WO2009046098A1

WO2009046098A1 - Novel cyclic boronate inhibitors of hcv replication

Info

Publication number: WO2009046098A1
Application number: PCT/US2008/078439
Authority: WO
Inventors: Dazhong Fan; Richard Lewis Jarvest; Linos Lazarides; Qun Li; Xianfeng Li; Yang Liu; Liang LIAO; Jacqueline Elizabeth Mordaunt; Zhi-Jie Ni; Jacob Plattner; Xuelei Qian; Martin John Slater; Gemma Victoria White; Yong Kang Zhang
Original assignee: Smithkline Beecham Corporation; Anacor Pharmaceuticals, Inc.
Priority date: 2007-10-03
Filing date: 2008-10-01
Publication date: 2009-04-09
Also published as: GB0719366D0

Abstract

Compounds of formula (I) or a salt thereof are provided; wherein R1, R2, R3, R4, R6, R8, R20, R30, Y, Z and n are as defined in the description. Uses of the compounds as medicaments, and in the manufacture of medicaments for treating viral infection, especially HCV infection are also disclosed. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof.

Description

NOVEL CYCLIC BORONATE INHIBITORS OF HCV REPLICATION

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of United Kingdom Pat. App. No. 0719366.7, filed October 3, 2007, and U.S. Provisional Pat. App. No. 61/055,116, filed May 21 , 2008, and U.S. Provisional Pat. App. No. 61/080,167, filed July 11 , 2008, each of which is incorporated by reference in its entirety for all purposes. FIELD OF THE INVENTION

The present invention relates to novel cyclic boronate compounds useful as anti-viral agents. Specifically, the present invention involves novel inhibitors of Hepatitis C Virus (HCV) replication. 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, (1997) Hepatology, 26 (suppl 1): 71S-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 responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon (Peg-IFN), 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 ef al (1989) Science, 244 359-362), HCV is now widely accepted as the most common causative agent of post-transfusion non A, non- B hepatitis (NANBH) (Kuo et al (1989) Science, 244 362-364) Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviπdae family Like the other members of the Flavivindae, such as flaviviruses (e g yellow fever virus and Dengue virus types 1-4) and pestiviruses (e g bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo ef al (1989) Science, 244 359-362, Miller and Purcell (1990) Proc Natl Acad Sc; USA, 87 2057-2061), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity The HCV genome is approximately 9 6 kilobases (kb) with a long, highly conserved, noncapped 5' nontraπslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang ef al , 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society 1(5) 526-537, 1995 JuI ) This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of ~3000 amino acids comprising both the structural and nonstructural viral proteins

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 (1996) in B N Fields, D M Knipe and P M Howley (eds) Virology 2^nd Edition, p931-960, Raven Press, N Y ) Following the termination codon at the end of the long ORF, there is a 3' NTR which roughly consists of three regions an ~ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrιmιdιne tract, and a highly conserved 98 base element also called the "3' X-taιl" (Kolykhalov ef al (1996) J Virology, 70, 3363-3371 , Tanaka ef al , (1995) Biochem Biophys Res Commuπ , 215, 744-749, Tanaka ef a/ (1996) J Virology, 70, 3307-3312, Yamada ef a/ (1996) Virology, 223 255-261) The 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication

Although the predominant HCV genotype worldwide is genotype 1, this itself has two main subtypes, denoted 1a and 1b As seen from entries into the Los Alamos HCV database (www hcv lanl gov) (Table 1) there are regional differences in the distribution of these subtypes while genotype 1a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1b The other genotypes with significant are genotypes 2 and 3, each of which also exists in several subtypes

Table 1

The NS3 protein is a 631 amino acid protein, and its first 180 amino acids encode a serine protease of the chymotrypsin family, the NS3-4A protease. Various of the properties of the NS3 protease are summarised in recent reviews by White ef al. (White ef al. (2006) Progress in Medicinal Chemistry, 44, 65-107), Griffith et al. (Griffith et al. (2004) Annual Reports in Medicinal Chemistry, 39, 223-237) and Chen ef al. (Chen et al. (2005) Current Medicinal Chemistry, 12, 2317-1342). The NS3-4A protease is considered to be essential for viral replication (Kolykhalov et al. (2000) Journal of Virology, 74, 2046-2051) and thus inhibition of NS3-4A protease activity is predicted to be useful to treat HCV infection.

Various inhibitors of the NS3-4A protease have been described, the majority of them being peptidomimetics (see White ef al. (2006), Griffith ef al. (2004) and Chen ef al. (2005) and references cited therein). Some of those protease inhibitors have been reported to have entered clinical trials. There remains a need for alternative HCV NS3-4A protease inhibitors.

SUMMARY OF THE INVENTION

The present invention involves novel cyclic boronate compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of Formula (I):

(I) wherein:

R¹ is selected from H; CrCβ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl and C₂-C₆ alkenyl, the C₁-Ce alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-Ce alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); or R¹, R⁴ and the atoms between them form a 7 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^Λ, S, and SO₂;

R^A is H or C₁-C₆ alkyl, optionally substituted with one or more fluoro groups; or R¹ and R⁸ together with the two carbon atoms between them form a C₃-C₇ cycloalkyl group, optionally substituted by one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups) and fluoro;

R² is a group -X-(CH₂)_m-R¹⁰, where m is 0, 1 or 2; X is selected from NH, O, O-C(O), S and bond;

R¹⁰ is selected from C₆-ioaryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^B, NR^BR^B, SR^B, SO₂R^B, NHSO₂R⁸, CONHR^B, NHCOR⁸, C_β._1o aryl, 5 to 10-membered heteroaryl and 5 to 10- membered heterocyclyl, which latter C₆.i₀ aryl, 5 to 10-membered heteroaryl and 5 to 10- membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from C₁-C₆ alkyl, OR^B, NR^BR^B, SR^B, SO₂R^B, NHSO₂R^B, CONHR^B and NHCOR^B; Each R^B is independently selected from H; Ci-C₆ alkyl optionally substituted with one or more groups selected from fluoro, C_M0 aryl (optionally substituted with one or more groups selected from halo and C_rC₆ alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl); C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro, C_M0 aryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and CrC₆ alkyl); C₆-io aryl optionally substituted with one or more groups selected from halo and CrC₆ alkyl; and 5 to 10-membered heteroaryl optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl;

R³ is H; or R² and R³ together with the two carbon atoms between them form a C₃-C₇ cycloalkyl group, wherein the cycloalkyl group is optionally substituted by one or more groups selected independently from C₁^ alkyl and halo; when X is bond, R²⁰ is H or OH; otherwise R²⁰ is H;

R⁴ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups). or R⁴, R^B and the atoms between them form an 8 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^A, S, and SO₂;

Z is selected from -NHR⁵, -OR⁵, -R^5a and

;

R⁵ is selected from C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; R^5a is selected from C₁-C₈ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-Ce alkenyl (optionally substituted with one or more fluoro groups); C₃- C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C_B-io aryl optionally substituted by one, two or three groups selected from C₁- C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A, hydroxy and halo; and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A, hydroxy and halo;

R^4a is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃- C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups).

R⁶ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); and

C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; n is 1, 2 or 3; each Y group is selected from C(H)_PR⁷, O and NR⁹, with the proviso that no two O or NR⁹ groups are adjacent to each other in the ring; p being 1 if the Y group is only single bonded; p being 0 if the Y group is part of an aryl, heteroaryl or heterocyclic ring; R⁷ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₅ alkenyl (optionally substituted with one or more fluoro groups); C₃- C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups;

R³ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-

C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl .group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups; C(O)R^B; CO₂R^B; S(O)R⁸; and SO₂R^B where R^B is independently as defined above;

R⁸ and R³⁰ are independently selected from H; C^Cealkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); or R⁸ and R³⁰ together with the carbon atom to which they are attached form a C₃.₆membered cyclic ring, for example spirocyclopropane; or R⁸ and an R⁷ together with the atoms between them, or two R⁷ groups together with the atoms between them, form a 5, 6 or 7 membered cyclic group which may be aromatic, which may include one or two heteroatom groups selected from O, NR^A, S, and SO₂; and which may be optionally substituted by one, two or three groups selected from C₁-C₅ alkyl (optionally substituted with one or more fluoro groups) and fluoro, R^3D is selected from H and Chalky!, or salts thereof.

It is to be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein.

The compounds of the present invention exhibit potency against the replication of HCV and therefore have the potential to achieve therapeutic efficacy in man. There is provided as a further aspect of the present invention a compound of Formula (I) or pharmaceutically acceptable salts thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly flavivirus infection, for example HCV infection. It will be appreciated that reference herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease. 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.

In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with viral infection, particularly HCV infection, which method comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof.

According to another aspect of the invention, there is provided the use of a compound of Formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection. It will be appreciated that the compounds of Formula (I) or salts thereof may contain one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. All of these racemic compounds, enantiomers and diastereoisomers are contemplated to be within the scope of the present invention. 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 Formula (I) or salts thereof. The compounds of Formula (I) may exist in different tautomeric forms, i.e. one or more tautomeric forms. All tautomers, and mixtures thereof, are contemplated to be within the scope of the present invention. For example, a claim to 2-hydroxyquinolinyl would also cover its tautomeric form, α-quinolinonyl.

Diastereoisomers of compounds of Formula (I) may be obtained according to methods well known in the literature, for example by preparative HPLC or by chromatographic purifications. In one aspect of the invention, R¹ is H or C₁-C₄ alkyl. In a further aspect of the invention, R¹ is H.

In one aspect of the invention, R¹, R⁴, and the atoms between them form a 11- to 17- membered heterocyclic ring (for example a 15-membered ring) which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds. In one aspect of the invention, R¹ and R⁸ together with the two carbon atoms between them form a C₃-C₇ cycloalkyl group, optionally substituted by one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), C₂-C₆ alkeπyl (optionally substituted with one or more fluoro groups) and fluoro. In one aspect of the invention, R² is a group -X-(CH₂)m-R¹⁰, where m is 0, 1 or 2. In one aspect of the invention, m is 0.

In one aspect of the invention, X is -O-, -OC(O)- or a bond. In a further aspect of the invention, X is -O- or -OC(O)-.

In one aspect of the invention, R¹⁰ is selected from C₆.₁₀ aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one, two or three groups selected from halo, Ci-C_BaIkyl (optionally substituted with one or more fiuoro groups), OR^B, NR^BR^B, SR^B, C₆.₁₀aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, which latter C₆.₁₀aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from CrC_Balkyl, OR^B, and NR^BR^B. R¹⁰ can be for example pyridazone. In a further aspect of the invention, R^1α is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo, CrCealkyl (optionally substituted with one or more fluoro groups), OR^B, NR^BR^B, SR^B, C_e.₁₀aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, which latter C₆.₁₀aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from Ci-C₆alkyl, OR^B, and NR^BR^B. In a further aspect of the invention, R¹⁰ is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo, OR^B and Ci-C₆ alkyl (optionally substituted with one or more fluoro groups). In a further aspect of the invention, R¹⁰ is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo and C₁-Ce alkyl (optionally substituted with one or more fluoro groups). In a further aspect of the invention, R¹⁰ is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo. In a further aspect of the invention, R¹⁰ is selected from triazolyl, tetrazolyl, pyridazinyl, quinilinyl, isoquinolinyl or 1,3-dihydro-2H-isoindolyl, all of which may be optionally substituted with one or more groups selected from halo, OR^B and C₁-C₆ alkyl (optionally substituted with one or more fluoro groups). In a further aspect of the invention, R¹⁰ is selected from quinolinyl, isoquinolinyl or 1 ,3-dihydro-2W-isoindolyl, each of which may be optionally substituted with one or more groups selected from fluoro, chloro, methyl and methoxy. In a further aspect of the invention, R^1G is selected from triazolyl, tetrazolyl, pyridazinyl, isoquinolinyl or 1,3-dihydro- 2H-isoindolyl, all of which may be optionally substituted with one or more fluoro groups. In a further aspect of the invention, R¹⁰ is selected from isoquinolinone or 1,3-dihydro-2H- isoindolyl, each of which may be optionally substituted with one or more fluoro groups. In a further aspect of the invention, R¹⁰ is selected from isoquinolinyl or 1,3-dihydro-2H-isoindolyl, all of which may be optionally substituted with one or more fluoro groups. In a further aspect of the invention, R¹⁰ is selected from

In one aspect of the invention, each R^B is independently selected from H and C₁-C₆ alkyl optionally substituted with one or more fluoro groups.

