (8.4 g, 32 mmol) in DCM (5 mL) was added dropwise EtOAc (3········ . Water (200 mL) was added and the aqueous layer was extracted with DCM (3 &gt;&lt; The combined organic layers were dried over anhydrous Na 2 EtOAc. After concentration under reduced pressure, the crude product was purified by column chromatography to afford 154005.doc: 145·201138786 1- -4-(2-bromoethyl)-2-fluorobenzene 3 g, 10.7 mmol, yield 62%). Step 4: 6-(N-(4-Bromo-3-fluorophenethyl)methylsulfonylamino)·5·cyclopropyl-2-(4-fluorophenyl)-N-methylbenzo Astringent-3-cartoamine will be 1-&gt; odor-4-(2-diethyl)-2-phenylene (2'3 g, 8.2 mmol), 5-cyclopropyl-N-indenyl- A solution of 6-(methylsulfonylamino)-2-phenylbenzofuran-3-carboxamide (3.3 g '8.2 mmol) and K2C03 (2.3 g, 16.4 mmol) in MeCN (100 mL) Heat at 80 ° C for 2 hours. The reaction mixture was poured into ice/water (100 mL) and aqueous layer was extracted with DCM (3×lOmL). The combined organic layers were dried over anhydrous Nad. After concentration under reduced pressure, 6-(#-(4-bromo-3-fluorophenethyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluoro) was obtained as a white solid. Phenyl)-N-mercaptobenzofuran-3-indoleamine (1.3 g, 2.16 mmol, crude yield 27%). Step 5: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzene Ethyl)methylsulfonylamino)_2_(4-fluorophenylmethylbenzofuran-3-carboxamide) 6-(iV-(4-bromo-3-fluorophenethyl) under nitrogen atmosphere Methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N-mercaptobenzofuran-3-carbamidamine (1.3 g ' 2.16 mmol), KOAc (0_447 g) , 3.24 mmol), a solution of Pin2B2 (0.82 g ' 3.24 mmol) and PdCl 2 (dppf) (84 mg, O.ll mmol) in DMF (50 mL) was heated at 1 ° C for 12 h. The organic layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over anhydrous Naj. 5_cyclopropyl·6·(ΛΓ_(3·4·5-fluoro-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl) as a white solid Phenylethyl)hydrazinosulfon 154005.doc -146- 201138786 Amidino)-2-(4-phenylene)-iV·methylbenzobenzo-3-enylamine (950 mg, 1.46 mmol, Yield 67%). Step 6: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine) Benzylfuran-6-yl)methylsulfonylamino)ethyl)-2-fluorophenyl self-peptic acid 5·cyclopropyl-6-(N-(3-fluoro-4-(4) ,4,5,5-tetradecyl-1,3,2-dioxoindol-2-yl)phenethyl)methylsulfonylamino)-2-(4-fluorophenyl)-N- A solution of methyl benzofuran-3-indolamine (950 mg, 1.46 mmol) and HCl (3 N aqueous solution, 4.8 mL, 14.6 mmol) in THF (20 mL) The reaction mixture was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (decylamine sulfhydryl)benzofuran-6-yl)methylsulfonylamino)ethyl)_

2-1 phenyl lysine (420 mg, 0.74 mmol, yield 51%). ! H-NMR (300 MHz, DMSO) δ: 8.47 (s, 1 Η), 8.10 (s, 1 Η), 7.99-7.98 (m, 2 Η), 7.85 (s, 1 Η), 7.50-7.37 (m , 3 Η), 7.08 (s, 1 Η), 6.99-6.93 (m, 2 Η), 3.94-3.89 (m, 2 Η), 3.14 (s, 3 Η), 2.85-2.76 (m, 5 Η) , 2.32-2.28 (m, 1H), 0.97-0.85 (m, 3H), 0.60 (m, 1H). LCMS (m/z, ES+) = 569 (M+l). Example 43 2 -Gas-4-(2-(N-(5-cyclohexyl)-2-(4-fluorophenyl)-3.(methylamine-methanol)benzofuran-6-yl) Sulfonamide)ethyl)phenyl-acid

Ηο'β'οη I54005.doc -147· 201138786 Step 1: 4-Allyl-1-bromo-2-epoxybenzene to 1-di-2-ox-4-epylene (3 g, 9.46 mmol Pd(PPh3)4 (〇.63 g, 0.57 mmol) was added in one portion to a solution of tributyltin oxide (3.7 g, 11.35 mmol) in DMF (60 mL). The mixture was heated at 100 &lt;0&gt;C for 12 h then poured over ice-water (100 mL)EtOAc. The combined organic layers were washed with aq. EtOAc (EtOAc/EtOAc). After the solvent was removed, the crude crystals were purified eluted eluted elut elut elut elut elut elut elut Step 2: 2-(4-Bromo-3-phenylphenyl)ethanol was saturated with 4-propane-1-bromo-2-phenylbenzene (0.95 g, 4.1 mmc^) at -78 °C. A solution in KMeOH/DCM (100 mL / 100 mL). The reaction solution was stirred for 30 minutes until the blue color was continued "purging the reaction solution with N2 for 30 minutes" and then NaBH4 (0.78 g, 20.6 mmol) was added. After the addition, the reaction solution was stirred at room temperature overnight. The mixture was poured into ice/water (1 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After the solvent was removed, the crude product was purified by column chromatography to afford 2-(4-bromo-3-chlorophenyl)ethanol (0.8 g, 3.4 mmol, yield: 85%). : 1-Bromo-4-(2-bromoethyl)-2-chlorobenzene to 2-(4-bromo-3-phenylphenyl)ethanol (0.8 g, 3.4 mmol) and NBS (1.21). A solution of PPh3 (1.78 g, 6.8 mmol) in DCM (5 mL) elute The reaction solution was poured into ice/water 154005.doc • 148·201138786 (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After removal of the solvent, the title compound was crystalljjjjjjjjjjjjjjj Step 4: 6-(N-(4-Bromo-3-phenylphenethyl)methylsulfonylamino)-5-cyclopropyl(4-fluorophenyl)-N-methylbenzopyran 3-carbalamine 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonylamino)benzofuran-3-carboxamide (〇_ 5 g, 1.2424 mmol), 1-bromo-4(2-bromoethyl)-2-fluoroindole (0.8 g, 2.681 mmol), hydrazine (206 mg, 1.24 mmol) and K2C03 (514 mg, 3.73 mmol) The solution was dried in anhydrous D.sub.3 (10 mL). EtOAc (EtOAc)EtOAc. After the solvent was purified by column chromatography to give 6-(iV-(4-bromo-3-phenethylethyl)methylsulfonylamino)-5-cyclopropyl as a brown solid. 2-(4-Fluorophenyl)-indole-mercaptobenzofuran-3-indoleamine (0.595 g, 0.96 mmol, 77%). Step 5: 6-(N-(3-chloro-4-( 4,4,5,5-tetramethyl-1,3,2-dioxane p-dong-2·yl) Ethyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenylmercaptobenzofuran-3-carboxamide) under nitrogen atmosphere 6-(Ν-(4· Bromo-3-chlorophenethyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-indole-methylbenzofuran-3-carboxamide (0.595 g ' 0.96 mmol), PdCl2(dppf)-CH2Cl2 adduct (190 mg '0.096 mmol), bis(pinacolyl)diboron (0.488 g, 1.92 mmol) and potassium acetate (282 mg, 2.88 mmol) 154005.doc • 149· 201138786 in dioxane (20 mL) The solution was heated at 1 oo ° C overnight. The reaction solution was cooled to room temperature and passed through 遽β. The filtrate was concentrated under reduced pressure and chromatographed. The residue was purified to give 6-(--- 4-(4-(4-(4-(4-(4-)))) Phenylethyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)·Ν_methylbenzo. Funan-3-decylamine (0.62 g, 0.93 mmol, 96 0/〇). Step 6: 2-Gas-4-(2-(Ν-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine)) °夫叫-6-基)Methyl continuation of amino)ethyl)phenyl phthalic acid 6-(#-(3- gas-4-( 4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)phenethyl)methylsulfonylamino)-5-cyclopropyl-2-(4- Fluorophenyl)-#·methylbenzo. a solution of fluran-3-amine (0.62 g, 0.93 mmol), HCl (5 N in water, 1.3 mL) and s-p-phthalic acid (1.6 g, 4.65 mmol) in THF (15 mL) Stir under overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by preparative hp~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Benzo benzofuran-6-yl)methylsulfonylamino)ethyl)phenyl-fatanoic acid (108 mg, 0.199 mmol, 21%). 4 NMR (300 MHz, methanol-d4) δ: 7.96-7.92 (m, 2 Η), 7.62 (s, 1 Η), 7.31-7.12 (m, 6 Η), 4.07-4.02 (t, 2 Η), 3.08 (s, 3 Η), 2.97-2.88 (m, 5 Η), 2.33 (m, 1 H)s 1.07-1.04 (d, 2 Η), 0·89 (m, 1 H), 0.71 (m, 1 H). LCMS (w/z, ES+) = 585.0 (M+H). Example 44 4-(2-(iV-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)methylsulfonamide Ethyl)-2-(trifluoromethyl)phenyl decanoic acid 154005.doc •150- 201138786

hA

^cf3 ho'b, oh Step 1 · 4-allylbromo-2-(trifluoromethyl)benzene 1-Bromo-4-iodo-2-(trifluoromethyl)benzene (3 g, 8.5 mmol A solution of allyltributylstannane (3_4 g, 10.3 mmol) and Pd(PPh3)4 (0.47 g, 0.4 mmol) in DMF (60 mL). The reaction solution was poured into ice/water (1 mL), and the solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with KF (10% aq. After removal of the solvent, the title compound was purified eluting eluting eluting eluting 0%). Step 2: 2-(4-Bromo-3-(trifluoromethyl)phenyl)ethanol was saturated with a 〇3 stream at -78 °C. 4-Allyl-i-bromo-2-(trifluoromethane) A solution of benzene (1.1 g, 4.15 mmol) in MeOH / DCM (100 mL / 100 mL). The reaction mixture was allowed to mix for 30 minutes' until the solution turned blue. The reaction solution was blown with n2 for 30 minutes' followed by the addition of NaBH4 (0.78 g, 20.7 mmol). The reaction mixture was allowed to warm to room temperature and was dropped overnight. The reaction solution was poured into ice/water (100 mL) and extracted with DCM (3.times. The combined organic layers were dried over anhydrous Nad. After the solvent was removed, the crude product was purified by column chromatography to afford 2-(4-(3-(trifluoromethyl)phenyl)ethanol as a colorless oil (0.85 g, 3.15 mmol, yield 77%) ). 154005.doc •151·201138786 Step 3: 1-Di- 4-(2-diethyl)-2-(trifluoromethyl)benzene under 2-nitrogen to 2-(4-bromo-3-(3) PPh3 (1.62 g, 6.2 mmol) was added dropwise to a solution of fluoromethyl)phenyl)ethanol (〇_85 g, 3.15 mmol) and NBS (1.12 g ' 6.2 mmol) in DCM (50 mL) A solution of DCM (5 mL) was obtained and the mixture was stirred at room temperature for 30 min. The mixture was poured into ice/water (50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After removal of the solvent, the title compound was purified eluting elut elut elut eluting , yield 77%). Step 4: 6-(N-(4-indol-3-(trifluoromethyl)phenethyl)methylindenyl)-5-cyclopropyl-2-(4-indoleylmethylbenzene And 5-bromopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonylamino)benzofuran_3_曱 under a nitrogen atmosphere Indoleamine (0 5 g, i 2424 mm〇1), bromo-4-(2-bromoethyl)-2-(trifluoromethyl)benzene (〇825 g, 2 48 mm〇1), KI ( A solution of 206 mg, 1.24 mm 〇1) and k2C 〇3 (514 mg, 3 73 mm 〇1) in dry DMF (10 mL) was heated for 2 h at 12 ° C. quenched with water (6 mL) After the filtration, the residue was dissolved in EtOAc. EtOAc (EtOAc)EtOAc. (three said methyl) phenethyl) fluorenyl aryl amine) _5 · cyclopropyl 2 - (4 - lactyl phenyl) _ n - methyl benzo acetoin 3-cartoamine (〇.69g, i 〇56_〇1,(10)). Step 5: 5-cyclopropyl_2♦ phenyl phenyl group 基 winter (ν_(4_(4,455· tetramethyl-1,3,2-dioxole _ 2•基)_3_(trimethylmethyl)phenethyl)methyl continuation of amines) benzohaffin-3 -Metformamide 154005.doc • 152· 201138786 6-(N-(4-Bromo-3-(trifluoromethyl)phenethyl)methylsulfonylamino)-5-cyclone under nitrogen atmosphere Propyl-2-(4-fluorophenyl)-N-mercaptobenzofuran_3_formamide (0.69 g, 1.056 mmol), PdCl2(dppf)-CH2Cl2 adduct (214 mg '0.2112 mmol), Bis (pinacolyl) diboron (ο. 〖% g, 2 112 mmol) and acetic acid unloading (310 mg ' 3.168 mmol) in 2. The solution in the ward (20 mL) was heated at 1 oo °c overnight. The reaction solution was cooled to room temperature and filtered. The residue was concentrated under reduced pressure and the residue was purified to purified crystals eluted -N-mercapto-6-(N_(4-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)-3-(trifluoroanthracene) Phenylethyl) fluorenyl decylamino)benzofuran-3-decylamine (0.51 g, 0.728 mmol, 69%). Step 6: 4-(2-(N-(5-cyclopropyl) -2-(4-Phenylphenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)decylsulfonylamino)-2-(trifluoromethyl)phenyl _acid 5-cyclopropyl-2-(4-fluorophenyl)-N-mercapto-6-(N-(4-(4,4,5,5) -tetramethyl-1,3,2-dioxaborin-2-yl)-3.(trifluoromethyl)phenethyl)methylsulfonylamino)benzofuran-3-decylamine ( A solution of 0.51 g, 0.728 mmol), HCl (5 N aqueous solution, 1_02 mL) and EtOAc (EtOAc) (1. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to give 4-(2·(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine fluorenyl) as a white solid. Benzofuran-6-yl)nonylsulfonylamino)ethyl)_2-(trifluoromethyl)phenyl-acid (95 mg, 0.154 mmo, 20%). A NMR (300 MHz, methanol-d4) δ: 7.96-7.91 (m, 2 Η), 7.60 (s, 1 Η), 7.49-7.14 (m, 6 Η), 4.12- 154005.doc • 153- 201138786

