WO2011103063A1

WO2011103063A1 - Therapeutic compounds

Info

Publication number: WO2011103063A1
Application number: PCT/US2011/024822
Authority: WO
Inventors: Brian Alvin Johns; John Brad Shotwell
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2010-02-19
Filing date: 2011-02-15
Publication date: 2011-08-25
Anticipated expiration: 2012-08-19
Also published as: TW201138786A; AR080185A1

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

THERAPEUTIC COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to novel compounds useful as anti-viral agents, specifically Hepatitis C Virus (HCV) inhibitors, 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.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end- stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of those treated, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon, both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359- 362), hepatitis C virus (HCV) is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). HCV is an enveloped virus containing a single strand RNA molecule of positive polarity.

Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2^nd Edition, p931 -960; Raven Press, N.Y.).

The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al. (2000) Journal of Virology, 74(4), p.2046- 2051 ). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to cure HCV infection.

Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit replication of both genotype 1 a and genotype

1 b of HCV.

SUMMARY OF THE INVENTION

The present invention provides benzofuran compounds substituted at the 6-position with a boron containing moiety, pharmaceutical compositions comprising said compounds, methods of synthesis and uses of such compounds in treating and/or preventing viral infections, such as flavivirus infections, for example, HCV infections.

DETAILED DESCRIPTION OF THE INVENTION

The pre und of formula (I):

(I)

wherein: R¹ is one or more substituents independently selected from the group consisting of halogen, C_1-6alkyl, alkoxy, -CN, -CF₃ , 0- C₆_ ioaryl optionally substituted by halogen, and -O- heteroaryl optionally substituted by halogen;

R² is hydrogen, hydroxy, Ci_-6alkyl or C_3-6cycloalkyl wherein Ci_-6alkyl or C₃-₆cycloalkyl may be optionally substituted with hydroxy;

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

R⁴ is -S(0)₂R⁵ , P(0)(OR⁵)R⁵ or P(0)(OH)R⁵ ;

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

X is Ci_-6alkylene optionally substituted with Ci_-6alkyl, hydroxy, amino or C_3-6cycloalkyl; R⁶ is

(a) heteroaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, Ci_-6alkoxy, -CF₃, Ci_-6alkyl, hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₃, and C_3-6cycloalkyl; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 8 -membered carbocyclic or

heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or Ci_-6alkyl; or

(b) C₆- ioaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkoxy, -CF₃, C_1-6alkyl, hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₃, and C_3-6cycloalkyl; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 8 -membered carbocyclic or

heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or Ci_-6alkyl;

R⁷ and R⁸ are hydrogen or Ci_-6alkyl;

or a pharmaceutically acceptable salt thereof.

The term "alkyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, Ci_-6alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 , 1-dimethylpropyl.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, unless specified otherwise. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

The term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci_-6alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, prop-1 -oxy, prop-2-oxy, but-1- oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.

The term "halogen" or "halo" refers to a fluorine (fluoro, F), chlorine (chloro, CI), bromine (bromo, Br) or iodine (iodo, I) atom.

The term "hydroxy" refers to a radical or substituent of the formula OH.

The term "cycloalkyl" refers to a saturated cyclic group containing 3 to 6 carbon ring- atoms (unless otherwise specified). Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, particularly from 6-10 carbon atoms.

Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like. Unless otherwise indicated, the term "aryl" also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4- phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10- phenanthridinyl. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.

The term "heteroaryl" refers to a 5-, 6-, 8-, 9- or 10-membered carbocyclic or bicyclic aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P. Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls. Also included within the scope of the term is a group in which a non-aromatic heteroatom- containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. Heteroaryl moieties include, but are not limited to, pyridine, pyrazine, thiazole, thiophene, oxadiazole, oxazole, pyrimidine, pyridazine, triazole, tetrazole, benzodioxole, benzofuran, benzodioxin, indole, benzimidazole, benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, benzisothiazole, benzotriazole, furopyridine, furopyrimidine, furopyridazine, furopyrazine, furotriazine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, pyrrolopyrazine, pyrrolotriazine, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine, thiazolopyrazine, thiazolotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine, oxazolopyrazine, oxazolotriazine, imidazopyridine, imidazopyrimidine, imidazopyridazine, imidazopyrazine, imidazotriazine, pyrazolopyridine, pyrazolopyrimidine, pyrazolopyridazine, pyrazolopyrazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, triazolopyridazine, triazolopyrazine, quinoline, naphthyridine, quinoxaline, quinazoline, isoquinoline, cinnoline, pyridopyridazine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, pteridine, pyrazinopyridazine, pyrimidopyridazine, pyrimidopyrimidine, imidazothiazole and thiazolooxazole. All isomers of the above heteroaryl groups are within the scope of this invention. Each heteroaryl group may be attached at any ring carbon or may be attached through nitrogen when the nitrogen is part of a 5-membered ring.

The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) {N⁺-0^"} and sulfur such as S(O) and S(0)₂, and the

quaternized form of any basic nitrogen.

The present invention features a compound of formula (I) wherein R¹ is one or two halogen.

The present invention features a compound of formula (I) wherein R² is Ci_-6alkyl. The present invention features a compound of formula (I) wherein R³ is C₃-₆cycloalkyl.

The present invention features a compound of formula (I) wherein R⁶ is C₆-ioaryl substituted with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

The present invention features a compound of formula (I) wherein R⁶ is heteroaryl substituted with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

The present invention features a compound of formula (I) wherein R¹ is halogen; R² is Ci_-6alkyl; R³ is C₃-₆cycloalkyl; and R⁶ is C₆-i₀aryl substituted with with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

The present invention features a compound of formula (I) wherein R¹ is halogen; R² is Ci_-6alkyl; R³ is C_3-6cycloalkyl; and R⁶ is heteroaryl substituted with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

The present invention features a compound of formula (I) wherein R¹ is halogen; R² is Ci_-6alkyl; R³ is C_3-6cycloalkyl; R⁴ is -S(0)₂R⁵ , and R⁶ is heteroaryl substituted with

B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

The present invention features a compound of formula (I) as described above wherein R⁴ is -S(0)₂R⁵. The present invention also provides a compound of formula (I)':

(I)'

wherein:

R¹ is one or more substituents independently selected from the group consisting of halogen, Ci_-6alkyl, alkoxy, -CN, -CF₃ , 0- C₆- ioaryl optionally substituted by halogen, and -O- heteroaryl optionally substituted by halogen;

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

R⁴ is hydrogen, -S(0)₂R⁵ , P(0)(OR⁵)R⁵ or P(0)(OH)R⁵ ;

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

(a) heteroaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, Ci_-6alkoxy, -CF₃, d. ₆alkyl, hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₃, and C_3-6cycloalkyl; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 8 -membered carbocyclic or heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or C_1-6alkyl; or

(b) C₆- ioaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, Ci_-6alkoxy, -CF₃, Ci_-6alkyl, hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₂, -OCF₃, -C(0)OR⁷, C_3-6cycloalkyl, and R⁹ substituted with N(R⁷)₂, NH(R⁷), alkoxy, or -R⁹OR⁹ substituted with alkoxy; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 10 -membered carbocyclic or heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or Ci_-6alkyl;

R⁷ and R⁸ are hydrogen or Ci_-6alkyl;

R⁹ is alkylene;

or a pharmaceutically acceptable salt thereof. The present invention features a compound of formula (I)' wherein R¹ is one or two halogen.

The present invention features a compound of formula (I)' wherein R² is C_1-6alkyl. The present invention features a compound of formula (I)' wherein R³ is C_3- ₆cycloalkyl.

The present invention features a compound of formula (I) as described above wherein R⁴ is -S(0)₂R⁵.

The present invention also features a compound selected from the group consisting of:

(6-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-3-pyridinyl)boronic acid;

(2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-4-pyridinyl)boronic acid;

(4-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(3-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(2-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1-methylethyl)oxy]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(3-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methoxyphenylboronic acid;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methylphenylboronic acid;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid;

4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid;

4-((N-((2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-fluorophenylboronic acid; 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid;

3- (2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid;

4-((N-(5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran- 6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid;

4- ((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran- 6-yl)methyl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluorophenylboronic acid;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-methoxyphenylboronic acid;

[4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6- yl](methylsulfonyl)amino]methyl}-2-(trifluoromethyl)phenyl]boronic acid;

(5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid;

4- ((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-(trifluoromethyl)phenylboronic acid;

5- cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6-((methylsulfonyl){[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]methyl}amino)-1 -benzofuran-3- carboxamide;

4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-fluorophenylboronic acid;

4-((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid;

4- ((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-methylphenylboronic acid;

(4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-1 -naphthalenyl)boronic acid;

(4-{[[5-Cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6- yl](methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid;

5- Cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3- carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)({3-(trifluoromethyl)-4- [(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1 .1.02,6]dec-4- yl]phenyl}methyl)amino]-1 -benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,6,6-tetramethyl-1 ,3,2- dioxaborinan-2-yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1 -benzofuran-3- carboxamide;

5-cyclopropyl-6-[{[3-fluoro-4-(6-methyl-4,8-dioxotetrahydro-4H-1 , 3,6,2- dioxazaborocin-2-yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)-N-methyl-1- benzofuran-3-carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-[({3-fluoro-4-[(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5- dioxa-4-boratricyclo[6.1.1 2,6]dec-4-yl]phenyl}methyl)(methylsulfonyl)amino]-N-methyl-1- benzofuran-3-carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(tetrahydro-3aH- cyclopenta[d][1 ,3,2]dioxaborol-2-yl)phenyl]methyl}(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)boronic acid;

(4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2,3-difluorophenyl)boronic acid;

(4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2,5-difluorophenyl)boronic acid;

(2-chloro-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

[4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluoro-3-(trifluoromethyl)phenyl]boronic acid;

{4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(difluoromethyl)oxy]phenyl}boronic acid;

4-(2-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-fluorophenylboronic acid;

2-chloro-4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid;

4-(2-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-(trifluoromethyl)phenylboronic acid;

[4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl) amino]methyl}-2-fluoro-5-(trifluoromethyl)phenyl]boronic acid;

4-(2-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-fluorophenylboronic acid;

4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-(trifluoromethyl)phenylboronic acid; {4-[({5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}amino)methyl]-2-fluorophenyl}boronic acid;

{4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(methyloxy)carbonyl]phenyl}boronic acid;

{4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(trifluoromethyl)oxy]phenyl}boronic acid;

{4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(methyloxy)methyl]phenyl}boronic acid;

{4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(dimethylamino)methyl]phenyl}boron acid;

{4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(m

yl}(methylsulfonyl)amino]methyl}-2-[(methylamino)methyl]phenyl}boron acid;

[4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluoro-6-({[(methyloxy)methyl]oxy}methyl)phen acid;

(4-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-6- yl](methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid;

4-(1-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)propan-2-yl)phenylboronic acid ; and

pharmaceutically acceptable salts thereof.

Certain compounds of formula (I) and (I)' may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers

(enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention also extends to conformational isomers of compounds of formula (I) and (I)' and any geometric (c/^'s and/or trans) isomers of said compounds.

Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.

Diastereoisomeric mixtures of compounds of formula (I) and (I)' may be separated according to methods well known in the literature, for example by preparative HPLC or by chromatographic purifications. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention. It is understood that compounds of formula (I) and (I)' may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

It will also be appreciated that compounds of the invention which exist as polymorphs, and mixtures thereof, are within the scope of the present invention.

The present invention also features a compound of formula (I) or (I)' or a

pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. The term

"pharmaceutically acceptable" when used in relation to an ingredient which may be included in a pharmaceutical composition for administration to a patient, refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical composition and not being deleterious to the recipient thereof.

Salts of compounds of formula (I) and (I)' which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) or (I)' and their pharmaceutically acceptable salts. It will be appreciated that for use in medicine the salts of formula (I) and (I)' should be physiologically (i.e. pharmaceutically) acceptable.

The compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters thereof.

Also included in the present invention are pharmaceutically acceptable salt complexes. The present invention also covers the pharmaceutically acceptable salts of the compounds of formula (I) and (I)'. As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Therefore, according to a further aspect, the invention provides a pharmaceutically acceptable salt of a compound of formula (I) or (I)' and embodiments thereof.

In certain embodiments, compounds of formula (I) or (I)' may contain an acidic functional group and may therefore be capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. A pharmaceutically acceptable base addition salt may be formed by reaction of a compound of formula (I) or (I)' with a suitable strong base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which may be isolated for example by crystallisation and filtration.

Pharmaceutically acceptable base salts include ammonium salts (for example ammonium or tetraalkylammonium), metal salts, for example alkali-metal or alkaline-earth-metal salts (such as hydroxides, sodium, potassium, calcium or magnesium), organic amines (such as tris [also known as tromethamine or tris(hydroxymethyl)aminomethane], ethanolamine, diethylamine, triethanolamine, choline, isopropylamine, dicyclohexylamine or N-methyl-D- glucamine), cationic amino acids (such as arginine, lysine or histidine) or bases for insoluble salts (such as procaine or benzathine).

In certain embodiments, compounds according to formula (I) or (I)' may contain a basic functional group and may therefore be capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. A pharmaceutically acceptable acid addition salt may be formed by reaction of a compound of formula (I) or (I)' with a suitable strong inorganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric or perchloric) or a suitable strong organic acid, for example, sulfonic acids [such as p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, naphthalenesulfonic (e.g. 2-naphthalenesulfonic)], carboxylic acids (such as acetic, propionic, fumaric, maleic, benzoic, salicylic or succinic), anionic amino acids (such as glutamaic or aspartic), hydroxyl acids (such as citric, lactic, tartaric or glycolic), fatty acids (such as caproic, caprylic, decanoic, oleic or stearic) or acids for insoluble salts (such as pamoic or resinic [e.g. polystyrene sulfonate]), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. In one embodiment, a pharmaceutically acceptable acid addition salt of a compound of formula (I) or (I)' is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.

It will be appreciated by those skilled in the art that organoboronic acids and/or their organoboronate esters may form "ate" complex addition salts, such as organoborate complex addition salts, in the presence of suitable nucleophilic complexing reagents. Suitable nucleophilic complexing reagents include, but are not limited to alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, or fluoride. Examples of organoborate complex addition salts and methods for their preparation will be readily apparent. For example, one such suitable organoborate complex addition salt is an alkali metal trihydroxyorganoborate salt, such as a sodium trihydroxyorganoborate salt. By way of illustration, sodium trihydroxyarylborate and sodium trihydroxyalkylborate complex addition salts and methods for their preparation are described in Cammidge, A.N. et al, Org. Lett., 2006, 8, 4071-4074. Pharmaceutically acceptable "ate" complex addition salts as described herein are also considered to be within the scope of this invention.

The present invention features suitable pharmaceutically acceptable salts of the compounds of formula (I) and (I)' including acid salts, for example sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and tris (tromethamine - tris(hydroxymethyl)aminomethane) salts and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.

The present invention features pharmaceutically acceptable base addition salts of a compound of formula (I) or (I)' which are salts of a strong base, for example, sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline, arginine (for example L-arginine) or magnesium. In a further aspect the salt is sodium, lysine, ammonium, N-methyl-D- glucamine, potassium, choline or arginine (for example L-arginine).

Other non-pharmaceutically acceptable salts, for example oxalates, may be used, for example in the isolation of compounds of formula (I) or (I)' and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I) and (I)'.

The salts of a compound of formula (I) and (I)' may be prepared by contacting appropriate stoichiometric amounts of the free acid with the appropriate base in a suitable solvent. The free acid of a compound of formula (I) or (I)' may for example be in solution with the appropriate base added as a solid or both the free acid of a compound of formula (I) or (I)' and the appropriate acid may independently be in solution.

Suitable solvents for solubilising a compound of formula (I) or (I)' free acid include for example alcohols such as isopropanol; ketones such as acetone; acetonitrile or toluene. If the base is to be added as a solution in a solvent, the solvent used may include acetone, methanol or water.

The salts of a compound of formula (I) or (I)' may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, a noncrystalline salt may be prepared by precipitation from solution, spray drying or freeze drying of solutions, evaporating a solution to a glass, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.

The salts of a compound of formula (I) and (I)' may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise crystallising a non-crystalline salt. For example, organic solvents such as acetone, acetonitrile, butanone, 1 -butanol, ethanol, 1 -propanol or tetrahydrofuran or mixtures of such solvents may be used. An improved yield of the salts may be obtained by the evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, for example in stages. Careful control of the precipitation temperature and seeding may 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 they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compounds of formula (I) and (I)' and solvates of the salts of the compounds of formula (I) and (I)' are included within the scope of the present invention.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or (I)' or a salt thereof) and a solvent. Such solvents for the purpose of the invention 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.

Solvates of compounds of formula (I) and (I)' which are suitable for use in medicine are those wherein the solvent is pharmaceutically acceptable. However, solvates having non- pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

Furthermore, some of the crystalline forms of the compounds of formula (I) and (I)' or salts and solvates thereof may exist in one or more polymorphic form, which are included in the present invention.

Prodrugs of the compounds of formula (I) and (I)' are included within the scope of the present invention.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I) or (I)', which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds defined in the first aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first aspect are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds of formula (I) or (I)'. Suitable prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals ketals, boronic esters and boronic acid anhydrides.

The compounds of the invention have been found to exhibit antiviral activity, specifically HCV inhibitory activity, and may therefore useful in treating or preventing viral infections, such as HCV infections, or diseases associated with such infections. In vitro studies have been performed which demonstrate the usefulness of compounds described herein as antiviral agents.

The present invention provides a compound of formula (I) or (I)' or a pharmaceutically acceptable salt thereof for use in medical therapy.

The present invention provides the use of a compound of formula (I) or (I)' or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and/or preventing viral infections, such as HCV infections, and/or diseases associated with such infections.

The present invention provides a compound of formula (I) or (I)' or a pharmaceutically acceptable salt thereof for use in treating and/or preventing viral infections, such as HCV infections, and/or diseases associated with such infections.

The present invention provides a method for treating and/or preventing viral infections, such as HCV infections, or diseases associated with such infections which method comprises administering to a subject, for example a human, a therapeutically effective amount of a compound of formula (I) or (I)' or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference herein to therapy or treatment may include, but is not limited to prevention, retardation, prophylaxis, and cure of the disease. The present invention provides compounds and pharmaceutical compositions for the treatment and prevention of viral infections, such as HCV infections, as well as diseases associated with viral infections in living hosts. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection include treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

Within the context of the present invention, the terms describing the indications used herein are classified in the Merck Manual of Diagnosis and Therapy, 17^th Edition and/or the International Classification of Diseases 10 Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention.

The compounds of formula (I) and (I)' may be made by the processes described herein or by any method known to those skilled in the art.

Processes for the preparation of compounds of formula (I) form, as described below, further aspects of the inventi

II III

Activated aryl/heteroaryl alkylating agents of the type III (R¹ = I, CI, Br, R³ = Br) can be prepared from direct radical bromination of I (X = N) using a bromide source (for example NBS) and a radical initiator (for example AIBN or benzoyl peroxide) in a suitable solvent (for example carbon tetrachloride) with heat (for example 90°C). Alternatively starting materials possessing pre-oxidized alkyl fragments like II (i.e. R² = C0₂H, C0₂Alk, CH₂OH) can be converted to III using standard chemistry known to those skilled in the art. For example, conversion of II (R² = CH₂OH) to III (R³ = Br) can be effected with a suitable bromide source (i.e bromine) and activating agent (for example triphenylphosphine) in solvent (for example dichloromethane). Additionally, II (R² = CH₂OH) can be accessed from related compounds (i.e. R² = C0₂H, C0₂Me) via treatment with a reducing agent (i.e. LAH or BH₃) in solvent (i.e. THF). Those skilled in the art will recognize that many examples of general formulae I and II are commercially available or h emical literature.

IV v

The chemistry described above are robust, allowing access to highly functionalized benzyl bromides (V) starting from a wide array of commercially available aryl compounds (IV) wherein R⁴ may represent H, OAlk, Br, I, CI, CF₃, CN or combinations thereof optionally substituted with one to four substituents.

Benzofurans of Type VIII are accessible via a two-step procedure involving first alkylation of VII under standard alkylation conditions including an alkylating agent (for example isopropyl bromide) and base (for example potassium carbonate) in solvent (for example DMF). Second, nitration of the intermediate can be effected using a nitrating agent (for example nitric acid) in solvent (for example sulfuric acid). Phenolic VII can be prepared by addition of VI to benzoquinione under suitable conditions including a Lewis Acid (i.e. zinc (II) chloride) and solvent (methanol). Ester VI is readily prepared by those skilled in the art by the reaction of potassium malonate and a suitably functionalized benzoyl chlorides (for example R⁵ = F, CI).

IX X

General Structures like IX (R⁶ = alkyl/cycloalkyl) are accessible directly from VIII utilizing a three-step process including dealkylation to afford the free phenol, using a Lewis acid (for example BCI₃) in solvent (for example dichloromethane), followed by conversion of the phenol to the corresponding trifluoromethanesulfonate, using, for example, a triflating source (for example triflic anhydride) and base (for example diisopropylethylamine). Finally, a Suzuki reaction using the derived triflate (IX for R⁶ = OTf), a palladium catalyst (for example Pd(PPh₃)₄), fluoride source (KF), and boronic acid (for example cyclopropylboronic acid) affords IX (R⁶ = alkyl/cycloalkyl). Amide X (R⁷ = Ci_₈ alkyl) is readily accessed via hydrolysis of IX using a suitable aqueous base (for example sodium hydroxide) in solvent (for example THF) followed by treatment with a suitable amide coupling reagent (for example HATU) and amine source (H₂NR⁷, for example methyl amine or methyl amine hydrogen chloride salt).

Key sulfonamide XI can be prepared from X via a two-step conversion of the nitro- functionality to the corresponding sulfonamide including first a reduction using a metal catalyst (for example palladium on carbon) and a reducing agent (for example hydrogen) in solvent (for example methanol) followed by subsequent sulfonation with a sulfating agent (for example methanesulfonyl chloride) and base (for example diisopropylethylamine).

Functionalized compounds XII, XIII, and XIV can be prepared by direct alkylation of XI with an activated alkylating agent (including III or V) via direct treatment with a base (for example potassium carbonate) in a suitable solvent (for example acetonitrile) with heating (for exa

Generation of aryl boronic acids (XV, XVI, and XVII) from the corresponding aryl bromides (XII, XIII, XIV) is well known to those skilled in the art, and can be effected via direct treatment of the aryl bromides with a palladium catalyst (for example PdCI₂(dppf)), base (for example potassium acetate), boron source (for example bispinacol diboron), and solvent (for example dioxane). The free boronic acids can be liberated from the intermediate pinacol boronic acids via hydrolysis by acid (for example HCI) in solvent/water mixtures (for example THF/H₂0).

XVIII XIX XX

In another embodiment, homologated alkylating agents (for example XIX) can be generated from the corresponding aryl iodides via a two step process involving a Stille Coupling reaction using a tin reagent (for example tributylvinyltin), and a palladium catalyst (for example Pd(PPh₃)₄) in solvent (for example DMF) followed by a hydroboration/oxidation sequence (for example using 9-BBN followed by hydrogen peroxide) to give XIX (R⁸ = OH). XIX (R⁸ = OH) can be converted to the corresponding bromide as described above for III and then converted to XX using chemistries known to those skilled in the art and analogous to those described for

XXI XXII

In another embodiment, boronic acids with the boron functionality either meta (XXI) or ortho (XXII) to the benzyl sulfonamide functionality can be prepared in a manner directly analogous to XV, wherein alkylating agents (III and IV) are derived from appropriately functionlized starting materials known to those skilled in the art.

In another embodiment, those skilled in the art will recognize that a variety of functionalized boronic acids and esters (for example XXIII and XXIV) are directly available from commercial sources or standard chemistries. One will recognize that XXIII and XIV are suitable for use as alkylating agents directly with XI to give functionalized structures of general formula XV upon treatment under standard alkylating conditions (including a base, for example potassium carbonate, and a solvent, for example acetonitrile).

Boronic acids can be converted to the corresponding boronic esters via treatement with an alcohol (for example ethanol) or diol (for example pinacol) in a suitable solvent (for example toluene) with a dehydrating agent (for example powedered molecular sieves).

The invention also includes a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt thereof together with at least one

pharmaceutically acceptable excipient. The term "excipient" refers to a compound that is useful in preparing a pharmaceutical composition, e.g. diluent, carrier.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The dosage forms and procedures may involve amporphous dispersions, molecular dispersions, hot melt extrusion, particle size reduction through micronization or wet bead milling (nanomilling), self emulsifying systems, or complexation, for example cyclodextrin.

The pharmaceutical compositions of the invention may be formulated for

administration by any route, and include those in a form adapted for oral, topical,

intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal or transmucosal administration.

For oral administration, the compounds can be formulated into any suitable dosage form, for example, tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile solutions or suspensions, syrups, elixirs and

concentrated drops.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example a hard gelatin capsule shell or a soft gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;

non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.

For injection (parenteral administration) e.g. intramuscular, intravenous,

intraperitoneal, subcutaneous, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water, saline solution, Hank's solution or Ringer's solution. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. In addition, the compounds of the invention may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories. A typical suppository formulation comprises a compound of formula (I) or (I)' or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional non-CFC propellant such as 1 ,1 , 1 ,2-tetrafluoroethane or 1 ,1 , 1 ,2,3,3,3-heptafluoropropane.

The topical formulations of the present invention may be presented as, for instance, ointments, creams, gels, salves or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.

Preparations may be suitably formulated to give controlled/extended release of the active compound.

The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound (IC₅o) potency, (EC₅o) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.

Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of

administration of the present compounds.

Preferably the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.

In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I) or (I)'; for salts or esters thereof, the weights would be increased 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 given on alternative days or other appropriate schedule, for example, weekly or monthly. These sub- doses may be administered in unit dosage forms, for example, containing 0.5 - 100 mg, 5 to 1000 mg or 50 to 500 mg, or 20 to 500 mg, or 50 to 400 mg of active ingredient per unit dosage form. It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by

conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using

conventional course of treatment determination tests.

The compounds of formula (I) or (I)' or pharmaceutically acceptable salt(s) thereof may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or (I)' or

pharmaceutically acceptable salt thereof together with one or more further therapeutic agent(s).

Compounds of the invention may be administered in combination with other therapeutic agents, for example immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs,

bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy.

Compounds of the invention may be administered in combination with other therapeutic anti-viral agents selected from the list: interferon, pegylated interferon, ribavirin, protease inhibitors, for example, filibuvir, polymerase inhibitors, for example, boceprevir, telaprevir, or compounds disclosed in PCT/US2010/046782, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs,

immunoglobulines, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds. For example, combination therapy may comprise providing a compound for formula (I) or (la) or pharmaceutically acceptable salt thereof with other anti-viral agents, such as acyclovir, famciclovir, valganciclovir and related compounds, ribavirin and related compounds, amantadine and related compounds, various interferons such as, interferon-alpha, interferon-beta, interferon-gamma and the like as well as alternative forms of interferons such as pegylated interferons.

When a compound of formula (I) or (I)' or pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with at least one pharmaceutically acceptable carrier and/or excipient comprise a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions by any convenient route.

When administration is sequential, either the HCV inhibitor or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

The following non-limiting examples illustrate the present invention.

EXAMPLES

It will be appreciated by those skilled in the art that when solvents are used in reactions it is desirable to use anhydrous solvents. It is further desirable to conduct reactions under an inert atmosphere, for example under nitrogen or argon, where appropriate.

Abbreviations

PS-BBA = Polymer Supported Benzene Boronic Acid

aq. = aqueous

uL = microliters

μΜ = micromolar

NMR = nuclear magnetic resonance

boc = tert-butoxycarbonyl

br = broad

Cbz = benzyloxycarbonyl

d = doublet

δ = chemical shift

°C = degrees celcius dichloromethane

doublet of doublets

Dulbeco's Modified Eagle's Medium

N,N-dimethylformamide

dimethylsulfoxide

ethyl acetate

gram

hours

hepatitus C virus

high performance liquid chromatography hertz

International Units

inhibitory concentration at 50% inhibition coupling constant (given in Hz unless otherwise indicated)

multiplet

molar

parent mass spectrum peak plus H⁺ milligram

milliliter

millimolar

millimole

mass spectrum

nanomolar

parts per million

sufficient amount

singlet

saturated

triplet

trifluoroacetic acid

Intermediate 1

Methyl 2-(4-fluorophenyl)-5-hvdroxy-1-benzofuran-3-carboxylate

Using oven dried glassware and under an atmosphere of nitrogen, anhydrous zinc chloride (25g, 183 mmol) was stirred in anhydrous methanol (60 mL) then heated to a 75 °C internal temperature. Methyl 4-fluorobenzoylacetate (39.6 g, 202 mmol) was added as a single portion followed by dropwise addition of a solution of p-benzoquinone (19.83 g, 183 mmol) in anhydrous diethyl ether (500 mL) over 4 hours. This was performed with a simultaneous distillation of ether from the reaction mixture such that the reaction volume remained approximately constant (a bath temperature of 140 °C maintained an internal temperature initially at 75°C then gradually increasing to a maximum of 1 15°C). 2.5 hours after the start of the benzoquinone addition, more methanol (20 mL) was added to facilitate stirring. After addition of benzoquinone was complete, heating of the reaction mixture at 100°C (internal) continued for 1 hour. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate (800 mL). The insoluble solids were removed from the biphasic solution by filtration and the organic layer was then separated, dried (Na₂S0₄), filtered and evaporated under vacuum. The brown residue was slurried in warm dichloromethane (-225 mL) and the mixture was left to stand in a refrigerator for 18 hours. The resulting solids were filtered from the dark brown solution, washed with a small volume of dichloromethane then dried under vacuum to give Methyl 2-(4-fluorophenyl)-5-hydroxy-1 - benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 285 (M-1 ). Intermediate 2

Methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxyl-1-benzofuran-3-carboxylate

A mixture of methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate (18.86 g, 65.9 mmol), isopropyl bromide (24.74 mL, 264 mmol) and cesium carbonate (42.9 g, 132 mmol) in dry N-Methyl-2-pyrrolidone (191 mL) was stirred at 60°C under nitrogen for 20 hours. The resultant thick suspension was allowed to cool to room temperature and then 7% aqueous ammonia solution (200 mL) was added with rapid stirring. This mixture was extracted with heptane (700 mL) and then the aqueous phase was separated off. Ethyl acetate (-100 mL) was added to the organic phase and the resultant mixture was shaken and then dried over Na₂S0₄ and evaporated to give a brown oil which crystallized on standing overnight. This material was recrystallized from hot methanol and the solid was collected by filtration, washed with methanol and finally dried under vacuum to give methyl 2-(4-fluorophenyl)-5-[(1- methylethyl)oxy]-1 -benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 329 (M+1 ). The mother liquors from the first recrystallization were crystallized a second time to give an additional batch of Methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1 -benzofuran-3-carboxylate. Intermediate 3

-(4-fluorophenyl)-5-[(1 -methylethyl)oxyl-6-nitro-1-benzofuran-3-carboxylate

To a solution of methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 -benzofuran-3-carboxylate (6.16 g, 18.76 mmol) in chloroform (22 mL) at -15 °C was added dropwise a cold solution of 70% nitric acid (1 1 mL, 172 mmol) in chloroform (22 mL). After stirring at 0°C for 1 hour, the reaction mixture was washed with water (50 mL) and the organic phase was separated by hydrophobic filter tube then evaporated under vacuum to afford a brown solid. The solid was triturated in methyl ferf-butyl ether (25 mL) and the resulting pale yellow powder was filtered off, washed with heptane and dried under vacuum to give methyl 2-(4-fluorophenyl)-5-[(1- methylethyl)oxy]-6-nitro-1 -benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 764 (2M+ NH₄)⁺.