In one aspect of the invention, R² and R³ together with the two carbon atoms between them form a C₃.₇ cycloalkyl group, optionally substituted by one or more groups selected from C₁^ alkyl (for example methyl) and fluoro. In a further aspect of the invention, R² and R³ together with the two carbon atoms between them form a C₃.₅ cycloalkyl group, optionally substituted by one or more groups selected from C₁^ alkyl (for example methyl) and fluoro. In a further aspect of the invention, R² and R³ together with the two carbon atoms between them form a C₃ cycloalkyl group or a C₅ cycloalkyl group, optionally substituted by one or more groups selected from C₁^ alkyl (for example methyl) and fluoro. In a further aspect of the invention, R² and R³ together with the two carbon atoms between them form a dimethyl substituted cyclopropyl ring. In a further aspect of the invention, R² and R³ together with the two carbon atoms between them form an unsubstituted cyclopentyl ring. In one aspect of the invention, R²⁰ is H.

In one aspect of the invention, R⁴ is selected from C₁-C₆ alkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups. In a further aspect of the invention, R⁴ is selected from C₁-C₆ alkyl, C₂-C₆ alkenyl and C₃-C₇ cycloalkyl. In one aspect of the invention, R⁴ is selected from C₁-C₆ alkyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups. In a further aspect of the invention, R⁴ is selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl. In a further aspect of the invention, R⁴ is tert-butyl or cyclohexyl. In a further aspect of the invention, R⁴ is tert-butyl.

In one aspect of the invention, R⁴, R⁸ and the atoms between them form an 8 to 17- membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^A, S, and SO₂. In a further aspect of the invention, R⁴, R⁸ and the atoms between them form an 12 to

17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds.

In one aspect of the invention, Z is In a further aspect

of the invention, Z is selected from

In a further aspect of the invention, Z is selected from -NHR⁵ or -OR⁵.

In a further aspect of the invention, Z is selected from -R^5a and

In one aspect of the invention, R⁵ is selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), C₃-C₇ cycloalkyl (optionally substituted with one or more fluoro groups), and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups). In a further aspect of the invention, R⁵ is selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl and C₂-C₆ alkenyl. In a further aspect of the invention, R⁵ is selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl For example R⁵ is tert-butyl or cyclohexyl In a further aspect of the invention, R⁵ is selected from tert-butyl, cyclopentyl and cyclopentenyl In a further aspect of the invention, R⁵ is selected from tert-butyl and cyclopentyl In a further aspect of the invention, R⁵ is selected from C₁-C₆ alkyl optionally substituted with one or more fluoro groups

In one aspect of the invention, R^5a is selected from CrC₆ alkyl optionally substituted with one or more fluoro groups, C3-C₇ cycloalkyl optionally substituted with one or more fluoro groups, Ce 10 aryl optionally substituted by one, two or three groups selected from Ci-Ce alkyl (optionally substituted with one or more fluoro groups), C₁-C₆ alkoxy (optionally substituted with one or more fluoro groups), hydroxy and halo, and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), C₁-C₆ alkoxy (optionally substituted with one or more fluoro groups), hydroxy and halo For example R^5a is tert-butyl or cyclohexyl In a further aspect of the invention, R^5a is selected from 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), Ci-C₆ alkoxy (optionally substituted with one or more fluoro groups), hydroxy and halo In a further aspect of the invention, R^5a is selected from 5 to 10- membered heteroaryl In a further aspect of the invention, R^5a is pyrazinyl, for example 2- pyraziπyl

In one aspect of the invention, R^4a is selected from Ci-C₆ alkyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups In a further aspect of the invention, R^4a is tert-butyl or cyclohexyl For example R^4a is cyclohexyl

In one aspect of the invention, R⁶ is H or C₁-C₆ alkyl optionally substituted with one or more fluoro groups For example, R⁶ is H

In one aspect of the invention, Y is C(H)_PR⁷ In a further aspect of the invention, n is 1 and Y is CH₂ In a further aspect of the invention, n is 2 and Y_n is CH₂CH₂ In a further aspect of the invention, n is 3 and Y_n is CH₂CH₂CH₂ (i e each of the three individual Y groups is CH₂)

In one aspect of the invention, R⁷ is H or C₁-C₆ alkyl optionally substituted with one or more fluoro groups In a further aspect of the invention, R⁷ is H

In one aspect of the invention, R⁸ is H, C_rC₆alkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups, or C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups In another aspect of the invention, R^s is H, methyl, ethyl, isopropyl, propenyl (for example, allyl), ethenyl or cyclopropyl In a further aspect of the invention, R^B is H, ethyl, isopropyl, ethenyl or cyclopropyl In a further aspect of the invention, R⁸ is H or C₁-C₆ alkyl optionally substituted with one or more fluoro groups In one aspect of the invention, R³⁰ is H, d-C₆aIkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups, or C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups. In a further aspect of the invention, R³⁰ is H or d-Caalkyl optionally substituted with one or more fluoro groups. In a further aspect of the invention, R³⁰ is H or methyl. In a further aspect of the invention, R³⁰ is H.

In one aspect of the invention, R^β and R³⁰ together with the carbon atom to which they are attached form a spirocyclopropane ring.

In one aspect of the invention, R⁹ is selected from H, C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro, C(O)R^B, and SO₂R^B.

In one aspect of the invention, R^B and an R⁷ together with the atoms between them, or two R⁷ groups together with the atoms between them, form a phenyl ring optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (oprtionally substitutes by one or more fluoro groups) and fluoro.

In one aspect of the invention, R⁸ and an R⁷ together with the atoms between them, or two R⁷ groups together with the atoms between them, form a phenyl ring.

In one aspect of the invention, n is 1 and Y is C(R⁷), n is 2 and Y_n is C(R⁷JCH₂, or n is 3 and Y_n is C(R⁷JCH₂CH₂; R⁷ and R⁸ together with the atoms between them (including R³⁰) form a phenyl ring optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (oprtionally substitutes by one or more fluoro groups) and fluoro.

In embodiments in which R⁷ and R⁸ together with the atoms between them form an aromatic ring and the carbon atom to which R⁷ is bonded is sp² hybridised, it is to be understould that the group R³⁰ forms part of the aromatic ring.

In one aspect of the invention, R¹ is H; R² is -X-(CH₂)_m-R¹⁰; m is 0; R^1D is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo and Ci-C₆alkyl (optionally

alkyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; R⁶ is H; n is 1 , 2 or 3; Y is C(H)_PR⁷; R⁷ is H; R^a is H, Ci-Cealkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups, or C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; and R³⁰ is H or CrC_βalkyl optionally substituted with one or more fluoro groups, or salts thereof.

In one aspect of the invention, R¹ is H; R²⁰ is H; R² and R³ together with the two carbon atoms between them form a C₃.₅cycloalkyl group, optionally substituted by one or more groups selected from C_halky! (for example methyl) and fluoro; R⁴ is selected from C₁-C₆

alkyl and C₃-C₇ cycloalkyl; Z is selected from -NHR⁵, -OR⁵, -R^5a and

;R⁶ is selected from CrCβalkyl and C₃-C₇cycloalkyl; R^5a is selected from 5 to 10-membered heteroaryl; R^4a is selected from C₁-C₆ alkyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; R⁶ is H; π is 1 , 2 or 3; Y is C(H)_PR⁷; R⁷ is H; R⁸ is H, C_rC_βaIkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups, or C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; and R³⁰ is H or CrCβalkyl optionally substituted with one or more fluoro groups, or salts thereof.

In one aspect of the invention, R¹ is H; R² is -X-(CHz)_n-R¹⁰, m is 0, X is -O- or -OC(O)- and R¹⁰ is selected from

R²⁰ is H; R⁴ is tert-butyl or cyclohexyl; Z is selected from -NHR⁵, -OR⁵, -R^5a and

pyrazinyl; R^4a is selected from cyclohexyl; R^s is H; n is 1 , 2 or 3; Y is C(H)_PR⁷; R⁷ is H; R⁸ is H, ethyl, ethylene, cyclopropane; and R³⁰ is H, or salts thereof.

thereof.

In another aspect of the invention, there is provided a compound of Formula (Ia):

(Ia) wherein:

R¹ is selected from H; Ci-C₆ aikyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); or R¹, R⁴ and the atoms between them form a 7 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^A, S, and SO₂;

R^A is H or Ci-C₆ alkyl, optionally substituted with one or more fluoro groups; or R¹ and R^β together with the two carbon atoms between them form a C₃-C₇ cycloalkyl group, optionally substituted by one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups) and fluoro;

R¹⁰ is selected from C^₁₀ aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from d-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^B, NR^BR^B, SR^B, SO₂R^B, NHSO₂R⁸, CONHR^B, NHCOR^B, C_S._1O aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, which latter C₃-io aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from C₁-C₆ alkyl, OR^B, NR^BR^B, SR^B, SO₂R^B, NHSO₂R⁸, CONHR⁸ and NHCOR⁸; each R^B is independently selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro, Ce-_Ki ary' (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and Ci-C₆ alkyl); C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro, C₆.₁₀ aryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl); C₆_i₀ aryl optionally substituted with one or more groups selected from halo and Ci-C₆ alkyl; and 5 to 10-membered heteroaryl optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl;

R³ is H; when X is bond, R²⁰ is H or OH; otherwise R²⁰ is H;

R⁴ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C_rC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C_rC₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); or R⁴, R⁸ and the atoms between them form an 8 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from Ci-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^A, S, and SO₂; Z is selected from -NHR⁵, -OR⁵, -R^5a and

;

R⁵ is selected from C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups;

R^5a is selected from C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₆-io aryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A, hydroxy and halo; and 5 to 10-rnembered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A, hydroxy and halo;

R^4a is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃- C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the CrC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups);

R⁶ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the CrC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; n is 1, 2 or 3; each Y group is selected from C(H)_PR⁷, O and NR⁹, with the proviso that no two O or NR⁹ groups are adjacent to each other in the ring; p being 1 if the Y group is only single bonded; p being 0 if the Y group is part of an aryl, heteroaryl or heterocyclic ring; R⁷ is selected from H; CrC₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C_B alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups;

R⁹ is selected from H; C_f-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, CrC₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the CrC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups; C(O)R^B; CO₂R^B; S(O)R^B; and SO₂R⁸ where R^B is independently as defined above; R⁸ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally 5 substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); or R⁸ and an R⁷ together with the atoms between them, or two R⁷ groups together with the 10 atoms between them, form a 5, 6 or 7 membered cyclic group which may be aromatic, which may include one or two heteroatom groups selected from O, NR^A, S, and SO₂; and which may be optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and fluoro,

15 or salts, solvates or esters thereof.