4.07 (t, 2 Η), 3.09 (s, 3 Η), 3.04-2.96 (m, 5 Η), 2.05 (m, 1 H), 1.05-1.03 (d, 2 Η), 0·89 (m, 1 η), 0.71 (m, 1 H). LCMS (m/z, ES+) = 619.1 (M+H). Example 45 [4-{丨{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]benzofuran-6-yl}(methylsulfonyl) Amino]methyl b 2_fluoro-5_(trifluoromethyl)phenyl]carboxylic acid

Step 1: [4-Amino-5-fluoro-2-(trifluoromethyl)phenyl]methanol [4-nitro-5.fluoro-2-(trifluoromethyl)phenyl]-methyl ( 6 5 g, 27.2 mmol) and a solution of palladium/activated carbon (0.6 g ' 2.72 mm 〇 1,1 〇 0/〇 loading) in THF (15 mL) and methanol (10 mL) in h2 atmosphere ( Stir at room temperature for about 20 hours at about 46 psi). The palladium was removed by filtration through celite, and the filtrate was concentrated and purified by flash column chromatography to afford [4-amino-5-fluoro-2-(trifluoromethyl) as a white solid. Phenyl] decyl alcohol (2 2 g, 52 mmol 'yield 38.7%). NMR (400 MHz, gas-a δ: 7 31 (d, Ηζ, 1 Η), 7.06 (d, /=8.4 Ηζ, 1 Η), 4.74 (s 2 Η) 3.83 (br. s·, 2 Η Step 2: [4-Amino-5-fluoro-2-(trifluoromethyl)phenyl]methanol [4-Amino-5-fluoro-2-(trifluoromethyl)phenyl]methanol ( 22 154005.doc ·154·201138786 mmol) The solution in acetonitrile (15 mL) was cooled to hydrazine in an ice bath. Then, a 48% aqueous solution of HBr (7 14 坩B, 63.1) was added dropwise from the syringe over 1 Torr. Methyl) 'The solution of sodium nitrite (〇 798 layer, 11.57 mmol) in 8 mL of water was then added dropwise over 30 minutes. After the addition, the solution was stirred under the agglutination for 20 minutes, followed by bromination in portions over 1 minute. Copper 〇 771 g, i2 w mmol). After the addition, the resulting mixture was heated to 7 ° C for 3 minutes. The solution was diluted with water, extracted with EtOAc (EtOAc) (EtOAc)EtOAc. _2_(Trifluoromethyl)phenyl]methanol (2"g' 769 _ 〇 yield 73.1%). 4 NMR (400 MHz, gas Α · δ · · 7.84 (d, *7 = 6.4 Hz, 1 Η), 7.58 (d, J = 9.4 Ηζ, 1 Η), 4.86 (s, 2 Η) » Step 3 : [4-Bromo-5-fluoro-2-(trifluoromethyl)phenyl]methyl sulfonic acid to [4-bromo-5-fluoro-2-(trifluoromethyl)benzene at room temperature Add hydrazine (1·065 mL·, 7.66 mmol) to a solution of methanol (1.9 g, 6.96 mmol) in DCM (1 mL), followed by decylsulfonium chloride (〇 592 mL, 7.66 mmol). The mixture was mixed with water and brine for 7 minutes, and the organic layer was dried over NazSO4, filtered, concentrated, and purified by column chromatography to give methanesulfonic acid as a white solid. ·Bromo-5-fluoro-2-((trifluoromethyl)benzyl] decyl ester (1_65 LV, 4.7 〇 111111 〇 1, yield 67.5%). 111 ^ ft (400 MHz, gas δ: 7 93 ( d, J = 6.4 Hz, i H), 7 46 (d, •/=8.8 Hz, 1 H), 5·35 (s, 2 H), 3.10 (s, 3 H). Step 4: 6-[ {[4-Bromo-5-fluoro-2-(trifluoromethyl)phenyl]methyl}(methyl decyl)amino]-5-cyclopropyl-2-(4-fluorophenyl) -N-methyl·benzofuran-3-carboxamide 154005.doc •155· 201138786 5-cyclopropyl-2-() 4-fluorophenyl)-indolyl-6-[(methylsulfonyl)amino]-1-indolopyran-3-carboxamide (1.529 g, 3.8 mmol), formazan acid [ 4-Mi-5-gas-2-(trimethyl)phenyl]anthracene (1.334 g, 3.80 mmol) and a solution of carbonic acid (0.630 g, 4.56 mmol) in DMF (6 mL) After 〇°C, the solution was maintained for 2 hours. The solution was diluted with EtOAc and water and dried over Na 2 EtOAc. Bromo-5-fluoro-2-(trifluoromethyl)phenyl]methyl}(methyl decyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-#-曱Alkyl-1-benzopyrene. Southern-3-indole amine (2.45 g, 3.73 mmol, yield 98%). NMR (400 MHz, DMSO-i/6) δ: 8.41 (d, J = 4.5 Hz, 1 H), 8.01 (d, /=6.4 Hz, 1 H), 7.97 (s, 1 H), 7.93 (dd, 7=8.8, 5.5 Hz, 2 H), 7.79 (d, /=9.6 Hz, 1 H), 7.38 (t, 7=8.9 Hz, 2 H), 6.94 (s, 1 H), 5.10-5.21 (m, 1 H), 4.93-5.04 (m, 1 H), 3.31 (s, 3 H ), 2.80 (d, J=4.5 Hz, 3 H), 2.23-2.34 (m, 1 H), 0.86-1.02 (m, 2 H), 0.64-0.74 (m, 1 H), 0.17 (d, *) 7=4.5 Hz, 1 H). Step 5: [4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino))]-1-benzofuran-6-yl}(曱Alkylsulfonyl)amino]methyl}_2_fluoro_5_(tris-methyl)phenyl]fosic acid in the atmosphere A will be 6-[{[4-bromo-5-fluoro-2-(three Fluorinyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-1phenyl)-#-methyl-i-benzoxofan- 3-decylamine (2.45 g, 3.73 mmol), 4,4,4,,4,5,5,5,5'_ octamethyl-2,2·-linked-indole, 3,2-di Boron oxyfluoride (1.893 g, 7.45 mmol), dioxane (tricyclohexylphosphine) palladium (11) (0.138 g '0.186 mmol) and acetic acid off (0.732 g, 7.45 mmol) in 1,4-dioxane (5 The solution in mL) was maintained at 80 C under stirring at 154005.doc -156 - 201138786 overnight. The solid was removed by passing through a pad of celite, and the filtrate was partitioned between water and Et.sub.sub.2. The organic layer was dried over sodium sulfate, filtered and concentrated to give a brown residue. The residue was dissolved in THF (5. (10) mL) and 3 mL of 6 M EtOAc. &lt;RTI ID=0.0&gt;&gt; Stir for 3 hours under 〇c. The solid was removed via vacuum filtration and the filtrate was extracted with EtOAc. The organic layer was concentrated and purified by reverse phase HPLC to afford [4·{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]丨_笨和furan_6_yl}(fluorenylsulfonyl)amino]methyl}-2-fluoro-5-(trifluoromethyl)phenyl]facial acid (1.1〇g, 1.76 mmol' The rate is 47.4%). NMR (400 MHz, DMSO-c/6) δ: 8.42 (d, J = 2.7 Hz, 2 H), 7.93 (br. s., 3 H), 7.82 (d, /=4.7 Hz, 1 H), 7.58 (d, /=9.4 Hz, 1 H), 7.37 (t, J=8.0 Hz, 2 H), 6.95 (br. s., 1 H), 5.17 (d, 1 H), 5.02 (d, 1 H), 3.30 (br. s., 3 H), 2.80 (d, J=2.3 Hz, 3 H), 2.31 (br. s., 1 H), 0.90 (br. s., 2 H), 0.75 (d, "7=1.2 Hz, 1 H), 0.21 (br. s·, 1 H). LC-MS (m/z, ES+) = 623 (M+H). Example 46 4-(2.(ΛΓ-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(decylaminecarbamimidyl)benzofuran-6-yl)methylsulfonamide Ethyl)_3_fluorophenyl-carboxylic acid

154005.doc •157- 201138786 Step 1: 4-Bromo-2-fluoro-1-vinyl stupid 4-bromo-2-fluoro-1-iodobenzene (25 g, 83 mmol, ALFA) under N2 atmosphere a solution of dibutyl(ethylene)tin (32 g, loo mmol) and hydrazine (triphenylphosphine) palladium (0) (4.80, 40 mmol) in DMF (1 mL) at 1 〇〇 . Heat under 48 for 48 hours. After cooling the reaction solution to room temperature, brine (丨〇〇 mL) was added, and the resulting solution was extracted with diethyl ether (3×50 mL). The combined organic layers were washed with kf (1% aqueous solution &apos; 100 mL) and brine (1 mL) and dried over anhydrous NaCI. After the solvent was removed, the crude product was purified by column chromatography (1% EtOAc) to afford 4-bromo-2-fluoro-1-vinylbenzene as colorless oil (12.9 g, 65 mmol, yield 78 °/〇). Step 2. 2-(4-Bromo-2-fluorophenyl)ethanol To 4-bromo-2-fluoro-1-vinylbenzene (1 g, 5 at room temperature under A atmosphere)

Add a solution of 9-BBN (0.5 Μ in THF < 12 mL, 6 mm 〇l) in THF (25 mL). The resulting reaction mixture was stirred overnight at room temperature. To this solution was added Na〇H (1 N aqueous solution, 25 mL) at 0 °C. After stirring at room temperature for 15 minutes, it was below 2 Torr. (3) Hydrogen peroxide (25 mL) was added and the resulting reaction mixture was stirred at room temperature for 2 hours. The separated organic layer was washed with brine (25 mL) and dried over anhydrous EtOAc. After purification, the crude product was purified by column chromatography (from 1 〇〇 % PE to PE containing 1% EA) to give 2-(4-bromo-2-fluorophenyl)ethanol as a colorless oil (527 mg ' 2.42 mmo yield 48%. LCMS (w/z, ES+) = 219 (M+H) Step 3: 4 ·Bromo-1-(2-bromoethyl)_2_fluorobenzene 2-(4 - Desert-2-fluorophenyl)ethanol (3"g, μmm〇l), NBS (3.8 g '21 mmol) and PPh3 (5.5 g '21 mmol) in DCM (100 mL) 154005.doc - 158- 201138786 The solution was stirred for 1 hour at room temperature τ. The reaction solution was concentrated under reduced pressure, and the residue was purified to purified crystals. 1 stupid (3.6 g, 129 _〇1, yield 92%). Step 4. 6-(N-(4- _3·fluorophenethyl)methylsulfonylamino)_5_cyclopropyl- 2-(4-Fluorophenylmethylbenzofuran_3_formamide, 5-cyclopropyl·2-(4-fluorophenyl)-indolemethyl_6_[(methylsulfonyl) Amino]-1-benzofuran-3-carboxamide (25 g , 6 21 mm 〇 1) ' 4 bromo_1 (2 bromine B)

a solution of 2-fluorobenzene (3.6 g '13.0 mm〇i), potassium carbonate (2 6 g, Μ mmol) and potassium iodide (1.0 g' 6.21 mmol) in DMF (50 mL) at 8 (TC) After heating for 4 hours, the reaction solution was cooled to room temperature, and diluted with ethyl acetate and water. The organic layer was evaporated. 6_(#_(4-bromo-3-fluorophenethyl)methylsulfonylamino>&gt;5_cyclopropyl_2·(4_fluorophenyl•methylbenzin. Fu 0南-3-曱Indoleamine (1.9 g, 3.1 mmol, yield 51%). LCMS (m/z, ES+)=603 (M+H) Step 5: 5-cyclopropyl-6-(N-(2-fluoro-4) -(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenethyl)methylsulfonylamino)-2-(4-fluorophenyl) -N-methyl benzofuran-3-carboxamide

5-cyclopropyl·6-(#-(2-fluoro-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)phenethyl ) fluorenylsulfonylamino)-2-(4-fluorophenyl)-fluorenyl-mercaptofuran-3-carboxamide (1.9 g, 3.1 mmol), potassium acetate (0.88 g, 9 mmol), A solution of bis(pinacolyl)diboron (1.52 g, 6.0 mmol) and PdCl2(dppf)-CH2Cl2 adduct (〇·219 g, 0.3 mmol) in 1,4-dioxane (100 mL) Degassed and refilled with nitrogen and heated overnight at 100 ° C 154005.doc -159 · 201138786. After the reaction solution was cooled to room temperature, water (100 mL) was added, and the solution was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After the solvent was removed, the residue was purified to purified crystals eluted eluted eluted eluted Mercapto-1,3,2-dioxaboron-2-yl)phenethyl)nonylsulfonylamino)_2_(4-fluorophenyl)-N-mercaptobenzofuran-3-carboxamidine Amine (l_5 g, 2.3 mmo yield 77%). LCMS (m/z, ES+) = 651 (M+H) Step 6: 4-(2-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine A) Benzyl)benzofuran-6-yl)methylsulfonylamino)ethyl)fluorophenylnonanoic acid 5-cyclopropyl-6-(iV-(2- gas-4-(4,4, 5,5-tetramethyl-1,3,2-dioxonon-2-yl)phenethyl)nonylsulfonylamino)-2-(4-fluorophenylmethylbenzofuran-3 a solution of meglumine (1.5 g, crude material, 2.3 mmol), PS-BBA (8.9 g, 23 mmol) and HCl (5 N aqueous solution, 5 mL) in THF (30 mL) The solid was removed by filtration, and the filtrate was evaporated,jjjjjjjjjjjj -fluorophenyl)-3-(methylaminoindenyl)benzofuran-6-yl)methylsulfonylamino)ethyl)-3-fluorophenyls-minic acid (745 mg ' 1.31 mmol, Yield 57%). 4 NMR (methanol-d4) δ: 7.96 (m, 2H), 7.59 (s, 1H), 7.36 (m, 6H), 4.87 (t, 2H), 3.17 (m, 8H), 2.37 (m, 1H), 1.07 (d, 2H), 0.94 (m, 1H), 0.69 (m, 1H). LCMS (w/z, ES+) = 569 (M+H). Example 47 4-(2 -(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(A Hydrazinyl)benzofuran-6-yl)methylsulfonylamino)ethyl)-3-(trifluoromethyl)phenyl decanoic acid 154005.doc •160- 201138786