Intermediate 4

Methyl 6-amino-2-(4-fluorophenyl)-5-[(1-methylethyl)oxyl-1 -benzofuran-3-carboxylate

A solution of methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-6-nitro-1 -benzofuran-3- carboxylate (391 mg, 1.047 mmol) in ethyl acetate (15 mL) was stirred with 10% palladium on carbon (1 1 1 mg, 0.105 mmol) under an atmosphere of hydrogen at 21 °C for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a brown gum. This was redissolved in a small volume of diethyl ether and evaporated to give the Methyl 6-amino-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1- benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 344 (M+ 1 ). Intermediate 5

Methyl 6-rbis(methylsulfonyl)aminol-2-(4-fluorophenyl)-5-r(1 -methylethyl)oxyl-1 -benzofuran- -carboxylate

To a stirred mixture of methyl 6-amino-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1- benzofuran-3-carboxylate (1 .49 g, 4.34 mmol) in dry dichloromethane (25 mL) at 0°C under nitrogen was added di-isopropylethylamine (1 .895 mL, 10.85 mmol) followed by methanesulfonyl chloride (0.744 mL, 9.55 mmol). The reaction mixture was stirred for 1 hour and warmed to room temperature, washed with water and evaporated under vacuum to give methyl 6-[bis(methylsulfonyl)amino]-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 -benzofuran- 3-carboxylate. LCMS {m/z, ES⁺) = 517 (M+ NH₄)⁺.

Intermediate 6

2-(4-Fluorophenyl)-5-r(1-methylethyl)oxyl-6-r(methylsulfonyl)aminol-1 -benzofuran-3- carboxylic acid

Methyl 6-[bis(methylsulfonyl)amino]-2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-1 -benzofuran- 3-carboxylate (2.199 g, 4.40 mmol) was heated at 80°C in a mixture of methanol (20 mL), tetrahydrofuran (20.00 mL) and 2M sodium hydroxide (20 mL, 40.0 mmol) for 16 hours. The solvent was partially evaporated under vacuum and the reaction mixture was partitioned between dilute aqueous HCI and dichloromethane. The organic phase was separated by hydrophobic filter tube and evaporated to dryness to give 2-(4-Fluorophenyl)-5-[(1- methylethyl)oxy]-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxylic acid. LCMS {m/z, ES⁺) = 406 (M- H). Intermediate 7

2- (4-Fluorophenyl)-/\/-methyl-5-r(1 -methylethyl)oxyl-6-r(methylsulfonyl)aminol-1-benzofuran-

3- carboxamide

2-(4-Fluorophenyl)-5-[(1-methylethyl)oxy]-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxylic acid (1 .738 g, 4.27 mmol) was stirred in dry N,N-dimethylformamide (20 mL) at 21 °C with diisopropylethylamine (1.639 mL, 9.39 mmol). HATU (1.946 g, 5.12 mmol) was added and, after 10 minutes, a 2M solution of methylamine in THF (10.66 mL, 21.33 mmol) was added. The reaction mixture was stirred for 18 hours and then evaporated under vacuum. The residue was partitioned between dichloromethane and water. The organic phase was separated, passed through a hydrophobic filter tube and evaporated under vacuum. The residue was purified by ISCO Companion automated flash chromatography, eluting over silica gel with a gradient of 30-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give 2-(4-Fluorophenyl)-/V-methyl- 5-[(1-methylethyl)oxy]-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide. LCMS {m/z, ES⁺) = 421 (M+ H).

Intermediate 9

Methyl 2-(4-fluorophenyl)-5-hvdroxy-6-nitro-1 -benzofuran-3-carboxylate

To a stirred solution of methyl 2-(4-fluorophenyl)-5-[(1 -methylethyl)oxy]-6-nitro-1-benzofuran- 3-carboxylate (5.237 g, 14.03 mmol) in dry dichloromethane (70 mL) at -15°C, under an atmosphere of nitrogen, was added a 1 M solution of boron trichloride in dichloromethane (23.85 mL, 23.85 mmol) over 30 minutes using a syringe pump. The dark brown-red reaction mixture was poured over ice (-250 mL). The ice was allowed to melt and the mixture extracted with dichloromethane (-450 mL). The organic phase was separated by

hydrophobic filter tube and evaporated under vacuum to give the methyl 2-(4-fluorophenyl)-5- hydroxy-6-nitro-1 -benzofuran-3-carboxylate. ¹H NMR (d₆-DMSO): δ 10.97 (1 H, br. s), 8.34 (1 H, s), 8.07 (2H, dd), 7.67 (1 H, s), 7.43 (2H, t), 3.86 (3H, s).

Intermediate 10

Methyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonylloxy}-1-benzofuran-3-carboxylate

To an ice-cooled stirred mixture of methyl 2-(4-fluorophenyl)-5-hydroxy-6-nitro-1-benzofuran- 3-carboxylate (4.915 g, 14.84 mmol) and 4-(dimethylamino)pyridine (0.181 g, 1.484 mmol) in anhydrous dichloromethane (130 mL) under nitrogen, was added triethylamine (3.10 mL, 22.26 mmol) then trifluoromethanesulfonic anhydride (3.76 mL, 22.26 mmol). After 50 minutes the reaction, still in an ice bath at 0°C, was quenched by addition of water. The reaction mixture was partitioned between dichloromethane and water and the organics were separated. The aqueous phase was extracted with more dichloromethane and the combined organics were washed with 2M HCI then water. The organics were dried by hydrophobic filter tube and evaporated to give the Methyl 2-(4-fluorophenyl)-6-nitro-5- {[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 481 (M+ NH₄)⁺.

Intermediate 1 1

Methyl 5-cvclopropyl-2-(4-fluorophenyl)-6-nitro-1 -benzofuran-3-carboxylate

Methyl 2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate (7.12 g, 15.37 mmol), cyclopropylboronic acid (2.19 g, 25.5 mmol), potassium fluoride (3.26 g, 56.1 mmol), sodium bromide (1.75 g, 17.01 mmol) and

tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.736 mmol) were stirred together under nitrogen in a mixture of toluene (90 mL) and water (2.25 mL) and heated at 100°C for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic phase was separated, dried by hydrophobic filter tube and evaporated under vacuum. The residue was purified by ISCO Companion automated flash chromatography, eluting over silica gel with a gradient of 0-5% ethyl acetate in cyclohexane. Product containing fractions were evaporated under vacuum to give the methyl 5-cyclopropyl-2-(4- fluorophenyl)-6-nitro-1 -benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 728 (2M+ NH₄)⁺.

Intermediate 12

Methyl 6-amino-5-cvclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate

A solution of methyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1 -benzofuran-3-carboxylate (3.175 g, 8.94 mmol) in ethyl acetate (250 mL) containing 2M HCI (17 drops) was stirred with 10% palladium on carbon (0.951 g, 0.894 mmol) under an atmosphere of hydrogen at 21 °C for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a dark green solid. This was dissolved in dichloromethane, washed with sodium bicarbonate solution, separated by hydrophobic frit, then evaporated to dryness and purified by ISCO Companion automated flash chromatography, eluting over silica gel with a gradient of 0-30% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give the methyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1 - benzofuran-3-carboxylate. LCMS {m/z, ES⁺) = 326 (M+ H).

Intermediate 13

Methyl 6-rbis(methylsulfonyl)aminol-5-cvclopropyl-2-(4-fluorophenyl)-1-benzofuran-3- carboxylate

A solution of methyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1 -benzofuran-3-carboxylate (1 .96 g, 6.02 mmol) and triethylamine (2.52 mL, 18.07 mmol) in dry dichloromethane (40 mL) was cooled (ice bath) to 0°C, then treated with methanesulfonyl chloride (1.174 mL, 15.06 mmol). The reaction was stirred at 0°C (ice bath) for 2 hours. TLC (1 :1 ethyl

acetate/cyclohexane) showed no strongly KMn0₄ positive starting material remaining in the reaction mixture. Water (100 mL) was added and the organics extracted 3 times with dichloromethane, dried using an hydrophobic frit and evaporated to dryness to give the methyl 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3- carboxylate. LCMS {m/z, ES⁺) = 482 (M+ H).

Intermediate 14

-Cvclopropyl-2-(4-fluorophenyl)-6-r(methylsulfonyl)aminol-1 -benzofuran-3-carboxylic acid

A suspension of methyl 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1- benzofuran-3-carboxylate (2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was treated with potassium hydroxide (6.71 g, 120 mmol) and heated at reflux for 1 hour (the suspension went into solution upon heating). The reaction was concentrated under vacuum, water (100 mL) was added and the solution acidified with 2M HCI (50 mL). The resulting precipitate was filtered, washed with 0.5 M HCI, 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]-1 -benzofuran-3-carboxylic acid. LCMS {m/z, ES⁺) = 390 (M+ H).

Intermediate 15

5-Cvclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-r(methylsulfonyl)aminol-1 -benzofuran-3- carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran-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 dry dichloromethane (100 mL) was stirred at room temperature for 1 hour, then treated with methylamine (16.18 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 dichloromethane (300 mL) and sodium bicarbonate solution (200 mL) and stirred for 10 minutes. The layers were separated and the aqueous layer extracted with further dichloromethane (150 ml_). The combined organics were washed with brine

(200 ml_), dried using an hydrophobic frit and evaporated to dryness to give an off-white solid. The crude product was slurried in dichloromethane and applied to the top of a pre- packed silica gel cartridge (Biotage SNAP, 100g), then eluted using an ISCO companion automated flash chromatography apparatus, eluting with 0-100% ethyl acetate/cyclohexane. Some product eluted in the 40-60% ethyl acetate range, but a low mass was recovered from the column. The column was flushed with 10% methanol/dichloromethane, however some white solid still remained on top of the silica cartridge. The eluted product, the

methanol/dichloromethane flushed solution and the residual white solid from the top of the column were combined in a single flask and evaporated to dryness. This material was dissolved in hot methanol-chloroform (10% v/v) (there was still some insoluble solid) and loose silica gel added. The mixture was evaporated and the resulting solid dry-loaded on top of 2 x 100 g Biotage SNAP prepacked silica gel columns, without pre-equilibration of the column in the starting elution solvent, and purified using ISCO Companion automated flash chromatography, eluting with 0-10% methanol/dichloromethane. The product containing fractions were combined and evaporated to give the 5-Cyclopropyl-2-(4-fluorophenyl)-/V- methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide. LCMS {m/z, ES⁺) = 403 (M+ H).

Example 1

(6-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl (methylsulfonyl)aminolmethyl}-3-pyridinyl)boronic acid

Step 1: 5-bromo-2-(bromomethyl)pyridine

A solution of 5-bromo-2-methylpyridine (4.41 g, 25.6 mmol) and NBS (5.02 g, 28.2 mmol) in carbon tetrachloride (150 ml.) was treated with benzoyl peroxide (0.310 g, 1 .282 mmol) and maintained at reflux for 16 hours. The solution was concentrated onto celite and purified by column chromatography to afford 5-bromo-2-(bromomethyl)pyridine (2.25 g, 8.97 mmol, 35.0 % yield) as a dark semisolid. ¹H NMR (DMSO-d₆) δ: 8.71 (d, J = 2.1 Hz, 1 H), 8.10 (dd, J = 8.3, 2.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 4.70 (s, 2H)

Step 2: 6-[[(5-bromo-2^yridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl- 1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (250 mg, 0.621 mmol), 5-bromo-2-(bromomethyl)pyridine (195 mg, 0.777 mmol), and potassium carbonate (172 mg, 1.242 mmol) in acetonitrile (10 ml.) was maintained at 80 °C for 3 hours. The solution was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-[[(5-bromo-2-pyridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (297 mg, 0.519 mmol, 84 % yield) as a white foam. LCMS {m/z, ES⁺) = 574 (M+H)

Step 3: (6-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-3-pyridinyl)boronic acid

A solution of 6-[[(5-bromo-2-pyridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (55 mg, 0.096 mmol), potassium acetate (37.7 mg, 0.384 mmol), bis(pinacolato)diboron (61.0 mg, 0.240 mmol), and

PdCI₂(dppf)-CH₂CI₂ adduct (7.85 mg, 9.61 mol) in 1 ,4-dioxane (15 ml.) in a thick-walled glass pressure vessel was maintained at 90 °C with stirring for 16 hours. The solution was cooled to room temperature, diluted with celite, concentrated, and passed through a silica gel plug with ethyl acetate. The filtrates were concentrated and purified by reverse phase hplc to afford (6-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-3-pyridinyl)boronic acid (18 mg, 0.033 mmol, 34.9 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 8.58 (br. s., 1 H), 8.38 (br. s., 1 H), 8.03 - 8.17 (m, 1 H), 7.79 - 7.95 (m, 2H), 7.58 (s, 1 H), 7.53 (br. s., 1 H), 7.15 - 7.30 (m, 2H), 7.05 (s, 1 H), 5.06 (s, 2H), 3.24 (s, 3H), 2.92 (br. s., 3H), 2.28 (br. s., 1 H), 1.00 (br. s., 1 H), 0.83 (d, J = 3.3 Hz, 2H), 0.38 (br. s., 1 H). LCMS {m/z, ES⁺) = 538 (M+H)

Example 2

(2-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-4-Pyridinyl)boronic acid

Step 1: 4-bromo-2-(bromomethyl)pyridine

A solution of 4-bromo-2-methylpyridine (6.7 g, 38.9 mmol) and NBS (7.28 g, 40.9 mmol) in carbon tetrachloride (200 mL) was treated with benzoyl peroxide (0.472 g, 1 .947 mmol) and maintained at reflux for 16 hours. The solution was concentrated onto celite and purified by column chromatography to afford 4-bromo-2-(bromomethyl)pyridine (3.32 g, 13.23 mmol, 34.0 % yield) as a dark brown oil. ¹H NMR (DMSO-d₆) d: 8.45 (d, J = 5.3 Hz, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.63 (dd, J = 5.4, 1.9 Hz, 1 H), 4.67 (s, 2H) Step 2: 6-[[(4-bromo-2^yridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (250 mg, 0.621 mmol) and 4-bromo-2-(bromomethyl)pyridine (234 mg, 0.932 mmol) in acetonitrile (10 mL) was treated with potassium carbonate (258 mg, 1.864 mmol) and maintained at 80 °C for 3 hours. The solution was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 6- [[(4-bromo-2-pyridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-1 -benzofuran-3-carboxamide (303 mg, 0.529 mmol, 85 % yield) as a white foam. LCMS {m/z, ES⁺) = 574 (M+H)

Step 3: (2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-4-pyridinyl)boronic acid

A solution of 6-[[(4-bromo-2-pyridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (285 mg, 0.498 mmol), potassium acetate (195 mg, 1 .991 mmol), bis(pinacolato)diboron (316 mg, 1.245 mmol), and

PdCI₂(dppf)-CH₂Cl2 adduct (40.7 mg, 0.050 mmol) in 1 ,4-dioxane (10 mL) was maintained at 90°C in a sealed pressure flask for 16 hours. The mixture was cooled, stripped onto celite, passed through a plug of silica gel, and the residue purified by reverse phase hplc to afford (2-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-4-pyridinyl)boronic acid (18 mg, 0.033 mmol, 6.73 % yield) as a white solid. ¹H NMR (METHANOL-d₄) d: 8.32 - 8.45 (m, 2H), 7.81 - 7.94 (m, 2H), 7.68 (br. s., 2H), 7.61 (s, 1 H), 7.16 - 7.33 (m, 2H), 7.04 (s, 1 H), 5.04 - 5.19 (m, 2H), 3.24 (s, 3H), 2.90 (s, 3H), 2.15 - 2.36 (m, 1 H), 0.93 - 1.03 (m, 1 H), 0.76 - 0.91 (m, 2H), 0.35 (br. s., 1 H). LCMS {m/z, ES⁺) = 538 (M+H)

Example 3

(4-{r{2-(4-Fluorophenyl)-3-r(methylamino)carbonyll-5-r(1 -methylethyl)oxyl-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

To a solution of 2-(4-fluorophenyl)-/V-methyl-5-[(1 -methylethyl)oxy]-6-[(methylsulfonyl)amino]- 1-benzofuran-3-carboxamide (100 mg; 0.24 mmol) in N,N-dimethylformamide (2.5 mL) was added [4-(bromomethyl)phenyl]boronic acid (102 mg; 0.48 mmol) and potassium carbonate (99 mg, 0.71 mmol). The reaction was heated in a microwave for 15 minutes at 120°C and 300 W. The reaction seemed to be 30% complete. The reaction was heated in a microwave again for 30 minutes at 120°C and 300 W. No change occurred, hence one equivalent each was added of potassium carbonate (33 mg, 0.24 mmol) and [4-(bromomethyl)phenyl]boronic acid (51 mg; 0.24 mmol) and the reaction heated in a microwave for 20 minutes at 120°C and 300 W. The reaction was evaporated in vacuo and purified by MDAP. Appropriate fractions were combined and evaporated in vacuo, then freeze-dried using 1 ,4 dioxane to give (4-{[{2- (4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid as a white solid. ¹H NMR (DMSO-d₆) δ: 8.37 - 8.47 (m, 1 H), 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), 7.1 1 (s, 1 H), 4.90 - 5.12 (m, 1 H), 4.75 - 4.89 (m, 1 H), 4.52 - 4.74 (m, 1 H), 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-{r{2-(4-Fluorophenyl)-3-r(methylamino)carbonyll-5-r(1 -methylethyl)oxyl-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

(3-{[{2-(4-Fluorophenyl)-3-[(methylam

yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid was prepared in an analogous manner to that described for (4-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1- methylethyl)oxy]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid, using [3-(bromomethyl)phenyl]boronic acid. ¹H NMR (DMSO-d₆) δ: 8.36 - 8.51 (m, 1 H), 8.12 (s, 2H), 7.81 - 7.96 (m, 2H), 7.68 (s, 1 H), 7.61 (d, J = 7.3 Hz, 1 H), 7.29 - 7.43 (m, 4H), 7.18 - 7.29 (m, 1 H), 7.10 (s, 1 H), 4.90 - 5.08 (m, 1 H), 4.76 - 4.91 (m, 1 H), 4.54 - 4.72 (m, 1 H), 3.13 (s, 3H), 2.80 (d, J = 4.5 Hz, 3H), 1 .40 (d, J = 5.8 Hz, 6H). LCMS {m/z, ES⁺) = 555 (M+ H).

Example 5

(2-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyll-5-[(1 -methylethyl)oxyl-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

To a solution of 2-(4-fluorophenyl)-/V-methyl-5-[(1 -methylethyl)oxy]-6-[(methylsulfonyl)amino]- 1-benzofuran-3-carboxamide (200 mg; 0.48 mmol) in THF (5 ml.) was added [2- (bromomethyl)phenyl]boronic acid (307 mg; 1.43 mmol) and sodium ferf-butoxide (91 mg, 0.95 mmol). The reaction was stirred overnight and then evaporated to dryness in vacuo. The crude product was washed with 2M HCI, then the organics were extracted with dichloromethane, separated from the aqueous, dried using an hydrophobic frit and concentrated in vacuo. The crude product was purified by MDAP. Appropriate fractions were combined and evaporated in vacuo, then freeze-dried using 1 ,4 dioxane to give (2-{[{2- (4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid. ¹H NMR (DMSO-d₆) δ: 8.37 - 8.44 (m, 1 H), 8.08 (s, 2H), 7.84 - 7.92 (m, 2H), 7.60 (d, J = 7.8 Hz, 1 H), 7.41 (s, 1 H), 7.29 - 7.39 (m, 4H), 7.10 - 7.17 (m, 1 H), 7.09 (s, 1 H), 5.06 (br. s., 2H), 4.70 - 4.86 (m, 1 H), 3.07 (s,

(d, J = 4.5 Hz, 3H), 1.40 (d, 6H). LCMS {m/z, ES⁺) = 555 (M+ H).

Example 6

(3-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

To an oven dried flask was added 5-Cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (201 mg, 0.5 mmol), [3- (bromomethyl)phenyl]boronic acid (322 mg, 1 .5 mmol, CombiBlocks), potasium tert-butoxide (1 12 mg, 1 mmol), and THF (5 mL). The mixture was stirred at room temperature for 2 days. 2N HCI (5 mL) was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and

concentrated to afford a crude residue which could be purified by preparative hplc to give (3- {[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6

yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid (55 mg, 20% Yield). ¹ H NMR (300 MHz, CD30D) δ: 7.89 (t, 2H), 7.47 (m, 3H), 7.24 (m, 4H), 7.01 (s, 1 H), 4.60 (s, 2H), 3.14 (s, 3H), 2.91 (s, 3H), 2.21 (m, 1 H), 0.93 (m, 1 H), 0.77 (m, 2H), 0.37 (m, 1 H). LCMS {m/z, ES⁺) = 537 (M+1 ).

Example 7

(4-{[{5-cvclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

To an oven dried flask was added 5-Cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (201 mg, 0.5 mmol), [4- (bromomethyl)phenyl]boronic acid (322 mg, 1.5 mmol, CombiBlocks), potassium tert- butoxide (1 12 mg, 1 mmol), and THF (5 mL). The mixture was stirred at room temperature for 2 days. 2N HCI (5 mL) was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford a crude residue which could be purified by preparative hplc to give (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6

yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid (130 mg, 49% Yield). ¹H NMR (300 MHz, CD30D) δ: 7.89 (t, 2H), 7.55 (m, 3H), 7.24 (m, 4H), 7.02 (s, 1 H), 4.59 (s, 2H), 3.14 (s, 3H), 2.92 (s, 3H), 2.21 (m, 1 H), 0.94 (m, 1 H), 0.78 (m, 2H), 0.34 (m, 1 H). LCMS {m/z, ES⁺) = 537 (M+1 ).

Example 8

(2-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

To an oven dried flask was added 5-cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (201 mg, 0.5 mmol), [2- (bromomethyl)phenyl]boronic acid (322 mg, 1.5 mmol, CombiBlocks), potassium tert- butoxide (1 12 mg, 1 mmol), and THF (5 mL). The mixture was stirred at room temperature for 1 day. 2N HCI (5 mL) was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford a crude residue which could be purified by preparative hplc to give (4- {[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6

yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid (32 mg, 14% Yield). ¹ H NMR (300 MHz, CHLOROFORM-d) δ: 8.39 (m, 1 H), 8.05 (s, 1 H), 7.91 (t, 2H), 7.62 (s, 1 H), 7.34 (m, 5H), 6.92 (s, 1 H), 5.14 (s, 2H), 3.18 (s, 3H), 2.80 (m, 3H), 2.22 (m, 1 H), 0.83 (m, 3H), 0.35 (m, 1 H). LCMS {m/z, ES⁺) = 537 (M+1 ).

Example 9

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

Step 1 :1 -bromo-4-(bromomethyl)-2-fluorobenzene

To a stirred solution of (4-bromo-3-fluorophenyl)methanol (500 mg, 2.45 mmol) in 10 mL of ether was added a solution of phosphorus tribromide (460 mg, 1 .72 mmol) in 2 mL of ether. Once the addition was completed, the mixture was stirred for 30 mins at room temperature, and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice-water (10 mL), the organic layer was separated, and the aqueous phase was extracted with ether (5 mL x 2). The combined organic layers were washed with saturated NaHC0₃ solution (10 mL) and brine (10 mL), dried over Na₂S0₄, concentrated in vacuo to give 1 -bromo-4- (bromomethyl)-2-fluorobenzene (593 mg, 91 % yield) which was used for the next step without further purification.

Step 2: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (400 mg, 1 .0 mmol), Kl (166 mg, 1.0 mmol) and K₂C0₃ (414 mg, 3.0mmol) in dry DMF (10 mL) was treated with 1 -bromo-4- (bromomethyl)-2-fluorobenzene (532 mg, 2.0 mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give N-(2-(benzyloxy)ethyl)-6-(N-(2- (benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (464 mg, 79% yield).

Step 3: 5-cyclopropyl-6-(N-(3-fluoro-4-(4, 4, 5, 5-tetra methyl- 1, 3, 2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (51 mg, 0.044 mmol) and N-(2-(benzyloxy)ethyl)-6-(N-(2-

(benzyloxymethyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3- carboxamide (256 mg, 0.44 mmol) were dissolved in dioxane (10 mL) under nitrogen atmosphere. Bis(pinacoiato)diboron (224 mg, 0.88 mmol) and potassium acetate (129 mg, 1.32 mmol) were added and the mixture stirred at 100 °C overnight. The cooled reaction mixture was poured into water (20 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (220 mg, 81 % yield).

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

5-Cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, crude, 1 .91 mmol) was dissolved in a solution of THF (10 mL) and 5 N HCI (10 mL), and the mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by pre-HPLC to give 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid (52 mg, 30% yield). ¹H NMR (300 MHz, CD₃OD) δ = 7.95 (m, 2H), 7.63 (s, 1 H), 7.30 (q, 3H), 7.08 (q,3H), 4.97( m, 2H), 3.38 (s, 3H), 2.95 (s, 3H), 2.04 (m, 1 H), 1 .03 (m, 1 H),0.83 (m, 2H), 0.39 (m, 1 H). LCMS( m/z) ES⁺=555(M+1 )

Example 10

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methoxyphenylboronic acid

Step 1: 1-bromo-4-(bromomethyl)-2-methoxybenzene

To a stirred solution of (4-bromo-3-methoxyphenyl)methanol (500 mg, 2.32 mmol) in 10 mL of ether was added a solution of phosphorus tribromide (435 mg, 1 .62 mmol) in 2 mL of ether dropwise. Once the addition was complete, the mixture was stirred for 30 mins at room temperature and then heated to reflux for 1 hour. The cooled reaction mixture was then poured into ice-water (10 mL), the organic layer was separated, and the aqueous phase was extracted with ether (5 mL x 2). The combined organic layers were washed with saturated NaHC0₃ solution (10 mL) and brine (10 mL), dried over Na₂S0₄, concentrated in vacuo to give 1-bromo-4-(bromomethyl)-2-methoxybenzene (574 mg, 85% yield) which was used for the next step without further purification.

Step 2: 6-(N-(4-bromo-3-methoxybenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (400 mg, 1 .0 mmol), Kl (166 mg, 1.0 mmol) and K₂C0₃ (414 mg, 3.0mmol) in dry DMF (10 mL) was treated with 1 -bromo-4- (bromomethyl)-2-methoxybenzene (556 mg, 2.0mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (15 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(4-bromo-3- methoxybenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (512 mg, 85% yield). Step 3: 5-cyclopropyl-2-(4-fluorophenyl) -(N-(3-methoxy-4-(4^

dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (37 mg, 0.032 mmol) and 6-(N-(4-bromo-3-methoxybenzyl)methylsulfonamido)-5-cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (192 mg, 0.32 mmol) were dissolved in dioxane (10 mL) under nitrogen atmosphere. Bis(pinacoiato)d!boron (163 mg, 0.64 mmol), potassium acetate (94 mg, 0.96 mmol) were added and the mixture stirred at 100 °C overnight. The cooled reaction mixture was poured into water (20 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methoxy-

4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-N- methylbenzofuran-3-carboxamide (170 mg, 83% yield, crude).

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methoxyphenylboronic acid

5- Cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (150 mg, crude,0.23 mmol) was dissolved in a solution of THF (10 mL) and 5 N HCI (10 mL), and the result reaction mixture was heated to 60 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by pre-HPLC to give 4-((N-(5- cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methoxyphenylboronic acid (40 mg, 31 % yield). ¹H NMR (300 MHz, CD₃OD-d4) δ = 7.94(m, 2H), 7.50 (s, 1 H), 7.30 (q, 3H), 7.07 (d,2H), 6.86(d,1 H), 4.91 ( m, 2H), 3.78(s, 3H), 3.16 (s, 3H), 2.95 (s, 3H),2.04 (m, 1 H), 1 .03 (m, 1 H), 0.83 (m, 2H), 0.39 (m, 1 H). LCMS( m/z) ES⁺=567(M+1 ) Example 1 1

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methylphenylboronic acid

Step 1: 1-bromo-4-(bromomethyl)-2-methylbenzene

To a stirred solution of (4-bromo-3-methylphenyl)methanol (400 mg, 2 mmol) in 10 mL of ether was added a solution of phosphorus tribromide (375 mg, 1 .4 mmol) in 2 mL of ether. Once the addition was complete, the mixture was stirred for 30 mins at room temperature, and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice-water (10 mL), the organic layer was separated, and the aqueous phase was extracted with ether (5 mL x 2). The combined organic layers were washed with saturated NaHC0₃ solution (10 mL) and brine (10 mL), dried over Na₂S0₄ and concentrated under reduced pressure to give 1-bromo-4-(bromomethyl)-2-methylbenzene (488 mg, 93% yield) which was used for the next step without further purification. Step 2: 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluoroph N-methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (400 mg, 1 .0 mmol), Kl (166 mg, 1.0 mmol) and K₂C0₃ (414 mg, 3.0 mmol) in dry DMF (10 mL) was treated with 1 -bromo-4- (bromomethyl)-2-methylbenzene (488 mg, 1.86mmol) and the reaction heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (15 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(4-bromo-3- methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (480 mg, 82% yield).

Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4_!4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide

1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (40 mg, 0.035 mmol) and 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (205 mg, 0.35 mmol) were dissolved in dioxane (10 mL) under nitrogen atmosphere. B!s(pinaco!ato)diboron (178 mg, 0.70 mmol), potassium acetate (103 mg, 1.05 mmol) were added and the mixture stirred at 100 °C overnight. The cooled reaction mixture was poured into water (20 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-

3- carboxamide (156 mg, 72% yield).

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-methylphenylboronic acid

5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (120 mg, crude, 0.19 mmol) was dissolved in THF (10 mL) and 5 N HCI (10 mL), and the result reaction mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by pre-HPLC to give 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-methylphenylboronic acid (20 mg, 19% yield). ¹H NMR (300 MHz, CD₃OD-d4) δ = 7.94(m, 2H), 7.57(s,1 H),7.27 (t, 2H),7.16 (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, 1 H), 0.83 (m, 2H), 0.30 (m, 1 H). LCMS( m/z) ES⁺=551 (M+1 )

Example 12

4- ((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

Step 1: 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene

1-Bromo-4-methyl-2-(trifluoromethyl)benzene (1 g, 4.2 mmol), benzoyl peroxide (0.1 g, 0.42 mmol) and N-bromosuccinimide (0.75 g, 4.2 mmol) were dissolved in 50 mL of CCI₄ and heated to reflux for 2 hours. The reaction mixture is filtered, and the filtrate was cooled and concentrated in vacuo. The residue was purified by column chromatography (eluting with petroleum) to give 1 -bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene (1.1 g, 86% yield).