In a further aspect of the invention, there is provided a compound of Formula (Ia) wherein:

R¹ is H; 20

R² is a group -X-R¹⁰;

X is selected from O, O-C(O) and bond;

25. R^1α is selected from C₆._1D aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^B and NR^BR^B;

Each R^B is independently selected from H and C₁-C₆ alkyl optionally substituted with one or 30 more fluoro groups;

R³ is H; or R² and R³ together with the two carbon atoms between them form a C₃.₇ cycloalkyl group, 35 optionally substituted by one or more groups selected from Ci__β alkyl (for example methyl) and fluoro;

R²⁰ is H;

40 R⁴ is selected from Ci-C₆ alkyl optionally substituted with one or more fluoro groups; C₃-C₇

. cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and

C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more fluoro groups; or R⁴, R^β and the atoms between them form an 8 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more heteroatoms selected from O, NR^A, S and SO₂;

Z is selected from -NHR⁵, -OR⁵, -R^5a and

;

R⁵ is selected from C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl; and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups);

R^5a is selected from C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl; C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro and C₁-C₆ alkyl (optionally substituted with one or more fluoro groups); C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl (optionally substituted with one or more fluoro groups); C₆.i₀ aryl optionally substituted by one, two or three groups selected from Ci-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A and halo; and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A and halo;

R^4a is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl; C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups); and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl (optionally substituted with one or more fluoro groups).

R^A is H or C₁-C₆ alkyl, optionally substituted with one or more fluoro groups;

R⁶ is selected from H; C₁-C₆ alkyl optionally substituted with one or more fluoro groups; and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the CrC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; n is 1, 2 or 3; each Y group is selected from C(H)R⁷, O and NR⁹, with the proviso that no two O or NR⁹ groups are adjacent to each other in the ring;

R⁷ and R⁹ are each independently selected from H and C₁-C₆ alkyl optionally substituted with one or more fluoro groups;

R⁸ is selected from H; C₁-C₆ alkyl optionally substituted with one or more fluoro groups; C₃-C₇ cycloalkyl optionally substituted with one or more fluroro groups; and C₂-C₆ alkenyl optionally substituted with one or more fluoro groups; or salts, solvates or esters thereof. In a yet further aspect of the invention, there is provided a compound of Formula (Ia) wherein:

R¹ is H; R² is a group -X-R¹⁰;

X is selected from O and O-C(O);

R¹⁰ is selected from C_β-io aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^B and NR^BR^B;

Each R^B is independently selected from H, C₁-C₆ alkyl optionally substituted with one or more fluoro groups;

R³ is H; or R² and R³ together with the two carbon atoms between them form a C₃.₇ cycloalkyl group, optionally substituted by one or more groups selected from Ci__β alkyl (optionally substituted with one or more fluoro groups) and fluoro;

R²⁰ is H;

R⁴ is selected from CrC₆ alkyl optionally substituted with one or more fluoro groups; C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro and C₁-C₆ alkyl (optionally substituted with one or more fluoro groups); and C₂-C₆ alkenyl optionally substituted with one or more fluoro groups; or R⁴, R⁸ and the atoms between them form an 12 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds;

Z is selected from -NHR⁵, -OR⁵ and

R⁵ is selected from Ci-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl; and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro and C₁-C₅ alkyl (optionally substituted with one or more fluoro groups);

R^5a is selected from C$-io aryl optionally substituted by one, two or three groups selected from C-_I-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^Λ, NR^AR^A and halo; and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^Λ, NR^AR^A and halo;

R^4a is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl; and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro and C₁-C₆ alkyl (optionally substituted with one or more fluoro groups).

R⁶ is selected from H and C₁-C₆ alkyl optionally substituted with one or more fluoro groups; n is 1 , 2 or 3; each Y group is CH₂;

R^B is selected from H; C₁-C₆ alkyl optionally substituted with one or more fluoro groups; C₃-C₇ cycloalkyl optionally substituted with one or more fluroro groups; and C₂-C₆ alkenyl optionally substituted with one or more fluoro groups; or salts, solvates or esters thereof.

In a further aspect of the invention, there is provided a compound of Formula (1a) as defined above, or salts thereof. In an exemplary embodiment, the compound has a structure which is a member selected from-

wherein R⁵, π, Y, R¹, R⁸ and R are as described herein. In an exemplary embodiment, the compound has a structure which is a member selected from

wherein R², R³, R⁴, R²⁰ and Z are as described herein.

It is to be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein. As used herein unless otherwise specified, "alkyl" refers to a hydrocarbon group. The alkyl hydrocarbon group may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, π-pentyl, isopentyl, neopentyl or hexyl and the like. If specified herein, the alkyl group may be substituted by one or more substituents.

As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds. In one aspect, the alkenyl group has from 2 to 6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like. If specified herein, the alkenyl group may be substituted by one or more substituents.

As used herein unless otherwise specified, "cycloalkyl" refers to a cyclic hydrocarbon group. The hydrocarbon group may be saturated or unsaturated, monocyclic or bridged bicyclic. Where the cycloalkyl group is saturated, examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like. Where the cycloalkyl group is unsaturated, examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like. In one aspect, the cycloalkyl group has from 5 to 7 carbon atoms. In one aspect, cycloalkyl moieties are cyclohexenyl, cyclopentenyl and cyclohexyl If specified herein, the cycloalkyl group may be substituted by one or more substituents

As used herein, the term "alkoxy" refers to an -O-alkyl group wherein alkyl is as defined herein Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like If specified herein, the alkoxy group may be substituted by one or more substituents

As used herein, "aryl" refers to an aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems "Aryl" includes carbocyclic aryl and biaryl groups In one aspect, "aryl" moieties contain 6-10 carbon atoms In one aspect, "aryl" may be phenyl If specified herein, the aryl group may be substituted by one or more substituents As used herein, "halogen" or "halo" refer to a fluorine, chlorine, bromine or iodine atom References to "fluoro", "chloro", "bromo" or "iodo" should be construed accordingly

As used herein, "heteroaryl" refers to a 5-, 6-, 8-, 9- or 10-membered cyclic or bicyclic group with at least one ring having a conjugated pi-electron system and comprising one to four heteroatoms selected from N, O and S In one aspect, "heteroaryl" moieties are selected from (where applicable) pyridine, pyrazine, thiazole, thiophene, oxadiazole, oxazole, pyπmidine, pyπdazine, tπazole, tetrazole, benzodioxole, benzofuran, benzodioxin, indole, benzimidazole, benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, benzisothiazole, benzotriazole, furopyπdiπe, furopyπmidine, furopyπdazine, furopyrazine, furotπazine, pyrrolopyridine, pyrrolopyπmidine, pyrrolopyπdazine, pyrrolopyrazine, pyrrolotπazine, thienopyπdine, thienopyπmidine, thienopyπdazine, thienopyrazine, thienotπazine, thiazolopyridine, thiazolopyπmidine, thiazolopyπdazine, thiazolopyrazine, thiazolotπazine, oxazolopyπdine, oxazolopyπmidine, oxazolopyπdazine, oxazolopyrazine, oxazolotπazine, imidazopyπdiπe, imidazopyπmidine, imidazopyπdazine, imidazopyrazine, imidazotπazine, pyrazolopyπdine, pyrazolopyπmidine, pyrazolopyπdazine, pyrazolopyrazine, pyrazolotπazine, tnazolopyπdine, tπazolopyπmidine, tπazolopyπdazine, tπazolopyrazine, quinoline, naphthyπdine, quinoxaline, quinazoline, isoquinoline, cinnoline, pyπdopyπdazine, pyridopyπmidine, pyπdopyrazine, pyrazinopyrazine, pteπdine, pyrazinopyπdazine, pyrimidopyπdazine, pyπmidopyπmidine, 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 If specified herein, the heteroaryl group may be substituted by one or more substituents As used herein, "heterocyclic" and "heterocyclyl" refer to a 5-, 6-, 7-, 8-, 9- or 10-membered cyclic or bicyclic group with at least one ring saturated or partially saturated, and containing 1 to 4 heteroatoms selected from N, O and S In a bicyclic heterocyclic group, the second ring may optionally not contain a heteroatom In a bicyclic heterocyclic group, the second ring may optionally have a conjugated pi-electron system. For example, the second ring may be a phenyl ring, such that the overall group is a fused bicyclic heterocycle comprising a 5- or 6- membered heterocycle fused to a phenyl group. In one aspect, "heterocyclic" moieties are selected from (where applicable) aziridinyl, oxetanyl, oxiranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxathiolanyl, oxathianyl, diazepanyl, dihydrofuranyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dithianyl, azepanyl, octahydroazocinyl, indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1W-3-benzazepine and tetrahydroisoquinolinyl . All isomers of the above heterocyclic groups are within the scope of this invention. Each heterocyclic group may be attached at any ring carbon or may be attached through nitrogen. If specified herein, the heterocyclic or heterocyclyl groups may be substituted by one or more substituents. As used herein, "oxo" refers to =0.

As used herein, the term "pinanediol borate" refers 2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0^2l6]decane. In a further aspect, the present invention provides a compound chosen from the group consisting of:

W-{[(1 , 1 -dimethyIethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-Λ/-(2-hydroxy-1 ,2-oxaborinan-3-yl)- 4-(1 -isoquinolinyloxy)-L-prolinamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(⁴-fl^uoro-1.³-^c|iⁿy^dro-²W-isoindol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1,2-oxaborinaπ-3-yl)-L-prolinamide;

(3R,5S)-1 -[(2S)-2-cyclohexyl-2-({[(1 , 1 -dimethylethylJoxylcarbonylJaminoJacetyll-δ-flCa- hydroxy-1 ,2-oxaboriπaπ-3-yl)amino]carboπyl}-3-pyrrolidinyl 1 ,3-dihydro-2/-/-isoindole-2- carboxylate;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-(2-hydroxy-1 ,2-oxaborinan-3-y[)-4- (isoquinolin-i-yloxy)-L-prolinamide;

(1 S,3aR,6aS)-2-(W-{(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acety[}-3-methyI-L- valyl)-Λ/-(2-hydroxy-1 ,2-oxaborinan-3-yI)octahydrocyclopenta[c]pyrrole-1-carboxamide;

Λ/-(fert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-Λ/-(2-hydroxy-1 ,2-oxaborepan-3-yl)-4- (isoquinolin-i-yloxy)-L-prolinamide;

/V-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2- yI)carbonyl]oxy}-Λ/-[(3R)-2-hydroxy-1 ,2-oxaborolan-3-yl]-L-proIinamide;

Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-W-(4-ethyl-2-hydroxy-1,2-

Λ/-[(cyclopentyIoxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-(4-ethyl-2-hydroxy-1 ,2-oxaborolan-3-yl)- 4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinamide;

N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valy!-(4R)-Λ/-[(3R)-4-etheπyl-2-hydroxy-1 ,2- oxaborolan-3-yl]-4-methyl-L-prolinamide - 1 (2H)-isoquinolinone;

Λ/-{[(1 , 1 -dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-Λ/-[(3R)-2-hydroxy-1 ,2-oxaborolan- 3-yl]-4-methyl-L-prolinamide - 1(2/-/)-isoquinolinone;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-[(3R)-2-hydroxy-1 ,2-oxaborolan-3-yl ] 4-(isoquinolin-1-yloxy)-L-proI

W-[(cyclopeπtyIoxy)carbonyl]-3-methyl-L-valyl-(4R)-N-(4-cyclopropyl-2-hydroxy-1 ,2- oxaborolan-3-yl)-4-(isoquinoliπ-1-yloxy)-L-prolinamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-(4-cyclopropyl-2-hydroxy-1 ,2- oxaborolan-3-yl)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinamide;