Step 1: Treatment of 4-bromo-2-(trifluoromethyl)aniline (25 g, 〇.U mol ' ALFA) with 涝-J-iodine 2吖_虞虞 difference j茗 with concentrated hydrochloric acid (60 mL) The solution in H2O (25 0 mL) was cooled to 〇 °c. A solution of NaNO2 (10 g, 150 mmol) in H.sub.2 (75 mL) was added dropwise to this solution over 30 min, then the mixture was warmed to room temperature and stirred for 1 hour, then Nal was added over 40 min. After a further 16 hours at room temperature, the reaction mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with aq. Na.sub.2.sub.3.sub.3 (3 N aqueous solution, 200 mL) and water (200 mL). After the solvent was removed, the crude product was purified by column chromatography eluting with EtOAc (EtOAc) Rate 66%). Step 2: 4-bromo-2-(trifluoromethyl)-1-vinylbenzene 4-bromo-1-iodo-2-[(trifluoromethyl)benzene (25 g, 71 mmol). a solution of dibutyl(vinyl)tin (27 g, % mm〇i) and hydrazine (triphenylphosphine) palladium (0) (4.0 g '40 mmol) in DMF (100 mL) for 48 hours. . To the reaction mixture was added brine (1 〇〇 〇〇 卩, and the mixture was extracted with diethyl ether (3×5 〇 mL). The combined organic layer was treated with MKF (1% aqueous solution, i〇〇mL) and stirred for 4 hours. 1 〇〇 mL) The separated organic layer was washed and dried over anhydrous Naj.sub.4. After the solvent was removed, the residue was purified by column chromatography (solvent with petroleum) to afford 4-bromo-2· 154005 as colorless oil. .doc • 161 - 201138786 (monomethyl)-1-ethenylbenzene (10.8 g, 43 mmol, yield 61%) Step 3: 2-(4·bromo-2-(trifluoromethyl) Phenyl)ethanol Add m9BBN to a solution of 4_bromo-2-(trifluoromethyl)-]vinylbenzene (3〇, 12 mmol) in 1 mL of THF under &amp; atmosphere 5 M, 28 mL, 14 mm 〇i) 所得 The resulting reaction mixture was stirred at room temperature overnight. NaOH solution (1 N aqueous solution, 1 〇〇 mL) was added under 〇 C. After stirring for 15 minutes, hydrogen peroxide was added ( 1 〇〇 mL), and the resulting mixture was stirred at room temperature for 2 hours. The organic layer was separated, washed with brine (1 mL) and dried over anhydrous NazSO4. The residue was purified by EtOAc (EtOAc) elute elute LCMS 〇/z, ES+) = 269 (M+H). Step 4: 4-Bromo-1-(2-bromoethyl)-2-(trifluoromethyl)benzene 2-(4-bromo-2-(trifluoromethyl)phenyl)ethanol (113 g, A solution of 42 mm 〇 1), NBS (1.12 g, 6.3 mmol) and PPh3 (1.65 g, 6.3 mmol) in DCM (100 mL) was stirred at room temperature for one hour. The solution was concentrated under reduced pressure and purified to purified crystals crystals crystals crystals g, 3.8 mmol, yield 89%). Step 5: 6-(N-(4-Bromo-3-(trifluoromethyl)phenethyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-N -methylbenzofuran-3-carboxamide 5·cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino] -1- Benzofuran-3-indoleamine (0.5 g, 1.2 mmol), 4-bromo-1-(2-bromoethyl)-2-(dimethylmethyl)benzene (1.24 g, 3.8 mmol), potassium carbonate (496 mg, 154005.doc •162·201138786 3.6 mmol) and a solution of potassium iodide (199 mg, 1.2 mmol) in DMF (15 mL) was heated at 80 ° C for 4 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated and dried over anhydrous Na2SO. After removal of the solvent, the crude material was purified eluting eluting elut elut elut eluting -5-cyclopropyl-2-(4-fluorophenyl)_N-methylbenzofuran_3-carbamamine (5 19 mg, yield of 66.96 mm, yield 66%). LCMS (m/z, ES+) = 653 (M+H) Step 6: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-2-(trifluoromethyl)phenethyl)methyl candidylamino)benzophenone 3-Benzylamine 6-(N-(4-bromo-3-(trifluoromethyl)phenethyl)indolylsulfonylamino)-5-cyclopropyl-2-(4-fluorobenzene Base)·ν_methylbenzofuran-3-indoleamine (519 mg, 0.8 mmol), acetic acid unloading (235 mg, 2.4 mmol), double (fractional) base (406 mg, 1.6 mmol) And a solution of PdCl 2 (dppf)-CH 2 Cl 2 adduct (58 mg, 0.08 mmol) in 1,4-dioxane (50 mL) was degassed and refilled with nitrogen three times, then at 1 ° C, Heat overnight under a nitrogen atmosphere "cool the solution to room temperature. Water (1 mL) was added and the mixture was extracted with EtOAc (3x 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration and concentrating under reduced pressure <RTI ID=0.0></RTI> to <RTI ID=0.0> N-(4-(4,4,5,5-tetradecyl-1,3,2-oxo-p-but-2-yl)-2-(trimethyl)phenethyl)methylindole Amino)benzoquino-3-indeneamine (444 mg, 0.63 mmol, yield 81%). LCMS {m/z, ES+) = 701 (M+H) Step 7: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylamine A)醯154005.doc •163- 201138786 】) stupid. 矢 ··6-yl) methyl aryl amino) hexyl (trimethyl) benzyl 5-cyclopropyl-2-(4-fluorobenzene -N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-2. (trifluoro Benzyl)phenethyl)methylsulfonylamino)benzoquinone-3-carboxamide (444 mg 'crude material' 0.63 mmol), HC1 (5 N aqueous solution, 5 mL) and PS-BBA (2.4 g, 6.3 mmol) EtOAc (3 mL EtOAc)EtOAc. 4·(2-(Ν-(5-cyclopropyl-2-(4-phenylphenyl)(methylamine-Acetyl)) and 1Ή-6-yl)indolylylamino)ethyl) Methyl) phenyl acid (245 mg, 0.39 mmol, yield 63%). H NMR (methanol 4) δ: 7.97 (m, 4H), 7.71 (s, 1H), 7.47 (m, 4H), 4.02 (t5 2j^\ - Λ n/t , 317 (m, 8H), 2· 37 (m, 1H), 1.06 (d, 2H), 0.94 (m, 1H)} 〇• ) (m, 1H). LCMS (m/z, ES+) = 619 (M+H). Example 48 {4-[({5·cyclopropyl'(4-like phenyl)-3-[(methylamino))]·1_benzofuran_6 rhyme)methyl]·2 Fluorophenyl}noic acid

154005.doc -164- 201138786 Step 1. 6-Amino-5- lysyl-2-(4-phenyl)-1-benzoa-am- _3-carboxylic acid ethyl acetonate with decyl alcohol (20 (5 mL) Treatment of ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-i-benzofuran-3-carboxylate (23.5 g, 63.6 mmol) and Pd/C (8.3 g, 28·48 mmol) in THF (35 mL). The resulting mixture was stirred at room temperature under a h2 atmosphere (about 50 psi) for 60 hours. The resulting residue was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) 4-Fluorophenyl)_1_ benzofuran-3-carboxylic acid B g (13.1 g' 38.6 mmol, yield 60.7%). 4 NMR (400 MHz, gas simulation, δ: 7.98-8.06 (m, 2 H), 7.72 (s, 1 Η), 7.15 (t, /=8.7 Hz, 2 Η), 6.83 (s5 1 Η), 4.40 (q, y=7.2 Hz, 2 H), 4.28 (br. s., 2 H), 1.72-1.83 (m, 1 H), 1.43 (t, «7=7.1 Hz, 3 H), 0.94-1.03 (m, 2 H), 0.65-0.73 (m, 2 H). Step 2: 6-{[(4-bromo-3-fluorophenyl)f-yl]amino}_5_cyclopropyl_2_(4_ Fluorophenyl)-1-benzopyran-3-carboxylic acid ethyl acetate to give 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzopyrene. South_3_carboxylic acid A solution of ethyl ester (13 g, 38.3 mmol), 4-bromo-3-fluorobenzaldehyde (7.78 g, 38.3 mmol) in ethanol (1 mL) was refluxed for 2 hrs. Dissolved in THF (1 mL). The solution was treated with acetic acid (1316 mL, 230 mmol) and then portionwise with sodium borohydride (4 35 g, 115 mmol). After addition, the solution was stirred at room temperature 2 The mixture was filtered and concentrated to give [('bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)- Ethyl benzofuran_3•carboxylate (19.4 g, 36.9 mmol, yield 96%). NMR (400 MHz, 154005.doc - 165- 201138786 Chloroform-c〇δ: 7·99 (dd,*/=8.7, 5.6 Hz, 2 H), 7.76 (s,1 H), 7.52 (t, 7=7.6 Hz, 1 H), 7.05- 7.21 (m, 4 H), 6.54 (s, 1 H), 5.06 (br. s., 1 H), 4.47 (s, 2 H), 4.40 (q, y=7.2 Hz, 2 H), 1.70- 1-81 (m, 1 H), 1.43 (t, 7=7.1 Hz, 3 H), 0.97-1.06 2 H), 0.65-0.75 (m, 2 H). Step 3: 6-{[(4·漠 fluorophenyl)indolyl]amino}·5 cyclopropyl carbyl)-1 - benzoin-3 -carboxylic acid to 6-{[(4-bromo-3-fluorophenyl)fluorenyl Aminobutyr 5_cyclopropyl·2_(4•fluorophenyl) small benzofuran_3·ethyl decanoate (1) 65 g, 2213 _〇ι) in THF (40 mL) and methanol (1 mL) A solution of 8 〇m]L 2 M NaOH was added to the solution (the mixture was heated to 5 (rc overnight) at 155 mmo, followed by heating to 80 C for 5 hours. Most of the solvent was removed under reduced pressure and the residue was acidified with &lt The solid was collected by filtration and washed with water to give 6-{[(4-bromo-3-trifluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl) as a yellow solid. _丨_benzofuran-3-carboxylic acid (11 g, 22.07 mmo yield: 1%). NMR (400 MHz, DMSO-^6) δ: 7.98 (dd, 7 = 8.8, 5.7 Hz, 2 H), 7.64 (t, ^=7.7 Hz, 1 H), 7.51 (s, 1 H), 7.38 ( Dd, J=10.0, 1.6 Hz, 1 H), 7.28 (t, 2 H), 7.21 (dd, J=8.2, 1.6 Hz, 1 H), 6.51 (s, 1 H), 6.32 (t, J= 6.3 Hz, 1 H), 4.49 (d, J=5.9 Hz, 2 H), 1.70-1.88 (m, 1 H), 0.96-1.06 (m, 2 H), 0.50-0.60 (m, 2 H) 〇 Step 4: 6-{[(4-Mo-3-phenylphenyl)methyl]aminopyridylcyclopropyl-2-(4-carbyl)-N-mercapto-1-benzox . South-3-cartoamine to 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(heart fluorobenzene I54005.doc -166- 201138786 DIPEA (7.69 mL, 44.1 mmol) and HATU (10.07 g, 26.5 mmol) were added sequentially to a suspension of 1-benzopyrano-3-indoleic acid (11 g, 22.07 mmol) in DMF (15 mL). ). After the addition, the yellow solid precipitated immediately. After 10 minutes, 22 mL of methylamine (1.371 g, 44, 1 mmol) in 2 M THF was then taken and stirred for 30 minutes. The mixture was passed through and the solid was washed with water to give 6-{[(4-bromo-3-fluorophenyl)methyl]amino}}-5-cyclopropyl-2-(4-fluoro) as a white solid. Stupid)-iV-methyl-1-benzofuran_3_formamide (7.2 g '14.08 mmol' yield 63.8%). 1H NMR (400 MHz, DMSO-d6) δ: 8.28 (d, /=4.5 Hz, 1 Η), 7.82 (dd, 7=8.7, 5.6 Hz, 2 H), 7.64 (t, J=7.B Hz, 1 H), 7.37 (d, J=9.8 Hz, 1 H), 7.27 (t, J=8.9 Hz, 2 H), 7.20 (d, /=8.0 Hz, 1 H), 7.14 (s, 1 H) , 6.51 (s, 1 H), 6.33 (t, 7=6.1 Hz, 1 H), 4.51 (d, 7=6.0 Hz, 2 H), 2.80 (d, /=4.5 Hz, 3 H), 1.71- 1.86 (m, 1 H), 0.95-1.04 (m, 2 H ), 0.55-0.62 (m, 2 H) = Step 5: {4-[({5-cyclopropyl-2-(4-fluorobenzene) Base)-3-[(methylamino)benzyl]-1-benzofuran-6-yl}amino)methyl]_2_fluorophenyl}-acid under N2 '6-{[( 4-bromo-3-fluorophenyl)indolyl]aminodibu 5_cyclopropyl-2-(4-fluorophenyl)-#_methyl-benzofuran-3-indoleamine (〇5 Trail, 0.978 mmol), 4,4,4',4',5,5,5',5'-octadecyl-2,2,-linked _1,3,2-diox shed (0_497 g , 1.956 mmol), dioxane (tricyclohexylphosphine) palladium (11) (0.036 g, 0.049 mmol) and potassium acetate (0.288 g, 2.93 mmol) in Μ-dioxane (5 mL) 〇t: After 4 hours. The solution was filtered through a pad of EtOAc, partitioned between EtOAc and EtOAc. The resulting residue (5.00 mL) was dissolved and treated with &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& The solid was removed via filtration and washed with ethyl acetate. The filtrate was concentrated and purified by reverse phase EtOAc (EtOAc:EtOAc: Ϊ́_笨和furan_6基}amino)indolyl]-2-fluorophenyl}-acid (80 mg, 〇.168 mm〇1, yield

17.18%). NMR (400 MHz, DMSO-c/6) δ: 8.29 (br s 1 Η), 7.83 (br. s·, 2 Η), 7·50 (br. s., 1 Η), 6.91.7.40 (m ,6 Η), 6.50 (br. s·, 1 H), 4.53 (br. s·, 2 H), 2.81 (br. s·, 3 Η) 1 80 (br· s·, 1 H), 1.01 (br. s., 2 H), 0.60 (br. s., 2 H). LC-MS « ES+) = 477 (M+H). 'Example 49 {4_{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl)]benzofuran-6-yl} (methyl styrene) Amino]methyl}-2-[(methoxy)methyl]phenyl hydrazine