Step 2: 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (1 g, 2.5 mmol), Kl (0.415 g, 2.5 mmol) and K₂C0₃ (1.04 g, 7.5 mmol) in dry DMF (10 mL) was treated with 1 -bromo-4-(bromomethyl)-2- (trifluoromethyl)benzene (1 .1 g, 3.5 mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried with anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0- 50% ethyl acetate in petroleum) to give 6-(N-(4-bromo-3- (trifluoromethyl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (1 .1 g, 69% yield).

Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl-1 ,3, 2- dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3-carboxamide 1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (185 mg, 0.16 mmol) and 6-(N-(4-bromo-3-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 g, 1 .6 mmol) were dissolved in dioxane (10 mL) under nitrogen atmosphere. Bis(pinacolaio)diboron (0.8 g, 3.2 mmol), potassium acetate (0.47 g, 4.8 mmol) were added and the mixture stirred at 100 °C overnight. The cooled reaction mixture was poured into water (20 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3- carboxamide (420 mg, 39% yield).

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (300 mg, crude, 0.43 mmol) was dissolved in a solution of THF (10 mL) and 5 N HCI (10 mL), and the reaction mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by pre-HPLC to give 4-((N-(5-cyclopropyl-2-(4- fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2- methylphenylboronic acid (125 mg, 47% yield). ¹H NMR (300 MHz, CD₃OD-d4) δ = 7.94(m, 2H), 7.65(d,2H),7.47 (d, 1 H),7.36 (t, 2H), 7.03 (s,1 H), 6.86(d,1 H),5.12( m, 2H), 3.21 (s, 3H), 2.94 (s, 3H), 2.25 (m, 1 H), 0.98 (m, 1 H), 0.83 (m, 2H), 0.30 (m, 1 H). LCMS( m/z)

ES⁺=605(M+1 ).

Example 13

4-((N-(2-(4-chlorophenyl)-5-cvclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

Step 1: ethyl 3-(4-chlorophenyl)-3-oxopropanoate

To a solution of 4-chlorobenzoic acid (30.0 g, 0.192 mol) in DCM (250 mL) was added oxalyl chloride (25 mL, 0.288 mol) and then DMF (0.5 mL) was added dropwise. The reaction mixture was refluxed for 2 hrs. The resulting clear yellow solution was concentrated in vacuo. The acid chloride was obtained as yellow liquid. To a solution of ethyl potassium malonate (41 g, 0.241 mol) in acetonitrile (537 mL) was added TEA (67 mL) and cooled in an ice-salt bath, MgCI₂ (27.4 g, 0.288 mol) was added, and the resulting mixture was stirred at that temperature for 3 hrs. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After the reaction was complete (as monitored by TLC), the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2N HCI (600 mL). This mixture was stirred in the ice bath for 1 .5 hrs then transferred to a separatory funnel and extracted with ethyl acetate (3^*200 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate (450 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product ethyl 3-(4-chlorophenyl)-3-oxopropanoate ( 48.6 g, 1 10 % yield) which was used without purification in subsequent steps.

Step 2: Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (28.3 g, 0.207 mol) was stirred in anhydrous ethanol (45 mL) then heated to 95 °C (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4- chlorobenzoylacetate (44 g, 0.194 mol) was added as a single portion followed by dropwise addition of a solution of benzoquinone (22.6 g, 0.21 mol) in anhydrous MTBE (500 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155 °C and an internal temperature of 75-95 °C maintained throughout most of the addition. Halfway through the addition more anhydrous ethanol (45 mL) was added because the reaction mixture became thick and a loss of some of the original volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm

dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give ethyl 2-(4-chlorophenyl)-5- hydroxybenzofuran-3-carboxylate (27 g, 43.9 %).

Step 3: ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (26 g, 0.051 mol) in NMP (160 mL) was added isopropyl bromide (15 mL), then cesium carbonate (33 g, 0.101 mol) was added. The reaction mixture was stirred in a 60 °C oil bath for 20 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3- carboxylate (15 g, 82 %). Step 4: ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.084 mol) was dissolved in chloroform (75 mL) and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in chloroform (75 mL) and cooled in an ice bath. The acid solution was added dropwise to the solution of ethyl 2-(4-chlorophenyl)-5- isopropoxybenzofuran-3-carboxylate over 1 hour, and the reaction mixture was then stirred at 0°C for 1 .5 hrs. The reaction mixture was then diluted with water (60 mL) and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil which was purified by column chromatography ( PE/EA = 5/1 ) to afford ethyl 2-(4-chlorophenyl)-5-isopropoxy-6- nitrobenzofuran-3-carboxylate as a brown solid (1 1 g, 32.4 %).

Step 5: Ethyl 2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (1 1 g, 27.2 mmol) was dissolved in anhydrous DCM (150 mL) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (41 mL, 41.0 mmol) was added over -20 minutes. After the reaction was complete, the reaction mixture was quenched by pouring into an ice/water mixture. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give ethyl 2-(4- chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate ( 10.2 g, 84 %).

Step 6: Ethyl-2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate

To a solution of ethyl 2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.2 g, 22.9 mmol) and DMAP (0.289 g, 2.3 mmol) in anhydrous DCM (300 mL) and anhydrous TEA (4.8 mL) in an ice bath under nitrogen was added trifluoromethane sulfonic anhydride (5.62mL, 34 mmol). The reaction mixture was stirred under nitrogen at 0°C for 30 min then quenched at 0 °C with water (200 mL) and extracted with DCM (3x200 mL). The combined organic layers were washed with water (3 x 600 mL), 2N HCI (2 x 300 mL), water (300mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Ethyl 2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (10 g, 80 %) was obtained as a yellow solid. It was used without further purification.

Step 7: Ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate

A mixture of 2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3- carboxylate (10 g, 18 mmol), KF (4.64 g, 79.9 mmol), NaBr (2.48 g, 24 mmol),

cyclopropylboronic acid (3.2 g, 37 mmol), and Pd(Ph₃P)₄ (1.33 g, 1.15 mmol) were added toluene (130 ml.) and water (2.8 ml_). The reaction flask was evacuated for ~3 minutes then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hrs then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (150 ml_), washed with water (3x200 ml_), brine (200 ml_), dried with anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ ethyl acetate = 30/1 -10/1 ) to afford ethyl 2-(4-chlorophenyl)-5-cyclopropyl- 6-nitrobenzofuran-3-carboxylate as a yellow solid (7.9 g, 99 %).

Step 8: Ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate

To a solution of ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate (8 g, 18.2 mmol) in ethyl acetate (450 ml.) was added 10% palladium on carbonate (1 .83 g), 1 N HCI solution (2.5 ml_), and stirred with under 0.4 MPa of hydrogen at room temperature for 8 hrs. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate as a brown solid (7.4 g, 99 %).

Step 9: Ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N- (methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate

To a solution of ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (7.4 g, 18.06 mmol) in dry dichloromethane (170 ml.) at -15 °C under N₂ atmosphere was added dry TEA (6.73 ml_, 45.15 mmol) and then methanesulfonyl chloride (4.91 ml_, 63.2 mmol) dropwise. The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100 ml.) and extracted with DCM (3x 150ml_). The organic layers were combined, dried with NaS0₄, filtered and evaporated under vacuum to afford ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-

(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate (9.2 g, 99 %).

Step 10: 5-Cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid

Potassium hydroxide(15.1 g, 270 mmol) was added to a solution of the ethyl 2-(4- chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3- carboxylate in ethanol(64 ml.) and water(32 ml.) under nitrogen atmosphere. The reaction was refluxed for 1 hour and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 N HCI (250 ml.) until a precipitate formed. The solid was filtered and then dried to afforded 5-cyclopropyl-2-(4-chlorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxylic acid (8.7 g, quantitative yield). Step 11: 5-Cyclopropyl-2-(4-chlorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide

A solution of 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (5 g, 1 1.52 mmol) in dry DMF (30 ml.) was added with DIPEA (3.3 g, 25.34 mmol), HATU (5.15 g, 13.5 mmol) at 20 °C. After 15 minutes, 2M Methylamine in THF(23.04 ml_, 46.08 mmol) was added dropwise and the mixture was stirred for another 2 hours before water (60 ml.) was added. The mixture was extracted with EA(3 x 200 ml_), washed with water (2^*200 ml_), dried and concentrated to afford 5-Cyclopropyl-2-(4-chlorophenyl)-N- methyl-6-(methylsulfonamido)benzofuran -3-carboxamide as a brown solid (4.7 g, 97 %).

Step 12: 1-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 (1.50 g, 8.4 mmol) were dissolved in 50 ml. of CCI₄ and heated to reflux for 2 hours. The reaction mixture is filtered, and the filtrate was cooled and concentrated in vacuo. The residue was purified by column chromatography (eluting with petroleum) to give 1 -bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene (2.20 g, 86 %).

Step 13: 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)methylsulfonamido)-2-(4-ch

cyclopropyl-N-methylbenzofuran-3-carboxamide

A suspension of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (500 mg, 1 .20 mmol), Kl (199 mg, 1 .20 mmol) and K₂C0₃ (497 mg, 3.60 mmol) in dry DMF (10 ml.) was treated with 1-bromo-4- (bromomethyl)-2-(trifluoromethyl)benzene (758 mg, 2.40 mmol) and the reaction was heated to reflux under nitrogen for 30 minutes. The reaction was cooled, diluted with water (20 ml_), and extracted with EtOAc (20 ml_x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column

chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(4-bromo-3- (trifluoromethyl)benzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N- methylbenzofuran-3-carboxamide (535 mg, 68 %).

Step 14: 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl- 1, 3, 2- dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)b

1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (95 mg, 0.082 mmol) and 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)methylsulfonamido)-2-(4- chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (535 mg, 0.82 mmol) were dissolved in dioxane (20 ml.) under nitrogen atmosphere. Bis(pinacolato)diboron (417 mg, 1 .64 mmol) and potassium acetate (241 mg, 2.46 mmol) were added and the mixture was stirred at 100 °C overnight. The cooled reaction mixture was poured into water (20 ml_), and extracted with EtOAc (20 ml. x 3). The combined organic layers were dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column

chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 2-(4-chlorophenyl)-5- cyclopropyl-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-

(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (423 mg, 73 %).

Step 15: 4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (423 mg, 0.60 mmol) was dissolved in THF (10 ml.) and treated with 5 N HCI (1.5 ml.) and PS-benzene boronic acid (1.16 g, 3.0 mmol). The suspension was stirred for 6 hours, filtrated, and concentrated under reduced pressure. The residue was purified by pre-HPLC to give 4-((N- (2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid (1 10 mg, 30% yield). ¹H NMR (300 MHz, CD₃OD) δ = 7.87-7.84 (d, 2H), 7.64-7.35 (m, 6H), 7.02 (s, 1 H), 5.1 1-4.84 (m, 2H), 3.19 (s, 3H), 2.93 (s, 3H), 2.24-2.18 (m, 1 H), 0.97-0.96 (m, 1 H), 0.80-0.71 (m, 2H), 0.29-0.28 (m, 1 H)

LCMS( m/z) ES+=621 (M+1 ).

Example 14

4-((N-((2-(4-chlorophenyl)-5-cvclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

Step 1: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl- N-methylbenzofuran-3-carboxamide

Potassium carbonate(494 mg, 3.58 mmol), Kl (198 mg, 1 .19 mmol) and 1 -bromo-4- (bromomethyl)-2-fluorobenzene (640 mg, 2.39 mmol) were added to a solution of 2-(4- chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (0.5 g, 1.194 mmol) in dry DMF (8 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, then diluted with water (30 mL) and filtered. The filtration residue was dissolved in EA, dried and concentrated in vacuo and purified by column chromatography (first EA/PE=1 :5, then EA/PE=1 :2) to give 6-(N-(4-bromo-3- fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3- carboxamide as a brown solid(536 mg, 74 %).

Step 2: 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4, 4, 5, 5-tetra methyl- 1, 3, 2- dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N- methylbenzofuran-3-carboxamide (536 mg, 0.885 mmol), bispinacolatodiboron (449 mg, 1 .77 mmol) and KOAc (260 mg, 2.655 mmol) were added in 1 ,4-dioxane (20 mL) under nitrogen atmosphere. Pd(dppf)₂CI₂(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 (first EA PE=1 :5, 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-dioxaborolan-2- yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (0.412 g, 72 %).

Step 3: 4-((N-((2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (0.412 g, 0.631 mmol) was dissolved in THF (15 mL) and treated with 5 N HCI (0.88 mL) and PS-benzene boronic acid (0.09 g, 3.155 mmol). The suspension was stirred overnight, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 4- ((N-((2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-fluorophenylboronic acid as a white solid (1 10 mg, 30.5 %). ¹H NMR (300MHz, CDCI₃) δ =7.88-7.83(d,2H),7.62-7.50 (m,3H), 7.30-7.26 (t,1 H), 7.07-6.98 (m,3H), 5.00-4.80 (m,2H), 3.17(s,3H), 2.93 (s,3H), 2.27-2.22 (m, 1 H), 0.98 (m,1 H), 0.84-0.80 (m,2H), 0.35-0.34 (m, 1 H). LCMS( m/z) ES+=571 .1 (M+1 ).

Example 15

4-(2-(N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid

Step 1: 1 -bromo-4-(2-bromoethyl) benzene

A stirred solution of 2-(4-bromophenyl)ethanol (1 g, 0.005 mmol) in 15 mL of ether was added dropwise a solution of phosphorus tribromide (0.94 g, 0.0035 mmol) in 10 mL of ether. Once the addition was complete, the mixture was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice-water (20 mL), the organic layer was separated, and the aqueous phase was extracted with ether (20 mL x 2). The combined organic layers were washed with saturated NaHC0₃ solution (25 mL) and brine (25 mL), dried over Na₂S0₄, and concentrated under reduced pressure to give 1-bromo-4-(2-bromoethyl)benzene (1 .10 g, 84 %) which was used for the next step without further purification.

Step 2: 6-(N-(4-bromophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (500 mg, 1 .24 mmol), Kl (208 mg, 1 .24 mmol) and K₂C0₃ (513 mg, 3.72 mmol) in dry DMF (15 mL) was treated with 1-bromo-4-(2- bromoethyl)benzene (650 mg, 2.48 mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0- 50% ethyl acetate in petroleum) to give 6-(N-(4-bromophenethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (336 mg, 46 %). Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl-1 , 3, 2- dioxaborolan-2-yl)phenethyl)methylsulfonamido)benzofuran-3-carboxamide

1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (66 mg, 0.057 mmol) and 6-(N-(4-bromophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (330 mg, 0.57 mmol) were dissolved in dioxane (20 mL) under nitrogen atmosphere. Bis(pinacolato)diboron (287 mg, 1 .13 mmol) and potassium acetate (168 mg, 1 .71 mmol) were added and the mixture was stirred at 100 °C overnight. The cooled reaction mixture was poured into water (25 mL), and extracted with EtOAc (20 mLx 3). The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenethyl)methylsulfonamido)benzofuran-3-carboxamide (256 mg,

71 %).

Step 4: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)benzofuran-3-carboxamide (250 mg, 0.40 mmol) was dissolved in a solution of THF (10 ml.) and 5 N HCI (1.5 ml_), and the resulting reaction mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by pre-HPLC to give 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)phenylboronic acid (59 mg, 27 %). ¹ H 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, 1 H), 1.07 (m, 1 H), 0.93 (m, 2H), 0.83 (m, 1 H). LC-MS( m/z) ES+=551 (M+1 ).

Example 16

3-(2-(N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid

Step 1: 1 -bromo-3-(2-bromoethyl) benzene

To a stirred solution of 2-(3-bromophenyl)ethanol (1 g, 0.005 mmol) in 15 mL of ether was added dropwise a solution of phosphorus tribromide (0.94 g, 0.0035 mmol) in 10 mL of ether. Once the addition was complete, the mixture was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice-water (20 mL), the organic layer was separated, and the aqueous phase was extracted with ether (20 mL x 2). The combined organic layers were washed with saturated NaHC0₃ solution (25 mL) and brine (25 mL), dried over Na₂S0₄ and concentrated in vacuo to give 1 -bromo-3-(2- bromoethyl)benzene (500 mg, 38%) which was used for the next step without further purification. Step 2: 6-(N-(3-bromophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (400 mg, 1 .00 mmol), Kl (166 mg, 1 .00 mmol) and K₂C0₃ (414 mg, 3.00 mmol) in dry DMF (15 ml.) was treated with 1-bromo-3-(2- bromoethyl)benzene (500 mg, 1.90 mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (20 ml.) and extracted with EtOAc (15 ml_x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0- 50% ethyl acetate in petroleum) to give 6-(N-(3-bromophenethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 34 %).

Step 3:

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)benzofuran-3-carboxamide

1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (39 mg, 0.034 mmol) and 6-(N-(3-bromophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.34 mmol) were dissolved in dixoane (15 ml.) under nitrogen atmosphere. Bis(pinacolato)diboron (174 mg, 0.69 mmol) and potassium acetate (100 mg, 1 .02 mmol) were added and the mixture stirred at 100 °C overnight. The cooled reaction mixture was poured into water (15 ml_), and extracted with EtOAc (15 ml_x 3). The combined organic layers were dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with 0- 50% ethyl acetate in petroleum) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenethyl)methylsulfonamido)benzofuran-3- carboxamide (196 mg, 91 %).

Step 4:

3-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)benzofuran-3-carboxamide (190 mg, crude,0.30 mmol) was dissolved in a solution of THF (10 ml.) and 5 N HCI (1.5 ml_), and the result reaction mixture was heated to 60 °C and stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by pre-HPLC to give 3-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)phenylboronic acid (50 mg, 30 %).¹H NMR (300 MHz, CD₃OD) δ = 7.97-7.92 (m, 2H), 7.62 (s, 1 H), 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, 1 H), 1.06 (d, 2H), 0.90 (m, 1 H), 0.70 (m, 1 H). LCMS( m/z) ES+=551 (M+1 ).

Example 17

4-((N-(5-cvclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

Step 1: ethyl 3-(4-bromophenyl)-3-oxopropanoate

A solution of 4-bromobenzoic acid (40.0 g, 0.199 mol) in DCM (300 mL) was added oxalyl chloride (27 mL, 0.31 1 mol) then DMF (0.5 mL) was added dropwise. The reaction mixture was refluxed for 2 hrs. The resulting clear solution was concentrated in vacuo. The acid chloride was obtained as yellow liquid. To a solution of ethyl potassium malonate (38g, 0.222 mol) in MeCN (550 mL) was added TEA (76 mL) and cooled in an ice-salt bath, MgCI₂ (28.4 g, 0.299 mol) was added, and the resulting mixture was stirred at that temperature for 3 hrs. The acid chloride prepared above was added, and the reaction mixture was warmed to ambient temperature and stirred overnight. After the reaction was completed (as monitored by TLC), the mixture was cooled in an ice bath and the intermediate was decarboxylated by careful addition of 2 N HCI (600 mL). This mixture was stirred in the ice bath for 1 .5 hrs then transferred to a separatory funnel and extracted with EA (3 x 200 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate (450 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford ethyl 3-(4- bromophenyl)-3-oxopropanoate ( 48.4 g, 89 %).

Step 2: ethyl 2-(4-bromophenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (26.8 g, 0.197 mol) was stirred in anhydrous ethanol (75 mL) then heated to 95 °C (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4- Bromobenzoylacetate (50 g, 0.184 mol) was added as a single portion followed by dropwise addition of a solution of benzoquinone (21.5 g, 0.199 mol) in anhydrous MTBE (550 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155 °C and an internal temperature of 75-95 °C was maintained throughout most of the addition. Half way through the addition more anhydrous ethanol (75 mL) was added because the reaction mixture became thick and a loss of some of the original volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried, and evaporated under vacuum. The residual brown solid was slurried in warm dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give ethyl 2-(4-bromophenyl)-5- hydroxybenzofuran-3-carboxylate (26.5 g, 39 %).

Step 3: ethyl 2-(4-bromophenyl)-5-isopropoxybenzofuran-3-carboxylate

To a solution of ethyl 2-(4-bromophenyl)-5-hydroxybenzofuran-3-carboxylate (26.5 g, 0.073 mol) in NMP (300 mL) was added 2-lodopropane (22 mL), then cesium carbonate (47.8 g, 0.147 mol) was added. The reaction mixture was stirred in a 60 °C oil bath for 4 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give ethyl 2-(4-bromophenyl)-5-isopropoxybenzofuran- 3-carboxylate (30 g, 102 %).

Step 4: ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-bromophenyl)-5-isopropoxybenzofuran-3-carboxylate (30 g, 0.073 mol) was dissolved in chloroform (60 mL) and the resulting solution was cooled in an ice bath. Nitric acid (49 mL) was also dissolved in chloroform (60 mL) and cooled in an ice bath. The acid solution was added dropwise to the solution of compound ethyl 2-(4-bromophenyl)-5- isopropoxybenzofuran-3-carboxylate over 0.5 hour, and the reaction mixture was then stirred at 0°C for 0.5 hour. The reaction mixture was then diluted with water (100 mL) , and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil .It was slurried in 15 mL MTBE then filtered to obtained ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as an orange solid (14.5 g, 44.6 %).

Step 5: ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate Ethyl 2-(4-bromophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (13.2 g, 29.45 mmol) was dissolved in toluene(80 mL) . Di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (2 g, 4.712 mmol), potassium phosphate (12.5 g, 58.9 mmol) and palladium diacetate (529 mg, 2.356 mmol) were added. The resulting solution was stirred under N₂ at 100 °C overnight. The reaction was cooled to room temperature and washed with water (3x 50 mL) The combined solution was dried and concentrated to afford ethyl 2-(4-(4-fluorophenoxy)phenyl)- 5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a yellow solid following recrystallization from ethanol (1 1 .1 g, 78.7 %).

Step 6: Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate Ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (1 1.1 g, 23.15mmol) was dissolved in anhydrous DCM (150 mL) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (35 mL, 34.7mmol) was added over -20 minutes. After the reaction was complete, the reaction mixture was quenched by pouring into an ice/water mixture. The reaction mixture was poured into the ice/water mixed with DCM. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give ethyl 2-(4-(4- fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.4 g, quantitative yield).

Step 7: Ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran- 3-carboxylate

To a solution of ethyl 2-(4-(4-fluorophenoxy)phenyl)-5-hydroxy-6-nitrobenzofuran-3- carboxylate (10.4 g, 23.15 mmol) and DMAP (0.292 g, 2.39 mmol) in anhydrous DCM (350 mL) and anhydrous TEA (4.85 mL) in an ice bath under nitrogen was added trifluoromethane sulfonic anhydride (5.68mL, 34.4 mmol). The reaction mixture was stirred under nitrogen at 0°C for 30 minutes then quenched at 0 °C with water (200 mL) and extracted with DCM (3x200 mL). The combined organic layers were washed with water (3x600 mL), 2N HCI (2x300 mL), water (300mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl 2-(4-(4-fluorophenoxy)phenyl)-6-nitro-5- (trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (13.25 g, 100 %) was obtained as a yellow solid. Step 8: Ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran-3-carboxylate To a mixture of 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), cyclopropylboronic acid (3.0 g, 34.91 mmol), and Pd(Ph₃P)₄ (1.34 g, 1 .16 mmol) were added toluene (130 mL) and water (3 mL). The reaction flask was evacuated for ~3 minutes then filled with nitrogen. The reaction mixture was refluxed under nitrogen for 20 hrs then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (150 mL), washed with water (3x200 mL), brine (200 mL), dried with anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified by column chromatography (first PE/EA=4/1 , then PE/EA=1/1 ) to afford ethyl 5- cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran-3-carboxylate as a yellow solid (8.4 g, 78 %).

Step 9: Ethyl 6-amino-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)benzofuran-3-carboxylate To a solution of ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-nitrobenzofuran-3- carboxylate (8.4 g, 18.2 mmol) in ethyl acetate (400 ml.) was added 10% palladium on carbon (1 .56 g), 1 N HCI aqueous solution (2.3 ml_), and stirred with under 0.4 MPa of hydrogen at room temperature for 8 hrs. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give the amine as a brown solid (8 g, 100 %).

Step 10: Ethyl 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(N- (methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate

To a solution of ethyl 6-amino-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)benzofuran-3- carboxylate (8 g, 18.54 mmol) in dry dichloromethane (180 ml.) at -15 °C under N₂ atmosphere was added dry TEA (6.91 ml_, 46.35 mmol) then added dropwise

methanesulfonyl chloride (5.05 ml_, 64.9 mmol). The stirred solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100ml_) and extracted with DCM (3x150ml_). The organic layers were combined, dried with Na₂S0₄, filtered and evaporated under vacuum to afford ethyl 5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3- carboxylate as a brown solid (9.5 g, 87 %). Step 11: 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-(methylsulfonamido)benzofuran-3- carboxylic acid

Potassium hydroxide(13.6 g, 243 mmol) was added to a solution of the ethyl 5-cyclopropyl-2- (4-(4-fluorophenoxy)phenyl)-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3- carboxylate in ethanol(70 ml.) and water(35 ml.) under nitrogen atmosphere. The reaction was refluxed for 1 hour and then concentrated in vacuo. The remaining solid was dissolved in water, and the solution was acidified with 2 N HCI (141 ml.) until a precipitate formed. The solid was filtered and then dried to afforded 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6- (methylsulfonamido)benzofuran-3-carboxylic acid a white solid (9 g, quant, yield). Step 12: 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide To a solution of 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-6-

(methylsulfonamido)benzofuran-3-carboxylic acid (9.9 g, 20.56 mmol) in dry DMF (50 mL) was added DIPEA (5.86 g, 45.23 mmol), and HATU (9.42 g, 24.67 mmol) at 20 °C. After 15 minutes, 2 M Methylamine in THF (41.12 mL, 82.24 mmol) was added dropwise and the mixture was stirred for another 2 hours, and then water as added(200ml). The mixture was extracted with EA (3x 250 mL), washed with water (2x 200 mL), dried and concentrated to afford 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide as a reddish brown thick oil (10 g, 98 %). Step 13: 1-bromo-4-(bromomethyl)-2-fluorobenzene

To a stirred solution of (4-bromo-3-fluorophenyl)methanol (15 g, 0.074 mol) in 40 mL of ether was added, a solution of phosphorus tribromide (14 g, 0.052 mol) in 10 mL of ether. Once the addition was complete, the mixture was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The cooled reaction mixture was poured into ice-water (50 mL), the organic layer was separated, and the aqueous phase was extracted with ether (2x 50 mL). The combined organic layers were washed with saturated NaHC0₃ solution (50 mL) and brine (50 mL), dried over Na₂S0₄, concentrated in vacuo to give 1 -bromo-4- (bromomethyl)-2-fluorobenzene (12.3 g, 62 %) which was used for the next step without further purification.

Step 14: 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide.

A suspension of 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-

(methylsulfonamido)benzofuran-3-carboxamide (500 mg, 1 .01 mmol), Kl (168 mg, 1 .01 mmol) and K₂C0₃ (418 mg, 3.03 mmol) in dry DMF (10 mL) was treated with 1-bromo-4- (bromomethyl)-2-fluorobenzene (537 mg, 2.02 mmol) and the reaction was heated to reflux under nitrogen for half an hour. The reaction was cooled, diluted with water (30 mL), and extracted with EtOAc (20 mL x3). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The crude product was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 6-(N-(4-bromo-3- fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N- methylbenzofuran-3-carboxamide (51 1 mg, 74 %).

Step 15: 5-cyclopropyl-6-(N-(3-fluoro-4-(4, 4, 5, 5-tetra methyl- 1, 3, 2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-(4-fluorophenoxy)phenyl)-N-methylbenzofuran-3- carboxamide 1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (87 mg, 0.075 mmol) and 6-(N-(4-bromo-3-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- (4-fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide (51 1 mg, 0.75 mmol) were dissolved in dioxane (20 mL) under nitrogen atmosphere. Bis(pinacolato)diboron (382 mg, 1.50 mmol) and potassium acetate (221 mg, 2.25 mmol) were added and the mixture stirred at 100 °C overnight. The cooled reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (eluting with 0- 50% ethyl acetate in petroleum) to give 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-2-(4-(4-fluorophenoxy)phenyl)-N- methylbenzofuran-3-carboxamide (387 mg, 71 %).

Step 16: 4-((N-(5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-fluorophenylboroni acid. 5-Cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-(4-fluorophenoxy)phenyl)-N-methylbenzofuran-3- carboxamide (380 mg, crude, 0.52 mmol) was dissolved in THF (10 mL) and treated with 5 N HCI (1 .5 mL) and PS-benzene boronic acid (1.0 g, 2.6 mmol). The suspension was stirred for 4 hours, filtrate, and concentrated in vacuo. The residue was purified by reverse phase HPLC to give 4-((N-(5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran- 6-yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid. (140 mg, 42 %). ¹H NMR (300 MHz, CD₃OD) δ = 7.87 (d, 2H), 7.58 (s, 1 H), 7.31 (m, 10H), 5.00 ( m, 2H), 3.17 (m, 3H), 2.93 (s, 3H), 2.24 (m, 1 H), 1.07 (m, 1 H), 0.81 (m, 2H), 0.68 (m, 1 H). LCMS( m/z) ES+=647(M+1 ). Example 18

4-((N-((5-cvclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

Step 1: 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)methylsulfonamido ^

fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide Potassium carbonate(418 mg, 3.03 mmol), Kl (168 mg, 1 .01 mmol) and 1 -bromo-4- (bromomethyl)-2-(trifluoromethyl)benzene (642 mg, 2.02 mmol) were added to a solution of

5- cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (0.5 g, 1.01 mmol) in dry DMF (8 mL) under nitrogen atmosphere. 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 (first EA/PE=1 :5, then EA/PE=1 :2) to give 6-(N-(4-bromo-3- (trifluoromethyl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N- methylbenzofuran-3-carboxamide as a brown solid (350 mg, 47 %).

Step 2: 5-Cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3- carboxamide

6- (N-(4-bromo-3-(trifluoromethyl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-(4- fluorophenoxy)phenyl)-N-methylbenzofuran-3-carboxamide (350 mg, 0.478 mmol), bis- pinacolatodiboron (243 mg, 0.957 mmol) and potassium acetate (141 mg, 1 .434 mmol) were added in 1 ,4-dioxane (20 mL) under nitrogen atmosphere. Pd(dppf)₂CI₂(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 (first EA/PE=1 :5, then EA/PE=1 :2) to give 5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-(N-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran- 3-carboxamide (0.379 g, quantitative yield).

Step 3: 4-((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran- 6-yl)methyl)methylsulfonamido)methyl)-2-(trifluoromethyl)ph acid

5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetra methyl- 1, 3, 2- dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (0.379 g, 0.487 mmol) was dissolved in THF (10 mL) and treated with 5 N HCI (0.68 mL) and PS-benzene boronic acid (0.84 g, 2.435 mmol). The suspension was stirred overnight, then filtrated and concentrated in vacuo. The crude product was purified by pre-HPLC to give 4- ((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid as a white solid (78 mg, 23 %). ¹ H NMR (300MHz, CDCI₃) δ =7.87-7.84(d,2H),7.61-7.59(d,2H), 7.48-7.45 (d,1 H), 7.37-7.35 (d, 1 H), 7.20-7.01 (m,7H), 5.10-4.95 (m,2H), 3.19(s,3H), 2.92 (s,3H), 2.20 (m, 1 H), 0.98 (m, 1 H), 0.92-0.85 (m,2H), 0.35-0.33 (m, 1 H).