W-[(cyclopentyloxy)carboπyl]-3-methyl-L-valyl-(4R)-W-(2-hydroxy-2,3-dihydro-1,2-

Λ/-[(cyclopeπtyloxy)carboπyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carboπyl]oxy}-/V-{2-hydroxy-2, ,2-benzoxaborol-3-yl)-L-prolinamide;

Λ/-(fert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2- yI)carboπyl]oxy}-Λ/-(2-hydroxy-1,2-oxaborepan-3-yl)-L-proliπamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-m8thyl-L-valyl-(4R)-Λ/-(2-hydroxy-1,2-oxaborepan-3-yl)-4- (isoquinolin-i-yloxy)-L-proliπamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-/V-(2-hydroxy-1,2-oxaborepan-3-yl)-L-prolinamicl8;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-(3-hydroxy-3,4-dihydro-1H-2,3- benzoxaborin-4-yl)-4-(1-isoqui

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-Λ/-(3-hydroxy-3,4-dihydro-1H-2,3-benzoxaborin-4-yl)-L-prolinamide;

(3R,5S)-1-[(2S)-2-cyclohexyl-2-({[(1,1-dimethylethyl)amino]carbonyl}amino)acetyl]-5-({[2- hydroxy-4-(1 -methylethyl)-1 ,2-oxaborolan-3-yl]amino}carbonyl)-3-pyrrolidinyl 4-fluoro-1 ,3- dihydro-2H-isoindole-2-carboxylate;

(3R,5S)-1-[(2S)-2-cyclohexyl-2-({[(1,1-dimethylethyl)amino]carbonyl}amino)acetyI]-5-

({[(SR^SJ-^ethyl^-hydroxy-i^-oxaborepan-S-ylJaminoJcarbonyO-S-pyrrolidinyU-fluoro-I.S- dihydro-2H-isoindole-2-carboxylate;

W-[(cyclopentyloxy)carboπyl]-3-methyl-L-valyI-(4R)-Λ/-[(3S,4S)-4-etheπyl-2-hydroxy-1,2-

(1R,2S,5S)-3-(N-{[{1 ,1-dimethylethyl)amino]carboπy^3-methyI-L-valyl)-W-[(3R)-2-hydroxy-

Λ/-{(1 S)-1 -cyclohexyl-2-[((1 S)-1-{[(1 S,3aR,6aS)-1 -({[(3R)-2-hydroxy-1 ,2-oxaborolan-3- yl]amino}methyl)hexahydrocyclopeπta[c]pyrrol-2(1H)-yl]carboπyl}-2,2-dimethylpropyl) amino]-

Λ/-[(cyclopentyloxy)oarboπyl]-3-methyl-L-valyl-(4R)-Λ/-[{3S)-2-hydroxy-1,2-oxaborolan-3-yl]-4- (i-ιsoquιnolιnyloxy)-L-prolιnamιde,

Λ/-t(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dιhydro-2H-ιsoιndol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaborolan-3-yl)-L-prolιnamιde,

W-[(cyclopentyloxy)carboπyl]-3-methyl-L-valyl-(4R)-Λ/-[(3S)-2-hydroxy-1 ,2-oxaboπnan-3-yl]-4- (i-ιsoquιnolιnyloxy)-L-prolιπam

(3R,5S)-1 -((S)-2-(cyclopentyloxycarbonylamιno)-3,3-dιmethylbutanoyl)-5-(2-hydroxy-4- isopropyl-i^-oxaborolan-S-ylcarbamoylJpyrrolidin-S-y^-fiuoroisoindoline^-carboxylate,

(3R,5S)-1-((S)-2-(cyclopentyioxycarbonylamιno)-3,3-dιmethylbutanoyl)-5-((3R)-4-ethyl-2- hydroxy-i^-oxaborepaπ-S-ylcarbamoyOpyrrolidin-S-yM-fluoroisoindoline^-carboxylate

(3R,5S)-1-((S)-2-(cyclopentyloxycarbonylamιno)-3,3-dιmethylbutanoyI)-5-(4-ethyl-2-hydroxy- 1 ,2-oxaborepan-3-ylcarbamoyl)pyrrolιdιn-3-yl 4-fluoroisoιndolιne-2-carboxylate,

(3R,5S)-5-((3R,4R)-4-allyl-2-hydroxy-1,2-oxaborolan-3-ylcarbamoyl)-1-((S)-2- (cyclopentyloxycarbonylaminoJ-S.S-dimethylbutanoylJpyrrohdin-S-yl 4-fluoroιsoiπdolιne-2- carboxylate,

(3R,5S)-5-((3R,4R)-4-a!lyl-2-hydroxy-1 ,2-oxaborolaπ-3-ylcarbamoyl)-1-{(S)-2- (cyclopentyloxycarbonylamιno)oct-7-enoyl)pyrrolιdιn-3-yl 4-fluoroιsoιndolιne-2-carboxylate,

cyclopentyl (S)-1 -((2S,4R)-2-((3R,4S)-2-hydroxy-4-methyl-1 ,2-oxaborιπaπ-3-ylcarbamoyl)-4- (ιsoquinoIιn-1-yloxy)pyrroIidιn-1-yI)-3,3-dιmethyl-1-oxobutan-2-ylcarbamate,

(3R)-1-((S)-2-(cyclopeπtyloxycarbonylamino)-3,3-dimethylbutanoyl)-5-((S)-2-hydroxy-1 ,2- oxaborepan-S-ylcarbamoylJpyrrolidin-S-yM-fluoroisoindoline^-carboxylate;

cyclopeπtyl (S)-1 -((2S,4R)-2-((R)-2-hydroxy-1 ,2-oxaborinan-3-ylcarbamoyl)-4-(isoquiπolin-1 -

(cyclopentyloxycarbonylaminoJ-S.S-dimethylbutanoyOpyrrolidiπ-S-yl 4-fluoroisoindoline-2- carboxylate;

{3R,5S)-1-((S)-2-(cyclopeπtyloxycarbonylamino)-3,3-dimethylbutanoyl)-5-((R)-2-hydroxy-1 ,2- oxaborinan-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate;

N-{[(1 , 1 -dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carboπyl] prolinamide;

W-{[(1 ,1-dimethylethyl)amino]carbonyI}-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-Λ/- linamide;

W-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4/^:?)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-Λ/- ,2-oxaborolan-3-yl)-L-prolinamide;

Λ/-{[(1 ,1-dimethyiethyl)amino]carbonyI}-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carbonylloxy}-A/-(2-hydroxy-1,2-oxaborolan-3-yl)-L-prolinamide;

>=o

(3aR, 11 S,15R, 16aS, 18aR,Z)-11-(cyclopentyloxycarbonylamino)-1 -hydroxy-12, 17-dioxo- 3,3a,4,7,8,9, 10₁11 , 12, 14, 15, 16, 16a,17,18, 18a-hexadecahydro-1 H-[1 ,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ^Jdiazacyclopentadeciπ-15-yI 4-fluoroisoindoliπe-2-carboxylate;

(3aR, 11 S, 15R, 16aS, 18aR,£)-11 -(cyclopentyloxycarbonylaminoH -hydroxy-12, 17-dioxo- 3,3a,4,7,8,9,10,11 ,12,14,15,16,16a,17,18,18a-hexadecahydro-1W-[1,2]oxaborolo[3,4- and

17-dioxo- 3,3a,4,7,8,9, 10,11 ,12,14, 15, 16, 16a, 17, 18, 18a-hexadecahydro-1 H-[1 ,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ^Idiazacyclopeπtadecin-15-yl 4-fluoroisoindoline-2-carboxylate, and salts thereof.

In one aspect of the invention, there is provided compounds of Examples 1 to 12, 15 or salts thereof.

In one aspect of the invention, there is provided compounds of Examples 1 to 12, 15 to 29 or salts thereof.

In one aspect of the invention, there is provided compounds of Examples 1 , 40 to 43 or salts thereof. In one aspect of the invention, there is provided compounds of Examples 44 and 45 or salts thereof.

In one aspect of the invention, there is provided compounds of Examples 1 to 16, N-{tβrt- butoxycarbonyl)-3-methyl-L-valyl-(4f?)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1,2-oxaborepan-3-yl)-L-prolinamide,

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-(2-hydroxy-1,2-oxaborepan-3-yl)-4- (isoquinolin-i-yloxy)-L-prolinamide, or Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dιhydro-2/-/-isoιπdol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1,2-oxaborepan-3-yl)-L-prolιnamιde, or salts thereof In one aspect of the invention, there is provided compounds of Examples 2-7, 9, 11 , 12 or 14, N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-(2-hydroxy-1 ,2-oxaborepan-3-yl)-4- (ιsoquιnolιn-1 -yloxy)-L-proIιnamιde, or Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4- {[(4-fluoro-1 ,3-dιhydro-2H-ιsoιndol-2-yl)carbonyl]oxy}-W-(2-hydroxy-1,2-oxaborepan-3-yl)-L- prolinamide, or salts thereof

In one aspect of the invention, there is provided a compound which is

Λ/-{[(1,1-dιmethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-Λ/-{3-hydroxy-1-[(1S,2S,6R,8S)- 2,9,9-trιmethyl-3,5-dιoxa-4-boratπcyclo[6 1 1 0^2β]dec-4-yl]propyl}-4-(1-ιsoquιnoIinyloxy)-L- prolinamide, or salts thereof

In one aspect of the invention, there is provided compounds of Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 18, 19, 22, 25, 26, 27, 28, 33, 34, 36, 37, 38 and 39, or salts thereof 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) 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) and embodiments thereof In certain embodiments, compounds of Formula 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 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 tπs(hydroxymethyl)amιnomethane], ethanolamine, diethylamine, tπethanolamine, 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 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 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, ethanesulfoπic, 2-hydroxyethanesulfonιc, 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), hydroxy! 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 resiπic [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 is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-tolueπesulfonιc, benzenesulfonic or methanesulfonic salt

Suitable pharmaceutically acceptable salts of the compounds of Formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or dι- 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- toluenesulfomc acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like Other non-pharmaceutically acceptable salts, for example oxalates, may be used, for example in the isolation of compounds of Formula (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)

The salts of a compound of Formula (I) may be prepared by contacting appropπate stoichiometric amounts of the free acid with the appropriate base in a suitable solvent The free acid of a compound of Formula (I) may for example be in solution with the appropπate base added as a solid or both the free acid of a compound of Formula (I) and the appropriate acid may independently be in solution Suitable solvents for solubilising a compound of Formula (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) may be isolated in solid form by conventional means from a solution thereof obtained as above For example, a non-crystalline 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) may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise crystallising a noncrystalline 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 compound of Formula (I) are within the scope of the invention Therefore, the present invention also relates to solvates of the compounds of Formula (I), for example hydrates

Salts and solvates of compounds of Formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable However, salts and solvates having non-pharmaceutically acceptable counteπons or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula (I) or salts, solvates or esters thereof and their pharmaceutically acceptable salts and solvates It will be appreciated by those skilled in the art that certain protected derivatives of compounds of Formula (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 descnbed 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 descnbed by H Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropπate functionalities when such functionalities are present within the compounds of Formula (I) Suitable prodrugs for compounds of Formula (I) or salts, solvates or esters thereof include esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals

The present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e g methoxymethyl), aralkyl (e g benzyl), aryloxyalkyl (e g phenoxymethyl), aryl (e g phenyl optionally substituted by halogen, -C_{1 4}alkyl or -C_1J(alkoxy or amino), or for example -CH₂OC(O)R' or - CH₂OCO₂R' in which R' is alkyl (e g R' is f-butyl) Unless otherwise specified, any alkyl moiety present in such esters preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms Any aryl moiety present in such esters preferably comprises a phenyl group In one aspect, the invention provides a pharmaceutically acceptable salt, solvate or prodrug of a compound of Formula (I)

In one aspect, the compound of Formula (I) is in the form of parent compound, a salt or a solvate

Furthermore, some of the crystalline forms of the compounds of Formula (I) or salts and solvates thereof may exist in one or more polymorphic form, which are included in the present invention As used herein, the term "pharmaceutically acceptable" used in relation to an ingredient (such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation 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 formulation and not being deleterious to the recipient thereof.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

It will further be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.