{4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonylbenzobenzo--6-yl}(methyl-decyl)amine 2-methyl}-2-[(methoxy)-yl]phenyl}-tanoic acid 2-n- 5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(decylamino) benzyl]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino] decyl} decyl benzoate (486 mg, 0.77 mmol), acetic acid _ (152 Mg, 1.54 mmol), double 154005.doc • 168 - 201138786 (pinacol root) diboron (25 5 mg, 1.00 mmol), sodium bromide (79 mg, 0.77 mmol) and bis(tricyclohexylphosphine) A mixture of vaporized palladium (II) (57 mg, 〇〇77 mmol) in 1,4-dioxane (1 mL) was degassed in a thick-walled glass pressure vessel' followed by stirring at 95. (: heating under 19 hours. Cooling the reaction mixture to room temperature). Filtered through a pad of diatomaceous earth and concentrated, and purified by gelatin chromatography (containing 0 to 100% of ethyl acetate) to give a colorless semi-solid. 5-{[{5-cyclopropyl-2-(4-fluorophenyl)_3-[(decylamino)carbonyl]_丨_benzofuran-6-yl}(fluorenylsulfonyl)amine Methyl hydrazide}_2_(4 4 5 5•tetradecyl _13 2 dioxoindol-2-yl)methyl benzoate (0.48 g, purity 80% by LC/MS). A portion (〇·24 g) was dissolved in thf (6 mL) and treated with 0.1 N ammonium acetate (4 mL) and sodium periodate (〇·38 g, ι·77 mmol) The mixture was poured for 2 days. The reaction mixture was poured with EtOAc (EtOAc) (EtOAc)EtOAc. Purification of 1 〇〇% ethyl acetate in dioxane methane and dichloromethane containing 0 to 3.50 / decyl alcohol, followed by lyophilization to give {4-{[{5·cyclopropyl-2) as a white solid -(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amine ]]][[(methoxy)carbonyl]]]}] (1 〇 7 mg, 47% in 2 steps) NMR (sterol-d4) δ: 7.84-7.93 (m, 3H), 7.60 (s, 1H), 7.47 (dd, J=7.5, 1.2 Hz, 1H), 7.18-7.31 (m, 3H), 6.99 (s, 1H), 4.81-5.07 (m, 2H), 3.86 (s, 3H), 3.17 (s, 3H), 2.90 (s, 3H), 2.18-2.28 (m, 1H), 0.90-1.01 (m, 1H), 0.65-0.83 (m, 2H), 0.18-0.30 (m, 1H). LCMS 〇 /z, ES+) = 595 (M+H). 154005.doc •169- 201138786 Example 50 {4-{[{5·Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]benzofuran-6-yl} (methylsulfonyl)amino]methyl b 2_[(trifluoromethyl)oxy]phenyl}decanoic acid

Step 1: 4-Bromo-3-[(trifluoromethyl)oxy]benzoic acid 4-amino-3-[(trifluoromethyl)oxy]benzoic acid (5 g, 22 61 mm 〇 1) The solution in acetonitrile (30 mL) was cooled to <RTI ID=0.0># </RTI> <RTI ID=0.0> A solution of sodium nitrite (1.716 g, 24.87 mmol) in 6 mL of water was then added dropwise while maintaining the internal temperature below 5 °C. After the addition, the solution was stirred for an additional 1 minute, followed by the addition of copper bromide (3.73 g '26.0 mmol), and the mixture was heated to 70 C for 30 minutes. The solution was diluted with water until the solution turned green, then extracted with EtOAc. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 4〇〇MHz, dms〇_ de) δ: 13.62 (br. s., 1 H), 7.98 (d5 J=8.0 Hz, 1 H), 7.81-7.92 (m, 2 H). Step 2: 4- Methyl bromo-3-[(trifluoromethyl)oxy]benzoate 154005.doc • 170· 201138786 4-Bromo-3-[(trifluoromethyl)oxy]benzoic acid (6 g, 27 "Claw melon 1) and 1 drop of concentrated sulfuric acid in 20 mL of decyl alcohol were heated to reflux for 3 hours. The solution was filtered through celite and the filtrate was concentrated and purified by flash column chromatography. 4-Bromo-3_[(trifluoromethyl)oxy]benzoic acid vinegar (5 g ' 16.72 mmol ' yield 61.6%) in light yellow oil. nmM4 〇〇 MHz, chloroform δ: 7.96 (s, 1 H), 7.85 (dd, "7=8.3, 1.7 Hz, 1 Η) 7 74 (d, 7= 8.4 Hz, 1 H), 3.95 (s, 3 H) Step 3: {4-Bromo-3-[(trifluorofyl)oxy]phenyl)ol was stirred at room temperature for 4-bromo- 3-[(Trifluoromethyl)oxy]benzoic acid methyl ester (4.60 g, 15.38 mm 〇l), sodium borohydride (1.746 g, 461 匪〇1) in methanol (5 mL) and THF (10 mL) Solution in the middle. The solution was quenched with water and extracted with EtOAc. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; %). 4 NMR (400 MHz, gas δ: 7.62 (d, 7 = 8.2 Hz, 1 H), 7.35 (s, 1 H), 7.18 (dd, J = 8.2, 1.8 Hz, 1 H), 4.71 (s, 2 H). Step 4 · 1-Bromo-4-(aeromethyl)-2-[(trifluoromethyl)oxy]benzene to {4-bromo-3-[(trifluoromethyl)oxy Methylsulfonium (2.082 mL, 26.9 mmol) was added to a solution of phenyl} decyl alcohol (4 〇 5 g, 1494 mmol) and TEA (3.74 mL, 26.9 mmol) in DCM (1 mL). The resulting solution was stirred at room temperature for 4 hours, then washed with water. The mixture was extracted with DCM, and the combined organic layer was dried over NaCI 4 and filtered and concentrated and purified by column chromatography to give a colorless oil. Bromo_4_(gastrienyl)_2_[(trifluoromethyl)oxy]benzene (2.488 g, 8.59 mmol, yield 57.5%). 154005.doc -171 - 201138786 D (400 MHz, gas-like Α δ : 7·64 (d, J=8 edge, i H), 7 35 (s, 1 H), 7.22 (dd, J=8, 1.8 Hz, 1 H), 4·55 (s, 2 h). Step 5: 6-[({4-Bromo-3-[(trifluoromethyl)oxy]phenyl}decyl)(methyl-decyl)amino]-5-cyclopropyl-2-( 4-fluorophenyl)_N_methyl-indole benzofuran-3- ψmm 1-bromo-4-(gas 曱-2-[(Trifluoromethyl)oxy]benzene (2 48 g, 8 57 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-fluorenylmethyl-6-[(methyl Sulfhydryl)amino]-1-benzol-fol-3-cartoamine (2.415 g, 6 mmol), Nal (0.045 g' 0.300 mmol) and K2C03 (1.159 g, 8.40 mmol) in ι,4 - 2. Mixture of oxane (20 mL) and EtOAc (5 mL) EtOAc (EtOAc)EtOAc. Purification by flash column chromatography gave 6-[({4-bromo-3-[(trifluoromethyl)oxy]phenyl}methyl)methylsulfonylamino) as a yellow solid. ]-5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran_3_decylamine (3.35 g ' 5.11 mmol, yield 85%). NMR (400 MHz, chloroform d) δ: 7.85 (dd, J=8.9, 5·4 Hz, 2 H), 7.56 (d, ^=8.2 Hz, 1 H), 7.28 (s, 1 H), 7.24 (s, 1 H), 7.19 (t, 3 H), 7.09 (dd5 /=8.2, 2.0 Hz, 1 H), 5.76 (br. s., 1 H), 4.97 (d, /=14.7 Hz, 1 H), 4.72 (d, J=14.5 Hz, 1 H), 3.03 (s, 3 H), 2.99 (d, 7=5.1 Hz, 3 H), 2.08-2.18 (m, 1 H), 0.99-1.11 (m, 1 H), 0.86-0 .97 (m, 2 H), 0.57 (d, *7 = 5.3 Hz, 1 H). Step 6: {4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino))]-1-benzofuran-6-yl} (A Alkylsulfonyl)amino]methyl}_2·[(trifluoromethyl)oxy]phenyl}-acid 154005.doc -172· 201138786 In the atmosphere of A, 6-[({4-bromo- 3·[(Trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-indenyl- 1-benzofuran-3-carboxamide (1.5 g, 2.288 mmol), 4,4,4',4,5,5,5,5,-octadecyl-2,2'-linked- 1,3,2-dioxaboron p East (1.162 g, 4.58 mmol), KOAc (0.674 g, 6.87 mmol) and dioxobis(tricyclohexylphosphine) sharp (11) (0.084 g, 0.114 mmol) in 1 The solution in 4-dioxane (10 mL) was heated to 80 ° C overnight. The solution was filtered through celite and the solid was washed with EtOAc. The filtrate was concentrated to give a residue which was dissolved in THF (15.00 <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Maintain overnight at °C. The solid was removed via filtration and the filtrate was concentrated and purified by reverse phase HPLC to afford of <4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(A) Amino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl-2-((trifluoromethyl)oxy]phenyl}carboxylic acid (72 mg , 0.116 mmol, yield 5.07%). 4 NMR (400 MHz, gas δ: 7.80-7.88 (m, 3 Η), 7.29 (s, 1 Η), 7.20-7.25 (m, 2 Η), 7.15-7.20 (m, 2 Η), 5.75 ( Br. s., 1 H), 5.05 (d, ./=14.6 Hz, 2 H), 4.76 (d, /=14.4 Hz, 1 H)s 3.03 (s, 3 H), 2.99 (d, /= 4.9 Hz, 3 H), 2.10-2.22 (m, 1 H), 1.00-1.13 (m, 1 H), 0.86-0.99 (m, 2 H), 0.53-0.63 (m, 1 H). LC-MS (w/z, ES+) = 621 (M+H). Example 51 {4-{[{S-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl) l·benzofuran-6-yl}(methylsulfonyl)amino]methyl b 2-[(methoxy)methyl]phenyl}folic acid 154005.doc •173- 201138786

Step 1: 6-[({4-Bromo-3-[(methoxy)methyl]phenyl}methyl)(fluorenylsulfonic acid)amino]-5-cyclopropyl-2-(4 -Fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide was treated with sodium decyl methoxide in methanol (2. HI mL, 9.42 mmol) in two portions. -5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino) benzyl]-1-benzofuran-6-yl}(methylsulfonate) A solution of the amino]methyl}phenyl)methyl ester (320 mg, 〇471 mmol) in methanol (4 mL). The mixture was maintained at ambient temperature for 5 hours with stirring. A thick white sap was formed. The solution was poured into water and diluted with ethyl acetate. The organic layer was separated, dried <RTI ID=0.0></RTI> <RTI ID=0.0> (methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-mercapto-1-benzofuran_3·carbenamide (276 mg ' 0.426 mmol ' Yield 90%). LCMS (/z, ES+) = 616 (M+H) Step 2: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino) M ]]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}_2_[(methoxy)methyl]pyridyl phthalic acid 6-[({4-bromo) -3-[(decyloxy)methyl]phenyl)methylmethylsulfonyl)amine 154005.doc -174- 201138786 base]-5-cyclopropyl-2-(4-fluorophenyl)- N-Mercapto-1-benzofuran_3·decylamine (276 mg, 0.448 mmol), potassium acetate (176 mg, 1.794 mmol), bis(pinacol), 228 mg, 0.897 mmol A solution of dioxobis(tricyclohexylphosphine) (11) (33.1 mg, 0.045 mmol) in 1,4-dioxin (12 mL) was maintained in a sealed pressure tube at 9 (rc) for 16 hours. The mixture was cooled and filtered through a glass filter paper. The filtrate was concentrated and dissolved in tetrahydrofuran (5 〇 5 mL) and polymer-supported benzoic acid (863, 2 and 6.0 N HCl (aq) (0.374 mL, 2 242 mm) 〇1) Treatment. The mixture was maintained at room temperature for 3 hours with stirring, and filtered over celite. The filtrate was diluted with ethyl acetate, and the organic layer was separated, concentrated, and dissolved in tetrahydrofuran 150 mL) and treated with polymer-supported benzoic acid (863, 2.242 mm〇1) and 6.〇N HC1 (aqueous solution) (〇374, 2 242 匪〇ι). The mixture was maintained under stirring. After the next 2 hours, it was filtered over EtOAc (EtOAc)EtOAc.EtOAc. {4-{[{5-cyclopropyl_2_(4-fluorophenyl)_3_[(decylamino) Ikyl]_1-benzofuran-6-ylindole (mercaptosulfonyl) Amino] hydrazino 2_[(methoxy)methyl]benyl} decanoic acid (58 nig ' 〇·1〇〇mm〇i, yield 22.28%) H NMR (f S|-d4) δ: 7.87 (dd, J=8.8, 5.3 Hz, 2H), 7.53 (s, 1H), 7.06-7.27 (m, 5H), 7.01 (s, iH), 4.91 (d, J=14.0 Hz, 1H) , 4.81 (d, J=13.9 Hz, 1H), 4.39 (s, 2H), 3.32 (s, 3H), 3.14 (s, 3H), 2.91 (s, 3H), 2.16-2.27 (m5 1H), 0.89 -1.01 (m, 1H), 0.77 (t, J = 6.0 Hz, 2H), 0.23-0.37 (m, 1H) 〇LCMS (m/z, ES+) = 581 (M+H). 154005.doc •175· 201138786 Example 52 {4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6 -yl}(methylsulfonyl)amino]methyl}-2-[(dimethylamino)methyl]phenyl}-acid