LCMS( m/z) ES+=697.1 (M+1 ) Example 19

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluorophenylboronic acid

Step 1: (4-bromo-2-fluorophenyl)methanol

Methyl 4-bromo-2-fluorobenzoate (1.0 g, 4.3 mmol) was dissolved in THF (25ml_), then cooled to -15 °C under N₂ and LiBH₄ (327 mg, 8.6 mmol) was added. The solution was stirred for 15 mins. The mixture was poured into water (15 ml), filtered, and extracted with Et₂0 (3^*20 mL), dried, and concentrated under reduced pressure to give methyl 4-bromo-2- fluorobenzoate (900 mg, 102 %) as a yellow oil which was used to next step without future purification.

Step 2: 4-bromo-1-(bromomethyl)-2-fluorobenzene

Phosphorus tribromide (825 mg, 3.08 mmol) in Et₂0 (3 mL) was added dropwise to the solution of methyl 4-bromo-2-fluorobenzoate (900 mg, 4.4 mmol) in Et₂0 (15 mL) under a nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature. The mixture was poured into ice/water (15 ml) and extracted with Et₂0 (3^*20 mL). The combined organic layers were washed with NaHC0₃ (30 mL) and brine (30 mL), dried over anhydrous Na₂S0₄, and evaporated to give 4-bromo-1 -(bromomethyl)-2-fluorobenzene (650 mg, 55 %) which was used in the next step without further purification.

Step 3: 6-(N-(4-bromo-2-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)- N-methylbenzofuran-3-carboxamide

A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (300 mg, 0.75 mmol), Kl (6 mg, 0.04 mmol) and K₂C0₃ (310 mg, 2.25 mmol) in dry DMF (15 mL) was treated with 4-bromo-1- (bromomethyl)-2-fluorobenzene (402 mg, 1 .5 mmol) and the reaction stirred at room temperature under nitrogen for 1 hour. The reaction was diluted with water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried with anhydrous Na₂S0₄, and evaporated. The crude product was purified by column chromatography (EA:PE = 1 :2) to give 6-(N-(4-bromo-2- fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofu carboxamide (278 mg, 62 %) as a brown solid.

Step 4: 5-cyclopropyl-6-(N-(2-fluoro-4-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamid

6-(N-(4-bromo-2-fluorobenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (275 mg, 0.47 mmol) was dissolved in dioxane (15 ml.) under nitrogen atmosphere. Bis(pinacolato)diboron (239 mg, 0.94 mmol), potassium acetate (138 mg, 1.41 mmol) and 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride (54 mg, 0.05 mmol) were added and the mixture was stirred at 100 °C overnight. The cooled reaction mixture was poured into water (20 ml.) and extracted with EtOAc (3^*20 ml_). The combined organic layers were dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with 0-50% ethyl acetate in petroleum) to give 5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (250 mg, 83 %) as a brown solid.

Step 5: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-fluorophenylboronic acid

5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (250 mg, 0.4 mmol) was dissolved in a solution of THF (15 ml.) and treated with 5 N HCI (0.56 ml.) and PS-BBA (750 mg, 2 mmol). The reaction mixture was stirred overnight at 30 °C. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by reverse phase HPLC to give 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3-fluorophenylboronic acid (90 mg, 40 %). LCMS (m/z) ES+ = 555.1 (M+1 ). ¹H NMR (300 MHz, CD₃OD) = 7.93-7.88 (m, 2H), 7.56 (S, 1 H), 7.28-7.22 (m, 5H), 7.03 (s, 1 H), 5.8-4.91 (m, 2H), 3.19 (s, 3H), 2.93 (S, 3H), 2.27-2.22 (m, 1 H), 0.99-0.76 (m, 3H), 0.35-0.30 (m, 1 H)

Example 20

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-methoxyphenylboronic acid

Step 1: (4-bromo-2-methoxyphenyl)methanol

LiBH₄ (4 ml, 2N/mol, 8.04 mmol) slowly to a solution of methyl 4-bromo-2-methoxybenzoate (1 g, 4.04mmol ) in THF (75 ml) maintained at 0°C. The solution was stirred at room temperature for 45 minutes, poured into ice/water (100 ml), extracted with EtOAc (100 ml ^*3), washed with brine (50 ml), dried over sodium sulfate, concentrated, and purified by column chromatography (EtOAc:hex = 1 : 10 ) to give (4-bromo-2-methoxyphenyl)methanol (850 mg, 96 % yield) as a colorless oil. Step 2: 4-bromo-1-(bromomethyl)-2-methoxybenzene

To a solution of (4-bromo-2-methoxyphenyl)methanol (850 mg, 3.93 mmol) in DCM(100 mL) was added PPh₃ (2.06 g, 8 mmol) and NBS (1 .36 g, 8 mmol) and stirred for 30 mins. Then the reaction mixture was poured into saturated aqueous sodium bicarbonate, extracted with DCM (3x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated. The crude product was purified by column chromatography (EtOAc:hex = 1 : 50 ) to afford 4-bromo-1 -(bromomethyl)-2-methoxybenzene (950 mg, 87 %) as a colorless oil.

Step 3: 6-(N-(4-bromo-2-methoxybenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (578 mg, 1 .42 mmol), 4-bromo-1 -(bromomethyl)-2-methoxybenzene (400 mg, 1.42 mmol), potassium carbonate (391 mg, 2.84mmol) was added to acetonitrile (50 ml) and heated at 70°C for 2 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc (100 ml) / water (100 ml), extracted with EtOAc (3x 100 mL), washed with brine (30 ml), dried over sodium sulfate, and purified by column chromatography (EtOAc : hex = 1 : 3 ) to give 6- (N-(4-bromo-2-methoxybenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (670 mg, 78 %) as a white solid.

Step 4: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-methoxy-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2- dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide 6-(N-(4-bromo-2-methoxybenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophen methylbenzofuran-3-carboxamide (670mg,1 .1 mmol), dicyclohexylphosphinobiphenyl (77 mg,0.22 mmol), HBPin (3.7 g, 33 mmol), triethylamine (224 mg, 2.2 mmol) was added in dioxane (50 ml) under nitrogen. Immersed in a 100°C oil bath and added PdOAc₂ (24.6 mg, 0.1 1 mol) quickly. The mixture was stirred until the reaction was completed by LCMS. The residue was concentrated under reduced pressure and purified by column chromatography (EtOAc : hex = 1 : 1 ) to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-methoxy-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3- carboxamide (560 mg, 76 %) as a white solid.

Step 5: 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1 -hydroxy-1 , 3-dihydrobenzo[c][ 1, 2]oxaborol-

5-yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Lithium borohydride (0.46 ml, 0.92 mmol) was added slowly to a solution of 5-cyclopropyl-2-

(4-fluorophenyl)-6-(N-(2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (300 mg, 0.46 mmol ) in THF (20 ml) at 0 °C. After stirring for 15 minutes, the mixture was poured into ice/water (100 ml) and extracted with EtOAc(100 ml x 3). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate, concentrated and purified by reverse phase HPLC to give 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (580 mg, 31 %) as a yellow solid. LCMS {m/z, ES⁺) = 567 (M+1 ). ¹H-NMR (300MHz, CDCI₃) 7.83(m,2H), 7.62- 7.55(m,2H), 7.25-7.1 1 (m,5H), 5.74(br, 1 H), 5.07-4.91 (m,2H), 3.81 (s,2H), 3.75(s,1 H), 3.10(s,3H), 3.00(m,3H), 2.21-2.16(m, 1 H), 1.01-0.90(m,3H), 0.53-0.50(m, 1 H). Example 21

r4-{rr5-cvclopropyl-3-r(ethylamino)carbonyll-2-(4-fluorophenyl)-1-benzofuran-6- yll(methylsulfonyl)aminolmethyl}-2-(trifluoromethyl)phenyllboronic acid

Step 1: 6-[{[4-bromo-3-(trifluoromethyl)phenyl]methyl}(methylsulfonyl)am

N-ethyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-N-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (750 mg, 1.801 mmol), 1 -bromo-4-(bromomethyl)-2- (trifluoromethyl)benzene (954 mg, 2.251 mmol), and potassium carbonate (498 mg, 3.60 mmol) in acetonitrile (25 mL) was maintained with stirring at 80 °C for 3 hours. The mixture was cooled and poured into water and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-[{[4-bromo-3- (trifluoromethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-N-ethyl-2-(4- fluorophenyl)-1 -benzofuran-3-carboxamide (1 .05 g, 1 .607 mmol, 89 % yield) as a yellow foam. LCMS {m/z, ES⁺) = 654 (M+H)

Step 2: [4-{[[5-cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6- yl](methylsulfonyl)amino]methyl}-2-(trifluoromethyl)phenyl]boronic acid

A solution of 6-[{[4-bromo-3-(trifluoromethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-N-ethyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide (51 1 mg, 0.782 mmol), potassium acetate (307 mg, 3.13 mmol), bis(pinacolato)diboron (496 mg, 1 .955 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (63.9 mg, 0.078 mmol) in 1 ,4-dioxane (7 mL) was maintained at 90°C for 20 hours. The mixture was cooled, filtered through celite, and rinsed with dichloromethane. The filtrates were concentrated, suspended in tetrahydrofuran (15 mL), treated with polymer-supported benzeneboronic acid (1505 mg, 3.91 mmol) and HCI (5. ON) (7.82 mL, 39.1 mmol), and maintained at 70°C for 5 hours. The solution was cooled to room temperature, filtered through celite, and the solids washed with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford [4-{[[5-cyclopropyl-3- [(ethylamino)carbonyl]-2-(4-fluorophenyl)-1 -benzofuran-6-yl](methylsulfonyl)amino]methyl}-2- (trifluoromethyl)phenyl]boronic acid (200 mg, 0.323 mmol, 41 .4 % yield) as a white foam. ¹H NMR (DMSO-d₆); 80°C; δ: 8.20 (br. s., 1 H), 7.86 - 7.99 (m, 3H), 7.71 (s, 1 H), 7.58 (br. s., 1 H), 7.44 (s, 1 H), 7.46 (s, 1 H), 7.34 (t, J = 8.9 Hz, 2H), 6.99 (d, J = 3.3 Hz, 1 H), 4.96 (br. s., 2H), 3.26 - 3.39 (m, 2H), 3.04 (s, 3H), 2.15 - 2.31 (m, 1 H), 1 .14 (t, J = 7.2 Hz, 3H), 0.91 (d, J = 17.2 Hz, 2H), 0.67 - 0.85 (m, 1 H), 0.19 - 0.36 (m, 1 H). LCMS {m/z, ES⁺) = 619 (M+H)

Example 22

(5-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-fluorophenyl)boronic acid

Step 1 : (3-bromo-4-fluorophenyl)methyl methanesulfonate

(3-bromo-4-fluorophenyl)methanol (500 mg, 2.439 mmol) was dissolved in tetrahydrofuran (5 ml.) and cooled in an ice bath. To this was added NaH (107 mg, 2.68 mmol) followed by methanesulfonyl chloride (0.285 ml_, 3.66 mmol). The mixture was maintained with stirring for 1 hour. The ice was removed and the reaction was poured into water and ether. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to afford an oil. The oil was loaded onto a silica column and eluted with 0 to 80 % EtOAc in hexanes to afford (3-bromo-4-fluorophenyl)methyl methanesulfonate (510 mg, 1.801 mmol, 73.9 % yield) as an impure mixture. Residue used without further purification in next step. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.60 (dd, J = 2.05, 6.35 Hz, 1 H), 7.32 (ddd, J = 2.15, 4.54, 8.35 Hz, 1 H), 7.12 (t, J = 8.40 Hz, 1 H), 5.14 (s, 2H), 2.97 (s, 3H).

Step 2: 6-[[(3-bromo-4-fluorophenyl)methyl](methylsulfonyl)ami

fluorophenyl)-N-methyl- 1-benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (350 mg, 0.870 mmol), (3-bromo-4-fluorophenyl)methyl methanesulfonate (492 mg, 1 .739 mmol), K₂C0₃ (120 mg, 0.870 mmol), and Kl (144 mg, 0.870 mmol) were combined in N,N-dimethylformamide (2 ml.) and heated to 60 °C until the reaction was complete. The reaction mixture was poured into water and the solid filtered off. The solid was purified on silica eluting with EtOAc and hexanes to afford 6-[[(3-bromo-4- fluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1- benzofuran-3-carboxamide (412.3 mg, 0.699 mmol, 80 % yield) as a white glass. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.73 (dd, J = 5.27, 8.79 Hz, 2H), 7.42 (dd, J = 2.05, 6.54 Hz, 1 H), 7.21 (s, 1 H), 7.12 (s, 1 H), 7.01 - 7.10 (m, 3H), 6.88 - 6.97 (m, 1 H), 6.15 (d, J = 4.69 Hz, 1 H), 4.61 - 4.81 (m, 2H), 2.97 (s, 3H), 2.87 (d, J = 4.88 Hz, 3H), 2.05 - 2.16 (m, 1 H), 0.90 - 1.00 (m, 1 H), 0.75 - 0.88 (m, 2H), 0.35 - 0.47 (m, 1 H). LCMS (m/Z, ES⁺) = 589 (M+H).

Step 3: (5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid 6-[[(3-bromo-4-fluorophenyl)methyl](methylsulfonyl)amin^

N-methyl-1-benzofuran-3-carboxamide (412 mg, 0.699 mmol), potassium acetate (274 mg, 2.80 mmol), bis(pinacolato)diboron (31 1 mg, 1 .223 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (42.8 mg, 0.052 mmol) were combined in a sealed tube with 1 ,4-dioxane (8 mL). The reaction vessel was purged with N₂ and stirred overnight. The reaction was filtered and the residue partitioned between water and EtOAc. The organic layer was dried over sodium sulfate filtered and evaporated to a residue. The residue was dissolved in THF and 5 equivalents of polymer supported benzene boronic acid was added. The mixture was stirred for 2 hours and LCMS indicated completion of reaction. The reaction was filtered and evaporated to a residue. The residue was purified by reverse phase HPLC to afford (5-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (97 mg, 0.170 mmol, 24.28 % yield) as a dark tan solid. ¹ H NMR (400 MHz, DMSO-d₆) δ: 8.29 - 8.50 (m, 1 H), 7.75 - 7.84 (m, 1 H), 7.65 - 7.98 (m, 3H), 7.29 - 7.53 (m, 2H), 7.13 - 7.29 (m, 1 H), 6.77 - 7.04 (m, 2H), 4.91 (d, J = 14.06 Hz, 1 H), 4.76 (d, J = 14.26 Hz, 1 H), 3.20 (d, J = 3.91 Hz, 3H), 2.73 - 2.85 (m, 3H), 2.15 - 2.34 (m, 1 H), 0.61 - 0.98 (m, 3H), 0.18 (d, J = 5.08 Hz, 1 H). LCMS (m/Z, ES⁺) = 555 (M+H).

Example 23

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-(trifluoromethyl)phenylboronic acid

Step 1: 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene

A solution of 4-bromo-1-methyl-2-(trifluoromethyl)benzene (460 mg, 1 .92 mmol), NBS (379 mg, 2.13 mmol) and benzoyl peroxide (47 mg, 0.19 mmol) in carbon tetrachloride (10 mL) was heated under reflux for 24 hours. The reaction solution was extracted with DCM (60 mL) and the organic layer was washed with brine and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 4- bromo-1 -(bromomethyl)-2-(trifluoromethyl)benzene (500 mg, 1.57 mmol, 82.0 % yield) as a colorless oil. GCMS {m/z, ES⁺) = 317 (M+H) Step 2: 6-(N-(4-bromo-2-(trifluoromethyl)benzyl)methylsulfonamido

fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (632 mg, 1.57 mmol), 4-bromo-1 -(bromomethyl)-2-

(trifluoromethyl)benzene (500 mg, 1 .57 mmol), and potassium carbonate (651 mg, 4.71 mmol) in acetonitrile (20 mL) was heated at 80 °C for 12 hours. The reaction solution was extracted with EtOAc (60 mL) and the separated organic layers were washed with brine and dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(N-(4-bromo-2-

(trifluoromethyl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (300 mg, 0.47 mmol, 30 % yield) as a white solid. LCMS {m/z, ES⁺) = 639 (M+H) Step 3: 5-(^clopropyl-2-(4-1luorophenyl)-N-methyl-6-(N-(4-(4 ,5,5-tetmm

dioxaborolan-2-yl)-2-(trifluoromethyl)benzyl)methylsulfonamid

A solution of 6-(/\/-('4-bromo-2-(trifluoromethyl)benzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-/V-methylbenzofuran-3-carboxamide (300 mg, 0.47 mmol), potassium acetate (138 mg, 1.41 mmol), bis(pinacolato)diboron (180 mg, 0.71 mmol) and PdCI₂(dppf) (17 mg, 0.023 mmol) in 1 ,4-dioxane (10 mL) was heated at 95 °C for 16 hours. The reaction solution was cooled to room temperature and extracted with EtOAc (60 mL). The organic layer was washed with brine and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)- A/-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (280 mg, 0.41 mmol, 87 % yield) as a white solid. LCMS {m/z, ES⁺) = 687 (M+H)

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-(trifluoromethyl)phenylboronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-(trifluoromethyl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (280 mg, 0.41 mmol), PS-BBA (707 mg, 2.05 mmol) and HCI (5N aq., 0.25 mL) in THF (10 mL) was stirred at room temperature for 12 hours. The reaction solution was diluted with water and EtOAc. The organic layer was separated and washed with brine and dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with reverse phase HPLC to afford 4-((/V-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3- (trifluoromethyl)phenylboronic acid (90 mg, 0.15 mmol, 36 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.80 -7.97 (m, 5H), 7.65 (s, 1 H), 7.20 - 7.27 (m, 2H), 7.02 (s, 1 H), 5.20 - 5.28 (m, 1 H), 5.06 -5.13 (m, 1 H),3.20 (s, 3H), 2.92 (s, 3H), 2.24 - 2.29 (m, 1 H) 0.97 - 1.03 (m, 1 H) 0.75 - 0.90 (m, 2H), 0.32 (br. s., 1 H). LCMS {m/z, ES⁺) = 605 (M+H).

Example 24

5-cvclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-((methylsulfonyl){r4-(4,4,5,5-tetramethyl-1 ,3,2-

A solution of [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]methyl}-2-(trifluoromethyl)phenyl]boronic acid (130 mg, 0.215 mmol) in toluene (5 mL) was treated with pinacol (30.5 mg, 0.258 mmol) and powdered 4A molecular sieves (100 mg, 0.215 mmol), maintained with heating at 90°C for 2 hours, and then at 60°C for 12 hours. The solution was cooled, mixed with celite, concentrated to a residue, and purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-6-((methylsulfonyl){[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)phenyl]methyl}amino)-1 -benzofuran-3-carboxamide (106 mg, 0.154 mmol, 71 .8 % yield) as a white solid. ¹H 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, 1 H), 7.23 (t, J = 8.8 Hz, 2H), 6.99 (s, 1 H), 5.07 (d, J = 14.2 Hz, 1 H), 4.85 (d, J = 14.2 Hz, 1 H), 3.16 (s, 3H), 2.90 (s, 3H), 2.13 - 2.27 (m, 1 H), 1 .32 (s, 12H), 0.89 - 1 .04 (m, 1 H), 0.62 - 0.84 (m, 2H), 0.17 - 0.35 (m, 1 H). LCMS {m/z, ES⁺) = 687 (M+H)

Example 25

4-((N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-fluorophenylboronic acid

Step 1: 6-(N-(4-bromo-3-fluorobenzyl)ethylsulfonamido)-5-cyclopropyl-2-(4-flu

methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (1.5 g, 3.6 mmol), 1-bromo-4-(bromomethyl)-2-fluorobenzene (0.965 g, 3.6 mmol U25285/1 19/1 ), Kl (598 mg, 3.6 mmol) and K₂C0₃ (1 .50 g, 10.8 mmol) in dry DMF (8 mL) was heated at 50 °C for 30 min. The reaction solution was quenched with water (20mL) After the filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(4-bromo-3-fluorobenzyl)ethylsulfonamido)-5-cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .72 g, 2.85 mmol, 79%) as a brown oil.

Step 2: 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)benzyl)ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 6-(/V-(4-bromo-3-fluorobenzyl)ethylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-/V-methylbenzofuran-3-carboxamide (1 .72 g, 2.85 mmol, PdCl2(dppf)-CH₂Cl2 adduct (289 mg, 0.285 mmol), bis(pinacolato)diboron (1 .09 g, 4.275 mmol) and potassium acetate (838 mg, 8.55 mmol) in dioxane (20 mL) was heated at 100 °C for 24 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to afford 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (2.2 g, 3.38 mmol, 1 19%, crude) as a brown solid.

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-fluorophenylboronic acid

A solution of 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.925 g, 1.42 mmol), HCI (5N aq., 2 mL) and PS-benzene boronic acid (2.45 g, 7.1 1 mmol) in THF (20 mL) was stirred at room temperature overnight. The reaction solution was filtered. After the removal of the solvent, the residue was purified with reverse phase HPLC to afford 4-((Λ/-(5- cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-fluorophenylboronic acid (270 mg, 0.475 mmol, 33%). ¹H NMR (300MHz, Methanol- d4) δ: 7.92 - 7.88 (m, 2 H), 7.54 (s, 1 H), 7.28 - 7.22 (m, 3 H), 7.03 (m, 3 H), 4.94 - 4.89 (m, 2 H), 3.36 - 3.31 (m, 2 H), 2.93 (s, 3 H), 2.05 (m, 1 H), 1 .47 - 1.43 (m, 3 H), 1.05 - 0.47 (m, 4 H). LCMS(m/z, ES⁺)= 569.1 (M+H).

Example 26

4-((/\/-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

Step 1: 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene

To a solution of 1-bromo-4-methyl-2-(trifluoromethyl)benzene (3.0 g, 12.61 mmol, Alfa) and NBS (2.24 g, 12.61 mmol) in carbon tetrachloride (45 ml.) was added benzoyl peroxide (0.305 g, 1.26 mmol) and the reaction solution was heated under reflux for 2 hours. After the removal of solvent, the residue was purified by column chromatography to afford 1 - bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene (1 .5 g, 4.75 mmol, 38.0 % yield) as a white solid. Step 2: 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)ethylsulfonamido)-5^

fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-6-(ethylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (1 .5 g, 3.6 mmol), 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene (1 .5 g, 4.75 mmol), Kl (598 mg, 3.6 mmol) and K₂C0₃ (1 .50 g, 10.8 mmol) in dry DMF (8 ml.) was heated at 50 °C for 0.5 h. The reaction was cooled to rt and quenched with water (50 ml_). After the filtration, the residue was dissolved in EtOAc. The solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)ethylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (2.2 g, 3.366 mmol, 93 %) as a brown oil. Step 3: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl-1 ,3, 2- dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)ethylsulfonamido)be

A solution of 6-(N-(4-bromo-3-(trifluoromethyl)benzyl)ethylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (2.2 g, 3.37 mmol, PdCl2(dppf)-CH₂Cl2 adduct (342 mg, 0.34 mmol), bis(pinacolato)diboron (1.28 g, 5.06 mmol) and potassium acetate (989 mg, 10.1 1 mmol) in dioxane (25 ml_) was heated at 100 °C for 24 hours under a nitrogen atmosphere. The reaction was cooled and filtered. After the removal of solvent, the residue was purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)benzyl)ethylsulfonamido)benzofuran-3-carboxamide (2.1 g, 3.00 mmol, 89%) as a brown solid.

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)benzyl)ethylsulfonamido)benzofuran-3-carboxamide (1 .05 g, 1 .5 mmol), 5 N HCI (2.1 ml.) and PS-benzene boronic acid (2.5 g, 7.5 mmol) in THF (15 ml.) was stirred at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified with reverse phase HPLC to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid (345 mg, 0.558 mmol, 37%) as a white solid. ¹H NMR (300MHz, Methanol- d4) δ: 7.93 - 7.90 (m, 2 H), 7.88 - 7.56 (m, 2 H), 7.38 - 7.23 (m, 4 H), 7.02 (s, 1 H), 5.04 - 4.94 (m, 2 H), 3.39 - 3.33 (m, 2 H), 2.93 (s, 3 H), 2.05 (m, 1 H), 1 .49 - 1.44 (m, 3 H), 1 .05 - 0.41 (m, 4 H). LCMS(m/z, ES⁺)= 619.0(M+H).

Example 27

4-((/\/-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-methylphenylboronic acid

Step 1: (4-bromo-2-methylphenyl)methanol To a solution of 4-bromo-2-methyl benzoic acid (2.0 g, 9.3 mmol) in dry THF (12 mL) was added BH₃ (1 M in THF, 10.2 mL, 10.2 mmol) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 1 hour and then the reaction mixture was cooled to 0 °C and was quenched with HCI (2N aq., 20mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with NaHC0₃ (10% aq. 30mL), water (30mL) and brine (30mL) and then dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (4-bromo-2-methylphenyl)methanol (1 .93g, 9.6 mmol, quant.) as a pale yellow liquid. Step 2: 4-bromo-1-(bromomethyl)-2-methylbenzene

A solution of (4-bromo-2-methylphenyl)methanol (1.93 g, 9.6 mmol), PPh₃ (5.03 g, 19.2 mmol) and NBS ( 3.42 g, 19.2 mmol) in DCM (50 mL) was stirred at room temperature for 5 minutes under a nitrogen atmosphere. The reaction mixture was poured into ice water (30 mL) and then extracted with CH₂CI₂ (3 x 30 mL). The combined organic layers were washed with NaHC0₃ (30 mL) and brine (30 mL) and dried over anhydrous Na₂S0₄. After concentration under reduced pressure, the crude product was purified with column chromatography to afford 4-bromo-1 -(bromomethyl)-2-methylbenzene (1.7 g, 6.5 mmol, 67 % yield) as a white solid. Step 3: 6-(N-(4-bromo-2-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)- N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-(methylsulfonamido) benzofuran-3- carboxamide (600 mg, 1.5 mmol), Kl (12 mg, 0.08 mmol), K₂C0₃ (621 mg, 4.5 mmol) and 4- bromo-l -(bromomethyl)- 2-methylbenzene (792 mg, 2 mmol) in dry DMF (20 mL) was stirred at room temperature under nitrogen for 1 hour. The reaction solution was diluted with water (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (60 mL) and brine (60 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(/V-(4-bromo- 2- methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3- carboxamide (806 mg, 1.37 mmol, 92 % yield) as a brown solid.

Step 4: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-methyl-4-(4_!4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide

A solution of 6-(/V-(4-bromo-2-methylbenzyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (800 mg, 1 .36 mmol),

bis(pinacolato)diboron (693 mg, 2.73 mmol), potassium acetate (392 mg, 4.10 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (161 mg, 0.14 mmol) in dioxane (25 mL) was degassed and refilled with nitrogen three times and then, the reaction solution was heated under reflux overnight. When the reaction mixture was cooled down, it was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, it was purified with column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-(/\/-(2-methyl-4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (750 mg, 1.2 mmol, 86 % yield) as a white solid.

Step 5: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-3-methylphenylboronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-(/\/-(2-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (400 mg, 0.63 mmol), HCI (5N aq.,0.9 mL) and PS-BBA (1 .2 g, 3.15 mmol) in THF (15 mL) was stirred at 30 °C overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with reverse phase HPLC to afford 4-((N-(5-cyclopropyl-2-(4- fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-3- methylphenylboronic acid (160 mg, 0.29 mmol, 40 % yield) as a white solid. ¹ H NMR

(METHANOL-d₄) δ: 7.95-7.90 (m, 2H), 7.74 (S, 1 H), 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, 1 H), 0.94-0.63 (m, 3H), 0.19-0.09 (m, 1 H). LCMS (m/z, ES⁺) = 551.0 (M+H)

Example 28

(4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-1 -naphthalenvDboronic acid

Step 1 : 6-[[(4-bromo-1-naphthalenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2^ fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (400 mg, 0.994 mmol), 1-bromo-4-(bromomethyl)naphthalene (298 mg, 0.994 mmol), and K₂C0₃ (137 mg, 0.994 mmol) were combined in acetonitrile and heated to 60 °C until the starting material was consumed. The reaction was partitioned between water and EtOAc; the organic layers were dried over MgS0₄ and evaporated to a residue. The residue was purified on silica eluting with EtOAc and hexanes to afford 6-[[(4-bromo-1 - naphthalenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1 - benzofuran-3-carboxamide (509 mg, 0.819 mmol, 82 % yield) as a solid. ¹ H NMR (400 MHz, Acetone) δ: 8.63 - 8.71 (m, 1 H), 8.19 - 8.26 (m, 1 H), 7.99 - 8.08 (m, 2H), 7.96 (s, 1 H), 7.64 - 7.72 (m, 2H), 7.53 (d, J = 7.62 Hz, 2H), 7.23 - 7.32 (m, 2H), 7.02 (d, J = 7.62 Hz, 1 H), 6.89 (s, 1 H), 5.80 (d, J = 13.68 Hz, 1 H), 5.07 (d, J = 13.48 Hz, 1 H), 3.28 (s, 3H), 2.89 (d, J = 4.69 Hz, 3H), 2.04 (dt, J = 2.17, 4.45 Hz, 1 H), 0.53 - 0.66 (m, 2H), -0.48 (dd, J = 4.49, 6.64 Hz, 1 H), -0.66 - -0.57 (m, 1 H). LCMS (m/Z, ES⁺) = 621 (M+H).

Step 2: (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofura yl}(methylsulfonyl)amino]methyl}-1-naphthalenyl)boronic acid

6-[[(4-bromo-1 -naphthalenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)- N-methyl-1-benzofuran-3-carboxamide (500 mg, 0.804 mmol), potassium acetate (316 mg, 3.22 mmol), bis(pinacolato)diboron (358 mg, 1 .408 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (49.3 mg, 0.060 mmol) were combined in 1 ,4-Dioxane (8 ml.) and degassed. The reaction mixture was heated in a sealed vessel overnight at 70 °C. The reaction was filtered through celite and evaporated to a small volume. The residue was stirred in THF and 6 N HCL for 5 hours then evaporated and re-purified by reverse phase HPLC to afford (4-{[{5-cyclopropyl-2- (4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}- 1-naphthalenyl)boronic acid (30.1 mg, 0.051 mmol, 6.38 % yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.54 (d, J = 8.40 Hz, 1 H), 8.35 - 8.45 (m, 2H), 8.14 (s, 1 H), 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, 1 H), 6.71 (s, 1 H), 5.65 (d, J = 13.28 Hz, 1 H), 5.05 (d, J = 13.47 Hz, 1 H), 3.29 (s, 3H), 2.75 (d, J = 4.49 Hz, 3H), 1.94 - 2.05 (m, 1 H), 0.47 - 0.68 (m, 2H), -0.50 - -0.35 (m, 1 H), -0.71 - -0.58 (m, 1 H). LCMS (m/Z, ES⁺) = 587 (M+H).