PROCESSES

Compounds of Formula (I) may be prepared from compounds of Formulae (II) and (III)

(M) wherein R², R²⁰, R³, R⁴, and Z are as defined above,

wherein R¹, R⁶, R⁸, R³⁰, Y and n are as defined above, by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF. Alternatively they may be prepared by treating compounds of Formula (II) with a chloroformate such as isobutyl chloroformate in the presence of a base such as N-methyl morpholine to form a mixed anhydride, followed by treatment with compounds of Formula (III).

Compounds of Formula (II) may be prepared using standard methods, for example methods described in White ef a/ (2006) and references cited therein. Compounds of Formula (II) in which R⁴, R⁸ and the atoms between them form an 8 to 17- membered heterocyclic ring as defined above may be prepared from compounds of Formula (II) in which both R⁴ and R⁸ contain alkenyl groups by standard ring macrocyclization reaction in the presence of a catalyst, for example Zhan-1 B catalyst ((1 ,3-dimesitylimidazolidin-2-yl)(5- (N,N-dimethylsulfamoyl)-2-isopropoxybenzylidene)ruthenium(V) chloride), in a suitable solvent such as dichloromethane or toluene at certain temperature such as r.t. to 111 ⁰C.

Compounds of Formula (I) may also be prepared from compounds of Formulae (H) and (IV) wherein R¹, R^θ, R⁸, R³⁰, Y and n are as defined above and P and P' are TMS groups, by use of HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.

Compounds of Formula (III) may be prepared by deprotection of compounds of Formula (IV):

wherein R¹, R⁶, R⁸, R³⁰, Y and n are as defined above and P and P' are suitable protecting groups. Suitable protecting groups include silane groups, for example TMS, TBDPS or TBDMS, or BOC groups. Deprotection may be achieved, for example, using TBAF when P and P' = TMS, TBDPS or TBDMS, preferably in the presence of acid, or by HCI or TFA when P and P'= BOC or TMS. In an alternative process, compounds of Formula (III) may be prepared from compounds of Formula (Ilia) by treatment with acid, for example aqueous hydrochloric acid or citric acid optionally in combination with a polymer supported phenyl boronic acid in a suitable solvent such as acetonitrile or water or combinations thereof.

(Ilia) Compounds of Formula (Ilia) may also be prepared from compounds of Formula (VIb) wherein R¹, R⁶, R⁸, R³⁰, Y and n are as defined above and P, P' and R" are suitable protecting groups, by treatment with acid, for example aqueous hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and optionally hexane.

Compounds of Formula (IV) may be prepared from compounds of Formula (V)

(V) wherein R¹, R⁸, R³⁰, Y, n, P and P' are as defined above and the R groups are selected from H and alkyl, or the two R groups together form a cyclic group, by treatment with acid, for example hydrochloric acid or citric acid optionally in combination with a polymer supported phenyl boronic acid in a suitable solvent such as acetonitrile or water or combinations thereof, or by dehydration preferably at elevated temperature such as 100-200°C, for example using phosphorous oxychloride.

Compounds of Formula (lllb) may be prepared from compounds of Formula (Ilia) through the removal of the R" protecting group. Compounds of Formula (lllb) may also be prepared from compounds of Formula (V) through the removal of the PP' protecting group;

(lllb) wherein R¹, R^β, R³⁰, R, Y and n are as defined above.

Compounds of Formula (IV) may also be prepared from compounds of Formula (IVb):

wherein R¹, R⁶, R⁸, R³⁰, Y and n are as defined above, by treatment with lithium hexamethyldisilylazide (where P and P' = TMS) in a suitable solvent such as THF at a suitable temperature, for example -78 to -20⁰C, optionally followed by warming to room temperature.

Compounds of Formula (IVb) wherein R⁶ is as defined above, R¹ is H, R⁸ is H, R³⁰ is H, Y is CH₂ and n =2, may be prepared from compounds of Formula (IVc)

OR⁶

(IVc) wherein and R^e are as defined above, by treatment with CH₂CI₂ or CH₂Br₂, zinc chloride and a base, for example LDA, in a suitable solvent, for example THF, at a suitable temperature, for example -78 to -20°C. Compounds of Formula (IVc) are well known in the art, for example when R⁶ = allyl, it may be prepared from allyl alcohol and sodium borohydride in a suitable solvent such as acetic acid.

In compounds of Formula (V), (Vl), (Via), (VIb), (VII), (VIII), (Xl), (XII) and (XIIa) various groups R may be interchanged by standard methods. For example a compound in which R is H can be converted into a compound in which R is alkyl (or the two R groups together form a cyclic group) by addition of an appropriate alcohol. Similarly, compounds in which R is alkyl (or the two R groups together form a cyclic group) can be converted into a compound in which R is H by reaction with, for example, sodium periodate, optionally in the presence of ammonium acetate, in a suitable solvent, for example aqueous methanol or aqueous acetone. Similarly, in compounds of Formula (IV), R⁶ groups may be interconverted such that a particular R⁶ group is provided in a particular required compound (IV).

Compounds of Formula (IV) may alternatively be prepared from compounds of Formula (Vl):

(Vl) wherein R¹, R⁸, R³⁰, Y, n, P, P' and R are as defined above and OR' is a suitable leaving group, for example methanesulphonate or trifluoromethane sulphonate in a suitable solvent, for example DMF, DCM or THF, in the presence of a base, for example pyridine, triethylamine or diiospropylamine, optionally with heating. Compounds of Formula (IV) may further alternatively be prepared from compounds of Formula (Via):

(Via) wherein R¹, R^B, R³⁰, Y, n, P, P' and R are as defined above (and the two R groups are preferably H) and X is a halide, for example bromide or iodide, in a suitable solvent, for example DMF, DCM or THF, in the presence of a base, for example pyridine, triethylamine or diiospropylamine, optionally with heating.

Compounds of Formula (Via) may be prepared from compounds of Formula (V) by treatment with triphenyl phosphine and carbon tetrabromide in a suitable solvent, for example DMF, DCM or acetonitrile (for X=Br), or by treatment with trifluoromethanesulfonic anhydride or methanesulfonyl chloride in the presence of a suitable base, for example pyridine, triethylamine, or diisopropylamine, in a suitable solvent for example DCM, and then displacing the sulfonate ester product with the halide, for example using lithium bromide or tetrabutyl ammonium bromide in a suitable solvent, for example DMF. Compounds of Formula (V) may be prepared from compounds of Formula (VIb):

(VIb) wherein R¹, R⁸, R³⁰, Y, n, P, P' and R are as defined above and R" is a protecting group, for example p-methoxy benzyl, by deprotection of the protecting group R". For example when R" = tert-butyldiphenylsilyl, deprotection may be achieved using a fluoride source such as tetrabutyl ammonium fluoride, in a suitable solvent, for example THF. Compounds of Formula (Via) may be prepared from compounds of Formula (V) by addition of the protecting group R" to the OH group.

Compounds of Formula (VIb) in which the R groups are alkyl groups, or the two R groups together form a cyclic group, may be prepared from compounds of Formula (VII)

wherein X, R¹, R⁸, R³⁰, Y, n and R" are as defined above and the R groups are alkyl groups, or the two R groups together form a cyclic group, by treatment with a lithium hexamethyldisilylazide (where P and P' = TMS) in a suitable solvent such as THF at a suitable temperature for example -78 to -20°C, optionally followed by warming to room temperature. Compounds of Formula (VII) may be prepared from compounds of Formula (VlII)

(VIII) wherein R⁶, Y, n, R and R" are as defined above for Formula (VII), by treatment with a compound R¹ -CHCI₂, zinc chloride and a base, for example LDA, in a suitable solvent, for example THF, at a suitable temperature, for example -78 to -20°C. When R¹ = H, the reagent is DCM. Compounds of Formula (VIIIb) may be prepared from compounds of Formula (VIIIc);

(VIlIb)

wherein R and R" are as defined above for Formula (VII), by treatment with a compound ROCH₂CI and a base, for example NaH, in a suitable solvent, for example DMF, at a suitable temperature, for example 0°C.

Compounds of Formula (VIII) may (VIIId)

(VIIId) wherein R^B, Y, n, R are as defined above for Formula (VIII), by treatment with a protective reagent, for example TBSCI, and an activating agent, for example imidazole, in a suitable solvent, for example DMF, at a suitable temperature, for example 20°C.

Compounds of Formula (VIII, when R⁸=H) may be prepared from compounds of Formula (VIIIe):

(VIIIe) wherein Y, n, R and R" are as defined above for Formula (VIII), by hydrogenation under H₂ in the presence of a catalyst, for example 5%Pd/C in a suitable solvent, for example MeOH, at a suitable temperature, for example room temperature.

Compounds of Formula (VIIIe) may be prepared from compounds of Formula (VIIIf) :

Y_n-OR" (VIIIf) wherein Y, n, and R" are as defined above for Formula (VIIIe), by treatment with a compound H-B(OR)2, Cp₂ZrHCI and a base, for example Et3N, at a suitable temperature, for example room temperature to 60°C, for certain time, for example 16 h.

Compounds of Formula (VII) may also be prepared from compounds of Formula (Villa)

(Villa) wherein R is as defined above by reaction with Grignard reagents of Formula RO-Y_n-CHR⁸- CHR¹- MgX in a suitable solvent such as THF. Grignard reagents of Formula RO-Y_n-CHR⁸- CHR¹-MgBr may be prepared from the corresponding halides of Formula RO-Y_n-CHR⁸- CHR¹-X where X is a halide, using magnesium, as is well known in the art. Compounds of Formula R'O-Y_π-CHR⁸-CHR¹-X are well known in the art. Compounds of Formula (VIII) are also very well known in the art and are prepared from compound of Formula (IX)

(IX) wherein R⁸, Y, n and R" are as defined above, using an alcohol ROH, for example methanol, or a diol, for example pinacol, catechol, pinene diol, (1 R), (2R)-1,2-dicyclohexyl-1 ,2- ethanediol, (1S), (2S)-1 ,2-dicyclohexyl-1 ,2-ethanediol, or ethylene glycol, in a suitable solvent, for example diethylether.

Compounds of Formula (VIII) may also be prepared by treatment of compounds of Formula B(OR)₃ with Grignard reagents of Formula RO-Y_n-CHR⁸- MgX in a suitable solvent such as THF. Grignard reagents of Formula RO-Y_n-CHR⁸- MgBr may be prepared from the corresponding halides of Formula R'O-Y_n-CHR⁸-X where X is a halide, using magnesium, as is well known in the art. Compounds of Formula R'O-Y_π-CHR⁸-X are well known in the art.

Compounds of Formula (VIII), may also be prepared by treatment of compounds of Formula (IXa) in which X is a halogen such as chloride, with Grignard reagents of Formula R¹O-Yn- MgX in a suitable solvent such as THF. Grignard reagents of Formula RO-Y_n-MgBr may be prepared from the corresponding halides of Formula RO-Y_n-X where X is a halide, using magnesium, as is well known in the art. Compounds of Formula R¹O-Y_n-X are well known in the art.

(IXa)

Compounds of Formula (IX) may be prepared from compounds of Formula (X)

(X) wherein R⁸, Y, n and R" are as defined above, by treatment with BH₃-Me₂S followed by treatment with water. Compounds of Formula (VIII) may similarly be prepared by treatment of compounds of Formula (X) with (RO)₂BH.