Step 1: 6-[({4-Bromo-3-[(dimethylamino)methyl]phenyl)methyl)(methylsulfonyl)aminocyclopropyl-2-(4-fluoro Phenylmethyl-1-benzophenone °-N--3-carbamamine treatment of 6-[{[4-bromo-3-(methyl)phenyl]methyl) with MsCl (0.083 mL, 1.067 mmol) (methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-mercapto-1-benzofuran·3-formamide (321 mg, 〇534^ ^❶^ and DIPEA (0.373 mL, 2.135 mmol) in di-methane (15 mL) and maintained at room temperature for 1 hour with stirring. The mixture was poured into saturated Ssc hydride and separated The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydro M (1G mL), and was taken with 2. The mixture was kept under 3 hours. The mixture was poured into saturated sodium bicarbonate, diluted with ethyl acetate, and the organic layer was separated, dried over sodium sulfate, filtered, and the residue was obtained under reduced pressure. Purification by chromatography to give 6-[({4-bromo-3-[(dimethylamino)methyl]phenyl) as a white 154005.doc 176·201138786 solid. (methanesulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-decylamine (110 mg ' 0.175 mmol , yield 32.8%). LCMS (m/z, ES+) = 629 (M+H) Step 2: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[ (Methylamino) benzyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-[(dimethylamino)methyl]phenyl} Capric acid 6-[({4-bromo-3-[(didecylamino)methyl]phenyl}indolyl)(fluorenylsulfonyl)amino]-5-cyclopropyl-2- (4-phenylphenyl)-N-mercapto-1-benzopyrene η-N--3-carbamamine (90 mg '0.143 mmol), potassium acetate (56.2 mg, 0.573 mmol), di- gas double (tricyclic) a solution of hexylphosphine)palladium (π) (ι 0.5 7 mg, 0.014 mmol) and acetic acid clock (56.2 mg '0.573 mmol) in 1,4-dialdehyde (12 mL) in a sealed pressure tube maintained under stirring For the next 24 hours. Add 卩 (1 (1:12 (4卩卩〇-€!112€:12 adduct (11.69 111§, 0.014 111111〇1) and additional bis (pinacol) diboron ( 72.7 mg, 0.286 mmol) and an acetic acid clock (56_2 mg, 0.573 mmol) with stirring at 8 Torr. (The mixture was further maintained for 24 hours. The mixture was filtered through celite, concentrated, and purified by reverse phase hplc (MeCN: H20 0.1% FA). Subsequent purification of the fractions containing the desired product was obtained {4-{ [{5-cyclopropyl-2-(4-fluorophenyl)·3·[(fluorenylamino)-yl]-1-benzo-b--6-yl}(fluorenyl)曱 曱 } } 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6 (5.6 mg, 9.44 μιηοΐ, yield 6.590 / 〇). 4 NMR (sterol-d4) δ: 8.26 (br· s.,1Η), 7.87 (dd J=8.8, 5.3 Hz, 2H), 7.46 (s, 1H), 7.38 (d, J=7.4 Hz, 1H)S 7.23 (t, J=8.7 Hz, 2H), 7.09 (d, J=7.4 Hz, 1H), 7.00 (s, 1H), 154005.doc -177- 201138786 6.96 (s, 1H), 4.76-4.86 (m, 2H), 3.87 (s, 2H), 3.14 (s, 3H), 2.91 (s, 3H), 2.49 (s, 6H), 2.12-2.26 (m, 1H), 0.88-1.02 (m, 1H), 0.68-0.85 (m, 2H), 0.25-0.41 (m, 1H). LCMS (w/z, ES+) = 594 (M+H). Example 53 {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[( F-aminoamino)carbonyl]-l-benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-[(methylamino)methyl]phenyl}-acid

Step 1: 2-Bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)methyl]-benzofuran-6-yl} (Methyl fluorenyl)amino]methyl benzoic acid methyl acetonate 5-cyclopropyl-2-(4-phenylene)-N-methyl-6-[(methyl aryl) amine ]]-1-Benzyl ° ° South-3 - methotrexate (2·75 g, 6.83 mmol), 2-bromo-5-(bromomethyl)benzoate decyl ester (:/2 means/5吟

Letters, 2009, 19(15), pp. 4416-4420) (4.73 g, 15.37 mmol) and a suspension of potassium carbonate (3.78 g, 27_3 mm〇i) in NN dimethylformamide (30 mL) Maintain 丨 hours at 80t. The mixture was cooled, poured into ethyl acetate, and dried over sodium sulfate and washed three times with 5% LiCI (aq). Isolation was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI></RTI> <RTIgt; 2-(4-fluorophenyl)-3-[(fluorenylamino)carbonyl]-indole-benzofuran-6-yl}(fluorenylsulfonyl)amino]indenyl}benzoic acid Oxime ester (3 42 g, 543 mmo yield 8 〇〇 / 0). LCMS (m/z, ES+) = 630 (M+H) Step 2: 6-[{[4-bromo-3-(hydroxymethyl)phenyl]methyl}(decylsulfonyl)amino] 5-5-cyclopropyl-2·(4-fluorophenyl)-N-methyl-1-benzofuran·$_carbamidine 2-bromo-5-{[{5-cyclopropyl-2 -(4-fluorophenyl)-3.[(decylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]indolyl} methyl benzoate (1.28 A solution of <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The mixture was stirred for additional 3 hours, diluted with 1.0 N NaOH (aq., 30 mL) and stirred for 3 min. The mixture was poured into ethyl acetate and washed three times with brine. The organic layer was separated, dried over sodium sulphate, filtered, and evaporated tolulululululululululululu Phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-mercapto-1-benzofuran-3-indole Amine (1.18 g, 1.962 mmo yield 96%) 〇LCMS (m/z, ES+)=602 (M+H) Step 3: Methyl benzoate (2-bromo-5-{[{5-cyclopropyl) 2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl) Methyl ester treated with MsCl (0.143 mL, 1.829 mmol) 6-[{[4-bromo-3-(methyl)phenyl]indolyl}(methylsulfonyl)amino]-5-cyclopropyl -2-(4-Fluorophenyl)-N-mercapto-1-benzoindole -3- 曱 胺 (880 mg, 1.463 mmol) and 154005.doc -179- 201138786 DIPEA (1.022 mL, 5.85 Ment) a solution of methylene chloride (15 ml) and maintained at room temperature for 45 minutes with stirring. The solution was poured into saturated sodium bicarbonate and the organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was obtained and purified by column chromatography. To a yellow foamy decanesulfonic acid (2_bromo-5_{[{5_cyclopropyl_2_(4-fluorophenyl)3_[(decylamino)carbonyl]-1-benzofuran_ 6-yl)(methylsulfonyl)amino]methyl}phenyl) anthracene (682 mg, 1.004 mmol, yield 68.6%). LCMS (m/z, ES+) = 680 (M+H) Step 4: 6-[({4-bromo-3-[(methylamino)methyl]phenyl)indolyl) Amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3- ψmm methanesulfonic acid (2-bromo-5-{[{5 -cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)methyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl A solution of the phenyl)methyl ester (250 mg '0.3 68 mmol) and 2.0 dimethylamine in THF (4_60 mL, 9.20 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 1 hour. The mixture was poured into saturated sodium bicarbonate (aq) and diluted with ethyl acetate. The organic layer was separated, dried <RTI ID=0.0> Methyl)(fluorenylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzo-1 1»South-3-cartoamine ( 224 mg '0.365 mmol, yield 99%). LCMS (m/z, ES+) = 615 (M+H) Step 5: [(2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[( Amino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl) 154005.doc -180 - 201138786 methyl]methylamino acid ι, 1 -[({4-bromo-3-[(methylamino)indolyl]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropane Benzyl-2-(4-fluorophenyl)-1\1-methyl-1-benzopyrene _3_carboxamide (223 mg, 0.363 mmol) and Boc2O (0.084 mL, 0.363 mmol) in dichloro The solution in decane (5 mL) was maintained at room temperature for 45 minutes with stirring. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography to afford [2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl) -3-[(Methylamino)-yl]-1-benzo-Bist 6-yl}(indenyl)amino]methyl}phenyl)methyl]methylamino hydrazine 1,1-dimethylethyl acid (218 mg, 0.305 mmo yield 84%). LCMS (m/z, ES + ) = 715 (M+H) Step 6 ··············· Alkyl]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino]methyl}_2-[(methylamino)methyl]phenyl}folic acid [[2- Bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonate) Amino]mercapto}phenyl)indolyl] 1,1-dimethylethyl methylamino decanoate (2 18 mg, 0.305 mmol), potassium acetate (120 mg, 1.220 mmol), bis ( Pinacol) diboron (155 mg '0.610 mmol) and dioxobis(tricyclohexylphosphine)palladium (π) (22.51 mg, 0.031 mmol) in 1,4-dioxane (12 mL) The suspension was maintained at 90 ° C for 16 hours in a sealed pressure tube. The solution was cooled, filtered through a glass filter and concentrated to give a crude residue. The residue was maintained at 60 ° C for 3 hours in tetrahydrofuran (20 mL) / 5.0 N HCl (aq) (5 mL, 0.394 mmol). The mixture was cooled to room temperature, neutralized by addition of sodium hydroxide, and the aqueous layer was washed three times with ethyl acetate. The organic layer 154005.doc -181 - 201138786 was dried over sodium sulfate, filtered, and the residue was obtained under reduced pressure and purified by reverse phase hplC, lyophilized to give a white solid. -cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino] fluorenyl} -2-[(decylamino)methyl]phenyl acid (15 mg, 0.026 mmo yield 6.57%). 4 NMR (methanol-d4) δ: 7.87 (dd, J=8.6, 5.3 Hz, 2H), 7.48 (s, 1H), 7.16-7.35 (m, 3H), 6.95-7.10 (m, 3H), 3.89 ( s, 2H), 3.13 (s, 3H), 2.91 (s, 3H), 2.44 (s, 3H), 2.14-2.30 (m, 1H), 0.89-1.00 (m, iH), 0.72.0.86 (m, 2H), 0.27-0.42 (m, 1 Η) β LCMS (m/z, ES+) = 580 (M+H). The two benzoquinone protons were masked by the methanol peak and had no obvious exchangeable protons. Example 54 [4-{丨{5-Cyclopropyl-2-(4-fluorophenyl)_3_[(methylamino)carbonyl] "·benzofuran-6-yl} (methyl fluorenyl) Amino]methyl}_2fluoro_6_(([(methoxy)methyl)oxy}methyl)phenyl]-acid

Step 1 · 6-[{[4_Bromoxyfluoromethylmethyl)phenylindole (Yinylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)_N_f Benzofuran_3_formamide was cooled in an ice bath 2H5·{[(5-cyclopropyl_2_(4·milylphenyl)-3·[(methyl 154005.doc •182- 201138786 amine Carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methylindole-3-fluorobenzoic acid methyl vinegar (11.18 g, 17.3 mmol) in tetrahydrofurfuran (200 mL) and a solution of decyl alcohol (20 mL) were added dropwise with lithium borohydride (22 mL, 44 mmol, 2.0 EtOAc in THF) over 20 min. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. 6-[{[4-bromo-3-fluoro-5-(hydroxymethyl)phenyl]indolyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(p) 4-fluorophenyl)-#-methyl-1-benzofuran-3-indoleamine (10.83 g, quantitative). 4 NMR (DMSO-d6) δ: 8.41 (m, 1H), 7.93 (dds J =8.6, 5.5 Hz, 2H), 7.88 (s, 1H), 7.28-7.44 (m, 3H), 7.13 (d, J=9.2 Hz, 1H), 6.92 (s, 1H), 5.54 (t, J=5.5 Hz, 1H), 4.92-5.03 (m, 1H), 4.80 (d, J=14.6 Hz, 1H), 4.46 (d, J=5.4 Hz, 2H), 3.18-3.28 (m, 3H), 2.80 (d, J=4.6 Hz, 3H), 2.22-2.37 (m, 1H), 0.61-1.02 (m, 3H), 0.12-0.26 (m, 1H). LCMS 〇/z, ES+) = 619 (M+H). Step 2: 6-[{[4-Bromo-3-fluoro-5-({[(methoxy)methyl)oxy)methyl)phenyl]methyl}(methylsulfonyl)amino) ]-5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide was cooled in an ice bath 6-[{[4-bromo-3- Fluoro-5-(hydroxymethyl)phenyl]fluorenyl}(fluorenylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-#-mercapto-1-benzene A solution of furan-3-indolamine (5.94 g, 9.59 mmol) in EtOAc (EtOAc) (EtOAc) The reaction was allowed to warm to room temperature overnight. The reaction mixture was treated with DMF (10 154 005. doc - 183 - 2011 38786 mL), and stirring was continued at room temperature for 1 hour, followed by heating to 60 ° C for 5 hours, followed by cooling to room temperature. A further portion of DIEA (2.0 mL, 11.5 mm 〇l) and m 〇MC1 (0.87 mL, 11.5 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was reheated to 60 C for 6.5 h then the reaction was cooled to room temperature, diluted with water and ethyl acetate (2 EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by gelatin chromatography (hexane containing 1% by weight of ethyl acetate) afforded 6-[{[4-bromo-3-fluoro-5-({[(methoxy))) as a colorless oil. Methyl]oxy}indenyl)phenyl]methyl}(methylsulfonyl)amino]_5_cyclopropyl_2_(4-fluorophenyl)-#-methyl-1-benzopyrene Methane·3·carbamide (6.06 g, 950/〇), which partially solidified upon drying. NMR: DMSO (dH): , 7.18-7.28 (m, 2H), 6.92 (s, 1H), 4.97 (d, J=14.5 Hz, 1H), 4.81 (d, J=14.4 Hz, 1H), 4.59 (s, 2H), 4.51 ( s, 2H), 3.15-3.28 (m, 6H), 2.80 (d, J=4.6 Hz, 3H), 2.16-