Example 29

(4-{rr5-Cvclopropyl-3-r(ethylamino)carbonyll-2-(4-fluorophenyl)-1-benzofuran-6- yll(methylsulfonyl)aminolmethyl}-2-fluorophenyl)boronic acid

Step 1: 6-[[(4-Bromo-3-fluorophenyl)methyl](methylsulfonyl)amino]-5-cyclop

(4-fluorophenyl)-1-benzofuran-3-carboxamide

A mixture of 5-cyclopropyl-/V-ethyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (1.00 g, 2.40 mmol), 1 -bromo-4-(bromomethyl)-2-fluorobenzene (0.97 g, 3.60 mmol), potassium iodide (0.40 g, 2.40 mmol) and potassium carbonate (1 .00 g, 7.20 mmol) in DMF (10 ml.) was heated to 60° for 1 h. The mixture was cooled to rt and poured into water (400 ml_). This was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated.

Purification by silica gel chromatography (0 to 75% ethyl acetate in hexanes) afforded 6-[[(4- bromo-3-fluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-/\/-ethyl-2-(4- fluorophenyl)-1 -benzofuran-3-carboxamide (1 .415 g, 98%) as an off-white foam. ¹H NMR (DMSO-d6) δ: 8.52 (t, J = 5.5 Hz, 1 H), 7.93 (dd, J = 8.7, 5.5 Hz, 2H), 7.84 (s, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.39 (t,

J = 8.8 Hz, 2H), 7.27 (dd, J = 9.7, 1 .3 Hz, 1 H), 7.04 (dd, J = 8.2, 1 .0 Hz, 1 H), 6.91 (s, 1 H), 4.95 (d, J = 14.5 Hz, 1 H), 4.78 (d, J = 14.5 Hz, 1 H), 3.18 - 3.34 (m, 5H), 2.15 - 2.29 (m, 1 H), 1.12 (t, J = 7.2 Hz, 3H), 0.88 - 0.99 (m, 1 H), 0.66 - 0.83 (m, 2H), 0.13 - 0.24 (m, 1 H).

Step 3: (4-{[[5-Cyclopropyl-3-[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1-benzofuran-6- yl](methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid

A mixture of 6-[[(4-bromo-3-fluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-/\/- ethyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxamide (1 .41 g, 2.34 mmol), potassium acetate (0.92 g, 9.35 mmol), bis(pinacolato)diboron (1 .48 g, 5.84 mmol) and

bis(tricyclohexylphosphine)palladium(ll) dichloride (0.172 g, 0.234 mmol) in 1 ,4-dioxane (30 ml.) in a thick-walled glass pressure vessel was degassed, then heated at 95°C with stirring for 24 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. The residue was dissolved in tetrahydrofuran (50 ml_), treated with PS-BBA (7.2 g, 2.6 mmol/g) and 6N HCI (50 ml.) and heated at 60° overnight. The reaction was cooled to rt, filtered, concentrated to remove the THF and diluted with ethyl acetate. The organic layer was washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. The residue was resubjected using THF (50 ml_), 6N HCI (50 ml.) and PS- BBA (4.49 g), heating to 60° for 3 h. The reaction was cooled to rt, filtered, concentrated to remove the THF and diluted with ethyl acetate. The organic layer was washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% acetonitrile in dichloromethane, then 0 to 5% methanol in dichloromethane), then trituration in diethyl ether afforded (4-{[[5-cyclopropyl-3-

[(ethylamino)carbonyl]-2-(4-fluorophenyl)-1 -benzofuran-6-yl](methylsulfonyl)amino]methyl}-2- fluorophenyl)boronic acid (563 mg, 42%) as an off-white solid. ¹H NMR (METHANOL-c/4) δ: 7.91 (dd, J = 8.6, 5.3 Hz, 2H), 7.60 (s, 1 H), 7.19 - 7.31 (m, 3H), 6.93 - 7.09 (m, 3H), 4.93 - 5.01 (m, 1 H), 4.77 - 4.85 (m, 1 H), 3.37 - 3.47 (m, 2H), 3.16 (s, 3H), 2.24 (quin, J = 6.8 Hz, 1 H), 1 .1 1 - 1 .26 (m, 3H), 0.91 - 1 .07 (m, 1 H), 0.79 (t, J = 5.8 Hz, 2H), 0.25 - 0.40 (m, 1 H). LCMS {m/z, ES⁺) = 569 (M+H).

Example 30

5-Cvclopropyl-2-(4-fluorophenyl)-6-r{r3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyllmethyl}(methylsulfonyl)aminol-/V-methyl-1 -benzofuran-3-carboxamide

5-Cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

A solution of (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (200 mg, 0.36 mmol) in toluene (10 ml.) was treated with pinacol (45 mg, 0.38 mmol) and heated to 90° for 5 min. The reaction mixture was cooled to room temperature and concentrated, then purified by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane). The resulting foam was triturated in hexanes (3x) and dried to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3- fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}(methylsulfonyl)amino]-/\/- methyl-1 -benzofuran-3-carboxamide (153 mg, 67%) as a white solid. ¹H NMR (METHANOL- d4) 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, 1 H), 4.80 - 4.86 (m, 1 H), 3.16 (s, 3H), 2.92 (s, 3H), 2.25 (quin, J = 6.8 Hz, 1 H), 1 .32 (s, 12H), 0.73 - 1 .07 (m, 4H), 0.27 - 0.46 (m, 1 H). LCMS {m/z, ES⁺) = 637 (M+H). Example 31

5-cvclopropyl-2-(4-fluorophenyl)-N-methyl-6-r(methylsulfonyl)({3-(trifluoromethyl)-4- id R.2R.6S.8RV2.9.9-trimethyl-3.5-dioxa-4-boratricvclor6.1 .1.02.61dec-4- yllphenyl}methyl)aminol-1 -benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)({3-(trifluoro

[(1R,2R, 6S, 8R)-2, 9, 9-trimet yl-3, 5-dioxa-4-boratricyclo[6.1.1.02, 6]dec-4- yl]phenyl}methyl)amino]-1-benzofuran-3-carboxamide

(1 S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1 .1 ]heptane-2,3-diol (42.3 mg, 0.248 mmol) was added to a suspension of [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-(trifluoromethyl)phenyl]boronic acid (150 mg, 0.248 mmol) in toluene (2.5 ml_). The reaction was heated to 90 °C until everything dissolved then molecular sieves were added to the reaction and the reaction was stirred overnight. The sieves were filtered off and the filtrate was evaporated to afford 5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)({3-(trifluoromethyl)-4- [(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4- yl]phenyl}methyl)amino]-1 -benzofuran-3-carboxamide (90.7 mg, 0.1 17 mmol, 47.0 % yield). ¹H 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, 1 H), 5.10 - 5.20 (m, 1 H), 4.96 - 5.05 (m, 1 H), 4.53 (dd, J = 8.9, 1 .9 Hz, 1 H), 3.22 (s, 3H), 2.92 (d, J = 4.7 Hz, 3H), 2.38 - 2.48 (m, 1 H), 2.32 (ddd, J = 8.5, 5.2, 3.1 Hz, 1 H), 2.21 - 2.29 (m, 1 H), 2.08 (t, J = 5.6 Hz, 1 H), 1 .85 - 1 .95 (m, 2H), 1.44 (s, 3H), 1.30 (s, 3H), 1.18 - 1.23 (m, 1 H), 0.91 - 1.00 (m, 1 H), 0.89 (s, 3H), 0.66 - 0.87 (m, 2H), 0.24 (dd, J = 9.1 , 4.4 Hz, 1 H). LCMS (m/Z, ES⁺) = 739 (M+H).

Example 32

5-cvclopropyl-2-(4-fluorophenyl)-6-r{r3-fluoro-4-(4,4,6,6-tetramethyl-1 ,3,2-dioxaborinan-2- yl)phenyllmethyl}(methylsulfonyl)aminol-N-methyl-1 -benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4, 4, 6, 6-tetramethyl- 1, 3, 2-dioxaborinan-2- yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide

2,4-dimethyl-2,4-pentanediol (47.7 mg, 0.361 mmol) was added to a suspension of(4-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (200 mg, 0.361 mmol) in toluene (2.5 ml_). The reaction was heated to 90 °C until everything dissolved and then molecular sieves were added to the reaction and the reaction was stirred for 1 hour. The sieves were filtered off and the filtrate was evaporated. The residue was dissolved in DCM purified by silica gel chromatography and eluted with 0 to 30 % EtOAc in DCM to afford 5- cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,6,6-tetramethyl-1 ,3,2-dioxaborinan-2- yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (189.3 mg, 0.276 mmol, 77 % yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.84 - 7.93 (m, 2H), 7.62 (t, J = 6.94 Hz, 1 H), 7.28 (s, 1 H), 7.23 (s, 1 H), 7.15 - 7.22 (m, 2H), 6.98 - 7.04 (m, 1 H), 6.90 (d, J = 9.97 Hz, 1 H), 5.76 (d, J = 4.49 Hz, 1 H), 5.04 (d, J = 14.46 Hz, 1 H), 4.65 (d, J = 14.46 Hz, 1 H), 2.93 - 3.04 (m, 6H), 2.24 (tt, J = 5.25, 8.33 Hz, 1 H), 1 .94 (s, 2H), 1 .43 (s, 12H), 0.98 - 1.1 1 (m, 2H), 0.93 (dd, J = 4.10, 8.99 Hz, 1 H), 0.54 - 0.65 (m, 1 H). LCMS (m/Z, ES⁺) = 651 (M+H).

Example 33

5-cvclopropyl-6-r{r3-fluoro-4-(6-methyl-4,8-dioxotetrahvdro-4H-1 ,3,6,2-dioxazaborocin-2- yl)phenyllmethyl}(methylsulfonyl)aminol-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3- carboxamide

5-cyclopropyl-6-[{[3-fluoro-4-( 6-methyl-4, 8-dioxotetrahydro-4H-1 , 3, 6, 2-dioxazaborocin-2- yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)-N-methyl-1-benzofuran carboxamide

(4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (200 mg, 0.361 mmol) was suspended in toluene (5 mL), dimethyl sulfoxide (1 mL) and 2,2'-(methylimino)diacetic acid (53.1 mg, 0.361 mmol) were added. The reaction was hated to reflux with a Dean-Stark trap for 4 hours. The solvent was evaporated to a small volume and poured into water. The precipitate that formed was filtered and dried under vacuum to afford 5-cyclopropyl-6-[{[3- fluoro-4-(6-methyl-4,8-dioxotetrahydro-4H-1 ,3,6,2-dioxazaborocin-2- yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3- carboxamide (234.4 mg, 0.335 mmol, 93 % yield) as a white solid. ¹H NMR (400 MHz, Acetone) δ: 7.98 - 8.06 (m, 2H), 7.65 (s, 1 H), 7.53 (d, J = 3.71 Hz, 1 H), 7.48 (t, J = 7.23 Hz, 1 H), 7.28 (t, J = 8.89 Hz, 2H), 7.14 (d, J = 7.62 Hz, 1 H), 7.10 (s, 1 H), 7.06 (d, J = 10.75 Hz, 1 H), 4.88 - 5.06 (m, 2H), 4.38 (d, J = 17.78 Hz, 2H), 4.13 (d, J = 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, J = 5.42, 5.67, 8.23, 8.23 Hz, 1 H), 0.90 - 1.00 (m, 1 H), 0.76 - 0.85 (m, 2H), 0.25 - 0.35 (m, 1 H). LCMS (m/Z, ES⁺) = 666 (M+H). Example 34

5-cvclopropyl-2-(4-fluorophenyl)-6-r({3-fluoro-4-r(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1 .02,6ldec-4-yllphenyl}methyl)(methylsulfonyl)aminol-N-methyl-1- benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-6-[({3-fluoro-4-[(1R, 2R, 6S, 8R)-2, 9, 9-trimethyl-3, 5-dioxa-4- boratricyclo[6.1.1.02, 6]dec-4-yl]phenyl}methyl)(methylsulfonyl)amino]-N-methyl-1- benzofuran-3-carboxamide

(1 S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1 .1 ]heptane-2,3-diol (61.4 mg, 0.361 mmol) was added to a suspension of (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (200 mg, 0.361 mmol) in toluene (2.5 mL). The reaction was heated to 90 °C until everything dissolved then molecular sieves were added to the reaction and the reaction was stirred for 1 hour. The sieves were filtered off and the filtrate was evaporated to afford 5-cyclopropyl-2-(4- fluorophenyl)-6-[({3-fluoro-4-[(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1 .02,6]dec-4-yl]phenyl}methyl)(methylsulfonyl)amino]-N-methyl-1- benzofuran-3-carboxamide (223 mg, 0.324 mmol, 90 % yield). ¹H NMR (400 MHz,

CHLOROFORM-d) δ: 7.86 (dd, J = 5.37, 8.49 Hz, 2H), 7.66 (t, J = 6.83 Hz, 1 H), 7.27 (s, 2H), 7.18 (t, J = 8.59 Hz, 2H), 7.05 (d, J = 7.61 Hz, 1 H), 6.97 (d, J = 9.76 Hz, 1 H), 5.76 (d, J = 4.29 Hz, 1 H), 4.97 - 5.06 (m, 1 H), 4.71 (d, J = 14.44 Hz, 1 H), 4.47 (d, J = 8.00 Hz, 1 H), 3.02 (s, 3H), 2.99 (d, J = 4.88 Hz, 3H), 2.35 - 2.46 (m, 1 H), 2.18 - 2.30 (m, 2H), 2.16 (t, J = 5.46 Hz, 1 H), 1.90 - 2.02 (m, 2H), 1.49 (s, 3H), 1.31 (s, 3H), 1.20 (d, J = 10.93 Hz, 1 H), 1 .05 (d, J = 4.10 Hz, 1 H), 0.90 - 1 .02 (m, 2H), 0.88 (s, 3H), 0.58 (d, J = 3.32 Hz, 1 H). LCMS (m/Z, ES⁺) = 689 (M+H).

Example 35

5-cvclopropyl-2-(4-fluorophenyl)-6-r{r3-fluoro-4-(tetrahvdro-3aH- cvclopentardiri ,3,2ldioxaborol-2-yl)phenyllmethyl}(methylsulfonyl)aminol-N-methyl-1 - benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(tetrahydro-3aH- cyclopenta[d][1,3,2]dioxaborol-2-yl)phenyl]methyl}(methylsulfonyl)amino]-N-me

benzofuran-3-carboxamide

1 ,2-cyclopentanediol (44.2 mg, 0.433 mmol) was added to a suspension of (4-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (200 mg, 0.361 mmol) in toluene (2.5 mL). The reaction was heated to 90 °C until everything dissolved then molecular sieves were added to the reaction and the reaction was stirred for one hour. The sieves were filtered off and the filtrate was evaporated. The residue was dissolved in DCM and purified via silica gel chromatography eluted with 0 to 30 % EtOAc in DCM to afford 5- cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(tetrahydro-3aH-cyclopenta[d][1 ,3,2]dioxaborol- 2-yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide (214 mg, 0.338 mmol, 94 % yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.73 (dd, J = 5.28, 8.79 Hz, 2H), 7.53 - 7.59 (m, 1 H), 7.20 (s, 1 H), 7.13 (s, 1 H), 7.06 (t, J = 8.60 Hz, 2H), 6.97 (d, J = 7.62 Hz, 1 H), 6.91 (d, J = 9.97 Hz, 1 H), 6.15 (q, J = 4.36 Hz, 1 H), 4.92 (br. s., 2H), 4.89 (d, J = 14.66 Hz, 1 H), 4.66 (d, J = 14.46 Hz, 1 H), 2.96 (s, 3H), 2.87 (d, J = 4.89 Hz, 3H), 2.09 - 2.18 (m, 1 H), 1 .90 - 1 .96 (m, 2H), 1.58 (s, 2H), 0.92 - 1 .00 (m, 1 H), 0.78 - 0.92 (m, 2H), 0.41 - 0.50 (m, 1 H).

Example 36

(3-cvano-4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

Step 1: 6-[[(4-bromo-2-cyanophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-^ fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran carboxamide (500 mg, 1.242 mmol), 5-bromo-2-(bromomethyl)benzonitrile (342 mg, 1.242 mmol), K₂C0₃ (172 mg, 1.242 mmol), and Kl (206 mg, 1.242 mmol) were suspended in N,N- dimethylformamide (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. The organic layer was dried over sodium sulfate and evaporated to a residue. The crude product was purified on silica eluting with 0 to 80 % EtOAc and hexanes to afford 6-[[(4-bromo-2- cyanophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1- benzofuran-3-carboxamide (719.2 mg, 1 .206 mmol, 97 % yield) as a glass. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.73 (dd, J = 5.28, 8.79 Hz, 2H), 7.59 - 7.64 (m, 1 H), 7.57 (d, J =

1.95 Hz, 1 H), 7.50 (d, J = 8.40 Hz, 1 H), 7.32 (s, 1 H), 7.03 - 7.1 1 (m, 3H), 6.15 (q, J = 4.43 Hz, 1 H), 4.97 (d, J = 0.98 Hz, 2H), 3.08 (s, 3H), 2.87 (d, J = 4.89 Hz, 3H), 2.04 - 2.13 (m, 1 H), 0.91 - 1 .01 (m, 1 H), 0.77 - 0.90 (m, 2H), 0.42 (d, J = 5.08 Hz, 1 H).

Step 2: (3-cyano-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid

A solution of 6-[[(4-bromo-2-cyanophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (500 mg, 0.838 mmol),

4,4,4\4\5,5,5\5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (426 mg, 1.677 mmol),

dichloro(tricyclohexylphophine)palladium (II) (30.9 mg, 0.042 mmol) and potassium acetate (247 mg, 2.51 mmol) in 1 ,4-dioxane (3 ml.) was maintained at 80°C overnight under a N₂ atmosphere. The mixture was filtered celite, and the filtrated were partitioned between water and EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to give a residue.

The residue was dissolved in THF, treated with PS-benzene boronic acid (1.6g, 4.19 mmol) (2.6-3.2mmol/g), and stirred at 50°C for 3hrs. The solids were removed via filtration and were washed with EtOAc. The filtrate was partitioned between water and EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC to give (3-cyano-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid (160mg, 0.285mmol, yield 33.97%) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ: 8.28 (s, 1 H), 7.89 -

7.96 (m, 1 H), 7.77 - 7.85 (m, 2 H), 7.66 (d, J=7.8 Hz, 1 H), 7.34 - 7.41 (m, 1 H), 7.17 (t, J=7.5 Hz, 3 H), 5.83 (d, J=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-cvclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2,3-difluorophenyl)boronic acid

Step 1 : 2, 3-difluoro-4-(4,4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzaldehyde

(2,3-difluoro-4-formylphenyl)boronic acid (2.00 g, 10.76 mmol) was suspended in toluene (20 ml.) and pinacol (1 .271 g, 10.76 mmol) was added. The reaction was heated to 90 °C until everything dissolved and then molecular sieves were added to the reaction and the reaction was stirred overnight. The sieves were filtered off and the filtrate was evaporated to afford 2,3-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzaldehyde (2.79 g, 10.41 mmol, 97 % yield) as a white solid with a small amount to pinacol as a contaminant. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.22 (s, 1 H), 7.61 - 7.69 (m, 1 H), 7.53 - 7.60 (m, 1 H), 1 .32 (s, 12H).

Step 2: [2, 3-difluoro-4-(4, 4, 5, 5-tetramet yl-1 , 3, 2-dioxaborolan-2-yl)phenyl]methanol 2,3-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzaldehyde (1.00 g, 3.73 mmol) was dissolved in methanol (3.7 ml.) and NaBH₄ (0.141 g, 3.73 mmol) was added. The reaction was worked up by pouring into pH7 buffer and extracting with EtOAc. The residue was purified on silica eluting with EtOAc and DCM to afford [2,3-difluoro-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanol (488.7 mg, 1.809 mmol, 48.5 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 7.37 - 7.46 (m, 1 H), 7.29 (t, J = 6.64 Hz, 1 H), 5.47 (t, 1 H), 4.59 (d, J = 5.47 Hz, 2H), 1.29 (s, 12H). Step 3: [2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen

methanesulfonate

[2,3-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanol (480 mg, 1 .777 mmol) was dissolved in tetrahydrofuran (5 ml.) and cooled in an ice bath. To this was added TEA (0.297 ml_, 2.133 mmol) followed by methanesulfonyl chloride (0.152 ml_, 1.955 mmol) and the resulting mixture was stirred for 1 hour. The ice was removed and the reaction was poured into water and ether. The organic layer was separated and dried over sodium sulfate and evaporated to an oil. The impure oil was chromatographed on silica eluting with 0 to 80 % ethyl acetate and hexanes to afford [2,3-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]methyl methanesulfonate (526.4 mg, 1 .512 mmol, 85 % yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ: 7.48 - 7.54 (m, 1 H), 7.20 (t, J = 6.74 Hz, 1 H), 5.26 - 5.37 (m, 2H), 3.01 (s, 3H), 1.36 (s, 12H).

Step 4: (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbon

yl}(methylsulfonyl)amino]methyl}-2,3-difluorophenyl)boronic acid

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (500 mg, 1.242 mmol) was dissolved in N,N-dimethylformamide (2 ml.) and [2,3-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl methanesulfonate (433 mg, 1 .242 mmol), K₂C0₃ (258 mg, 1.864 mmol) and Kl (206 mg, 1.242 mmol) were added to the reaction. The reaction was heated to 60 °C until the starting material was consumed. The reaction was poured into water and partitioned with EtOAc. The organic layer was dried over sodium sulfate and evaporated to a residue. The residue was purified on silica eluting with EtOAc and hexanes to give an oil which was treated with sodium periodate (266 mg, 1 .242 mmol) in THF overnight to afford (4-{[{5-cyclopropyl-2-(4- fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}- 2,3-difluorophenyl)boronic acid (51 .8 mg, 0.086 mmol, 6.92 % yield) as a tan solid. ¹H NMR (400 MHz, METHANOL-d₄) δ: 7.82 - 7.91 (m, 2H), 7.60 (s, 1 H), 7.21 (t, J = 8.79 Hz, 2H), 6.95 - 7.04 (m, 3H), 5.08 (d, J = 13.87 Hz, 1 H), 4.83 - 4.95 (m, 1 H), 3.16 (s, 3H), 2.84 - 2.91 (m, 3H), 2.13 - 2.29 (m, 1 H), 0.87 - 0.99 (m, 1 H), 0.63 - 0.85 (m, 2H), 0.23 (d, J = 4.69 Hz, 1 H). LCMS (m/Z, ES⁺) = 573 (M+H). Example 38

(4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl (methylsulfonyl)aminolmethyl}-2,5-difluorophenyl)boronic acid

Step 1: 6-[[(4-bromo-2,5-difluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (436 mg, 1.08 mmol), 1-bromo-4-(bromomethyl)-2,5- difluorobenzene (310 mg, 1 .08 mmol), and potassium carbonate (300 mg, 2.17 mmol) in DMF (15 mL) was maintained at 65 °C for 3 hours. The solution was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography eluting with 1 :1 hexanes : EtOAc to afford 6-[[(5-bromo-2- pyridinyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1 - benzofuran-3-carboxamide (570 mg, 0.938 mmol, 87 % yield). LCMS {m/z, ES⁺) = 607 (M+H)

Step 2: (4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofura yl}(methylsulfonyl)amino]methyl}-2,5-difluorophenyl)boronic acid

A solution of 6-[[(4-bromo-2,5-difluorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2- (4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (570 mg, 0.938 mmol), potassium acetate (184 mg, 1 .87 mmol), bis(pinacolato)diboron (286 mg, 1.12 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (69.3 mg, 0.094 mmol) in 1 ,4-dioxane (5 mL) in a thick-walled glass pressure vessel was maintained at 90 °C with stirring for 16 hours. The solution was cooled to room temperature, THF : NH₄OAc (0.1 M aq) 6:4 (50 mL) was added and then sodium periodate was added (2007 mg, 9.38 mmol) and the mixture was stirred at RT for 6 hrs. The reaction was filtered, and purified on silica yielding the product as an off white powder (4-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2,5-difluorophenyl)boronic acid (80 mg, 15% yield). ¹H NMR (DMSO-d₆) δ: 8.45 (m, 1 H), 8.32 (br. s., 2H), 7.93 (m, 2H), 7.84 (s, 1 H), 7.39 (m, 2H), 7.18 (m, 1 H), 7.03 (m, 1 H), 6.94 (s, 1 H), 4.91 (m, 2H), 3.24 (s, 3H), 2.79 (s, 3H), 2.24 (m, 1 H), 0.91 (m, 1 H), 0.77 (m, 2H), 0.19 (m, 1 H). LCMS {m/z, ES⁺) = 573 (M+H)

Example 39

(2-chloro-4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl)aminolmethyl}phenyl)boronic acid

Step 1: 6-[[(4-bromo-3-chlorophenyl)methyl](methylsulfonyl)amino]-5-cyclop

fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (850 mg, 2.1 12 mmol), 1-bromo-4-(bromomethyl)-2- chlorobenzene (601 mg, 2.1 12 mmol), and potassium carbonate (584 mg, 4.22 mmol) in N,N-dimethylformamide (5 mL) was maintained at 80°C with stirring for 3 hours. The mixture was cooled, poured into ethyl acetate, and washed with water and 5% LiCI (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-[[(4-bromo-3- chlorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1 - benzofuran-3-carboxamide (1 .07 g, 1 .766 mmol, 84 % yield) as a white solid. LCMS {m/z, ES⁺) = 605 (M+H)

Step 2: (2-chloro-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid

A solution of 6-[[(4-bromo-3-chlorophenyl)methyl](methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (150 mg, 0.248 mmol), potassium acetate (97 mg, 0.990 mmol), bis(pinacolato)diboron (126 mg, 0.495 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (20.22 mg, 0.025 mmol) in 1 ,4-dioxane (5 mL) was maintained with stirring at 90 °C for 24 hours. The mixture was cooled to room temperature, filtered through glass filter paper, and concentrated under reduced pressure. The residue was dissolved in

tetrahydrofuran (150 mL) and treated with 5. ON HCI (aq) (100 mL) and polymer supported benzene boronic acid (572 mg, 1 .485 mmol). The mixture was maintained with stirring, filtered through celite, and diluted with water and ethyl acetate. The organic layer was separated, concentrated, re-suspended in tetrahydrofuran \ (150 mL), treated with 5. ON HCI (aq) (100 mL) and polymer supported benzene boronic acid (572 mg, 1 .485 mmol), and maintained with stirring for an additional 5 hours. The mixture was filtered through celite, diluted with ethyl acetate and water, and the organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford (2-chloro-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid (52 mg, 0.091 mmol, 36.8 % yield) as a white solid following lyophilization. ¹H NMR (METHANOL-d₄) δ: 7.89 (dd, J = 8.7, 5.4 Hz, 2H), 7.60 (s, 1 H), 7.10 - 7.30 (m, 5H), 7.01 (s, 1 H), 4.96 (d, J = 14.0 Hz, 1 H), 4.76 (d, J = 14.0 Hz, 1 H), 3.16 (s, 3H), 2.91 (s, 3H), 2.17 - 2.28 (m, 1 H), 0.90 - 1.02 (m, 1 H), 0.71 - 0.84 (m, 2H), 0.24 - 0.35 (m, 1 H). LCMS {m/z, ES⁺) = 568 (M+H) Example 40

r4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- l}(methylsulfonyl)aminolmethyl}-2-fluoro-3-(trifluoromethyl)phenyllboronic acid

Step 1: 6-bromo-2-fluoro-3-(trifluoromethyl)aniline

A solution of 2-fluoro-3-(trifluoromethyl)aniline (4.48 g, 25 mmol) in DMF (5 ml.) was treated with 8ml_ DMF solution of NBS (4.45 g, 25.00 mmol) drop wise over 2hrs, and then stirred under room temperature for another hour. The solution was diluted with water and quenched with 10% aqueous sodium thiosulphate solution, and extracted with ether. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash column

chromatography to give 6-bromo-2-fluoro-3-(trifluoromethyl)aniline (5.65g, 21.90 mmol, 88 % yield) as a red liquid. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.23 - 7.30 (m, 1 H), 6.79 (t, J=8.6 Hz, 1 H), 3.93 (br. s., 2 H). Step 2: methyl 4-amino-3-fluoro-2-(trifluoromethyl)benzoate

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)aniline (5.6g, 21 .70 mmol), TEA (2.416 g, 23.87 mmol), palladium acetate (0.974 g, 4.34 mmol) and dppf (3.61 g, 6.51 mmol) in DMSO (20 ml.) and methanol (20 ml.) under CO atmosphere (~70psi) was heated to 80°C with stirring overnight. The solution was filtered through celite and the filtrate was diluted with EtOAc (100ML), washed with water. The organic phase was dried over sodium sulfate, filtered, concentrated, and purified by silica column chromatography to give methyl 4-amino- 3-fluoro-2-(trifluoromethyl)benzoate (4.5g, 18.98 mmol, 87 % yield) as a purple liquid. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.24 - 7.33 (m, 1 H), 6.90 (t, J=8.3 Hz, 1 H), 4.12 (br. s., 2 H), 3.88 (s, 3 H). Step 3: methyl 4-bromo-3-fluoro-2-(trifluoromethyl)benzoate

A solution of methyl 4-amino-3-fluoro-2-(trifluoromethyl)benzoate (4.5g, 18.98 mmol) in acetonitrile (30 mL) was cooled to 0°C and 48% aqueous hydrobromide (21 .47 mL, 190 mmol) was added drop wise via dropping funnel over 10min. Sodium nitrite (1.440 g, 20.87 mmol) in 10mL water was added drop wise over 30min. After addition, the mixture was stirred under 0°C for 30min, and copper bromide (3.19 g, 21 .82 mmol) was added portion wise over 10min. After addition, the solution was heated to reflux (~85°C) for 20 minutes. The solution was diluted with water, extracted with EtOAc, and the organic phase was dried over Na₂S0₄, filtered, concentrated, and purified by column chromatography to give methyl 4- bromo-3-fluoro-2-(trifluoromethyl)benzoate (3.2g, 10.63 mmol, 56.0 % yield) as a yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.82 (dd, J=8.0, 6.3 Hz, 1 H), 7.23 - 7.29 (m, 1 H), 3.94 (s, 3 H).

Step 4: [4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]methanol

A solution of methyl 4-bromo-3-fluoro-2-(trifluoromethyl)benzoate (3.2g, 10.63 mmol) and lithium borohydride (26mL, 51.8 mmol) (2.0M solution in THF) in THF (10 mL) was stirred at room temperature until all the starting material was consumed. The solution was quenched with water, neutralized with 10% HCI solution, and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by column to give [4- bromo-3-fluoro-2-(trifluoromethyl)phenyl]methanol (1 .2g, 4.4mmol, yield 41 .3%) as a off- white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.54 (m, 1 H), 7.13 (m, 1 H), 4.90 (s, 2 H).