In an alternative process, compounds of Formula (I) may be prepared from compounds of Formula (Xl):

(Xi) wherein R², R²⁰, R³, R³⁰, R⁴, Z, R¹, R⁸, Y and n are as defined above and the R groups are selected from H and alkyl, or the two R groups together form a cyclic group, by a process analogous to the process for preparing compound (IV) from compound (V), for example using aqueous hydrochloric acid. In an alternative process, compounds of Formula (I) may be prepared from compounds of Formula (Xl), by treatment with a boronic acid such as isobutyl boroπic acid in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol or hexanes or combinations thereof. Compounds of Formula (Xl) may be prepared from compounds of Formula (Ilia) by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. Subsequent deprotectioπ of a protecting group R" according to methods described herein or to methods generally known in the art will produce a compound of Formula (Xl).

Compounds of Formula (Xl) may be prepared from compounds of Formula (MIb) by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.

Compounds of Formula (Xl) may be prepared from compounds of Formula (V) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. When P and P' are TMS groups, then compounds of Formula (Xl) may be prepared from compounds of Formula (V) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.

Compounds of Formula (Xl) may be prepared from compounds of Formula (Vl) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. When P and P' are TMS groups, then compounds of Formula (Xl) may be prepared from compounds of Formula (Vl) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. Subsequent removal of the leaving group R' (by hydrolysis, for example) according to methods described herein or to methods generally known in the art will produce a compound of Formula (Xl).

Compounds of Formula (Xl) may be prepared from compounds of Formula (VIb) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. When P and P' are TMS groups, then compounds of Formula (Xl) may be prepared from compounds of Formula (VIb) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. Subsequent deprotection of a protecting group R" according to methods described herein or to methods generally known in the art will produce a compound of Formula (Xl). Similarly, compounds of Formula (Xl) may be prepared from compounds of Formula (XIa):

(XIa) wherein R², R²⁰, R³⁰, R³, R⁴, Z, R¹, R⁸, Y, R and n are as defined above and R" is a protecting group, by a process analogous to the process for preparing compound (V) from compound (VIb). In an example, R" is a hydroxy protecting group, for example para- methoxybenzyl, by treatment with DDQ (2,3-dichloro-5,6-dicyano-benzoquinone) in a suitable solvent such as dichloromethane and water or combinations thereof, or by treatment with hydrochloric acid in suitable solvent such as dioxane.

In an alternative process, compounds of Formula (I) may be prepared from compounds of Formula (XIa) in which R" is a para-methoxybenzyl protecting group, by treatment with a boronic acid such as isobutyl boronic acid in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol or hexanes or combinations thereof, or alternatively using DDQ (2,3-dichloro-5,6-dicyano-benzoquinone) in a suitable solvent such as dichloromethane and water or combinations thereof, or by treatment with hydrochloric acid in suitable solvent such as dioxane, or alternatively in combination of these two deprotection methods. Compounds of Formula (XIa) in which R⁴, R^β and the atoms between them form an 8 to 17- membered heterocyclic ring as defined above may be prepared from compounds of Formula (XIa) in which both R⁴ and R⁸ contain alkenyl groups by standard ring macrocyclization reaction in the presence of a catalyst, for example Zhan-1B catalyst ((1,3- dimesitylimidazolidin-2-yl)(5-(N,N-dimethylsulfamoyl)-2-isopropoxybenzylidene)ruthenium(V) chloride), in a suitable solvent such as dichloromethane or toluene at certain temperature such as r.t. to 111 ⁰C.

Compounds of Formula (XIa) may be prepared from compounds of Formula (Ilia) by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.

Compounds of Formula (XIa) may be prepared from compounds of Formula (Vl) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF. When P and P' are TWIS groups, then compounds of Formula (XIa) may be prepared from compounds of Formula (Vl) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF. Subsequent replacement of the leaving group R' with a protecting group R" according to methods described herein or to methods generally known in the art will produce a compound of Formula (XIa). Compounds of Formula (XIa) may be prepared from compounds of Formula (VIb) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. When P and P' are TMS groups, then compounds of Formula (XIa) may be prepared from compounds of Formula (VIb) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.

Similarly, compounds of Formula (Xl) may be prepared from compounds of Formula (XIb)

(XIb) wherein R², R²⁰, R³, R³⁰, R⁴, Z, R¹, R⁸, Y, R and n are as defined above and OR' is a suitable leaving group, for example methanesulphoπate or trifluoromethaπe sulphonate, by a process analogous to the process for preparing compound (IV) from compound (Vl).

Compounds of Formula (XIb) may be prepared from compounds of Formula (Vl) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. When P and P' are TMS groups, then compounds of Formula (Xl) may be prepared from compounds of Formula (Vl) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.

Compounds of Formula (III)

wherein R¹, R⁶, R⁸, R³⁰, Y and n are as defined above, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (III) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (III) wherein the compound is selected from the group consisting of 3-amino-1 ,2-oxaborinan-2-ol; 3-amino-1 ,2-oxaborepan-2-ol; 3-aminobenzo[d][1 ,2]oxaborol-2(3H)-ol; or a salt thereof.

In a further aspect of the invention, there is provided a compound of Formula (III) wherein the compound is selected from the group consisting of 3-amino-1,2-oxaborinan-2-ol hydrochloride;

3-amino-1,2-oxaborepan-2-ol hydrochloride; or 3-aminobenzo[d][1 ,2]oxaborol-2(3H)-ol hydrochloride.

Compounds of Formula (IMb)

wherein R¹, R⁸, R, R³⁰, Y and n are as defined above, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (HIb) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (IMb) wherein the compound is (3R)-3-Amino-3-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^{2 β}]dec-4-yl]-1- propanol(3R)-3-amino-3-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.

0^{2 β}]dec-4-yl]-1 -propanol hydrochloride;

(4R)_-4-Amino-4-[(1 S,2S,6f?,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^{2 β}]dec-4-yl]-1- butanol hydrochloride; (1R, 2R, 3S, 5R)-Pinanediol-1-amino-4-hydroxy-butyl borate hydrochloride;

[1R₁ 2R, 3S, 5R)-Pinanediol 1 S-amino-3-hydroxy-propyl borate hydrochloride;

(S)-5-Amino-5-((1 R,2R,8R)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²'^θ]deo4-yi)- pentan-1-ol hydrochloride;

[1R₁ 2R, 3S, 5R)-Pinanediol 1 S-amino-3-hydroxy-propyl borate hydrochloride or a salt thereof. Compounds of Formula (IV)

wherein R¹, R⁶, R⁸, R³⁰, Y and n are as defined above and P and P' are suitable protecting groups as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (IV) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (IV) wherein the compound is [2-(Butyloxy)-1,2-oxaborinan-3-yl]bis(trimethylsilyl)amine or a salt thereof.

Compounds of Formula (VIb)

wherein R¹, R⁸, R³⁰, Y, n, P, P' and R are as defined above and R" is a protecting group, as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIb) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (VIb) wherein the compound is selected from the group consisting of

[5-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-1-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pentyl]bis(trimethylsilyl)amine; {(1 R)-3-({[4-(methyloxy)phenyl]methyl}oxy)-1 -[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.02,6]dec-4-yl]propyl}bis(trimethylsilyl)amine;

Isomer 1 of {2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9-trimethyl- 3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]butyl}bis(trimethylsilyl)amine; {2-[({[4-(Methyloxy)phenyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.02,6]dec-4-yl]-3-buten-1 -yl}bis(trimethylsilyl)amine; [(2-{[(Methyloxy)methyl]oxy}phenyl)(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolaπ-2- yl)methyl]bis(trimethylsilyl)amine;

(1R, 2R, 3S, 5R)-Pinanediol-1-bis(trimethylsilyl)amino-4-(f-butyl-dimethylsilyloxy)-butyl borate;

{2-[({[4-(Methyloxy)phenyl]methyl}oxy)methyl]-2R-cyclopropyl-1R-[(1S,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec^4-yl]ethyl}bis(trimethylsilyl)amine;

(1 R,2R,8R)-4-[(S)-5-(fert-Butyl-dimethyl-silanyloxy)-1 -(1 ,3-di-ferf-butyl-1 , 1 ,3,3-tetramethyl- disilazan-2-yl)-pentyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²'⁶]decane; 2-(Bis(trimethylsilyl)amino(2-((methoxymethoxy)methyl)phenyl)methyl)-4,4,5,5-tetramethyl-

1 ,3,2-dioxaborolane;

(1S,2S,3R,5S)-(+)Pinanediol (1R,2R)-2-(benzyloxymethyl)-1-[bis(trimethylsilyl)amino]-3- methylbutyl Borate; (1 S,2S,3R,5S)-(+)-Pinanediol (1 R,2S)- 1 -(Bis(trimethylsilyl)amino)-2-Ethyl -5-(benzyloxy)pentyl

Borate;

{2-[({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-2S-methyl-1R-[(1 S, 2S, 6R 8S)-2,9,9-trimethyl-

3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]ethyl}bis(trimethylsilyl)amine;

(1 S,2S,3R,5S)-(+)Pinanediol (1 R,2R)-2-(benzyloxymethyl)-1-[bis(trimethylsilyl)amino]-3- methylbutyl Borate;

(1 S,2S,3R,5S)-(+)-Pinanediol (1 R,2S)- 1 -(Bis(trimethylsilyl)amino)-2-Ethyl -5-(benzyloxy)pentyl

Borate;

{2-[({[4-(methyloxy)pheπyl]methyl}oxy)ethyl]-2S-methyl-1R-[(1S, 2S, 6R, 8S)-2,9,9-trimethyl-

3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]ethyl}bis(trimethylsilyl)amine; (1S,2S,6R,8S)-4-{(1R), (2R)-1-(bis(trimethyIsilyl))-2-[({[4-(methyloxy)phenyl]methyl}oxy) methyl]-4-penten-1 -yl}-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2lβ]decaπe;

{2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1 R, 2R, 6S, 8R)-2, 9, 9-trimethyl-3,5-dioxa-

4-boratricyclo [6.1.1.0²'⁶] dec-5-yl]penteπyl}bis(trimethylsilyl)amine;

{2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1R, 2R, 6S, 8R)-2, 9, 9-trimethyl-3,5-dioxa- 4-boratricyclo [6.1.1.0^{Zl e}] dec-5-yl]butenyl}bis(trimethylsilyl)amine;

2-(Bis(trimethylsilyl)amino(2-((methoxymethoxy)methyl)phenyl)methyl)-4,4,5₁5-tetramethyl-

1 ,3,2-dioxaborolane or a salt thereof.