2.31 (m, 1H), 0.59-0.99 (m, 3H), 0.08-0.28 (m, 1H). LCMS (w/z, ES+) = 663 (M+H). Step 3: [4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(f-amino)yl)-1-benzofuran-6-yl} (A Alkylsulfonyl)amino]methyl-2-fluoro-6-({[(indolyl)methyl]oxy}methyl)phenyl]facic acid 6-[{[4-bromo-3) -fluoro-5-({[(indolyl)indolyl)oxy}methyl)phenyl]indolyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- Fluorophenyl)-#-mercapto-1-benzocypan-3-ylideneamine (6.05 g, 9.12 mmol), potassium acetate (1.79 g, 18.24 mmol), bis(pinacolyl)diboron (3.01 g, 11.85 mmol), 154005.doc -184 - 201138786 Sodium bromide (938 mg, 9.12 mmol) and bis(tricyclohexylphosphine) dipalladium (11) (673 mg, 0.91 mmol) at 1, The mixture in 4-dioxane (1 〇〇 mL) was degassed in a thick-walled glass pressure vessel, followed by stirring at 95. (: heating for 19 hours. Add bis(pinacol) diboron (1.16 g, 4.56 mmol) and bis(dicyclohexylsulphate)-chlorinated (11) (337 mg, 0.46 mmol), and The reaction was heated for 20 hours. The reaction mixture was cooled to room temperature, filtered over EtOAc EtOAc EtOAc (EtOAc) -cyclopropyl-6-[{[3- 4 -5-({[(methoxy)methyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxoin-2-yl)phenyl]methyl}(fluorenylsulfonyl)amino]_2_(4-fluorophenyl)-mercapto-1-benzofuran-3 -Procarbamide (6.38 g '85% purity by LC/MS). Dissolve the foam in THF (10 mL) using 〇·ΐ N acetic acid (6.5 mL) and over-acid ( 〇.3〇g, 1.41 mmol), and stirred at room temperature for 4 days. Additional sodium periodate (100 mg, 0.47 mmol) was added and the reaction mixture was shaken for 4 hours. The reaction mixture was poured into water and Extraction with ethyl acetate (2X). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification of dioxane methane with hydrazine to 1 〇〇% ethyl acetate and methylene chloride containing 0 to 3.5% decyl alcohol, followed by lyophilization to give a white solid [4-{[{5 -cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]indolyl 2_ Fluoro-6-({[(methoxy)indolyl)oxy)indolyl)phenyl]carboxylic acid (121 mg, 68%). 4 NMR (sterol-d4) δ: 7.83-7.94 (m , 2H), 7.58 (s, 1H), 7.24 (t, J=8.7 Hz, 2H), 7.02 (s, 1H), 6.94 (s, 1H), 6.87 (d, J=8.9 Hz, 1H), 4.92 -4.99 (m, 1H), 4.74-4.82 (m, 1H), 154005.doc •185- 201138786 4.59 (s,2H),4.49 (s,2H),3.32 (s, 3H),3·16 (s , 3H), 2.91 (S, 3H), 2·17·2·30 (m, 1H), 0.92-1.04 (m, 1H), 0.71-0.85 (m' 2H), 0.26-0.39 (m, m) lCMS (w/z, ES+)=629 (M+H) 〇 Example 55 (4-{[[3-(Aminocarbonyl))5-cyclopropyl-2 (4 fluorophenyl benzofuran·6 · 】 (methylsulfonyl) amine] methyl}-2-fluorophenyl)

Step 1 '5_Cyclopropyl_2_(4_Denylphenyl)_6[(methylsulfonyl)amine oxime Benzene. Fuming-3-carbamamine 5_cyclopropyl_2-(4.fluorophenyl)_6_[(methylsulfonyl)amino] benzofuran 3-carboxylic acid (1 g, 2· 57 mmol), HATU (1.221 g ' 3.21 Curry 1) and DIPEA (〇.897 machine, 5_14 _imN, N_ dimethylformamide (10 mL) were maintained in the mixed τ, which was stable on the same day. The ammonia gas stream was bubbled through the solution for 45 minutes. The ammonia bubbler was removed and the flask was sealed with a rubber septum and kept stirring overnight. The mixture was diluted with ethyl acetate and washed with 5% LiCl (water/cold) The organic layer was washed with sodium sulfate (aq.). Base-2-(4-fluorophenyl)·6_[(methylsulfonyl)amino]-indole benzofuran-methyl 154005.doc -186- 201138786 amine (760 mg, 1.957 mmol, yield 76 %) LCMS (m/z, ES+) = 389 (M+H) Step 2: (4-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)) 1-benzofuran-6-yl](methylsulfonyl)amino]mercaptofluorophenyl)-acid 5-cyclopropyl-2-(4-fluorophenyl) -6-[(decylsulfonyl)amino]-1-benzofuran-3-carboxamide (315 mg '0.811 mmol), [4-(bromomethyl)-2-fluorophenyl]_ A solution of the acid (236 mg, 1.014 mmol), KI (135 mg, 0.811 mmol) &amp; K2C03 (235 mg, 1.703 mmol) in N,N-didecylamine (5 mL) The mixture was kept at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed three times with 5% LiCl (aq) and washed once with saturated sodium sulfate (aq). The organic layer was separated and dried over sodium sulfate. The residue was obtained under reduced pressure and purified to purified crystals crystals crystalssssssssssssssss Fluorophenyl)-i-benzofuran-6-yl](fluorenylsulfonyl)amino]methyl}•2-fluorophenyl)folic acid (290 mg, 0.537 mm 〇 yield 66 2% lH NMR (f #-d4) δ: 7.94-8.01 (m, 2Η), 7.60 (s, 1Η), 7.20-7.30 (m, 3H), 7.10 (s, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.98 (d, J=9.6 Hz, 1H), 4.97 (d, J=14.3 Hz, 1H), 4.82 (d, J=14.1 Hz, 1H), 3.16 (s, 3H), 2.18 -2.29 (m, 1H), 0.93-1.03 (m, 1H), 0.73-0 .86 (m, 2H), 0.28-0.40 (m, iH) 〇 LCMS (m/z, ES+) = 541 (M+H). Example 56 4-(l-(iV-(5-cyclopropyl_2·(4-fluorophenyl)_3-(methylamine-methylhydrazino)benzofuran-6-yl)methylsulfonylamino) Propionyl-2-yl)phenyl-acid 154005.doc •187· 201138786

Step 1 : 1-Di- 4-(prop-1-en-2-yl)benzene at -78 ° C, N 2 to decyltriphenylphosphonium bromide (19·9 g, 56 mmol, Alfa) n-BuLi (56 mL, 56 mmol, 1 Μ in THF) was added dropwise to a solution in THF (100 mL), and, after the addition, the reaction solution was stirred at -78 ° C for 15 minutes. The reaction was allowed to warm to 〇 ° C. After stirring for 15 minutes, the reaction mixture was cooled to -60 ° C, and 1-(4-bromophenyl)ethanone (10.0 g &apos; 51 mmol &apos; Alfa) was added over 30 minutes. The reaction mixture was slowly warmed to rt EtOAc (EtOAc)EtOAc. The separated organic layer was washed with brine (1 mL) and dried over anhydrous NaHSO. After removal of the solvent, the title compound was crystalljjjjjjjjjjjjj ). Step 2: 1-Bromo-4-(3-bromoprop-1-en-2-yl)benzene 1-bromo-4-(propan-1-en-2-yl)benzene (4.〇g, 20.3 A solution of mm〇i) and nbs (2.2 g, 12.1 mmol) in CHCi3 (5 mL) was warmed to reflux overnight. After the solvent was removed, it was purified by column chromatography to give bromo 4-(3-bromopropyl) benzene (29 g </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 154005.doc 188· 201138786 Step 3: 6-(N-(2-(4-Bromophenyl)allyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl) -N-methylbenzofuran-3-carbamidamine 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(nonylsulfonylamino) under nitrogen ) Stupid and cowardly -3 - brewing amine (400 mg, 1 mmol), KI (166 mg '1 mmol), K2C〇3 (414 mg, 3 mmol) and 1- desert-4-(3- A solution of flupropan-1-en-2-yl)benzene (552 mg, 2 mmol) in anhydrous DMF (15 mL). The reaction solution was diluted with water (30 mL) andEtOAc. The combined organic layers were washed with water (50 mL) brine brine After the solvent was removed, the crude product was purified by column chromatography to afford 6-(iV-(2-(4-bromophenyl) allyl) decylsulfonylamino)-5- as a yellow solid. Cyclopropyl-2-(4-fluorophenyl)-#-mercaptobenzoxan-3-decylamine (500 mg, 0.84 mmol, yield 78%). Step 4: 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-(4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenyl)allyl)nonylsulfonylamino)benzofuran-3-carboxamide 6-(iV-(2-(4-bromobenzene) Allyl)methylsulfonylamino)-5-cyclopropyl-2-(4-fluorophenyl)-#-mercaptobenzofuran-3-carboxamide (500 mg, 0.84 mmol) Bis (pinacol) diboron (0.426 mg, 1.68 mmol), potassium acetate (247 mg '2.52 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (96 mg, 0.08 mmol) in dioxane (20 The solution in mL) was degassed and refilled three times with nitrogen' followed by 95. (:, heating under a nitrogen atmosphere overnight. After the reaction mixture was cooled to room temperature, then filtered and concentrated under reduced pressure. 2-(4-fluorophenylmethyl-6-(jv_(2-(4-(4,4,5,5-tetramethyl-1,3,2- 154005.doc •189- 201138786) boron dioxide Indole-2-yl)phenyl)allyl)methylsulfonylamino)benzofuran_3-carbamide (0.21 g, 0,33 mmol, yield 38%) Step 5: 5-ring Propyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Born-2-yl)phenyl)propyl)methylsulfonylamino)benzobenzoin-3-cartoamine 5-cyclopropyl-2-(4-fluorobenzene) under &amp; atmosphere Base)-#-methyl·6-(Ν-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl) A solution of allyl)methylsulfonylamino)benzofuran-3-cartoamine (0.21 g, 0.33 mmol) and palladium/activated carbon (21 mg, 10%) in EtOAc (20 mL) After stirring for 5 hours at ° C. The reaction mixture was filtered and evaporated tolulululululululululululu ( 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)propyl)indolylsulfonylamino)benzophenan -3-decylamine (0.205 g, 0.32 mmol, yield 98%). Step 6. 4-(1-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-) Methylamine methyl benzofuran-6-yl)methylsulfonylamino)propan-2-yl)phenyl ruthenic acid 5-cyclopropyl-2-(4-fluorophenyl)-N -Methyl-6-(N-(2-(4-(4,4,5,5-tetradecyl-1,3,2-dioxoindol-2-yl)phenyl)propyl)) Phytosulfonyl)benzofuran-3-indoleamine (205 mg, 0.32 mmol), HCl (5 N, 0.45 mL) and PS-BBA (0.6 g, 1.6 mmol) in THF (15 mL) The solution was stirred overnight at 30 ° C. The reaction mixture was filtered and evaporated tolulululu (4-fluorophenyl)-3-(methylaminoindenyl)benzofuran-6-yl)methylsulfonylamino)propan-2-yl)phenylg-acid (38 mg, 0.06 mmol , yield 154005.doc • 190·201138786 21%). NMR (methanol-d4) δ: 7.96-7.88 (m, 2H), 7.57-7.48 (m, 2H), 7.30-7.03 (m, 6H), 4.95 .3.95 (m, 2H), 3 .05 (s, 3H), 2.97 (d, 3H), 2.79 (s , 1H), 2.45-2.39 (m, 1H), 2.05-1.92 (m, 1H), 1.35-1.26 (m, 3H), 0.96 -0.70 (m, 4H). LCMS (w/z, ES+) = 565.2 (M+H). Example 57 4-((N-(5-Cyclopropyl-2-(4-fluorophenyl)_3-(methylamine-carbamoyl)benzofuran-6-yl)methyl hydrazinyl)methyl _2-fluorophenyl-folic acid

Steps.·5-Cyclopropyl-2-(4-fluorophenyl)-indole methyl-6-[(methyl sulfhydryl)amino]-1-benzofuran-3-carboxamide 5-Cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylic acid (27.5 kg '70.6 mol), guanamine The mixture of hydrochloride (5.3 kg, 77.7 mol) and HBTU (34.8 kg, 91.8 mol) in DMF (137.5 L) was cooled to 10-20 °C. N,N-Diisopropylethylamine (22.8 1 &lt;^'176.6 111〇1) was added over about 30 minutes while maintaining the temperature below 25. (: at 20: (: stirring the reactants until until the reaction is completed by HPLC analysis (about 3 minutes). Heat the batch to 55-65 ° C ' and add acetonitrile (137.5 L). Adjust the temperature to Approximately 60-65 ° C. Add water (5 5 L) and seed the batch 154005.doc -191 - 201138786 The mixture is aged at 60 C for about 60 minutes. Then add at least 1 hour. Water (55 L) 'and slowly cool the slurry to 2 〇 -25 ° C. The batch was filtered, washed with water (165 L) and dried under vacuum at about 60 ° C with A to dry to give a tan. 5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methyl succinyl)amino]-i-benzopyrano- 3-carbamamine as a solid (21.3 let Lu, 53 mol, yield 75%). iH NMR (500 MHz, DMSO-d6: CDC13, 1:1) δ: 9.08 (s, 1 Η), 8.20 (m, 1H), 7.96 (m) , 2H)S 7.58 (s, 1H), 7.21 (m, 3 H), 3.02 (s, 3H), 2.90 (d, 7=4.5 Hz, 3H), 2.29 (m, 1H), 1.02 (m, 2H) ), 0.73 (m, 2H). Step 2: [2-Fluoro-4-(hydroxymethyl)phenyl]-tanoic acid (2-carb-4-phenylmercaptophenyl)-acid (15 kg, 89.3) Ment) dissolved in methanol (75 L) And cooling the solution to 〇·1〇π^ slowly fed a 12% w/w solution of sodium borohydride in 14 N sodium hydroxide (8.55 kg) while maintaining the batch temperature below 10 C. At about 10 ° The reaction was stirred at C for at least 3 minutes and 6 N hydrochloric acid (45 L) was slowly fed into the batch while maintaining the batch temperature below 10 ° C. Feeded in water (30 L) and transferred via vacuum distillation Except methanol, until the final volume is 75 L (solid precipitates during distillation). Oj N hydrochloric acid (45 L) is fed into the batch' and the reaction is heated to about 75 ° C. Cool at about 〇5.〇/min. The reaction was kept at 2 ° C for 1 hour and filtered. The solid was washed with cold water (2×30 L), then dried under nitrogen at 50 ° C under full vacuum to give a white solid. 4-(Methyl)phenyl]g-acid (13.5 kg, 79 4 mo, 89%). NMR (500 MHz, DMSO-d6 + 20 pL Η 20) δ. 8.16 (s, 2 H), 7.53 ( t, *7=7.1 Hz, 1H), 7·1〇 (d, J=7.6 Hz, 1H), 7.02 (d, *7=10.4 Hz, 1H), 5.41 (s, 1 H), 4.52 (d , J=3.5 154005.doc •192- 201138786

Hz, 2H).