Step 5: [4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]methyl methanesulfonate

A solution of [4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]methanol (1 .2g, 4.40 mmol) and TEA (0.673 mL, 4.83 mmol) in DCM (10 mL) was treated with methylsulfonylchloride (0.376 mL, 4.83 mmol) drop wise. The solution was stirred under room temperature for 1 hour, then washed with water and brine sequentially. The organic layer was dried over Na₂S0_4, filtered, concentrated, and purified by column chromatography to give [4-bromo-3-fluoro-2- (trifluoromethyl)phenyl]methyl methanesulfonate (1 .3, 3.70mmol, yield 84%) as a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.57 - 7.64 (m, 1 H), 7.44 (d, 1 H), 5.41 (d, J=1.4 Hz, 2 H), 3.06 (s, 3H). Step 6: 6-[{[4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]methyl}(m

cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (1 .248 g, 3.1 mmol), [4-bromo-3-fluoro-2- (trifluoromethyl)phenyl]methyl methanesulfonate (1 .3 g, 3.70 mmol), potassium carbonate (0.471 g, 3.41 mmol) in DMF (6 mL) was warmed to 50°C for 1 hour. The solution was diluted with EtOAc and water. The organic layer was dried over Na₂S0₄, filtered,

concentrated, and purified by column chromatography to give 6-[{[4-bromo-3-fluoro-2- (trifluoromethyl)phenyl]methyl} (methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-1 -benzofuran-3-carboxamide (2.6g, 2.434mmol, yield 79%) as a pale yellow foam. LC-MS (m/z, ES⁺)= 657 (659).

Step 7: [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluoro-3-(trifluoromethyl)phenyl]boronic acid

A solution of 6-[{[4-bromo-3-fluoro-2-(trifluoromethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (0.3g, 0.456 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (0.232 g, 0.913 mmol),

dichloro(tricyclohexylphophine)palladium (II) (0.017 g, 0.023 mmol) and potassium acetate (0.134 g, 1.369 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C for 2 hours under a N₂ atmosphere. The solution was filtered over celite, and the filtrated was partitioned between water and EtOAc. The organic layer was collected and concentrated to give residue. The residue was dissolved in THF (5.00 mL) and 3mL 6M HCI, treated with PS-benzene boronic acid (0.8g, 2.282 mmol) (2.6-3.2mmol/g), and stirred at room temperature for 1 hour. The solids were removed via filtration and washed with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC to give [4-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluoro-3-(trifluoromethyl)phenyl]boronic acid (47mg, 0.076mmol, Yield 16.55%). ¹H NMR (400 MHz, DMSO-d₆) 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). LC-MS (m/z, ES⁺)= 623 (M+H).

Example 41

{4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-r(difluoromethyl)oxylphenyl}boronic acid

Step 1: Methyl 4-bromo-3-[(difluoromethyl)oxy]benzoate

A solution of methyl 4-bromo-3-hydroxybenzoate (2.7 g, 1 1.69 mmol) in N,N- dimethylformamide (40 mL) was treated with cesium carbonate (7.62 g, 23.37 mmol) and sodium chlorodifluoroacetate (3.56 g, 23.37 mmol) and maintained with stirring at 80°C 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 over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford methyl 4-bromo-3- [(difluoromethyl)oxy]benzoate (2.36 g, 8.40 mmol, 71.9 % yield) as a white solid. ¹H NMR (CHLOROFORM-d) δ: 7.86 (s, 1 H), 7.78 (dd, J = 8.3, 1.7 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 6.60 (t, J = 72 Hz, 1 H), 3.94 (s, 3H)

Step 2: {4-bromo-3-[(difluoromethyl)oxy]phenyl}methanol

A solution of methyl 4-bromo-3-[(difluoromethyl)oxy]benzoate (2.3 g, 8.18 mmol) in tetrahydrofuran (100 mL) was cooled to 0°C, treated with DIBALH (32.7 mL, 32.7 mmol) as a solution in toluene, and allowed to warm to room temperature where stirring was continued for 5 hours. The solution was quenched via slow addition of 10% Rochelle's salt and diluted further with ethyl acetate. The mixture was maintained with constant stirring for 6 hours, and the organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford {4-bromo-3-

[(difluoromethyl)oxy]phenyl}methanol (2.3 g, 8.18 mmol) as a clear oil. ¹ H NMR

(CHLOROFORM-d) δ: 7.60 (d, J = 8.2 Hz, 1 H), 7.25 (s, 1 H), 7.1 1 (d, J = 8.2 Hz, 1 H), 6.55 (t, J = 72 Hz, 1 H), 4.68 (br. s., 2H), 1 .92 (br. s., 1 H) Step 3: 1-bromo-4-(bromomethyl)-2-[(difluoromethyl)oxy]benzene

A solution of {4-bromo-3-[(difluoromethyl)oxy]phenyl}methanol (1 .90 g, 7.51 mmol) in diethyl ether (50 mL) was treated drop wise with phosphorus tribromide (0.744 mL, 7.88 mmol) and maintained with stirring at room temperature for 2 hours. The mixture was poured into ice water and the organic layer was washed with brine, separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1-bromo-4-(bromomethyl)-2-[(difluoromethyl)oxy]benzene (475 mg, 1.503 mmol, 20 % yield) as a clear oil. ¹H NMR (CHLOROFORM-d) δ: 7.60 (d, J = 8.2 Hz, 1 H), 7.26 (d, J = 4.9 Hz, 1 H), 7.16 (dd, J = 8.3, 2.1 Hz, 1 H), 6.56 (t, J = 72 Hz, 1 H), 4.43 (s, 2H)

Step 4: 6-[({4-bromo-3-[(difluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amin

cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (550 mg, 1.367 mmol), 1 -bromo-4-(bromomethyl)-2- [(difluoromethyl)oxy]benzene (475 mg, 1.503 mmol), and potassium carbonate (378 mg, 2.73 mmol) in N,N-dimethylformamide (5 mL) was maintained at 80 °C for 4 hours. The mixture was cooled, poured into water, and diluted with ethyl acetate. The organic layer was washed with 5% LiCI (aq), separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue purified by column chromatography to afford 6-[({4- bromo-3-[(difluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (805 mg, 1 .263 mmol, 92 % yield) as a yellow foam. LCMS {m/z, ES⁺) = 639 (M+H)

Step 5: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(difluoromethyl)oxy]phenyl}boronic acid

A solution of 6-[({4-bromo-3-[(difluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (225 mg, 0.353 mmol), potassium acetate (139 mg, 1.412 mmol), bis(pinacolato)diboron (179 mg, 0.706 mmol), and dichlorobis(tricyclohexylphosphine)palladium (II) (26.0 mg, 0.035 mmol) in 1 ,4-dioxane (5 mL) was maintained with stirring at 90°C in a sealed pressure tube for 16 hours. The mixture was cooled and filtered through glass filter paper. The filtrates were concentrated, dissolved in tetrahydrofuran (150 mL), and treated with 5. ON HCI (aq) (100 mL) and polymer supported benzene boronic acid (815 mg, 2.1 18 mmol). The mixture was maintained with stirring for 4 hours, filtered through celite, rinsed with ethyl acetate, and diluted with water. The organic layer was separated, concentrated, diluted with tetrahydrofuran (150 mL), treated with 5. ON HCI (aq) (100 mL) and polymer supported benzene boronic acid (815 mg, 2.1 18 mmol), and maintained with stirring for 16 hours. The mixture was filtered through celite, rinsed with ethyl acetate, diluted with water, and the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran- 6-yl}(methylsulfonyl)amino]methyl}-2-[(difluoromethyl)oxy]phenyl}boronic acid (87 mg, 0.144 mmol, 40.9 % yield) as a white foam following lyophlization. ¹H NMR (METHANOL-d₄) δ: 8.39 (d, J = 4.1 Hz, 1 H), 7.88 (dd, J = 8.9, 5.4 Hz, 2H), 7.57 (s, 1 H), 7.17 - 7.30 (m, 3H), 6.98 - 7.12 (m, 3H), 6.67 (t, J = 72 Hz, 1 H), 4.95 (d, J = 14.0 Hz, 1 H), 4.83 (d, J = 14.2 Hz, 1 H), 3.15 (s, 3H), 2.91 (d, J = 4.7 Hz, 3H), 2.14 - 2.27 (m, 1 H), 0.90 - 1 .03 (m, 1 H), 0.70 - 0.84 (m, 2H), 0.28 - 0.41 (m, 1 H). LCMS {m/z, ES⁺) = 603 (M+H).

Example 42

4-(2-(/V-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-fluorophenylboronic acid

Step 1: 4-allyl-1-bromo-2-fluorobenzene

To a solution of 1-bromo-2-fluoro-4-iodobenzene (10 g, 33.2 mmol) and Pd(PPh₃)₄ (2.3 g, 3 mmol) in DMF (100 ml.) was added allyltributylstannane (1 1.9 g, 36 mmol) at room temperature and heated at 100 °C for 12 hours. The reaction mixture was poured into ice/water (500 ml.) and the aqueous layer was extracted with EtOAc (3 x 300 ml_). The combined organic layers were washed with KF (10% aq., 3 x 100 ml_), brine (100 ml.) and dried over anhydrous Na₂S0₄. After concentration under reduced pressure, the crude product was purified with column chromatography to afford 4-allyl-1-bromo-2-fluorobenzene (6.5 g, 30.3 mmol, 91 .5 % yield).

Step 2: 2-(4-bromo-3-fluorophenyl)ethanol

A solution of 4-allyl-1-bromo-2-fluorobenzene (6.5 g, 30.3 mmol) in DCM/MeOH (100 mL/100 ml.) was saturated with a stream of gaseous 0₃ at -78 °C. The reaction mixture was stirred for 30 min until the solution turned to blue. After purging with N₂ for 30 min, NaBH₄ (5.7 g, 0.15 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The solution was poured into ice/water and the aqueous layer was extracted with DCM (3 x 100 ml_). The combined organic layers were dried over anhydrous Na₂S0₄. After concentration under reduced pressure, the crude product was purified with column chromatography to afford 2-(4-bromo-3-fluorophenyl)ethanol (3.5 g, 16 mmol, 53 % yield) as a colorless oil. Step 3: 1-bromo-4-(2-bromoethyl)-2-fluorobenzene

To a solution of NBS (5.6 g, 32 mmol) and 2-(4-bromo-3-fluorophenyl)ethanol (3.5 g, 16 mmol) in DCM (100 mL) was added PPh₃ (8.4 g, 32 mmol) in DCM (5 mL) drop wise at rt under nitrogen atmosphere and then stirred for 2 hours. Water (200 mL) was added and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After concentration under reduced pressure, the crude product was purified with column chromatography to afford 1-bromo-4-(2-bromoethyl)-2- fluorobenzene (3 g, 10.7 mmol, 62 % yield) as a light yellow liquid.

Step 4: 6-(N-(4-bromo-3-fluorophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 1-bromo-4-(2-bromoethyl)-2-fluorobenzene (2.3 g, 8.2 mmol), 5-cyclopropyl-N- methyl-6-(methylsulfonamido)-2-phenylbenzofuran-3-carboxamide (3.3 g, 8.2 mmol) and K₂C0₃ (2.3 g, 16.4 mmol) in MeCN (100 mL) was heated at 80 °C for 2 hours. The reaction mixture was poured into ice/water (100 mL) and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0_4. After concentration under reduced pressure, it afforded 6-(/V-(4-bromo-3- fluorophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (1.3 g, 2.16 mmol, 27 % crude yield) as a white solid.

Step 5: 5-cyclopropyl-6-(N-(3-fluoro-4-(4, 4, 5, 5-tetra methyl- 1, 3, 2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzo

A solution of 6-(/V-(4-bromo-3-fluorophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .3 g, 2.16 mmol), KOAc (0.447 g, 3.24 mmol), Pin₂B₂ (0.82 g, 3.24 mmol) and PdCI₂(dppf) (84 mg, 0.1 1 mmol) in DMF (50 mL) was heated at 100 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into ice/water (100 mL) and the aqueous layer was extracted with EtOAc (3x 100 mL). The combined organic layers were dried over anhydrous Na₂S0_4. After concentration under reduced pressure, the crude product was purified with column chromatography to afford 5-cyclopropyl-6-(/V-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide (950 mg, 1 .46 mmol, 67 % yield) as a white solid. Step 6: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-fluorophenylboronic acid A solution of 5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetra

yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (950 mg, 1 .46 mmol) and HCI (3N aq., 4.8 mL, 14.6 mmol,) in THF (20 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified with reverse phase HPLC to afford 4-(2-(/V-(5-cyclopropyl-2-(4- fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)-2- fluorophenylboronic acid (420 mg, 0.74 mmol, 51 % yield) as an off-white solid. ¹H-NMR (300MHz, DMSO) δ: 8.47 (s, 1 H), 8.10 (s, 1 H), 7.99 - 7.98 (m, 2 H),7.85 (s, 1 H), 7.50 - 7.37 (m, 3 H), 7.08 (s, 1 H), 6.99 - 6.93 (m, 2 H), 3.94 - 3.89 (m, 2 H), 3.14 (s, 3 H), 2.85 - 2.76 (m, 5 H), 2.32 - 2.28 (m, 1 H), 0.97 - 0.85 (m, 3 H), 0.60 (m, 1 H). LCMS(m/z, ES⁺)= 569(M+1 ).

Example 43

2-chloro-4-(2-(N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid

Step 1: 4-allyl-1-bromo-2-chlorobenzene

To a solution of 1-bromo-2-chloro-4-iodobenzene (3 g, 9.46 mmol), allyltributylstannane (3.7 g, 1 1 .35 mmol) in DMF (60 mL) was added Pd(PPh₃)₄ (0.63 g, 0.57 mmol) in one portion. The mixture was heated at 100 °C for 12 hours and then poured into ice/water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with KF (10% aq., 3 x 100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 4-allyl-1-bromo-2-chlorobenzene (1 .4 g, 6.06 mmol, 67 % yield) as a colorless oil.

Step 2: 2-(4-bromo-3-chlorophenyl)ethanol

A solution of 4-allyl-1-bromo-2-chlorobenzene (0.95 g, 4.1 mmol) in MeOH/DCM (100 mL/100 mL) was saturated with a stream of gaseous 0₃ at -78 °C. The reaction solution was stirred for 30 min until a blue color persisted. The reaction solution was purged with N₂ for 30 minutes followed by the addition of NaBH₄ (0.78 g, 20.6 mmol). After the addition, the reaction solution was stirred at room temperature overnight. The mixture was poured into ice/water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 2-(4-bromo-3-chlorophenyl)ethanol (0.8 g, 3.4 mmol, 85 % yield) as a colorless oil.

Step 3: 1-bromo-4-(2-bromoethyl)-2-chlorobenzene

To a solution of 2-(4-bromo-3-chlorophenyl)ethanol (0.8 g, 3.4 mmol) and NBS (1 .21 g, 6.8 mmol) in DCM (50 mL) was added PPh₃ (1.78 g, 6.8 mmol) in DCM (5 mL) drop wise under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice/water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography to give 1- bromo-4-(2-bromoethyl)-2-chlorobenzene (0.85 g, 2.85 mmol, 84 % yield) as a yellow oil.

Step 4: 6-(N-(4-bromo-3-chlorophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (0.5 g, 1.2424 mmol), 1 -bromo-4-(2-bromoethyl)-2-fluorobenzene (0.8 g, 2.681 mmol), Kl (206 mg, 1 .24 mmol) and K₂C0₃ (514 mg, 3.73 mmol) in dry DMF (10 mL) was heated at 60 °C for 30 min. The reaction solution was quenched with water (50mL). After the filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(/V-(4-bromo-3-chlorophenethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.595 g, 0.96 mmol, 77%) as a brown solid.

Step 5: 6-(N-(3-chloro-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofura carboxamide

A solution of 6-(N-(4-bromo-3-chlorophenethyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.595 g, 0.96 mmol, PdCI₂(dppf)-CH₂CI₂ adduct (190 mg, 0.096 mmol), bis(pinacolato)diboron (0.488 g, 1.92 mmol) and potassium acetate (282 mg, 2.88 mmol) in dioxane (20 mL) was heated at 100 °C overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography to afford 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methy

carboxamide (0.62 g, 0.93 mmol, 96%) as a brown solid.

Step 6: 2-chloro-4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran- 6-yl)methylsulfonamido)ethyl)phenylboronic acid

A solution of 6-(/V-(3-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran-3- carboxamide (0.62 g, 0.93 mmol), HCI (5N aq., 1.3 mL) and PS-benzene boronic acid (1.6 g, 4.65 mmol) in THF (15 mL) was stirred at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified with pre- HPLC to afford 2-chloro-4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)phenylboronic acid (108 mg, 0.199 mmol, 21 % ) as a white solid. ¹H NMR (300MHz, Methanol- d₄) δ: 7.96 - 7.92 (m, 2 H), 7.62 (s, 1 H), 7.31 - 7.12 (m, 6 H), 4.07 - 4.02 (t, 2 H), 3.08 (s, 3 H), 2.97 - 2.88 (m, 5 H), 2.33 (m, 1 H), 1.07 - 1.04 (d, 2 H), 0.89 (m, 1 H), 0.71 (m, 1 H). LCMS(m/z, ES⁺)= 585.0 (M+H).

Example 44

4-(2-(A/-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-(trifluoromethyl)phenylboronic acid

Step 1: 4-allyl-1-bromo-2-(trifluoromethyl)benzene

A solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (3 g, 8.5 mmol), allyltributylstannane (3.4 g, 10.3 mmol) and Pd(PPh₃)₄ (0.47 g, 0.4 mmol) in DMF (60 mL) was heated at 100°C for 12 hours. The reaction solution was poured into ice/water (100 mL) and the solution was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with KF (10% aq., 3 x 100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 4-allyl-1-bromo-2- (trifluoromethyl)benzene (1 .1 g, 4.15 mmol, 50 % yield) as a colorless oil. Step 2: 2-(4-bromo-3-(trifluoromethyl)phenyl)ethanol

A solution of 4-allyl-1-bromo-2-(trifluoromethyl)benzene (1.1 g, 4.15 mmol) in MeOH/DCM (100 mL/100 mL) was saturated with a stream of gaseous 0₃ at -78 °C. The reaction mixture was stirred for 30 min until the solution turned to blue. The reaction solution was purged with N₂ for 30 min followed by the addition of NaBH₄ (0.78 g, 20.7 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was poured into ice/water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 2-(4-bromo-3-(trifluoromethyl)phenyl)ethanol (0.85 g, 3.15 mmol, 77 % yield) as a colorless oil.

Step 3: 1-bromo-4-(2-bromoethyl)-2-(trifluoromethyl)benzene

To a solution of 2-(4-bromo-3-(trifluoromethyl)phenyl)ethanol (0.85 g, 3.15 mmol) and NBS (1 .12 g, 6.2 mmol) in DCM (50 mL) was added PPh₃ (1.62 g, 6.2 mmol) in DCM (5 mL) drop wise under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice/water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 1-bromo-4-(2- bromoethyl)-2-(trifluoromethyl)benzene (0.8 g, 2.4 mmol, 77% yield) as a yellow oil.

Step 4: 6-(N-(4-bromo-3-(trifluoromethyl)phenethyl)methylsulfonamido

fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (0.5 g, 1.2424 mmol), 1 -bromo-4-(2-bromoethyl)-2-(trifluoromethyl)benzene (0.825 g, 2.48 mmol), Kl (206 mg, 1.24 mmol) and K₂C0₃ (514 mg, 3.73 mmol) in dry DMF (10 mL) was heated at 120 °C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched with water (60mL). After the filtration, the residue was dissolved in EtOAc. The organic solution was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(/V-(4-bromo-3- (trifluoromethyl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (0.69g, 1 .056 mmol, 85%) as a brown solid.

Step 5: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl-1 ,3, 2- dioxaborolan-2-yl)-3-(trifluoromethyl)phenethyl)methylsulfonam

carboxamide

A solution of 6-(N-(4-bromo-3-(trifluoromethyl)phenethyl)methylsulfonamido)-5-cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.69 g, 1.056 mmol, PdCI₂(dppf)- CH₂CI₂ adduct (214 mg, 0.21 12 mmol), bis(pinacolato)diboron (0.536 g, 2.1 12 mmol) and potassium acetate (310 mg, 3.168 mmol) in dioxane (20 mL) was heated at 100 °C overnight under a nitrogen atmosphere. The reaction solution was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- (N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-

(trifluoromethyl)phenethyl)methylsulfonamido)benzofuran-3-carboxamide (0.51 g, 0.728 mmol, 69%) as a brown solid. Step 6: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-(trifluoromethyl)phenylboronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)phenethyl)methylsulfonamido)benzofuran-3- carboxamide (0.51 g, 0.728 mmol), HCI (5N aq., 1.02 mL) and PS-benzene boronic acid (1 .26 g, 3.64 mmol) in THF (15 mL) was stirred overnight. The reaction solution was filtrated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford 4-(2-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-2-(trifluoromethyl)phenylboronic acid (95 mg, 0.154 mmol, 20%) as a white solid. ¹H NMR (300MHz, Methanol- d4) δ: 7.96 - 7.91 (m, 2 H), 7.60 (s, 1 H), 7.49 - 7.14 (m, 6 H), 4.12 - 4.07 (t, 2 H), 3.09 (s, 3 H), 3.04 - 2.96 (m, 5 H), 2.05 (m, 1 H), 1.05 - 1.03 (d, 2 H), 0.89 (m, 1 H), 0.71 (m, 1 H). LCMS(m/z, ES 619.1 (M+H).

Example 45

r4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1 -benzofuran-6- yl}(methylsulfonyl) aminolmethyl}-2-fluoro-5-(trifluoromethyl)phenyllboronic acid

Step 1: [4-amino-5-fluoro-2-(trifluoromethyl)phenyl]methanol

A solution of [4-nitro-5-fluoro-2-(trifluoromethyl)phenyl]methanol (6.5g, 27.2 mmol) and palladium on activated carbon (0.6g, 2.72 mmol, 10% loading) in THF (15 mL) and methanol (10 mL) was stirred under H₂ atmosphere (~46psi) at room temperature for 20 hours. The palladium was removed via filtration over celite and the filtrates were concentrated and purified by flash column chromatography to give [4-amino-5-fluoro-2- (trifluoromethyl)phenyl]methanol (2.2g, 10.52 mmol, 38.7 % yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) 5 : 7.31 (d, J=^ ^ .7 Hz, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 4.74 (s, 2 H), 3.83 (br. s., 2 H).

Step 2: [4-bromo-5-fluoro-2-(trifluoromethyl)phenyl]methanol

A solution of [4-amino-5-fluoro-2-(trifluoromethyl)phenyl]methanol (2.2g, 10.52 mmol in acetonitrile (15 ml.) was cooled to 0°C in ice bath, then 48% aqueous HBr (7.14 ml_, 63.1 mmol) was added drop wise by syringe over 10min, then sodium nitrite (0.798 g, 1 1.57 mmol) in 8ml_ water was added drop wise over 30 min . After addition, the solution was stirred under 0°C for 20min, then copper bromide (1 .771 g, 12.10 mmol) was added portion wise over 10 minutes. After addition, the resulting mixture was heated to 70°C for 30 minutes. The solution was diluted with water, extracted with EtOAc, and the organic layer was dried over Na₂S0₄, filtered, concentrated, and purified by flash column chromatography to give [4- bromo-5-fluoro-2-(trifluoromethyl)phenyl]methanol (2.1 g, 7.69 mmol, 73.1 % yield) as a pale yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.84 (d, J=6.4 Hz, 1 H), 7.58 (d, J=9.4 Hz, 1 H), 4.86 (s, 2 H).

Step 3: [4-bromo-5-fluoro-2-(trifluoromethyl)phenyl]methyl methanesulfonate

To a solution of [4-bromo-5-fluoro-2-(trifluoromethyl)phenyl]methanol (1.9g, 6.96 mmol) in DCM (10 ml.) was added TEA (1 .065 ml_, 7.66 mmol) at room temperature, followed by methylsulfonylchloride (0.592 ml_, 7.66 mmol). The resulting solution was stirred for 30 minutes, and washed sequentially with water and brine. The organic layer was dried over Na₂S0_4, filtered, concentrated and purified by column chromatography to give [4-bromo-5- fluoro-2-(trifluoromethyl)phenyl]methyl methanesulfonate (1.65g, 4.70 mmol, 67.5 % yield) as an off-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.93 (d, J=6.4 Hz, 1 H), 7.46 (d, J=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}(methylsulfonyl)am

cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (1 .529g, 3.8 mmol), [4-bromo-5-fluoro-2-(trifluoromethyl) phenyl]methyl methanesulfonate (1.334g, 3.80 mmol), and potassium carbonate (0.630 g, 4.56 mmol) in DMF (6 ml.) was warmed to 50°C for 2 hours. The solution was diluted with EtOAc and water and the organic layer was dried over Na₂S0₄, filtered, concentrated and purified by column chromatography to give 6-[{[4-bromo-5-fluoro-2- (trifluoromethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (2.45g, 3.73 mmol, 98 % yield) as a off-white foam. ¹H NMR (400 MHz, DMSO-d₆) δ : 8.41 (d, J=4.5 Hz, 1 H), 8.01 (d, J=6.4 Hz, 1 H), 7.97 (s, 1 H), 7.93 (dd, J=8.8, 5.5 Hz, 2 H), 7.79 (d, J=9.6 Hz, 1 H), 7.38 (t, J=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, J=4.5 Hz, 1 H).

Step 5: [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofu yl}(methylsulfonyl)amino]methyl}-2-fluoro-5-(trifluoromethyl)phenyl]boronic acid

A solution of 6-[{[4-bromo-5-fluoro-2-(trifluoromethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (2.45g, 3.73 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1.893 g, 7.45 mmol),

dichloro(tricyclohexylphophine)palladium (II) (0.138 g, 0.186 mmol) and potassium acetate (0.732 g, 7.45 mmol) in 1 ,4-dioxane (5 ml.) was maintained at 80°C with stirring overnight under an atmosphere of N₂. Solids were removed via filtration over celite and the filtrates were partitioned between water and EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to give a brown residue. The residue was dissolved in THF (5.00 ml.) and 3ml_ 6M HCI, treated with PS-benzene boronic acid (1.4g, 3.73 mmol) (2.6- 3.2mmol/g), and stirred at 50°C for 3 hours. Solids were removed via vacuum filtration and the filtrates were extracted EtOAc. The organic layer was concentrated and purified by reverse phase HPLC to give [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-

[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl) amino]methyl}-2-fluoro-5- (trifluoromethyl)phenyl]boronic acid (1 .1 Og, 1 .76mmol, 47.4% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ : 8.42 (d, J=2.7 Hz, 2 H), 7.93 (br. s., 3 H), 7.82 (d, J=4.7 Hz, 1 H), 7.58 (d, J=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, J=1.2 Hz, 1 H), 0.21 (br. s., 1 H). LC-MS (m/z, ES⁺)= 623 (M+H)

Example 46

4-(2-(/\/-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-fluorophenylboronic acid

Step 1: 4-bromo-2-fluoro-1 -vinylbenzene A solution of 4-bromo-2-fluoro-1 -iodobenzene (25 g, 83 mmol, ALFA), tributyl(vinyl)tin (32 g, 100 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.80, 40 mmol) in DMF (100 mL) was heated at 100 °C for 48 hours under an N₂ atmosphere. After the reaction solution was cooled to room temperature, brine (100 mL) was added and the resulting solution was extracted with ether (3 x 50 mL). The combined organic layers were washed with KF (10% aq. 100 mL) and brine (100 mL) and dried over anhydrous Na₂S0_4. After the removal of solvent, the crude product was purified with column chromatography (100% petroleum) to afford 4-bromo-2-fluoro-1 -vinylbenzene (12.9 g, 65 mmol, 78% yield) as a colorless oil. Step 2: 2-(4-bromo-2-fluorophenyl)ethanol

To a solution of 4-bromo-2-fluoro-1 -vinylbenzene (1 g, 5 mmol) in THF (25mL) was added 9- BBN (0.5 M in THF, 12 mL, 6 mmol) at room temperature under N₂ atmosphere. The resulting reaction mixture was stirred overnight at room temperature. To this solution, NaOH (1 N aq, 25 mL) was added at 0 °C. After stirring at room temperature for 15 minutes, hydrogen peroxide (25 mL) was added below 20 °C and the resulting reaction mixture was stirred at room temperature for another 2 hours. The separated organic layer was washed with brine (25 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography (from 100% PE to 10 % EA in PE) to afford 2-(4-bromo-2-fluorophenyl)ethanol (527 mg, 2.42 mmol, 48% yield) as a colorless oil. LCMS {m/z, ES 219 (M+H)

Step 3: 4-bromo-1-(2-bromoethyl)-2-fluorobenzene

A solution of 2-(4-bromo-2-fluorophenyl)ethanol (3.1 g, 14 mmol), NBS (3.8g, 21 mmol) and PPh₃ (5.5g, 21 mmol) in DCM (100 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified with column chromatography to afford 4-bromo-1 -(2-bromoethyl)-2-fluorobenzene (3.6g, 12.9 mmol, 92 % yield) as a colorless oil.

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (2.5 g, 6.21 mmol), 4-bromo-1 -(2-bromoethyl)-2-fluorobenzene (3.6 g, 13.0 mmol), potassium carbonate (2.6 g, 19 mmol) and potassium iodide (1.0 g, 6.21 mmol) in DMF (50 mL) was heated at 80 °C for 4 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified with column chromatography to afford 6-(/V-(4-bromo-3-fluorophenethyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-/V-methylbenzofuran-3-carboxamide (1 .9 g, 3.1 mmol, 51 % yield) as a white solid. LCMS {m/z, ES⁺) = 603 (M+H)

Step 5: 5-cyclopropyl-6-(N-(2-fluoro-4-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzo

A solution of 5-cyclopropyl-6-(/V-(2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .9g, 3.1 mmol), potassium acetate (0.88 g, 9 mmol), bis(pinacolato)diboron (1 .52 g, 6.0 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.219 g, 0.3 mmol) in 1 ,4-dioxane (100 mL) was degassed and refilled with nitrogen and heated at 100 °C overnight. After the reaction solution was cooled to room temperature, water (100 mL) was added and the solution was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography to afford 5-cyclopropyl-6-(/V-(2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1 .5 g, 2.3 mmol, 77% yield) as a white solid. LCMS (m/z, ES⁺) = 651 (M+H)

Step 6: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-fluorophenylboronic acid

A solution of 5-cyclopropyl-6-(/V-(2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenethyl)methylsulfonamido)-2-(4-fluorophenyl)-/\/-methylbenzofuran-3-carboxamide (1.5 g, crude, 2.3 mmol), PS-BBA (8.9 g, 23 mmol) and HCI (5N aq., 5 mL) in THF (30 mL) was stirred at room temperature overnight. The solids were removed via filtration and the filtrates were concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford 4-(2-(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-fluorophenylboronic acid (745 mg, 1.31 mmol, 57% yield) as a white solid. ¹ H NMR (METHANOL-d₄) δ: 7.96 (m, 2H), 7.59 (s, 1 H), 7.36 (m, 6H), 4.87 ( t, 2H), 3.17 (m, 8H), 2.37 (m, 1 H), 1.07 (d, 2H), 0.94 (m, 1 H), 0.69 (m, 1 H). LCMS {m/z, ES⁺) = 569 (M+H)

Example 47

4-(2-(N-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-(trifluoromethyl)phenylboronic acid

Step 1 : 4-bromo-1-iodo-2-(trifluoromethyl)benzene

A solution of 4-bromo-2-(trifluoromethyl)benzenamine (25 g, 0.1 1 mol, ALFA) in H₂0 (250 mL) was treated with concentrated HCI (60 mL) and cooled to 0 °C. To this solution, NaN0₂ (10 g, 150 mmol) in H₂0 (75 mL) was added drop wise over 30 minutes and then the reaction mixture was warmed to room temperature and stirred for 1 hour followed by the addition of Nal (56 g, 0.37 mol) in H₂0 (25 mL) over 40 minutes. After stirring at room temperature for another 16 hours, the reaction mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with Na₂S₂0₃ (3N aq. 200 mL) and water (200 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography (eluting with petroleum) to afford 4-bromo-1 -iodo-2- (trifluoromethyl)benzene (25.1 g, 71.9 mmol, 66% yield) as a white solid.