Compounds of Formula (VII)

wherein X, R¹, R⁸, R³⁰, Y, n and R" are as defined herein and the R groups are alkyl groups, or the two R groups together form a cyclic group, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (VII) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (VII) wherein the compound is selected from the group consisting of {[5-Chloro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pentyl]oxy}(1 ,1- dimethylethyl)dimethylsilane;

(1S,2S,6R,8S)-4-[(1 S)-1-bromo-3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]-2,9,9-trimethyl- 3,5-dioxa-4-boratricyclo[6.1.1 ,02,6]decane; (1 S,2S,6R,8S)-4-[(1 S)-1 -Bromo-2-({[4Kmethyloxy)phenyl]methyl}oxy)ethyl]-2,9,9-trirnethyl- 3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane;

Isomer 1 of (1S,2S,6R,8S)-4-{1-bromo-2-[({[4-(methyloxy)phenyl]methyl}oxy)metriyl]butyl}- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane; (1 S,2S,6R,8S)-4-{1 -Bromo-2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-3-buten-1 -ylJ-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane;

2-[Chloro(2-{[(methyloxy)methyl]oxy}phenyl)methyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane;

(1 S, 2S, 3R, 5S)-Pinanediol 1 S-chloro-3-(4-methoxybenzyloxy)-propyl borate

{1R, 2R, 3S, 5f?)-Pinaπediol-1-chloro-4-(f-butyl-dimethylsilyloxy)-butyl borate; (1R, 2R, 3S, 5R)-Pinanediol 1R-chloro-3-(4-methoxybenzyloxy)-propyl borate;

(1 S,2S,6R,8S)-4-{1 S-Bromo-2-[({[4-(methyloxy)phenyl]methyl}oxy)methyI]-2S-cyclopropyI- ethyl}-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane;

(IR^R.SRJ^-tCRJ-δ-tterf-Butyl-dimethyl-silanyloxyJ-i-chloro-pentyll^.θ.θ-trimethyl-S.δ-dioxa-

4-bora-tricyclo[6.1.1.0^{z e}]decane; 2-[Chloro(2-{[(methyloxy)methyl]oxy}phenyl)methyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaboroIane;

(1 S,2S,3R,5S)-(+)-Pinanediol 1 (R)-chloro-2-(p-Methoxybenzyloxy)-ethyl Borate;

(1S,2S,3R_l5S)-(+)-Pinaπediol (1 S,2S)-1-chIoro-2-((4-methoxybeπzyloxy)methyl)-3-methylbutyl

Borate;

(1 S,2S,3R,5S)-(+)-Pinanediol (1 S)-1-Chloro-3-(benzyloxy)butyl Borate; (1 S,2S,3R,5S)-(+)-Piπaπediol (1S,2S)-1-Chloro-2-Ethyl-5-(benzy!oxy)pentyl Borate;

(1 S, 2S, 6R, 8S)-4-[(1S)-1-chloro-(2S)-2-methyl-4-({[4-(methyloxy)phenyl]methyl}oxy)butyl]-

2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2>6]decane; (1S,2S,3R,5S)-(+)-Pinanediol

(1 S,2S)-1 -chloro-2-((4-methoxybeπzyloxy)methyl)-3-methylbutyl Borate;

(1S,2S,3R,5S)-(+)-Pinaπediol (1S)-1-Chloro-3-(beπzyloxy)butyl Borate; (1S,2S,3R,5S)-(+)-Pinanediol (1S,2S)-1-Chloro-2-Ethyl-5-(benzyloxy)pentyl Borate; (1S, 2S,

6R, 8S)-4-[(1 S)-1 -chIoro-(2S)-2-methyl-4-({[4-(methyloxy)phenyl]methyl}oxy)butyl]-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]decane;

(1 S,2S,6R,8S)-4-{(1 S), (2S)-1 -chloro-2-[({[4-(methyloxy)phenyl]methyl}oxy) methyl]-4-peπten- i-ylJ^.Θ.Θ-trimethyl-S.S-dioxa^-boratricyclop.i .i.O^^decane; (1 R, 2R, 6S, 8R)-4-[(1 R)-1 -chloro-2-({[4-(methyloxy)phenyl]methyl}oxy)-ethyl]-2, 9, 9- trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.0²'⁶] decane;

(1 R, 2R, 6S, 8R)- 4-{(1R)-1-chloro-2-[({[4-(methyloxy)pheny[]methyl}oxy)methyl]-4-peπten-1- yl-2, 9, 9-trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.0²'⁶] decane;

(1 R, 2R, 6S, 8R)- 4-{(1R)-1-chloro-2-[({[4-(methyloxy)phenyl]methy[}oxy)methyl]-4-buten-1-yl- 2, 9, 9-trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.0^{2 6}] decane;

(1S, 2S, 3R, 5S)-Pinanediol 1S-chloro-3-(4-methoxybenzyloxy)-propyl borate or a salt thereof.

Compounds of Formula (VIII)

OR

B

/ ^NOR n-OR" (VIM) wherein R⁸, Y, n, R and R" are as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I) Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIII) or a salt thereof In a further aspect of the invention, there is provided a compound of Formula (VIII) wherein the compound is selected from the group consisting of (1 ,1-Dιmethylethyl)(dιmethyl){[4-(4,4,5,5-tetramethyl-1 ,3,2-dιoxaborolan-2-yl)butyl]oxy}sιlane,

(1S,2S,6R,8S)-2,9,9-tπmethyl-4-[2-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-3,5-dιoxa-4- boratπcyclo[β 1 1 02,6]decane,

(1 S,2S,6R,8S)-2,9,9-tπmethyl-4-{(1 S)-1 -[({[4-(methyloxy)phenyl]methyl}oxy)methyl] propyl}- 3,5-dιoxa~4-boratπcyclo[6 1 1 02,6]decane,

(1S,2S,6R,8S)-2,9,9-Tπmethyl-4-{(1S)-1-[({[4-(methyloxy)phenyl]methyl}oxy)methyl] -2- propen-1-yl}-3,5-dιoxa-4-boratrιcyclo[6 1 1 02,6]decane, (1R, 2R, 3S, 5R)-Pιnanediol f-butyl-dimethylsilyloxypropyl borate,

(1R, 2R, ZS, 5R)-Pιnanedιol 4-methoxybenzyloxymethyl borate,

(1R, 2R, 3S, 5R)-Pιnanedιol 4-methoxybenzyloxyethyl borate,

(1S,2S,6R,8S)-2,9,9-Tπmethyl-4-{(1 S)-1-[({[4-(methyloxy)phenyl]methyl}oxy)methyI]-1- cyclopropyl-methyl}-3,5-dιoxa-4-boratrιcyclo[6 1 1 02,6]decane (1R,2R,8R)-4-[4-(tert-Butyl-dιmethyl-sιlanyloxy)-butyl]-2,9,9-tπmethyl-3,5-dιoxa-4-bora- trιcyclo[6 1 1 O^{2 6}]decane,

(1S,2S,3R,5S)-(+)Pιnanedιol (1S)-1-(4-methoxybenzyloxy)-3-methylbutan-2-yl Borate,

(1 S,2S,3R,5S)-(+)-Pιnanedιol 3-(benzyloxy)-propyl Borate (OK now)

(1 S,2S,3R,5S)-(+)-Pinanediol (S)-1 -Ethyl-4-(benzyloxy)butyl Borate (OK now) (1 S, 2S, 6R, 8S)-4-[(1 S)-1 -methyl-3-({[4-(methylαxy)phenyl]methyl}oxy)propyl]-2,9,9- trιmethyl-3,5-dιoxa-4-boratrιcyclo[6 1 1 0²⁶]decane,

(1 S,2S,3R,5S)-(+)Pιnanediol (1 S)-1 -(4-methoxybenzyloxy)-3-methylbutan-2-yl Borate,

(1S,2S,3R,5S)-(+)-Pιnanedιol (S)-1-Ethyl-4-(benzyloxy)butyl Borate,

(1 S, 2S, 6R, 8S)-4-[(1S)-1-methyl-3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]-2,9,9- tπmethyl-3,5-dιoxa-4-boratrιcyclo[6 1 1 0²⁶]decane

(1 S,2S,6R,8S)-2,9,9-tπmethyl-4-{(1S)-1-[({[4-(methyloxy)phenyl]methyl}oxy) methyl] -3-buten-

1-yl}-3,5-dιoxa-4-boratπcyclo[6 1 1 0²⁶]decane,

(1 R, 2R, 6S, 8R)- 2, 9, 9-trιmethyl-4-[({[4-(methyloxy)phenyl]methyl}oxy)-methyl]-3,5-dιoxa-4- boratπcyclo [6 1 1 O^{2 6}] decane, (1 R, 2R, 6S, 8R)- 2, 9, 9-trιmethyl-4-{[(1 S)- 1 [{{[4-(methyloxy)phenyl]methyl}-oxy)methyl]-3- buten-1-yl-3,5-dιoxa-4-boratrιcyclo [6 1 1 O^{2 e}] decane,

(1R, 2R, 6S, 8R)- 2, 9, 9-trιmethyl-4-{[(1S)- 1 [({[4-(methyloxy)phenyl]methyl} oxy)methyl]-2- propen-1-yl-3,5-dιoxa-4-boratrιcyclo [6 1 1 O^{2 6}] decane, or a salt thereof Compounds of Formula (VIIIb) or Formula (VIIIc);

(VIIIb)

wherein R and R" are as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIIIb) or a salt thereof. Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIIIc) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (VIIIb) wherein the compound is 2-(2- ((Methoxymethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane; or a salt thereof.

Compounds of Formula (VIIId)

(VIIId) wherein R⁸, Y, n, R are as defined above for Formula (VIII), may be useful as intermediates for the synthesis of compounds described herein. Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIIId) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (VIIId) wherein the compound is (IR, 2R, 3S, 5R)-Pinanediol 3-hydroxy-propyl borate; or a salt thereof.

Compounds of Formula (VIII, when R⁸=H)

(VIIIe) wherein Y, n, R and R" are as defined above for Formula (VIII), may be useful as intermediates for the synthesis of compounds described herein. Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIIIe) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (VIIIe) wherein the compound is

(1R,2R,8R)-4-[(E)-4-(fert-Butyl-dimethyl-silanyloxy)-but-1-enyl]-2,9,9-trimethyl-3,5-dioxa-4- bora-tricyclo[6.1.1.0²'⁶]decane or a salt thereof. Compounds of Formula (Xl)

(Xl) wherein R², R²⁰, R³⁰, R³, R⁴, Z, R¹, R⁸, Y and n are as defined above and the R groups are selected from H and alkyl, or the two R groups together form a cyclic group, are as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (Xl) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (Xl) wherein the compound is selected from the group consisting of

Λ/-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2W-isoindol-2- yl)carbonyl]oxy}-Λ/-{(1 R)-3-hydroxy-1 -[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0^2l6]dec-4-yl]propyl}-L-prolinamide; N-[(Cydopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-{(1 R)-3-hydroxy-1-[(1 S,2S,6R,8S)-

2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2|6]dec-4-yl]propyI}-4-(1-isoquinolinyloxy)-L- prolinamide;

Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyI}-3-methyl-L-valyl-(4R)-W-{3-hydroxy-1-[(1 S,2S,6R,8S)-

2,9,9-trimethyl-3,5-dioxa-4-boratricycIo[6.1.1.θ2.6]dec-4-yl]propyl}-4-(1-isoquinolinyloxy)-L- prolinamide; or a salt thereof.