Step 3: [2-Fluoro-4-(bromomethyl)phenyl]carboxylic acid [2-fluoro-4-(sulfenyl)phenyl]-acid (13.5 kg, 79,4 mol) in 48% The w/w is concentrated in a concentrated acid (1 〇 8 l) and heated to about § 5 ° C. At 85. The reaction was held for 1 hour under the armpit. The reaction was cooled to 2 ° C and filtered. The mixture was washed with water (330 L), then dried under nitrogen, and then evaporated to dryness to give [2-fluoro-4-(bromomethyl)phenyl]gic acid as a white solid. 6 kg, 71.2 mo yield 90%). 4 NMR (500 MHz, DMSO-d6+10 pL Η20) δ: 8.3 (bs, 2 Η), 7.54 (t, 7=7.1 Hz, 1H), 7.24 (d, 7=7.6

Hz, 1H), 7.18 (d, "7=9.9 Hz, 1H), 4.69 (s, 2H). Step 4: 4-((N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl)decylsulfonylamino ) mercaptofluorophenyl benzoic acid, intermediate level to 5-cyclopropyl-2-(4-fluorophenyl)-N-indolyl-6-[(methylsulfonyl)amino]-1- Stupid and furan-3-carboxamide (16.5 kg, 41 mol) and [4-(bromoindolyl)-2·fluorophenyl]-acid (11.〇kg, 47.1 mol) in acetone (136 L) and A solution of potassium carbonate k2c〇3 (13.0 kg, 94·3 mol) in water (16·5 L) was added to the mixture in DMF (16.5 L). The resulting mixture was stirred at 20-251 for 4-6 hours. Water (16.5 L)' then slowly add 6 N HCl (28.9 L) (gas evolution). Heat the batch to 5 〇 -55 ° C. Slowly add water (74.3 L) while maintaining the temperature at 50-55. (3 The batch was seeded and kept at 50_55. (: for at least 1 hour. Water (41.2 L) was fed over at least 30 minutes. The slurry was slowly cooled to 20-30 ° C. The product was isolated by filtration and water (66) L) Washing. The product is dried by &amp; blowing under vacuum at about 60 ° C to give 4-((N-(5-cyclopropyl-2-) as a white solid 154005.doc • 193·201138786. 4-fluorophenyl)-3-(decylamine-mercapto)benzofuran-6-yl)methylsulfonylamino)mercapto)-2-fluorophenyl-s-minic acid, intermediate level (18.6 Kg, 33.6 mol, yield 82%). 4 NMR (500 MHz, DMSO) δ: 8.42 (q, 7 = 4.5 Hz, 1 Η), 8.13 (s, 2H), 7.93 (dd, J=9.0, 5.5 Hz, 2 H), 7.81 (s, 1H), 7.44 (t, /=7.0 Hz, 1 H), 7.38 (t, J=9.0 Hz, 2 H), 7.05 (d, /=7.5 Hz, 1 H ), 7.00 (d, /=10.0 Hz, 1 H), 6.94 (s, 1H), 4.94 (d, 7=15.0 Hz, 1 H), 4.82 (d, /=15.0 Hz, 1 H), 3.24 ( s, 3H), 2.81 (d, /=4.5 Hz, 3 H), 2.27 (m, 1H), 0.94 (m, 1H), 〇-81 (m, 2H), 0.28 (m, 1H). Step 5 : 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-%(methylaminecarbaryl)benzofuran-6-yl)nonylsulfonylamino) fluorenyl -2-fluorophenyl-acid to 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimidyl)benzofuran-6-yl) Add 0.25 Μ HC1 (18.6 L) and a mixture of intermediate grade (18.6 kg, 33.6 mol) in acetonitrile (93 L) with sulfhydryl hydrazinyl) fluorenyl)-2-fluorophenyl phthalic acid Propanol (27.9 L). The mixture was heated to 72-75 ° C to dissolve all solids. The reaction was cooled to 67-72 ° C and the solution was filtered. The mixture was reheated to 72-75 C to ensure dissolution. The reaction was cooled to 6 - 63 ° C and seeded. Adjust the temperature to 58-62. (:, and at this temperature, stir for at least i hours. Cool the reactants to about 〇 l l ° ° ° ° ° ° °

L) Wash 154005.doc N2 is blown to dry the product to give white fluorophenyl)-3-(methylamine guanidino) fluorenyl)-2-fluorophenyl gamic acid (15.7 • 194·201138786 kg) , 28·4 mo1 'yield 84%). See step 4 for NMR data. Example 58: Pharmaceutical Composition Components --- Quantity (mg/ingot) Compound*, Mist Drying Dispersion 14.00 Microcrystalline Cellulose (about 100 μηι) 5.50 Microcrystalline Cellulose (about 2〇 Μιη) 4.31 Parent carboxymethylcellulose sodium 0.752 Colloidal cerium oxide 0.25 Magnesium stearate 1 -*------ 0.188 Total tablet weight (3⁄43⁄4 25.0 M_((N~(5_cyclopropyl) · 2 &lt; 4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Propyl_2_(4· phenylmethylamine-based) stupid screams ·6.yl)methylglycosyl)methyl)·2_fluorophenyl-acid and acetic acid butyric acid The solution of the cellulose in the propylene solution is spray-dried. The solution is spray-dried, followed by drying, and the original material is obtained. This gives the amorphous spray dried knives the squirting liquid. / knife liquid dispersion and microcrystalline cellulose (particle size of about 20 μιηη) blended. Add croscarmellose sodium, osmium tetroxide and microcrystalline fiber only quartic acid magnesium and into the people About (10) (iv) and blending 1 plus stearin, cedar &amp; The blend is compressed into a tablet. Example 59: Biological Activity Based Replicon Luciferase Cell Assay Method 154005.doc -195- 201138786 Transfer 1 50 μL of each test compound to 1 mM stock solution in DMSO to the 96-well V-bottom microassay plate In a row, 'this is 200 times the highest concentration of the desired dilution series. Add a 50 μί aliquot to each well containing 1 〇〇 DMSO and get at 1 point! : 3 dilution Lines 11 and 12 containing only DMSO were used as positive and negative controls, respectively. Transfer 10 μί solution of each well to supplemented with 5% v/v fetal bovine serum, 1% v/v non-essential amine Base acid solution, 1 〇〇 unit/ml penicillin (penicillin), 100 pg/ml streptomycin and 2 mM L-face lysine 90 pL DMEM medium (Invitrogen, #41965-039) It is 20 times the southernmost concentration of the desired dilution series. Suspensions are prepared from cultures of Huh-7 cells that are linked to the genotype lb of the firefly luciferase reporter gene (Pietschmann, T., Lohmann , V., Kaul, A., Krieger, N., Rinck, G., Rutter, G.,

Strand, D. and Bartenschlager, R., Jowrwa/ 〇/Firo/og;;, 2002, 76, 4008-4021 ET subfamily), genotype ia (autologously constructed subfamily 1.19) or genotype Lb C316N (autologously constructed) subgenomic HCV NS3-NS5B replicon stably transfected with β from a growth flask containing a velvet (membrane) membrane protease solution, stripped close to the confluent monolayer, and resuspended in DMEM containing cells In the assay medium. Add 95 μL of a suspension containing 15,000 cells (genotype lb luciferase replicon) or 2 〇, one cell (genotype luciferin torsion replicon) to a 96-well plate (Perkin Elmer, Of all the wells in #6005686, except for the medium control in the 12th row of the assay plate. 5 pL of the compound solution was added to the cell suspension, and the plate was incubated at 37 ° C for 48 hours in a 5% C 2 atmosphere. 154005.doc -196- 201138786 For toxicity, cells in a plate were treated with Cell Titer Glo (Promega, #G7573). A solution of Cell Titer Glo was prepared according to the manufacturer's instructions and 100 pL of solution was added to each well. The illuminating of the disc is then read on Envision. For potency, a solution of Steady Glo (Promega, #E25 50) was prepared according to the manufacturer's instructions and a 100 μl solution was added to each well. After 20 minutes of incubation, the light of the disk was then read on Envision. Data Analysis Toxicity: The average of the luminescence values from duplicate wells was calculated and expressed as the percentage of the mean absorbance of the control wells without compounds to determine cell viability. The cytotoxicity of the compound was expressed as the lowest concentration or 50% toxic concentration (CCID5G) at which a significant decrease in viability was observed. CCID5G was plotted against the curve by the XC50 module using ActivityBase (IDBS software). Determined based on the curve of compound concentration. Efficacy: The average of the luminescence values from all the no compound wells containing cells was obtained to obtain positive control values. Negative (background) control values were provided using the average luminescence value from the no compound wells that had not received the cells. The well readings at each compound concentration were taken and the background mean was subtracted from all values and expressed as a percentage of the positive control signal. Fluorescent signals can be quantified and specifically reduced in the presence of a drug as a direct measure of repressor inhibition. BioAssay Enterprise (Camebridge Soft) with XC50 module for curve fitting was used to plot the percent inhibition versus 154005.doc-197-201138786 for compound indifference and to give a 50% inhibitory concentration of compound (IC5()). Find the average of the ICso values of the two identical discs. The results are presented in Table 1. Table 1 Example No. la wild type (nM) lb wild type (nM) lb316N(nM) 1 氺* 2 氺3 氺氺氺氺氺4 氺氺氺5 * ------------- * + 6 *** 氺氺7 * Fortunately 8 * Wood + 9 *** 氺氺氺氺氺氺10 氺氺11 氺*氺*** 氺氺本12 氺♦氺氺*氺氺氺本13 氺氺木14 *** 氺氺丰15 *氺* **氺氺* 16 氺* 氺氺幸氺17 — ------- 氺氺氺氺氺18 氺氺19 氺* umbrella- 氺%% 20 氺氺氺氺21 *氺氺氺* 22 *氺氺木氺154005.doc •198- 201138786 23 氺氺24 氺氺氺氺氺氺25 氺氺* 氺氺26 氺氺氺*氺氺*本27氺氺氺氺氺氺氺* 28 氺氺氺氺氺承氺氺29 氺氺* 氺氺氺氺氺30 *氺氺氺氺氺氺** 31 氺氺氺*氺氺nd 32 氺氺氺nd 33氺氺氺nd 34 氺氺氺氺氺氺nd 35 氺氺氺氺氺氺nd 36 氺氺氺氺*氺37 氺氺氺氺氺氺氺氺氺38 氺氺氺氺氺氺39 氺氺氺本氺氺40 氺氺水氺氺氺41 氺氺!*C 氺氺氺本氺氺42 *氺氺氺氺氺* ♦氺43 *氺氺本氺水氺氺44 氺氺* *氺氺氺氺45 氺氺氺氺氺46 *氺伞氺氺47 氺丰氺氺氺氺48 氺氺氺氺氺49 氺氺氺氺氺50 *氺氺氺氺* 氺氺51 氺氺氺氺氺氺氺氺-199- 154005.doc 201138786 52 ** 氺氺丰本53 氺氺氺氺54 氺氺* * 55 氺氺本氺氺氺氺氺氺56 氺氺氺氺氺+&gt;5000 *200-3000 nM **10-200 nM ***&lt;10 nM nd=not measured 154005.doc 200-

Claims (1)