Step 2: 4-bromo-2-(trifluoromethyl)-1-vinylbenzene

A solution of 4-bromo-1 -iodo-2-(trifluoromethyl)benzene (25 g, 71 mmol), tributyl(vinyl)tin (27 g, 86 mmol), and tetrakis(triphenylphosphine)palladium(0) (4.0 g, 40 mmol) in DMF (100 mL) was heated at 100 °C for 48 hours under an N₂ atmosphere. To the reaction mixture, brine (100 mL) was added and the mixture was extracted with ether (3 x 50 mL). The combined organic layers were treated with KF (10% aq., 100 mL) and stirred for 4 hours. The separated organic layer was washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography (eluting with petroleum) to afford 4-bromo-2-(trifluoromethyl)-1-vinylbenzene (10.8 g, 43 mmol, 61 % yield) as a colorless oil. Step 3: 2-(4-bromo-2-(trifluoromethyl)phenyl)ethanol

To a solution of 4-bromo-2-(trifluoromethyl)-1-vinylbenzene (3.0 g, 12 mmol) in 100 mL of THF was added 9-BBN (0.5 M, 28 mL, 14 mmol) under an N₂ atmosphere. The resulting reaction mixture was stirred at room temperature overnight. NaOH solution (1 N aq., 100 mL) was added at 0 °C. After stirring for 15 min, hydrogen peroxide (100 mL) was added and the resulting mixture was stirred for 2 hours at room temperature. The organic layer was separated, washed with brine (100 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the residue was purified by column chromatography (eluting with PE to 10 % EA in PE) to afford 2-(4-bromo-2-(trifluoromethyl)phenyl)ethanol (1.13 g, 4.2 mmol, 35 % yield) as a colorless oil. LCMS {m/z, ES⁺) = 269 (M+H)

Step 4: 4-bromo-1-(2-bromoethyl)-2-(trifluoromethyl)benzene

A solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)ethanol (1.13 g, 4.2 mmol), 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 1 hour. The solution was concentrated under reduced pressure and the residue was purified by column chromatography to afford 4-bromo-1-(2-bromoethyl)-2-(trifluoromethyl)benzene (1 .24 g, 3.8 mmol, 89 % yield) as a colorless oil.

Step 5: 6-(N-(4-bromo-3-(trifluoromethyl)phenethyl)methylsulfonamido

fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (0.5 g, 1.2 mmol), 4-bromo-1 -(2-bromoethyl)-2- (trifluoromethyl)benzene (1 .24 g, 3.8 mmol), potassium carbonate (496 mg, 3.6 mmol) and potassium iodide (199 mg, 1.2 mmol) in DMF (15 mL) was heated at 80 °C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified by column chromatography to afford 6-(N-(4-bromo-3- (trifluoromethyl)phenethyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (519 mg, 0.796 mmol, 66 % yield) as a white solid. 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- dioxaborolan-2-yl)-2-(trifluoromethyl)phenethyl)methylsulfonam

carboxamide

A solution of 6-(N-(4-bromo-3-(trifluoromethyl)phenethyl)methylsulfonamido)-5-cyclopropyl-2- (4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (519 mg, 0.8 mmol), potassium acetate (235 mg, 2.4 mmol), bis(pinacolato)diboron (406 mg, 1 .6 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (58 mg, 0.08 mmol) in 1 ,4-dioxane (50 mL) was degassed and refilled with nitrogen three times and then heated at 100 °C overnight under a nitrogen atmosphere. The solution was cooled to room temperature. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄. After the filtration and concentration under reduced pressure, the residue was purified by column chromatography to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenethyl)methylsulfonamido)benzofuran-3-carboxamid (444 mg, 0.63 mmol, 81 % yield) as a white solid. LCMS {m/z, ES⁺) = 701 (M+H)

Step 7: 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-(trifluoromethyl)phenylboronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-(trifluoromethyl)phenethyl)methylsulfonamido)benzofuran-3- carboxamide (444 mg, crude, 0.63 mmol), HCI (5N aq., 5 ml.) and PS-BBA (2.4 g, 6.3 mmol) in THF (30 ml.) was stirred overnight at room temperature. The reaction mixture was filtered and the filtrates were concentrated under reduced pressure and the resulting residue purified by reverse phase HPLC to afford 4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)ethyl)-3-(trifluoromethyl)phenylboronic acid (245 mg, 0.39mmol, 63% yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.97 (m, 4H), 7.71 (s, 1 H), 7.47 (m, 4H), 4.02 ( t, 2H), 3.17 (m, 8H), 2.37 (m, 1 H), 1.06 (d, 2H), 0.94 (m, 1 H), 0.65 (m, 1 H). LCMS {m/z, ES⁺) = 619 (M+H)

Example 48

{4-[({5-cvclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyll-1-benzofuran-6- l}amino)methvH-2-fluorophenyl}boronic acid

Step 1: ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate

A solution of ethyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate (23.5g, 63.6 mmol) and Pd/C (8.3g, 28.48 mmol) in THF (35 ml.) was treated with methanol (20 ml_). The resulting mixture was stirred under H₂ atmosphere ( ~50psi) at room temperature for 60 hours. The solids were removed via filtration over celite and the filtrates were concentrated and the resulting residue was purified by flash column chromatography to give ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1 -benzofuran-3-carboxylate (13.1 g, 38.6 mmol, 60.7 % yield) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.98 - 8.06 (m, 2 H), 7.72 (s, 1 H), 7.15 (t, J=8.7 Hz, 2 H), 6.83 (s, 1 H), 4.40 (q, J=7.2 Hz, 2 H), 4.28 (br. s., 2 H), 1 .72 - 1 .83 (m, 1 H), 1 .43 (t, J=7.1 Hz, 3 H), 0.94 - 1.03 (m, 2 H), 0.65 - 0.73 (m, 2 H). Step 2: ethyl 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)-1^ benzofuran-3-carboxylate

A solution of ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1 -benzofuran-3-carboxylate (13 g, 38.3 mmol), 4-bromo-3-fluorobenzaldehyde (7.78 g, 38.3 mmol) in ethanol (100 mL) were refluxed for 20 hours. The solids were collected via vacuum filtration and re-dissolved in THF (100 mL). The solution was treated with acetic acid (13.16 mL, 230 mmol) and then sodium borohydride (4.35 g, 1 15 mmol) portion wise. After addition, the solution was stirred at room temperature for 2 hours. The mixture was filtered and concentrated to give ethyl 6-{[(4- bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)-1 -benzofuran-3- carboxylate (19.4g, 36.9 mmol, 96 % yield) as a pale yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.99 (dd, J=8.7, 5.6 Hz, 2 H), 7.76 (s, 1 H), 7.52 (t, J=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, J=7.2 Hz, 2 H), 1.70 - 1.81 (m, 1 H), 1.43 (t, J=7.1 Hz, 3 H), 0.97 - 1 .06 (m, 2 H), 0.65 - 0.75 (m, 2 H). Step 3: 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)-1- benzofuran-3-carboxylic acid

To a solution of ethyl 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4- fluorophenyl)-1 -benzofuran-3-carboxylate (1 1.65g, 22.13 mmol) in THF (40 mL) and methanol (10 mL) was added 80mL 2M NaOH aqueous solution (155 mmol). The mixture was heated to 50°C overnight and then to 80°C for 5 hours. Most of the solvent was removed under reduced pressure and the residue was acidified with 1 N HCI after which a yellow solid precipitated. The solids were collected via filtration and washed with water to afford 6-{[(4- bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)-1 -benzofuran-3- carboxylic acid (1 1 g, 22.07 mmol, 100 % yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.98 (dd, J=8.8, 5.7 Hz, 2 H), 7.64 (t, J=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). Step 4: 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-1-benzofuran-3-carboxamide

To a suspension of 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4- fluorophenyl)-1 -benzofuran-3-carboxylic acid (1 1 g, 22.07 mmol) in DMF (15 mL) was added DIPEA (7.69 mL, 44.1 mmol) and HATU (10.07 g, 26.5 mmol) sequentially. Upon addition, a yellow solid precipitated immediately. After 10min, 22mL 2M THF solution of methyl amine (1 .371 g, 44.1 mmol) was added and stirred for 30 minutes. The mixture was filtered and the solids were washed with water to give 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5- cyclopropyl-2-(4-fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (7.2g, 14.08 mmol, 63.8 % yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d₆) δ : 8.28 (d, J=4.5 Hz, 1 H), 7.82 (dd, J=8.7, 5.6 Hz, 2 H), 7.64 (t, J=7.8 Hz, 1 H), 7.37 (d, J=9.8 Hz, 1 H), 7.27 (t, J=8.9 Hz, 2 H), 7.20 (d, J=8.0 Hz, 1 H), 7.14 (s, 1 H), 6.51 (s, 1 H), 6.33 (t, J=6.1 Hz, 1 H), 4.51 (d, J=6.0 Hz, 2 H), 2.80 (d, J=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-fluorophenyl)-3-[(methylamino

yl}amino)methyl]-2-fluorophenyl}boronic acid

A solution of 6-{[(4-bromo-3-fluorophenyl)methyl]amino}-5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-1 -benzofuran-3-carboxamide (0.5g, 0.978 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane (0.497 g, 1 .956 mmol), dichloro(tricyclohexylphosphine)palladium (II) (0.036 g, 0.049 mmol) and potassium acetate (0.288 g, 2.93 mmol) in 1 ,4-dioxane (5 ml.) was heated to 80°C for 4 hours under N₂. The solution was filtered over a pad of celite, partitioned between water and EtOAc, and the organic layer was concentrated. The resulting residue was dissolved (5.00 ml_), treated with PS-benzene boronic acid (1.8g, 4.89 mmol) (2.6-3.2mmol/g) and maintained at 50°C for 1 hour. The solid was removed via filtration and washed with ethyl acetate. The filtrates were concentrated and purified by reverse phase HPLC to give {4-[({5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran- 6-yl}amino)methyl]-2-fluorophenyl}boronic acid (80 mg, 0.168 mmol, 17.18 % yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.29 (br. s., 1 H), 7.83 (br. s., 2 H), 7.50 (br. s., 1 H), 6.91 - 7.40 (m, 6 H), 6.50 (br. s., 1 H), 4.53 (br. s., 2 H), 2.81 (br. s., 3 H), 1.80 (br. s., 1 H), 1 .01 (br. s., 2 H), 0.60 (br. s., 2 H). LC-MS(m/z, ES⁺)=477 (M+H). Example 49

{4-{r{5-Cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-r(methyloxy)carbonyllphenyl}boronic acid

{4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(methyloxy)carbonyl]phenyl}boronic acid A mixture of methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]- 1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate (486 mg, 0.77 mmol), potassium acetate (152 mg, 1 .54 mmol), bis(pinacolato)diboron (255 mg, 1.00 mmol), sodium bromide (79 mg, 0.77 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (57 mg, 0.077 mmol) in 1 ,4-dioxane (10 ml.) in a thick-walled glass pressure vessel was degassed, then heated at 95°C with stirring for 19 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded methyl 5-{[{5-cyclopropyl-2- (4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}- 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (0.48 g, 80% pure by LC/MS) as a colorless semisolid. Part (0.24 g) of this residue was dissolved in THF (6 ml_), treated with 0.1 N ammonium acetate (4 ml.) and sodium periodate (0.38 g, 1 .77 mmol) and allowed to stir at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization afforded {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2- [(methyloxy)carbonyl]phenyl}boronic acid (107 mg, 47% over 2 steps) as a white solid. ¹ H NMR (METHANOL-d₄) : 7.84 - 7.93 (m, 3H), 7.60 (s, 1 H), 7.47 (dd, J = 7.5, 1.2 Hz, 1 H),

7.18 - 7.31 (m, 3H), 6.99 (s, 1 H), 4.81 - 5.07 (m, 2H), 3.86 (s, 3H), 3.17 (s, 3H), 2.90 (s, 3H), 2.18 - 2.28 (m, 1 H), 0.90 - 1 .01 (m, 1 H), 0.65 - 0.83 (m, 2H), 0.18 - 0.30 (m, 1 H). LCMS {m/z, ES⁺) = 595 (M+H). Example 50

{4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-r(trifluoromethyl)oxylphenyl}boronic acid

Step 1: 4-bromo-3-[(trifluoromethyl)oxy]benzoic acid A solution of 4-amino-3-[(trifluoromethyl)oxy]benzoic acid (5g, 22.61 mmol) in acetonitrile (30 ml.) was cooled below 0°C in ice-NaCI bath and treated with hydrobromic acid (15.35 ml_, 136 mmol). Then sodium nitrite (1 .716 g, 24.87 mmol) in 6ml_ water was added drop wise while maintaining the internal temperature below 5°C. After addition, the solution was stirred for another 10 minutes, then copper bromide (3.73 g, 26.0 mmol) was added portion wise. The mixture was heated to 70°C for 30 minutes after the addition. The solution was diluted with water until the solution became green, then extracted with EtOAc. The organic layer was dried over Na₂S0₄, filtered, and concentrated to afford 4-bromo-3- [(trifluoromethyl)oxy]benzoic acid (6g, 21.05 mmol, 93 % yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ : 13.62 (br. s., 1 H), 7.98 (d, J=8.0 Hz, 1 H), 7.81 - 7.92 (m, 2 H).

Step 2: methyl 4-bromo-3-[(trifluoromethyl)oxy]benzoate

A solution of 4-bromo-3-[(trifluoromethyl)oxy]benzoic acid (6g, 27.1 mmol) and one drop of concentrated sulfuric acid in 20ml_ methanol was heated to reflux for 3 hours. The solution was filtered through celite and the filtrate was concentrated and purified by flash column chromatography to give methyl 4-bromo-3-[(trifluoromethyl)oxy]benzoate (5g, 16.72 mmol, 61 .6 % yield) as a light yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ : 7.96 (s, 1 H), 7.85 (dd, J=8.3, 1 .7 Hz, 1 H), 7.74 (d, J=8.4 Hz, 1 H), 3.95 (s, 3 H). Step 3: {4-bromo-3-[(trifluoromethyl)oxy]phenyl}methanol

A solution of methyl 4-bromo-3-[(trifluoromethyl)oxy]benzoate (4.60g, 15.38 mmol), sodium borohydride (1.746 g, 46.1 mmol) in methanol (5 ml.) and THF (10 mL) was stirred at room temperature. The solution was quenched with water and extracted with EtOAc. The organic layer was dried over Na₂S0₄, filtered, and concentrated to afford {4-bromo-3- [(trifluoromethyl)oxy]phenyl}methanol (4.05g, 14.94 mmol, 97 % yield) as a golden oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.62 (d, J=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-(chloromethyl)-2-[(trifluoromethyl)oxy]benzene

To a solution of {4-bromo-3-[(trifluoromethyl)oxy]phenyl}methanol (4.05g, 14.94 mmol) and TEA (3.74 mL, 26.9 mmol) in DCM (10 mL) was added methylsulfonylchloride (2.082 mL, 26.9 mmol). The resulting solution was stirred under room temperature for 4 hours and then washed with water. The mixture was extracted with DCM and the combined the organic layers were dried over Na₂S0₄, filtered, concentrated and purified by silica gel column chromatography to give 1-bromo-4-(chloromethyl)-2-[(trifluoromethyl)oxy]benzene (2.488g, 8.59 mmol, 57.5 % yield) as a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.64 (d, J=8 Hz, 1 H), 7.35 (s, 1 H), 7.22 (dd, J=8, 1.8 Hz, 1 H), 4.55 (s, 2 H).

I l l Step 5: 6-[({4-bromo-3-[(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)am

cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A mixture of 1 -bromo-4-(chloromethyl)-2-[(trifluoromethyl)oxy]benzene (2.48 g, 8.57 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (2.415 g, 6 mmol), Nal (0.045 g, 0.300 mmol) and K₂C0₃ (1.159 g, 8.40 mmol) in 1 ,4-dioxane (20 ml.) and DMF (5 ml.) was heated to 80°C overnight. The solution was quenched with water, extracted with EtOAc, and the combined organic layers were dried over Na₂S0₄, filtered, concentrated and purified by flash column chromatography to give 6-[({4- bromo-3-[(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl) amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (3.35g, 5.1 1 mmol, 85 % yield) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 7.85 (dd, J=8.9, 5.4 Hz, 2 H), 7.56 (d, J=8.2 Hz, 1 H), 7.28 (s, 1 H), 7.24 (s, 1 H), 7.19 (t, 3 H), 7.09 (dd, J=8.2, 2.0 Hz, 1 H), 5.76 (br. s., 1 H), 4.97 (d, J=14.7 Hz, 1 H), 4.72 (d, J=14.5 Hz, 1 H), 3.03 (s, 3 H), 2.99 (d, J=5.1 Hz, 3 H), 2.08 - 2.18 (m, 1 H), 0.99 - 1 .1 1 (m, 1 H), 0.86 - 0.97 (m, 2 H), 0.57 (d, J=5.3 Hz, 1 H).

Step 6: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(trifluoromethyl)oxy]phenyl}boronic acid

A solution of 6-[({4-bromo-3-[(trifluoromethyl)oxy]phenyl}methyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (1 .5g, 2.288 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1.162 g, 4.58 mmol), KOAc (0.674 g, 6.87 mmol) and dichlorobis(tricyclohexylphophine)palladium(ll) (0.084 g, 0.1 14 mmol) in 1 ,4-dioxane (10 ml.) was heated to 80°C overnight under an N₂ atmosphere. The solution was filtered over celite and the solids were washed with EtOAc. The filtrates were

concentrated to give a residue which was dissolved in THF (15.00 ml.) and 1.5ml_ 6M HCI, treated with PS-benzene boronic acid (4.2g, 1 1.44 mmol) (2.6-3.2mmol/g) and maintained at 50°C overnight. The solids were removed via filtration and the filtrated was concentrated and purified by reverse phase HPLC to afford {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl) amino]methyl}-2-

[(trifluoromethyl)oxy]phenyl}boronic acid (72mg, 0.1 16 mmol, 5.07 % yield) as an off-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ : 7.80 - 7.88 (m, 3 H), 7.29 (s, 1 H), 7.20 - 7.25 (m, 2 H), 7.15 - 7.20 (m, 2 H), 5.75 (br. s., 1 H), 5.05 (d, J=14.6 Hz, 2 H), 4.76 (d, j=14.4 Hz, 1 H), 3.03 (s, 3 H), 2.99 (d, J=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 (m/z, ES⁺) =621 (M+H).

Example 51 {4-{[{5-cvclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-[(methyloxy)methyllphenv^ acid

Step 1 : 6-[({4-bromo-3-[(methyloxy)methyl]phenyl}methyl)(methylsulfonyl)am

cyclopropyl-2-(4-fluorophenyl)-N-methyl-1 -benzofuran-3-carboxamide

A solution of (2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)methyl methanesulfonate (320 mg, 0.471 mmol) in methanol (4 mL) was treated with sodium methoxide in methanol (2.141 mL, 9.42 mmol) in two portions. The mixture was maintained with stirring at room temperature for 5 hours. A thick white precipitate formed. The solution was poured into water and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford 6-[({4-bromo-3-

[(methyloxy)methyl]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-1 -benzofuran-3-carboxamide (276 mg, 0.426 mmol, 90 % yield) as a white solid. LCMS {m/z, ES⁺) = 616 (M+H)

Step 2: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofura yl}(methylsulfonyl)amino]methyl}-2-[(methyloxy)methyl]phenyl}boronic acid A solution of 6-[({4-bromo-3-[(methyloxy)methyl]phenyl}methyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (276 mg, 0.448 mmol), potassium acetate (176 mg, 1.794 mmol), bis(pinacolato)diboron (228 mg, 0.897 mmol), and dichlorobis(tricyclohexylphosphine)palladium (II) (33.1 mg, 0.045 mmol) in 1 ,4-dioxane (12 mL) was maintained at 90°C in a sealed pressure tube for 16 hours. The mixture was cooled and filtered through glass filter paper. The filtrates were concentrated, dissolved in tetrahydrofuran (150 mL), and treated with polymer supported benzene boronic acid (863 mg, 2.242 mmol) and 6. ON HCI (aq) (0.374 mL, 2.242 mmol). The mixture was maintained with stirring at room temperature for 3 hours and filtered through celite. The filtrates were diluted with ethyl acetate and the organic layer was separated, concentrated, re-dissolved in tetrahydrofuran (150 mL), and re-treated with polymer supported benzene boronic acid (863 mg, 2.242 mmol) and 6. ON HCI (aq) (0.374 mL, 2.242 mmol). The mixture was maintained with stirring for 2 hours, filtered through celite, and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford {4-{[{5-cyclopropyl-2-(4-fluorophenyl)- 3-[(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2- [(methyloxy)methyl]phenyl}boronic acid (58 mg, 0.100 mmol, 22.28 % yield) as a white solid following lyophillization. ¹H NMR (METHANOL-d₄) δ: 7.87 (dd, J = 8.8, 5.3 Hz, 2H), 7.53 (s, 1 H), 7.06 - 7.27 (m, 5H), 7.01 (s, 1 H), 4.91 (d, J = 14.0 Hz, 1 H), 4.81 (d, J = 13.9 Hz, 1 H), 4.39 (s, 2H), 3.32 (s, 3H), 3.14 (s, 3H), 2.91 (s, 3H), 2.16 - 2.27 (m, 1 H), 0.89 - 1.01 (m, 1 H), 0.77 (t, J = 6.0 Hz, 2H), 0.23 - 0.37 (m, 1 H). LCMS {m/z, ES⁺) = 581 (M+H)

Example 52

{4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-r(dimethylamino)methyllphenyl}boronic acid

Step 1 : 6-[( {4-bromo-3-[(dimethylamino)methyl]phenyl}methyl)(methylsulfon

cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide A solution of 6-[{[4-bromo-3-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (321 mg, 0.534 mmol) and DIPEA (0.373 mL, 2.135 mmol) in dichloromethane (15 mL) was treated with MsCI (0.083 mL, 1.067 mmol) and maintained with stirring at room temperature for 1 hour. The mixture was poured into saturated sodium bicarbonate and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and treated with 2.0M dimethyl amine in THF (2.67 mL, 5.34 mmol) and maintained with stirring at room temperature for 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, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-[({4-bromo-3- [(dimethylamino)methyl]phenyl}methyl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (1 10 mg, 0.175 mmol, 32.8 % yield) as a white solid. LCMS {m/z, ES⁺) = 629 (M+H)

Step 2: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofura yl}(methylsulfonyl)amino]methyl}-2-[(dimethylamino)methyl]phe acid

A solution of 6-[({4-bromo-3-[(dimethylamino)methyl]phenyl}methyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (90 mg, 0.143 mmol), potassium acetate (56.2 mg, 0.573 mmol), dichlorobis(tricyclohexylphosphine)palladium (II) (10.57 mg, 0.014 mmol), and potassium acetate (56.2 mg, 0.573 mmol) in 1 ,4-dioxane (12 ml.) was maintained with stirring in a sealed pressure tube for 24 hours. PdCl2(dppf)-CH₂Cl2 adduct (1 1.69 mg, 0.014 mmol) and additional bis(pinacolato)diboron (72.7 mg, 0.286 mmol) and potassium acetate (56.2 mg, 0.573 mmol) were added and the mixture was maintained with stirring at 80°C for an additional 24 hours. The mixture was filtered through celite, concentrated, and purified by reverse phase hplc (MeCN:H20 0.1 %FA). Subsequent repurification of the fractions containing desired products afforded {4-{[{5-cyclopropyl-2-(4- fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2- [(dimethylamino)methyl]phenyl}boronic acid (5.6 mg, 9.44 μηηοΙ, 6.59 % yield). ¹ H NMR (METHANOL-d₄) δ: 8.26 (br. s., 1 H), 7.87 (dd, J = 8.8, 5.3 Hz, 2H), 7.46 (s, 1 H), 7.38 (d, J = 7.4 Hz, 1 H), 7.23 (t, J = 8.7 Hz, 2H), 7.09 (d, J = 7.4 Hz, 1 H), 7.00 (s, 1 H), 6.96 (s, 1 H), 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, 1 H), 0.88

- 1.02 (m, 1 H), 0.68 - 0.85 (m, 2H), 0.25 - 0.41 (m, 1 H). LCMS {m/z, ES⁺) = 594 (M+H) Example 53

{4-{r{5-cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-r(methylamino)methyllphenyl}boronic acid

Step 1: methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate A suspension of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1- benzofuran-3-carboxamide (2.75 g, 6.83 mmol), methyl 2-bromo-5-(bromomethyl)benzoate {Bioorganic and Medicinal Chemistry Letters, 2009, 19(15) p. 4416-4420); (4.73 g, 15.37 mmol), and potassium carbonate (3.78 g, 27.3 mmol) in N,N-dimethylformamide (30 mL) was maintained at 80°C for 1 hour. The mixture was cooled, poured into ethyl acetate, and washed with 5% LiCI (aq) three times. The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue purified by column chromatography to afford methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate (3.42 g, 5.43 mmol, 80 % yield) as a yellow solid. LCMS {m/z, ES⁺) = 630 (M+H)

Step 2: 6-[{[4-bromo-3-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl- 2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]- 1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}benzoate (1 .28 g, 2.033 mmol) in

tetrahydrofuran(35 ml_)/methanol (3.50 mL) was cooled to 0°C, treated with lithium

borohydride in THF (5.08 mL, 10.17 mmol), and allowed to warm to room temperature. The mixture was stirred an additional 3 hours, diluted with 1.0N NaOH (aq, 30 mL) and stirred for 30 minutes. The mixture was poured into ethyl acetate and washed three times with brine. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-[{[4-bromo-3- (hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N- methyl-1 -benzofuran-3-carboxamide (1.18 g, 1.962 mmol, 96 % yield) as an orange solid. LCMS {m/z, ES⁺) = 602 (M+H)

Step 3: (2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]- 1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)methyl methanesulfonate

A solution of 6-[{[4-bromo-3-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (880 mg, 1.463 mmol) and DIPEA (1.022 mL, 5.85 mmol) in dichloromethane (15 mL) was treated with MsCI (0.143 mL, 1 .829 mmol) and maintained with stirring at room temperature for 45 minutes. The solution was poured into saturated sodium bicarbonate and the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford (2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1-benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)methyl methanesulfonate (682 mg, 1 .004 mmol, 68.6 % yield) as a yellow foam. LCMS {m/z, ES⁺) = 680 (M+H) Step 4: 6-[( {4-bromo-3-[(methylamino)methyl]phenyl}methyl)(methylsulfonyl)amin cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of (2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 - benzofuran-6-yl}(methylsulfonyl)amino]methyl}phenyl)methyl methanesulfonate (250 mg, 0.368 mmol) and 2.0M methylamine in THF (4.60 mL, 9.20 mmol) in tetrahydrofuran (4 mL) was maintained with stirring 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 over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford 6-[({4-bromo-3-[(methylamino)methyl]phenyl}methyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (224 mg, 0.365 mmol, 99 % yield) as a white solid. LCMS {m/z, ES⁺) = 615 (M+H)

Step 5: 1, 1-dimethylethyl [(2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)methyl]methylcarbamate

A solution of 6-[({4-bromo-3-[(methylamino)methyl]phenyl}methyl)(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide (223 mg, 0.363 mmol) and Boc₂0 (0.084 mL, 0.363 mmol) in dichloromethane (5 mL) was maintained with stirring at room temperature for 45 minutes. The solution was concentrated under reduced pressure and the residue purified by column chromatography to afford 1 , 1 -dimethylethyl [(2-bromo-5- {[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)methyl]methylcarbamate (218 mg, 0.305 mmol, 84 % yield) as a white foam. LCMS {m/z, ES⁺) = 715 (M+H)

Step 6: {4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(methylamino)methyl]phenyl}boronic acid

A suspension of 1 , 1-dimethylethyl [(2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-

[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)methyl]methylcarbamate (218 mg, 0.305 mmol), potassium acetate (120 mg, 1.220 mmol), bis(pinacolato)diboron (155 mg, 0.610 mmol), and dichlorobis(tricyclohexylphosphine)palladium (II) (22.51 mg, 0.031 mmol) in 1 ,4-dioxane (12 mL) was maintained at 90 °C in a sealed pressure tube for 16 hours. The solution was cooled, filtered through glass filter paper, and concentrated to afford a crude residue. The residue was maintained with stirring in tetrahydrofuran (20 mL)/5.0N HCI (aq) (5 mL, 0.394 mmol) for 3 hours at 60°C. The mixture was cooled to room temperature, neutralized via addition of sodium hydroxide, and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford {4-{[{5- cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(methylamino)methyl]phenyl}boronic acid (15 mg, 0.026 mmol, 6.57 % yield) as a white solid following lyophilization. ¹ H NMR (METHANOL-d₄) δ: 7.87 (dd, J = 8.6, 5.3 Hz, 2H), 7.48 (s, 1 H), 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, 1 H), 0.89 - 1.00 (m, 1 H), 0.72 - 0.86 (m, 2H), 0.27 - 0.42 (m, 1 H). LCMS {m/z, ES⁺) = 580 (M+H). 2 benzyl protons obscured by methanol peak; no exchangeable protons evident.

Example 54

r4-{r{5-Cvclopropyl-2-(4-fluorophenyl)-3-r(methylamino)carbonyll-1-benzofuran-6- yl}(methylsulfonyl)aminolmethyl}-2-fluoro-6-({r(methyloxy)methylloxy}methyl)phenyllboronic acid

Step 1: 6-[{[4-Bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amin cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of methyl 2-bromo-5-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-

1- benzofuran-6-yl}(methylsulfonyl)amino]methyl}-3-fluorobenzoate (1 1.18 g, 17.3 mmol) in tetrahydrofuran (200 mL) and methanol (20 mL) was cooled in an ice bath and treated with lithium borohydride (22 mL, 44 mmol, 2.0 M in THF), added drop wise over 20 min. After 2 h, the reaction was quenched with 1 N sodium hydroxide (20 mL) and stirred 10 minutes. The resulting gel was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford 6-[{[4-bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-

2- (4-fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (10.83 g, quant.) as an off-white solid. ¹H NMR (DMSO-d₆) δ: 8.41 (m, 1 H), 7.93 (dd, J = 8.6, 5.5 Hz, 2H), 7.88 (s, 1 H), 7.28 - 7.44 (m, 3H), 7.13 (d, J = 9.2 Hz, 1 H), 6.92 (s, 1 H), 5.54 (t, J = 5.5 Hz, 1 H), 4.92 - 5.03 (m, 1 H), 4.80 (d, J = 14.6 Hz, 1 H), 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, 1 H), 0.61 - 1.02 (m, 3H), 0.12 - 0.26 (m, 1 H). LCMS {m/z, ES⁺) = 619 (M+H).

Step 2: 6-[{[4-Bromo-3-fluoro-5- ({[(methyloxy)methyl]oxy}methyl)phenyl]methyl}(methylsulfonyl)amino

fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide

A solution of 6-[{[4-bromo-3-fluoro-5-(hydroxymethyl)phenyl]methyl}(methylsulfonyl)amino]-5- cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3-carboxamide (5.94 g, 9.59 mmol) in THF (100 mL) was cooled in an ice bath and treated with DIEA (2.0 mL, 1 1.5 mmol) and MOMCI (0.87 mL, 1 1 .5 mmol). The reaction was allowed to warm to room temperature overnight. The reaction mixture was treated with DMF (10 mL) and stirring was continued for 1 hour at room temperature, then heated to 60° for 5 hours before cooling to room

temperature. Additional portions of DIEA (2.0 mL, 1 1 .5 mmol) and MOMCI (0.87 mL, 1 1 .5 mmol) were added and the reaction stirred at room temperature overnight. The reaction was reheated to 60° for 6.5 hours, then the reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 6-[{[4-bromo-3-fluoro-5- ({[(methyloxy)methyl]oxy}methyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (6.06 g, 95%) as a colorless oil which partially solidified upon drying. ¹H NMR (DMSO-d₆) δ: 8.35 - 8.45 (m, 1 H), 7.93 (dd, J = 8.7, 5.5 Hz, 2H), 7.87 (s, 1 H), 7.38 (t, J = 8.8 Hz, 2H), 7.18 - 7.28 (m, 2H), 6.92 (s, 1 H), 4.97 (d, J = 14.5 Hz, 1 H), 4.81 (d, J = 14.4 Hz, 1 H), 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, 1 H), 0.59 - 0.99 (m, 3H), 0.08 - 0.28 (m, 1 H). LCMS {m/z, ES⁺) = 663 (M+H).

Step 3: [4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]- 1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluoro-6-({[(methyloxy)m

acid

A mixture of 6-[{[4-bromo-3-fluoro-5-

({[(methyloxy)methyl]oxy}methyl)phenyl]methyl}(methylsulfonyl)amino]-5-cyclopropyl-2-(4- fluorophenyl)-/V-methyl-1-benzofuran-3-carboxamide (6.05 g, 9.12 mmol), potassium acetate (1 .79 g, 18.24 mmol), bis(pinacolato)diboron (3.01 g, 1 1 .85 mmol), sodium bromide (938 mg, 9.12 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (673 mg, 0.91 mmol) in 1 ,4-dioxane (100 mL) in a thick-walled glass pressure vessel was degassed, then heated at 95°C with stirring for 19 hours. Additional bis(pinacolato)diboron (1.16 g, 4.56 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (337 mg, 0.46 mmol) were added and the reaction was heated for another 20 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in hexanes) afforded 5-cyclopropyl-6-[{[3-fluoro-5- ({[(methyloxy)methyl]oxy}methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)-/\/-methyl-1-benzofuran-3- carboxamide (6.38 g, 85% pure by LC/MS) as an off-white foam. The foam was dissolved in THF (10 mL), treated with 0.1 N ammonium acetate (6.5 mL) and sodium periodate (0.30 g, 1.41 mmol) and allowed to stir at rt for 4 days. Additional sodium periodate (100 mg, 0.47 mmol) was added and the reaction was stirred for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane, then 0 to 3.5% methanol in dichloromethane) followed by lyophilization afforded [4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3- [(methylamino)carbonyl]-1 -benzofuran-6-yl}(methylsulfonyl)amino]methyl}-2-fluoro-6- ({[(methyloxy)methyl]oxy}methyl)phenyl]boronic acid (121 mg, 68%) as a fluffy white solid. ¹H NMR (METHANOL-d₄) : 7.83 - 7.94 (m, 2H), 7.58 (s, 1 H), 7.24 (t, J = 8.7 Hz, 2H), 7.02 (s, 1 H), 6.94 (s, 1 H), 6.87 (d, J = 8.9 Hz, 1 H), 4.92 - 4.99 (m, 1 H), 4.74 - 4.82 (m, 1 H), 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, 1 H), 0.92 - 1 .04 (m, 1 H), 0.71 - 0.85 (m, 2H), 0.26 - 0.39 (m, 1 H). LCMS {m/z, ES⁺) = 629 (M+H).

Example 55

(4-{rr3-(aminocarbonyl)-5-cvclopropyl-2-(4-fluorophenyl)-1 -benzofuran-6- yll(methylsulfonyl)aminolmethyl}-2-fluorophenyl)boronic acid

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3- carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxylic acid (1 g, 2.57 mmol),HATU (1 .221 g, 3.21 mmol), and DIPEA (0.897 mL, 5.14 mmol) in N,N-dimethylformamide (10 mL) was maintained with stirring while a steady stream of ammonia gas was bubbled through the solution for 45 minutes. The ammonia bubbler was removed, the flask was sealed with a rubber septa, and stirring was maintained overnight. The mixture was diluted with ethyl acetate and washed three times with 5% LiCI (aq) and once with saturated sodium chloride (aq). The organic layer was dried over sodium sulfate, filtered, concentrated, and the resulting solids were triturated with diethyl ether and collected via vacuum filtration to afford 5-cyclopropyl-2-(4-fluorophenyl)-6-

[(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (760 mg, 1 .957 mmol, 76 % yield) as a white solid. LCMS {m/z, ES⁺) = 389 (M+H)

Step 2: (4-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-6- yl](methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxamide (315 mg, 0.81 1 mmol), [4-(bromomethyl)-2-fluorophenyl]boronic acid (236 mg, 1.014 mmol), Kl (135 mg, 0.81 1 mmol), and K₂C0₃ (235 mg, 1 .703 mmol) in N,N- dimethylformamide (5 mL) was maintained with stirring at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed three times with 5% LiCI (aq) and once with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue purified by reverse phase column chromatography to afford (4-{[[3-(aminocarbonyl)-5-cyclopropyl-2-(4- fluorophenyl)-1 -benzofuran-6-yl](methylsulfonyl)amino]methyl}-2-fluorophenyl)boronic acid (290 mg, 0.537 mmol, 66.2 % yield) as a white solid. ¹H NMR (METHANOL-d₄) δ: 7.94 - 8.01 (m, 2H), 7.60 (s, 1 H), 7.20 - 7.30 (m, 3H), 7.10 (s, 1 H), 7.04 (d, J = 7.4 Hz, 1 H), 6.98 (d, J = 9.6 Hz, 1 H), 4.97 (d, J = 14.3 Hz, 1 H), 4.82 (d, J = 14.1 Hz, 1 H), 3.16 (s, 3H), 2.18 - 2.29 (m, 1 H), 0.93 - 1 .03 (m, 1 H), 0.73 - 0.86 (m, 2H), 0.28 - 0.40 (m, 1 H). LCMS {m/z, ES⁺) = 541 (M+H)

Example 56

4-(1-(/\/-(5-cvclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)propan-2-yl)phenylboronic acid

Step 1: 1-bromo-4-(prop-1-en-2-yl)benzene To a solution of methyltriphenylbromophosphine (19.9 g, 56 mmol, Alfa) in THF (100 mL) was added n-BuLi (56 mL, 56 mmol, 1 M in THF) drop wise at -78 °C under N₂ and after the addition, the reaction solution was stirred at -78 °C for 15 minutes. The reaction was warmed to 0 °C. After stirring for 15 minutes, the reaction mixture was cooled down to -60 °C and 1 - (4-bromophenyl)ethanone (10.0 g, 51 mmol, Alfa) was added over 30 minutes. The reaction mixture was allowed to slowly warm to room temperature and stirred for 1 hour and then it was quenched with NH₄CI (100 mL) and diluted with hexane (200 mL). The separated organic layer was washed with brine (100 mL), dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 1 - bromo-4-(prop-1 -en- 2-yl)benzene (8.7 g, 44 mmol, 87 % yield) as a colorless oil.

Step 2: 1-bromo-4-(3-bromoprop-1-en-2-yl)benzene

A solution of 1-bromo-4-(prop-1-en-2-yl)benzene (4.0 g, 20.3 mmol) and NBS (2.2 g, 12.1 mmol) in CHCI₃ (50mL) was heated under reflux overnight. After the removal of solvents, it was purified with column chromatography to afford 1 -bromo-4-(3-bromoprop-1 -en-2- yl)benzene (2.9g, 10.5 mmol, 51 % yield) as a colorless liquid.

Step 3: 6-(N-(2-(4-bromophenyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)- N-methylbenzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3- carboxamide (400 mg, 1 mmol), Kl (166 mg, 1 mmol), K₂C0₃ (414 mg, 3 mmol) and 1 -bromo- 4- (3-bromoprop-1 -en-2-yl)benzene (552 mg, 2 mmol) in dry DMF (15 mL) was heated at 80 °C under nitrogen for 0.5 h. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na₂S0₄. After the removal of solvent, the crude product was purified with column chromatography to afford 6-(Λ/-(2-(4- bromophenyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-/\/-methylbenzofuran- 3-carboxamide (500 mg, 0.84 mmol, 78 % yield) as a yellow solid. Step 4: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-(4-(4,4,5,5-tetram 1,3,2- dioxaborolan-2-yl)phenyl)allyl)methylsulfonamido)benzofuran-3-carboxamide

A solution of 6-(/V-(2-(4-bromophenyl)allyl)methylsulfonamido)-5-cyclopropyl-2-(4- fluorophenyl)-/V-methylbenzofuran-3-carboxamide (500 mg, 0.84 mmol),

bis(pinacolato)diboron (0.426 mg, 1.68 mmol), potassium acetate (247 mg,2.52 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (96 mg, 0.08 mmol) in dixoane (20 mL) was degassed and refilled with nitrogent three times and then it was heated at 95°C under nitrogen atmosphere overnight. After the reaction mixture was cooled to room temperature it was filtered and concentrated under reduced pressure. The residue was purified with column

chromatography to afford 5-cyclopropyl-2- (4-fluorophenyl)-/V-methyl-6-(/\/-(2-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)allyl)methylsulfonamido)benzofuran-3- carboxamide (0.21 g, 0.33 mmol, 38 % yield) as a yellow solid.

Step 5: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-(4-(4,4,5,5-tetram 1,3,2- dioxaborolan-2-yl)phenyl)propyl)methylsulfonamido)benzofuran-3-carboxamide

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-/\/-methyl-6-(N-(2-(4-(4, 4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)allyl)methylsulfonamido)benzofuran-3-carboxamide (0.21 g, 0.33 mmol) and palladium on activated carbon (21 mg, 10%) in EtOAc (20 ml.) was stirred at 25 °C for 5 hours under an atomosphere of H₂. The reaction mixture was filtered and

concentrated under reduced pressure to afford the crude 5-cyclopropyl-2-(4-fluorophenyl)-/\/- methyl-6-(/V-(2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)propyl)methylsulfonamido)benzofuran-3-carboxamide (0.205 g, 0.32 mmol, 98 % yield) as a yellow solid.

Step 6: 4-( 1-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)propan-2-yl)phenylboronic acid

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)propyl)methylsulfonamido)benzofuran-3-carboxamide (205 mg,

0.32 mmol), HCI (5N, 0.45 mL) and PS-BBA (0.6 g, 1.6 mmol) in THF (15 mL) was stirred at 30 °C overnight. The reaction mixture was filtered and concentrated under reduce pressure. The residue was purified with pre-HPLC to afford 4-(1 -(/V-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)propan-2-yl)phenylboronic acid (38 mg, 0.06 mmol, 21 % yield) as a white solid. ¹H 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 , 1 H), 2.45 - 2.39 (m, 1 H), 2.05 - 1 .92 (m, 1 H), 1.35-1.26 (m, 3H), 0.96-0.70 (m, 4H). LCMS (m/z, ES⁺)= 565.2 (M+H) Example 57

Step 1: 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl- 6- [(methylsulfonyl)amino]-1 -benzofuran- 3-carboxamide

A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1 -benzofuran-3- carboxylic acid (27.5 kg, 70.6 mol), methylamine 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 kg, 176.6 mol) was added over approx. 30 min keeping the temperature below 25 °C. The reaction was stirred at 20 °C until complete by HPLC (approx. 30 minutes). The batch was heated to 55-65 °C and acetonitrile (137.5 L) was added. The batch temperature was adjusted to approx. 60-65 °C. Water (55 L) was added and the batch was seeded. The resulting mixture was aged at 65 °C for approx. 60 minutes. Additional water (55 L) was then added over at least 1 hour and the slurry was cooled slowly to 20-25 °C. The batch was filtered, washing with water (165 L) and the product was dried at approx. 60 °C under vacuum with a N₂ bleed to afford 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6- [(methylsulfonyl)amino]-1 -benzofuran-3-carboxamide (21.3 kg, 53 mol, 75% yield) as a tan solid. ¹H NMR (500 MHz, DMSO- d₆: CDCIs, 1 :1 ) 5: 9.08 (s, 1 H), 8.20 (m, 1 H), 7.96 (m, 2H), 7.58 (s, 1 H), 7.21 (m, 3 H), 3.02 (s, 3H), 2.90 (d, J = 4.5 Hz, 3H), 2.29 (m, 1 H), 1.02 (m, 2H), 0.73 (m, 2H).

Step 2: [2-fluoro-4-(hydroxymethyl)phenyl]boronic acid

(2-Fluoro-4-formylphenyl)boronic acid (15kg, 89.3 mmol) was dissolved in methanol (75 L) and the solution was cooled to 0-10 °C. Sodium borohydride as a 12%w/w solution in 14N sodium hydroxide (8.55 kg) was charged slowly while keeping the batch temperature below 10 degrees. The reaction was stirred at approx. 10 °C for at least 30 minutes, and 6N hydrochloric acid (45 L) was slowly charged into the batch while keeping the batch temperature below 10 °C. Water (30 L) was charged and the methanol was removed via vacuum distillation until a final volume of 75 L (solids precipitate during distillation). 0.1 N hydrochloric acid (45 L) was charged into the batch and the reaction was heated to approx. 75 °C. The reaction was cooled to 2 °C at approx. 0.5 °C per minute, held for 1 hour and filtered. The solids were washed with cold water (2 x 30 L) then dried under full vacuum with a nitrogen bleed at 50 °C to afford [2-fluoro-4-(hydroxymethyl)phenyl]boronic acid (13.5 kg, 79.4 mol, 89%) as a white solid. ¹H NMR (500 MHz, DMSO- d₆ + 20 _μΙ_ H₂0) δ: 8.16 (s, 2 H), 7.53 (t, J = 7.1 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 10.4 Hz, 1 H), 5.41 (s, 1 H), 4.52 (d, J = 3.5 Hz, 2H).

Step 3: [2-fluoro-4-(bromomethyl)phenyl]boronic acid

[2-Fluoro-4-(hydroxymethyl)phenyl]boronic acid (13.5 kg, 79.4 mol) was slurried in concentrated 48% w/w hydrobromic acid (108 L) and heated to approx. 85 °C. The reaction was held at 85 °C for 1 hour. The reaction was cooled to 20 °C and filtered. The solids were washed with water (330 L) then dried under vacuum with a nitrogen bleed at 50 °C to afford [2-fluoro-4-(bromomethyl)phenyl]boronic acid (16.6 kg, 71 .2 mol, 90% yield) as a white solid. ¹H NMR (500 MHz, DMSO- d₆ + 10 μΐ H₂0) δ: 8.3 (bs, 2 H), 7.54 (t, J = 7.1 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.18 (d, J = 9.9 Hz, 1 H), 4.69 (s, 2H).

Step 4: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid, Intermediate Grade.

To mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1 - benzofuran-3-carboxamide (16.5 kg, 41 mol) and [4-(bromomethyl)-2-fluorophenyl]boronic acid (1 1.0 kg, 47.1 mol) in acetone (136 L) and DMF (16.5 L) was added a solution of potassium carbonate K₂C0₃ (13.0 kg, 94.3 mol.) in water (16.5 L). The resulting mixture was stirred at 20-25 °C for 4-6 hr. Water (16.5 L) was added followed by slow addition of 6N HCI (28.9 L) (gas evolution). The batch was heated to 50-55 °C. Water (74.3 L) was added slowly while maintaining the temperature at 50-55 °C. The batch was seeded and held at 50- 55 °C for at least 1 hour. Water (41 .2 L) was charged over at least 30 min. The slurry was cooled slowly to 20-30 °C. The product was isolated by filtration, and washed with water (66L). The product was dried at approx. 60 °C under vacuum with a N₂ bleed to afford 4-((N- (5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid, Intermediate Grade (18.6 kg, 33.6 mol, 82% yield) as a white solid. ¹H NMR (500 MHz, DMSO) δ: 8.42 (q, J = 4.5 Hz, 1 H), 8.13 (s, 2H), 7.93 (dd, J = 9.0, 5.5 Hz, 2 H), 7.81 (s, 1 H), 7.44 (t, J = 7.0 Hz, 1 H), 7.38 (t, J = 9.0 Hz, 2 H), 7.05 (d, J = 7.5 Hz, 1 H), 7.00 (d, J = 10.0 Hz, 1 H), 6.94 (s, 1 H), 4.94 (d, J = 15.0 Hz, 1 H), 4.82 (d, J = 15.0 Hz, 1 H), 3.24 (s, 3H), 2.81 (d, J = 4.5 Hz, 3 H), 2.27 (m, 1 H), 0.94 (m, 1 H), 0.81 (m, 2H), 0.28 (m, 1 H).

Step 5: 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

To a mixture of 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid, Intermediate Grade. (18.6 kg, 33.6 mol) in acetonitrile (93 L) was added 0.25 M HCI (18.6 L) and 1 -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 re-heated to 72-75 °C to ensure dissolution. The reaction was cooled to 60-63 °C and was seeded. The temperature was adjusted to 58 - 62 °C and was stirred at that temperature for at least 1 hour. The reaction was cooled to approx 0 °C at up to 0.1 °C/min and held for at least 3 hours. The product was isolated by filtration, and was washed with 2:1 watenacetonitrile (55.8 L). The product was dried at approx. 60 °C under vacuum with a N₂ bleed to afford 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)- 3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido) methyl)-2-fluorophenylboronic acid (15.7 kg, 28.4 mol, 84% yield) as a white solid. See NMR data for Step 4.

Example 58: Pharmaceutical Composition

^* 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid

A solution of 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid and hypromellose acetate succinate was prepared in acetone for spray drying. The solution was spray dired and then the resulting powder dried. This provided an amorphous spray dried dispersion. The spray dried dispersion was blended with microcrystalline cellulose (~20μηι particle size).

Croscarmellose Sodium, Colloidal Silicon Dioxide and microcrystalline cellulose (~100μηΊ particle size) were then added and blended. Magnesium stearate was added and blended further. The blend was compressed into tablets.

Example 59: Biological Activity Replicon Luciferase cell based assay

Method

150μΙ_ of a 1 mM stock solution in DMSO of each test compound was transferred into in the first column of a 96 well, V-bottom microplate, to give 200 times the top concentration of the required dilution series. Aliquots of 50μΙ_ were added to each well of the remaining rows containing 100μΙ_ of DMSO giving a 1 :3 dilution series over ten points. Columns 1 1 and 12 contained DMSO only for the positive and negative control, respectively. 10μΙ_ of each well were transferred into 90μΙ_ of DMEM medium (Invitrogen #41965-039) supplemented with 5% v/v foetal calf serum, 1 % v/v non-essential amino acids solution, 100 units/ml penicillin, 100μg/ml streptomycin and 2mM L-glutamine to give 20 times the top concentration of the required dilution series.

Suspensions were prepared from cultures of Huh-7 cells stably transfected with sub-genomic HCV NS3-NS5B replicons of either genotype 1 b (the ET subline described by

Pietschmann,T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D. & Bartenschlager, R., Journal of Virology, 2002, 76, 4008-4021 ), genotype 1 a (subline 1.19 constructed in-house) or genotype 1 b C316N (constructed in-house) linked to a firefly luciferase reporter gene. Monolayers nearing confluency were stripped from growth flasks with versene-trypsin solution and the cells re-suspended in assay medium comprising

DMEM. 95μΙ_ of suspension containing either 15,000 cells (genotype 1 b luciferase replicon) or 20,000 cells (genotype 1 a luciferase replicon) were added to all wells of a 96 well plate (Perkin Elmer, #6005686), except medium controls in column 12 of the assay plate. The cell suspension was dosed with 5μΙ_ of compound solution and the plate was incubated for 48 hours at 37°C in a 5% C0₂ atmosphere.

For toxicity the cells in one 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 μΙ_ added to each well. The plate was then read for luminescence on an Envision.

For potency a solution of Steady Glo (Promega, #E2550) was prepared according to the manufacturer's instructions and 100μΙ_ added to each well. After a twenty minute incubation the plate was then read for luminescence on an Envision.

Data Analysis

Toxicity: The luminescence values from duplicate wells were averaged and expressed as a percentage of the mean absorbance of compound free control wells to determine

comparative cell viability. Compound cytotoxicity was expressed either as the lowest concentration at which a significant reduction in viability was observed or a 50% toxic concentration (CCID₅₀) was determined by plotting percentage cytotoxicity against compound concentration using ActivityBase (IDBS Software) with curve fitting done through the XC50 module.

Potency: The luminescence values from all compound-free wells containing cells were averaged to obtain a positive control value. The mean luminescence value from the compound-free wells that had received no cells was used to provide the negative

(background) control value. The readings from the wells at each compound concentration were taken and after the subtraction of the mean background from all values, were expressed as a percentage of the positive control signal. The quantifiable and specific reduction of luciferase signal in the presence of a drug is a direct measure of replicon inhibition. BioAssay Enterprise (CamebridgeSoft) with the XC50 module for curve fitting was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC₅₀) for the compound. The IC₅₀ values of two identical plates were averaged. The results are presented in Table 1.

Table 1

19 _{*** *** ***}

20 _** _** _**

21 _*** _*** _**

22 _*** _*** _**

23 _*** _*** _**

24 _*** _*** _***

25 _*** _*** _**

26 _*** _*** _**

27 _*** _*** _**

28 _*** _*** _**

29 _*** _*** _**

30 _*** _*** _***

31 _*** _*** nd

32 _*** _*** nd

33 _*** _*** nd

34 _*** _*** nd

35 _*** _*** nd

36 _** _** _**

37 _*** _*** _***

38 _*** _*** _***

39 _*** _*** _***

40 _*** _*** _***

41 _*** _*** _***

42 _*** _*** _***

43 _*** _*** _**

44 _*** _*** _**

45 _*** _*** _**

46 _** _*** _**

47 _** _** _**

48 _** _** _*

49 _** _** _*

50 _*** _*** _**

51 _*** _*** _**

52 _** _** _**

53 _* _** _* 54 ** ** **

55 *** *** ***

56 ** ** *

+ >5000

* 200- 3000 nM

** 10-200nM

*** <10nM

nd = not determined

Claims

1. A compound of formula (I):

R¹ is one or more substituents independently selected from the group consisting of halogen, Ci_-6alkyl, alkoxy, -CN, -CF₃ , 0- C₆ - ioaryl optionally substituted by halogen, and -O- heteroaryl optionally substituted by halogen;

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy; R⁴ is -S(0)₂R⁵, P(0)(OR⁵)R⁵ or P(0)(OH)R⁵ ;

R⁵ is C_1-6alkyl or C_3-6cycloalkyl;

X is C_1-6alkylene optionally substituted with C_1-6alkyl, hydroxy, amino or C_3-6cycloalkyl;

R⁶ is

(a) heteroaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, Ci_-6alkoxy, -CF₃, Ci_-6alkyl, hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₃, and C_3-6cycloalkyl; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 8 -membered carbocyclic or heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or Ci_-6alkyl; or (b) C₆- ioaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkoxy, -CF₃, C_1-6alkyl, hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₃, and C_3-6cycloalkyl; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 8 -membered carbocyclic or heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or Ci_-6alkyl;

R⁷ and R⁸ are hydrogen or Ci_-6alkyl; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) according to claim 1 wherein R¹ is one or two halogen.

3. A compound of formula (I) according to claim 1 wherein R² is Ci_-6alkyl.

4. A compound of formula (I) according to claim 1 wherein R³ is C₃-₆cycloalkyl.

5. A compound of formula (I) according to claim 1 wherein R⁶ is C_6-ioaryl substituted with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

6. A compound of formula (I) according to claim 1 wherein R⁶ is heteroaryl substituted with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

7. A compound of formula (I) according to claim 1 wherein R¹ is halogen; R² is Ci_-6alkyl; R³ is C_3-6cycloalkyl; and R⁶ is C₆-i₀aryl substituted with with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of halogen and -CF_3.

8. A compound of formula (I) according to claim 1 wherein R¹ is halogen; R² is Ci_-6alkyl; R³ is C_3-6cycloalkyl; and R⁶ is heteroaryl substituted with B(OR⁷)(OR⁸), wherein R⁷ and R⁸ are both hydrogen, and optionally substituted with one or more substituents independently selected from the group consisting of haologen and -CF_3.

9. A compound of formula (I)':

(I)'

wherein:

R³ is Ci_-6alkyl, C_3-6cycloalkyl or Ci_-6alkoxy;

R⁴ is hydrogen, -S(0)₂R⁵ , P(0)(OR⁵)R⁵ or P(0)(OH)R⁵ ;

R⁵ is Ci_-6alkyl or C_3-6cycloalkyl;

X is Ci_-6alkylene optionally substituted with Ci_-6alkyl, hydroxy, amino or C_3-6cycloalkyl;

R⁶ is

(a) heteroaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkoxy, -CF₃, C_1-6alkyl hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₃, and C_3-6cycloalkyl; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 8 -membered carbocyclic or heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or Ci_-6alkyl; or

(b) C₆- ioaryl substituted with B(OR⁷)(OR⁸) and optionally substituted with one or more substituents selected from the group consisting of halogen, Ci_-6alkoxy, -CF₃, Ci_-6alkyl hydroxy, S0₂ R⁵, S0₂NH₂, -CN, -OCF₂, -OCF₃, -C(0)OR⁷, C_3-6cycloalkyl, and R⁹ substituted with N(R⁷)₂, NH(R⁷), alkoxy, or -R⁹OR⁹ substituted with alkoxy; or R⁷ and R⁸ together with the oxygen atoms to which they are attached form a 5 to 10 -membered carbocyclic or heterocyclic ring, which can be monocyclic or bicyclic, and optionally substituted with one or more oxo or C_{1 -6}alkyl;

R⁷ and R⁸ are hydrogen or Ci_-6alkyl;

R⁹ is alkylene;

or a pharmaceutically acceptable salt thereof.

10. A compound according to any of claims 1 - 9 wherein R⁴ is -S(0)₂R⁵.

1 1 . A compound selected from the group consisting of:

(4-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(3-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

(2-{[{2-(4-Fluorophenyl)-3-[(methylamino)carbonyl]-5-[(1 -methylethyl)oxy]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

4-((N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid; 4-((N-((2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-fluorophenylboronic acid;

4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)phenylboronic acid;

4- ((N-(5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)methyl)-2-fluorophenylboronic acid;

4-((N-((5-cyclopropyl-2-(4-(4-fluorophenoxy)phenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methyl)methylsulfonamido)methyl)-2-(trifluoromethyl)phenylboronic acid;

5- cyclopropyl-2-(4-fluorophenyl)-/V-methyl-6-((methylsulfonyl){[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]methyl}amino)-1-benzofuran-3-carboxamide; 4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)ethylsulfonamido)methyl)-2-fluorophenylboronic acid;

5- Cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}(methylsulfonyl)amino]-/\/-methyl-1 -benzofuran-3-carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)({3-(trifluoromethyl)-4-

[(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1 .1 .02,6]dec-4- yl]phenyl}methyl)amino]-1 -benzofuran-3-carboxamide; 5-cyclopropyl-2-(4-fluorophenyl)-6-[{[3-fluoro-4-(4,4,6,6-tetramethyl-1 ,3,2-dioxaborinan-2- yl)phenyl]methyl}(methylsulfonyl)amino]-N-methyl-1 -benzofuran-3-carboxamide;

5-cyclopropyl-6-[{[3-fluoro-4-(6-methyl-4,8-dioxotetrahydro-4H-1 ,3,6,2-dioxazaborocin-2- yl)phenyl]methyl}(methylsulfonyl)amino]-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3- carboxamide;

5-cyclopropyl-2-(4-fluorophenyl)-6-[({3-fluoro-4-[(1 R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1 .02,6]dec-4-yl]phenyl}methyl)(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)boronic acid;

(2-chloro-4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}phenyl)boronic acid;

4-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)methylsulfonamido)ethyl)-3-(trifluoromethyl)phenylboronic acid;

{4-[({5-cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}amino)methyl]-2-fluorophenyl}boronic acid; {4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1-benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-[(methyloxy)carbonyl]phenyl}boronic acid;

{4-{[{5-cyclopropyl-2-(4-fluorophenyl)-3-[(m

yl}(methylsulfonyl)amino]methyl}-2-[(methylamino)methyl]phenyl}boron acid;

[4-{[{5-Cyclopropyl-2-(4-fluorophenyl)-3-[(methylamino)carbonyl]-1 -benzofuran-6- yl}(methylsulfonyl)amino]methyl}-2-fluoro-6-({[(methyloxy)methyl]oxy}methyl)phen

acid;

pharmaceutically acceptable salts thereof.

12. A pharmaceutically acceptable salt of a compound as claimed in any of claims 1 to 1 1 .

13. A pharmaceutical composition comprising a compound according to any of claims 1 to 12 together with at least one pharmaceutically acceptable excipient.

14. A compound according to any of claims 1 to 12 for use in medical therapy.

15. Use of a compound according to any of claims 1 - 12 in the manufacture of a medicament for treating or preventing a viral infection or disease associated with such infection.

16. Use according to claim 15 wherein the viral infection is HCV infection.

17. A compound according to any of claims 1 to 12 for use in treating or preventing a viral infection or disease associated with such infection.

18. A compound according to claim 17 wherein the viral infection is HCV infection.

19. A method of treating or preventing a viral infection or disease associated with such infection in a human comprising administering to a human a therapeutically effective amount of compound as claimed in any one of claims 1 to 12.

20. A method according to claim 19 wherein the viral infection is HCV infection.

21. A compound of formula as claimed in any one of claims 1 to 12 in combination with one or more active anti-viral agents.