201138786 VII. Patent application scope: 1 · A compound of formula (1), R1 is one or more substituents independently selected from the group consisting of halogen, C -6 alkyl, alkoxy, -CN, -CF3, optionally substituted by halogen - C6-1〇 And, optionally, halogen-substituted-fluorene-heteroaryl; R2 is hydrogen, hydroxy, Cw alkyl or c3.6 cycloalkyl, wherein Cw alkyl or C.6 cycloalkyl is optionally substituted with hydroxy; Ruler 3 is (^.6 alkyl, (: 3 6 cycloalkyl or Cl-6 alkoxy; R44?-S(0)2R5 &gt; P(〇)(〇R5)R5^p(〇)( 〇H)R5; R5acN6 alkyl or (:3_6 cycloalkyl; X is a C1-6 alkyl group optionally substituted by Cw alkyl, hydroxy, amine or C3 6 cycloalkyl; R6 is: (a) a heteroaryl group which is substituted by B(〇R7)(〇R8) and optionally substituted by T or a plurality of substituents selected from the group consisting of dentate, Cm oxy-CF3, Cl-6 a hydroxyl group, a hydroxyl group, a so2r5, a so2nh2, a CF3, and a C3·6% stimuli group; or r7 and an oxygen atom to which it is bonded form a 5- to 8-membered carbocyclic or heterocyclic ring which may be monocyclic or bicyclic and optionally _ Or a plurality of pendant oxy (-) or Cw alkyl groups; or 154005.doc 201138786 (b) C6-10 square group, the C6-10 square group via B (〇R7)(〇r8) is substituted and optionally substituted with one or more substituents selected from the group consisting of dentate, C!.6 alkoxy, -CF3, Ck, ketone, s 〇2R5, S02NH2, -CN, -OCF3&amp;C3-6 cycloalkyl; or Ruler 7 and Ruler 8 together with the oxygen atom to which they are attached form a 5 to 8 membered carbocyclic or heterocyclic ring which may be monocyclic or bicyclic and Optionally substituted with one or more pendant oxy or Cl.6 alkyl; R7 and R8 are hydrogen or Cw alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I) according to claim 1 Wherein Ri is one or two halogens. 3. A compound of formula (I), wherein R 2 is Ci 6 alkyl. 4. A compound of formula (1), wherein R 3 is c36 cycloalkyl. 5. The compound of formula (1), wherein R6 is C6 i〇 aryl, the C6 aryl is substituted by B(〇R7)(〇R«), wherein "and the ruler 8 are both hydrogen, and optionally One or more substituents independently selected from the group consisting of halogen and _CF3. 6. A compound of formula (1), wherein R6 is a heteroaryl group, and the heteroaryl group is B (〇R7) (〇) R8) substitution, wherein R7 and R8 are both argon, and as appropriate And wherein one or more substituents independently selected from the group consisting of halogen and _CF3 are substituted. 7. The compound of the formula (1) of the formula [1] wherein ...... is dentate; r2 is Ci6 alkyl, and R is 〇3. 6cycloalkyl, and R is C6.1Q aryl, which is substituted by B(〇R7)(〇R8), wherein R7 and R8 are both hydrogen and, as the case may be, independently selected from one or more The halogen and the substituent of the group of _CF&gt;3 are substituted. 8. The compound of the formula (1) of claim 1 which is a dentate; r2 is a Ci6 alkane 154005.doc 201138786 base; R is a C3-6 cycloalkyl group; and R6 is a heteroaryl group, the heteroaryl group is B (〇) R7) (OR8) is substituted wherein R7 and R8 are both hydrogen and, as the case may be, substituted by one or more substituents independently selected from the group consisting of halogen and -CF3. 9. A formula (iy compound, Wherein: R1 is one or more substituents independently selected from the group consisting of halogen, C.6 alkyl, alkoxy, -CN, -CF3, O-C6, optionally substituted by halogen! . An aryl group, and optionally a halogen-substituted _〇_heteroaryl group; R2 is hydrogen, hydroxy, C.·6 alkyl or C. 6 cycloalkyl, wherein Cl-6 alkyl or (: 3-6 ring The alkyl group may be optionally substituted by a hydroxyl group; R3 is C -6 alkyl, C 3-6 cycloalkyl or CN 6 alkoxy; R 4 is hydrogen, -S(0) 2 R 5 , P (0) (〇R 5 ) R 5 or p(0)(0H)R5 ; R5 is a Ci_6 alkyl or C3.6 cycloalkyl; X is a C 1.6 alkyl which is optionally substituted by a Cw alkyl group, a trans group, an amine group or a €3-6 cycloalkyl group. R6 is: (a) Heteroaryl 'The heteroaryl is substituted by B(〇R7)(〇r8) and optionally substituted with one or more substituents selected from the group consisting of halogen, c丨.6 alkoxy, -CF3, Ci_6 alkyl, perylene, SO2R5, so2nh2, -CN, -OCF3 and C3·6 cycloalkyl, or r7 and r8 with the oxygenator attached to it 154005.doc 201138786, _( b) C6·丨〇aryl, the C6, aryl group substituted by B(〇R7K〇R8) and optionally substituted by one or more substituents selected from the group consisting of: halogen, C|_6 Oxy, -cf,, Γ ρ 甘 3 Cl-6 alkyl, thiol, S 〇 2R 5 , S 02 NH 2 , -CN, yl, and -r9〇r9 _〇 substituted by n(r7) 2 group Cf2, -〇cf3, {(9)(10), c3 6 cycloalkane, NH(R7), alkoxy substituted R9, or alkoxy: or R7 and R8 together with the oxygen atom to which they are attached form a 5 to 10 membered carbocyclic ring or a heterocyclic ring which may be monocyclic or bicyclic and optionally substituted with one or more pendant oxy groups or C 6 alkyl groups; R 7 and R 8 are hydrogen or C 6.7 alkyl; R is a stretching group; or a pharmaceutical thereof The compound of any one of items 1 to 9, wherein the rule 4 is _8 (〇) 2115. 11. A compound selected from the group consisting of: (6 -{[{5-cyclopropyl_2-(4-fluorophenyl)_3.[(methylamino)carbonyl]-b-benzofuran-6-yl}(fluorenylsulfonyl)amino]曱 卜 3 3 pyridyl) pyridyl acid; (2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-1-] -6-yl}(methylsulfonyl)amino]indolyl 4_pyridylminic acid; (4-{[{2-(4-fluorophenyl)-3-[(decylamino)) Carbonyl]_5-[(1-methylethyl)oxy]-1-benzofuran-6-yl}(fluorenylsulfonyl)amino]methyl}phenyl)Siifl acid; (3-{ [{2-(4-Fluorophenyl)-3-[(decylamino)carbonyl]-5-[(l-decylethyl)oxy]-1 -benzofuran-6-yl}(fluorenylsulfonyl)amino]methyl} stupid 154005.doc -4- 201138786 base)s-p-acid; (2-{[{2-(4-fluorophenyl) ··3-[(decylamino)carbonyl]-5-[(1•methylethyl)oxy]-1·benzofuran-6-yl}(methylsulfonyl)amino]methyl }phenyl)folate; cyclopropyl-2_(4-fluorophenyl)_3_[(methylamino)carbonylbenzofuran-6-yl}(fluorenylsulfonyl)amino]methyl }phenyl) sun-acid; (4 {[5-cyclopropyl-2-(4-oxophenyl)-3-[(methylamino))]-1·benzone-6- (2){[{5-cyclopropyl·2_(4-fluorophenyl)-3-[(methylamino) )carbonyl]]•benzophenanol _6_yl}(methylsulfonyl)amino]mercapto}phenyl) lysine; 4_((N-(5-cyclopropyl-2-() 4-defenyl)-3-(decylamine fluorenyl) benzo. Furan-6-yl)methylsulfonylamino)hydrazino)_2_fluorophenyl acid; 4-((Ν·(5-cyclopropyl-2-(4-fluorophenyl)-3- (hydrazinocarbamimidyl)benzoxanol-6-yl)nonylsulfonylamino)hydrazino)_2-methoxyphenyl-fat acid; 4-((N-(5-cyclopropyl) -2-(4-fluorophenyl)-3-(decylamine decyl) benzofuran, fluorenyl-6-yl) decylsulfonylamino)methyl)_2-methylphenyl phthalic acid; 4-((N-(5-cyclopropyl-2-(4-fluoro)phenyl)-3-(decylamine decyl)benzofol-6-yl)nonylsulfonylamino)曱))_2_(trifluoromethyl)phenylg-acid; 4-((N-(2-(4-)phenyl)-5-cyclopropyl-3-(methylaminemethyl) benzene And 夫 -6-6-yl)methyl hydrazinyl) fluorenyl)-2-(trifluoromethyl) phenyl crotonate; 4_((Ν-((2)(4-chlorophenyl)-) 5-cyclopropyl-3-(decylamine fluorenyl) benzoate. ketone-6-yl) fluorenyl) fluorenylamino) fluorenyl) _2 fluorophenyl face acid; 4-( 2-(Ν-(5·cyclopropyl-2-(4-fluorophenyl)-3-(indolylcarbamoyl)benzofuran-6-yl)indolylsulfonylamino)ethyl) Phenyl-acid; 154005.doc 201138786 3- (2·(Ν-(5-cyclopropyl-2-(4-fluorophenyl) )-3-(methylaminoindenyl)benzofuran-6-yl)nonylsulfonylamino)ethyl)phenyl-acid; 4-((Ν·(5-cyclopropyl-2-) (4-(4-Fluorophenoxy)phenyl)-3-(decylaminecarbamimidyl)benzofuran-6-yl)methylsulfonylamino)indenyl)-2-fluorophenylg Acidic acid; 4-((N-((5-cyclopropyl)-2-(4-(4-fluorophenoxy)phenyl)-3-(methylaminoindolyl)benzofuran-6-) Methyl sulfonyl)methyl)-2-(trifluoromethyl)phenyl phthalic acid; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)) )-3-(methylaminoindenyl)benzofuran-6-yl)indolylsulfonylamino)methyl)-3-fluorophenyl-pyruic acid; 4-((N-(5-cyclopropyl) -2-(4-Fluorophenyl)-3-(decylaminecarboxylidene)benzofuran-6-yl)methylsulfonylamino)indolyl)-3-methoxyoxyphenyl acid; 4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6-yl](methylsulfonyl) Amino]mercapto}_2-(trifluoromethyl)phenyl]-acid; (5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino) )carbonyl]-丨-benzofuran-6-yl}(methylsulfonyl)amino]mercaptofluorophenyl)_ ; 4·((Ν-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminoindolyl)benzofuran-6-yl)methylsulfonylamino) A )3-(trifluoromethyl)phenyl acid; 5-cyclopropyl-2-(4-fluorophenyl)-#_methyl-6·((fluorenylsulfonyl) {[4- (4,4,5,5-tetramethyl-1,3,2·dioxaborin-2-yl)-3-(trifluoromethyl)phenyl]subunit}amino)-1-benzene and. 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine)methyl)benzofuran-6-yl) Ethylsulfonylamino)methyl)_2-fluorophenylfolic acid; 154005.doc 201138786 4·((#-(5·cyclopropyl-2-(4-fluorophenyl)-3-(methyl) Amine oxime) benzofuran-6-yl)ethylsulfonylamino)hydrazino)-2_(trifluoromethyl)phenyl acid; 4-((#-(5·cyclopropyl-2) -(4-Fluorophenyl)-3-(methylamine methyl)pyrene and 6-yl)nonylsulfonylamino)indolyl)_3_methylphenylidene; (4_{ [{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amine (4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzopyran-) 6-yl](fluorenylsulfonyl)amino]methyl b-2-fluorophenyl acid; 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3·fluoro-4) -(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl]fluorenyl}(fluorenylsulfonic acid)amino]methyl-1- Benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(fluorenylsulfonyl) ({3-( Fluoromethyl)_4_[(111,211,68,811)_2,9,9-trimethyl-3,5-dioxo-4-borane tricyclo[cardiac 2,6]癸_4_yl]phenyl丨Methyl)amino-benzofuran-N--3-decylamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3_ fluoro-4-(4,4, 6,6-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl_1_benzofuran _3-carbamamine; 5-cyclopropyl-6-[{[3-fluoro-4-(6-fluorenyl-4,8-di-oxytetrahydro-41^ 1,3,6,2 -dioxazoboron 4-2-yl)phenyl]fluorenyl}(fluorenylsulfonyl)amino]-2-(4-fluorophenyl)_N-methyl-benzofuran_3·曱Indoleamine; 5-cyclopropyl-2-(4-fluorophenyl)-6-[({3_fluoro-4-[(111, 2 ft, 68,811) -2,9,9-tridecyl] 3,5-dioxo_4-boratricyclo[6.1.1.02,6]indol-4-yl]phenyl}methyl)(methylsulfonyl)amino]-N-methyl-b-benzo Furan _3_ formazan 154005.doc 201138786 amine; 5-cyclopropyl-2-(4-fluorophenyl)_6-[{[3_fluoro_4_(tetra argon_3aH_cyclopentamidine [d][ l,3,2]diboron-2-yl)phenyl]methyl κmethylsulfonyl)amino]-N-methyl-1-benzo[beta]. South_3·Artemis; (3-cyano-4-{[{5-cyclopropyl-2-(4-fluorophenyl)_3_[(decylamino)carbonyl]-1-benzofuran) -6-yl}(fluorenylsulfonyl)amino]methylphosphonium phenyl) offic acid; (4-{[{5-cyclopropyl-2-(4-fluorophenyl)_3_[(fluorenyl) Amino)carbonyl]-丨· benzofuran-6-yl}(methylsulfonyl)amino]hydrazino 2,3-difluorophenyl)-acid; (4-{[{5-ring Propyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]_1- benzofuran-6-yl}(methylsulfonyl)amino]indolyl 2,5 _Difluorophenyl)furfuric acid; (2-Ga-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- Stupidfuran-6-yl}(methylsulfonyl)amino]mercapto}phenyl)phosphonate; [4-{[{5-cyclopropyl-2-(4-fluorophenyl)- 3-[(Methylamino)carbonyl]-1-benzof-Nan-6-yl}(indolyl)amino]methyl}· 2-oxa-3-(trifluoromethyl) Phenyl]-acid; {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]_1_benzofuran_6-yl} (methylsulfonyl)amino]methyl-2-((difluoroindolyl)oxy]phenyl}-acid; 4-(2-(iV-(5-cyclopropyl-2-)4 - defeated phenyl)-3 -(decylamine methyl) benzofuran-6-yl)methylsulfonylamino)ethyl)-2-fluorophenyl-acid; I54005.doc 201138786 2-gas-4-(2-( Ν-(5·cyclopropyl-2-(4-fluorophenyl)-3-(methylaminecarbamimido)benzofuran-6-yl)methyl hydrazinyl)ethyl)phenyl Butyric acid; 4-(2-(#-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylaminemethane))benzofuran-6-yl)methylsulfonate Amino)ethyl)-2-(trifluoromethyl)phenylphosphonate; [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamine) Carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]mercapto}-2-fluoro-5-(trifluoromethyl)phenyl]-acid; 4-( 2-(#-(5-cyclopropyl-2-(4-fluorophenyl)-3-(indolylcarbamoyl)benzofuran-6-yl)methylsulfonylamino)ethyl) 3-fluorophenyl-piconic acid; 4-(2.(Ν-(5-cyclopropyl-2-(4-fluorophenyl)-3-(decylamine decyl) benzofuran-6 -yl)nonylsulfonylamino)ethyl)-3-(trifluoromethyl)phenyl tanning acid; {4-[({5-cyclopropyl-2-(4-fluorophenyl)-3) -[(decylamino)carbonyl]-1-benzofuran-6-yl}amino)methyl]-2-fluorophenyl} lyxate; {4-{ [{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]_1_benzofuran-6-yl}(fluorenylsulfonyl)amino]曱}}-2-[(decyloxy)carbonyl]phenylhydrazine; {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)) Carbonylbenzofuran-6-yl}(fluorenylsulfonyl)amino]mercapto}_2_[(trifluoromethyl)oxy]phenyl}-teroic acid; {4-{ [{5-cyclopropyl -2-(4-Fluorophenyl)-3-[(decylamino)carbonyl]-1·benzofuran-6-yl}(methylsulfonyl)amino]indenyl}_2·[(曱oxy)methyl]phenyl}re-acid; 154005.doc -9- 201138786 {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino) Carbonyl] benzofuran-6-yl}(methylsulfonyl)amino]pyridyl 2_[(dimethylamino)indolyl]phenyl}facial acid; {4-{ [{5- Cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]-oxime-benzofuran-6-yl}(methylsulfonyl)amino]methyl b 2 [(Methylamino)methyl]phenyl}-acid; [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(decylamino)carbonyl]- Benzofuran-6-yl}(methylsulfonyl)amino]methyl b 2fluoro_6_({[(methoxy)methyl]oxy) (曱))phenyl]-acid; (4-{[[3-(aminocarbonyl)&gt; 5-cyclopropyl-2·(4-fluorophenyl)-1_benzofuran-6-yl] (methylsulfonyl)amino]methyl b-2-fluorophenyl) tert-butyl; 4-(1-(#-(5·cyclopropyl-2-(4-fluorophenyl)-3-() Methylamine-methyl indenyl)benzofuran-6-yl)nonylsulfonylamino)propan-2-ylphenylphosphonic acid; and a pharmaceutically acceptable salt thereof. 12. A pharmaceutically acceptable salt of a compound as claimed in any one of the following items. 13. A pharmaceutical composition comprising a compound of any one of claims 12 to 12 and at least one pharmaceutically acceptable excipient. 14. A compound according to any one of the preceding claims, which is for use in medical therapy. 15. The use of a compound according to any one of claims 1 to 12 for use in the manufacture of a medicament for the treatment or &lt; prevention of a viral infection or a disease associated with the infection. The use of the virus infection is hcv infection. The compound of any one of claims 1 to 12 for use in the treatment or prevention of a viral infection or a disease associated with the infection. 18. The compound of claim 17, wherein the viral infection is an HCV infection. 19. The compound of any one of claims 1 to 12 in combination with one or more active antiviral agents. -11 - 154005.doc 201138786 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic 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: 154005.doc