Compounds of Formula (XIa)

(XIa) wherein R², R²⁰, R³, R³⁰, R⁴, Z, R¹, R^B, Y, R and n are as defined above and R" is a hydroxy protecting group, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (XIa) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (XIa) wherein the compound is selected from the group consisting of

Isomer 1 of W-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-methyI-N-{2-[({[4- (methyloxy)phenyl]methyl}oxy)methyl]-1-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²'⁶]dec-4-yl]butyl}-L-prolinamide - 1 (2H)-isoquinolinone (1 :1);

Isomer 1 of Λ/-[(cyclopentyloxy)carbonyI]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yI)carbonyl]oxy}-Λ/-{2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1- [(IS^S.eR.βS^.g.θ-trimethyl-S.δ-dioxa^-boratricycloie.i .i .O^^dec^-yllbutyl^L- proliπamide;

W-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-Λ/-{2-[({[4- (methyloxy)phenyl]methyl}oxy)methyl]-1-t(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²⁶]dec-4-yl]-3-buten-1 -yl}-4-(2-quinolinyloxy)-L-proIinamide;

Λ/-{[(1 ,1-Dimethylethyl)oxy]carbonyI}-3-methyl-L-valyl-(4R)-4-(1-isoquinolinyloxy)-Λ/-{(1R)-3- ({[4-(methyloxy)phenyl]methyl}oxy)-1-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0^2|6]dec-4-yl]propyl}-L-proIinamide;

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-{2-cyclopropyl-3-({[4-

(methyloxy)phenyl]methyl}oxy)-1-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²⁶]dec-4-yl]propyl}-4-(1 -isoquinolinyloxy)-L-prolinamide; Λ/-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-{2-cyclopropyl-3-({[4-

(methyloxy)phenyl]methyl}oxy)-1-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²'⁶]dec-4-yl]propyl}-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-

L-prolinamide;

Λ/-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-{2-cyclopropyl-3-({[4- (methyloxy)phenyl]methyl}oxy)-1 -[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²⁶]dec-4-yl]propyl}-4-(1-isoquinolinyloxy)-L-prolinamide;

Λ/-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-{2-cyclopropyl-3-({[4-

(methyloxy)phenyl]methyl}oxy)-1-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1 ,0²'⁶]dec-4-yl]propyl}-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2-y[)carbonyl]oxy}- L-prolinamide;

N-{[(1 , 1 -dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-W-{3-hydroxy-1 -[(1 S,2S,6R,8S)-

2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²-6]dec-4-yl]propyl}-4-(1-isoquinolinyloxy)-L- prolinamide;

(3R, 5S)-1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)-5-((1 R, 2S) -1- (ethoxycarbonyI)-2-vinylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- carboxylate;

Intermediates C11-C20; or a salt thereof.

Methods of making the compounds described herein may be useful to provide compounds, or salts thereof, of a Formula provided herein in a higher yield than with methods currently known in the art. Therefore, in a further aspect of the invention, there is provided a method of making a compound, or a salt thereof, having a Formula provided herein according to a method described herein. In a further aspect of the invention, there is provided a method of making a compound, or a salt thereof, which is a member selected from Formulae (I), (II), (III), (Ilia), (1Mb), (IV)₁ (IVb), (IVc), (V), (Vl), (Via), (VIb), (VII), (VIII), (Villa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (IX), (IXa) and (X) according to a method described herein. In a further aspect of the invention, there is provided a method of making a compound, or a salt thereof, according to a member selected from Formulae (Xl), (XIa) and (XIb) according to a method described herein.

With appropriate manipulation and protection of any chemical functionality, synthesis of compounds of Formula (I) is accomplished by methods analogous to those above. In any particular case, particular protecting groups may be required. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3^rd Ed (1999), J Wiley and Sons.

Various of the synthetic procedures described above in general terms (and below in specific terms) may involve heating the reactants. It will be appreciated that heating may be carried out by various conventional methods but also with the use of a microwave reactor.

EXPERIMENTAL

Abbreviations

ACN acetonitrile

BOC t-butoxy carbonyl

CDI N.N'-carbonyldiimidazole

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-benzoquinone

DIEA N,N-di-isopropylethylamine

DIPEA di-isopropylethylamine

DMF Λ/,Λ/-dimethylformamide

EDC Λ/-ethyl-Λ/'-(3-dimethylaminopropyl)carbodiimide h hours

HATU 2-(1 H-7-azabeπzotriazol-1 -yl) — 1 , 1 ,3,3-tetramethyl uranium hexafluorophosphate

HRMS High Resolution Mass Spectroscopy

LDA lithium diisopropylamine

LHMDS lithium hexamethyldisylazide mins minutes

MOM methoxymethyl

PMB p-methoxy benzyl

TBAF tetra-n-butylammonium fluoride

TBDMS t-butyldimethylsilyloxy TBDPS (or TBS) t-butyldiphenylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TMS trimethylsilyl

Intermediate A1

W-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-(1-isoquinolinyloxy)-L- proline

The reaction was operated in two batches: To a solution of Λ/-{[(1 ,1- dimethyIethyI)oxy]carbonyI}-3-methyl-L-valyl-(4R)-4-hydroxy-L-proline¹ (10.5 g, 30.5 mmol) in redistilled DMSO (250 mL) was added potassium t-butoxide (10.3 g). The formed solution was stirred at room temperature for 1 h before addition of 1-chloroisoquinoline (5.0 g, 30.6 mmol). The final solution was left to stir overnight. The two batches were combined and ice water added, then acidified with 1M HCI to pH 4. The mixture was extracted with EtOAc (400 mL x 3). The combined organic phase was washed with water, brine, and dried over MgSO₄.The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with O-50% ethyl acetate in petroleum ether to give the title compound.

MS calcd for (C₂₅H₃₃N₃O₆+ H)⁺: 472. MS found (electrospray): (M+H)⁺ =472 and (2M + Na)⁺

965

¹ WO2006122188A2, WO2005051410A2, WO2003099274A1 Intermediate A2

N-KCycIopentyloxyJcarbonyll-S-methyl-L-valyl-^RJ^-fi-isoquinolinyloxyJ-L-proline

The reaction was operated in two batches: To a solution of Λ/-[(cyclopentyloxy)carbonyl]-3- methyl-L-valyl-(4R)-4-hydroxy-L-proline² (10 g, 28.1 mmol) in redistilled DMSO (250 mL) was added potassium t-butoxide (9.4 g) at O⁰C. The formed solution was stirred at room temperature for 1 h before addition of 1-chloroisoquinoline (5.0 g, 30.6 mmol). The final solution was stirred at room temperature overnight. The two batches were combined and iced water added, then acidified with 1M HCI to pH 4. The mixture was extracted with EtOAc (150 mL x 3). The combined organic phase was washed with water, brine, and dried over MgSO₄.The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-5% methanol in dichloromethane to give the title compound.

MS calcd for (C₂₆H₃₃N₃O₆+ H)*: 484. WIS found (electrospray): (WH-H)⁺ = 484 and (2M + Na)⁺ = 991

²WO2006/020276A2

Intermediate A3-Me

Methyl N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-L-prolinate

To a mixture of methyl Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4f?)-4-hydroxy-L- prolinate (12 g, 32.4 mmol)⁴ in DCWI (200 mL) was added CDI (6.63 g, 40.9 mmol) at room temperature and left to stir for 48 h. 4-Fluoro-2,3-dihydro-1H-isoindole, hydrochloride³ (6.79 g, 39.1 mmol) and triethylamine (4.9 g) were added. The mixture was stirred at room temperature overnight. DCWI (200 mL) was added and the mixture washed with 1 N HCI (200 mL x 4), NaHCO₃ aq (200 mL x 2), brine (300 mL) dried (Na₂SO₄) and concentrated. This was purified by silica gel, eluted with petroleum ether/ethyl acetate 8:1 then 5:1 then 1 :1 to give the title compound.

¹H NWIR (CD₃OD) 57.3 (1 H, m), 7.2-6.9 (2H, m), 5.3 (1 H, m), 4.7 (5H, m), 4.5 (1 H, m), 4.4 (1H, m), 4.1 (1 H, d), 3.8 (1 H, m), 3.7 (3H, s), 2.55 (1H, m), 2.2 (1H, m), 1.6-1.3 (8H, m), 1.0 (9H, s). NH assumed to be exchanged with solvent 3 WO2007/015824A2 4 WO2006/020276A2

Intermediate A3

Λf-[(CycIopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-L-proline

To a mixture of methyl Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3- dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate (Intermediate A3) (15 g, 28.1 mmol) in THF (100 mL) and MeOH (100 mL) was added 2N LiOH (28 mL) at room temperature and the mixture stirred overnight. The mixture was concentrated, water (100 mL) and EtOAc (150 mL) were added to the residue, the water phase was further washed with EtOAc (150 ml), then adjusted to pH 2. DCM (150 mL) was added and the organic layer was separated, dried with Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluted with DCIWMeOH 20:1 to 10:1. Further purification was by preparative HPLC (Gilson GX-281 , Luna column (300 x 50mm), eluting with TFA (0.1%)/MeCN, 0.1% TFA/water 40% to 55% over a 20 min gradient with a flow rate of 80 mL/min). Dried by lyophilation to give the title compound. MS calcd for (C₂₆H₃₄FN₃O₆+ H)⁺: 520. MS found (electrospray): (M+H)⁺ =520 and (2M+Na)⁺ = 1061

Intermediate A4

W-(fert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-L-proline

Intermediate A4 was prepared from commercially available starting materials by the process outlined in the following scheme. K₂CO₃

15min

A4 1,2-bis (bromomethyl)-3-fluorobeπzeπe 2

A solution of 1-fluoro-2, 3-dimethylbenzene (30 g, 0.242 mol) and Bz₂O₂ (3 g, 0.012 mol) in CCI₄ (400 mL) was heated to 60⁰C. NBS (88 g, 0.494 mol) was added portionwise. After the addition, the reaction mixture was heated to 9O⁰C for 16 h and cooled to room temperature, filtered. The filtrate was concentrated and the residue was purified by column chromatography (eluting with petroleum ether) on silica gel to give pale yellow oil (65 g, 95

%).

LC-MS: 282 (M + H)⁺. 2-benzyl-4-fluoroisoindoliπe 3

A solution of 2 (50 g, 0.177 mol) and benzylamine (19 g, 0.178 mol) in CH₃CN (200 mL) was added K₂CO₃ (50 g, 0.362 mol). The reaction mixture was stirred at 10°C for 3 h. Water (150 mL) was added and the solution was extracted with Et₂O (200 mL*2). The combined organic layers was washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =50:1) on silica gel to give the product (10 g, 25 %). LC-MS: 228 (M + H)⁺.

4-fluoroisoindoline hydrochloride 4 To a solution of 3 (56 g, 0.246 mol) in CH₃OH (300 mL) was added concentrated HCI (30 mL, 0.36 mol) and 5% Pd/C (20 g). The reaction mixture was stirred at H₂ atmosphere for 48 h and filtered. The filtrate was concentrated to give the product as a yellow solid (38 g, 89 %). ¹H NMR (300 MHz, D₂O): δ l M-1.22 (m, 1H), 7.00-7.03 (m, 1H), 6.88-6.94 (m, 1H), 4.50- 4.52 (d, 4H). LC-MS: 138 (M + H)⁺.

(2S, 4R)-1-tert-butyl 2-m ethyl 4-(4-fluoroisoindoline-2-carbonyloxy) pyrrolidine-1, 2- dicarboxylate 6

To a solution of 5 (2.0 g, 8.2 mmol) in CH₂CI₂ (20 mL) was added CDI (1.5 g, 9 mmol) and the resulting solution was stirred at RT for 20 h. 4-fluoroisoindoline hydrochloride (4, 2.0 g,

11.5 mmol) and Et₃N (1.5 mL) was added. The reaction mixture was stirred at RT for 24 h.

Water (20 mL) was added and the reaction mixture was extracted with CH₂CI₂ (20 mL*3).

The combined organic layers was washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =3:1) on silica gel to give the product as a white solid (2.0 g, 60 %).

LC-MS: 409 (M + H)⁺.

(3R, 5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate hydrochloride 7

A solution of 6 (22 g, 53.9 mmol) in CH₂CI₂ (20 mL) in 1 N HCI/dioxane was stirred at RT for 2 h and then concentrated under vacuum to give the product 7 as a white solid (18 g, 97 %). ¹H NMR (300 MHz, D₂O): δ 7.44-7.51 (m, 1 H), 7.15-7.28 (m, 2H), 5.60 (s, 1 H), 4.83-4.93 (m, 4H), 3.40 (s, 3H), 3.80-3.93 (m, 3H), 2.86-2.93 (m, 1 H), 2.58-2.68 (m, 1H). LC-MS: 309 (M + H)⁺. (3R,5S)-1 -((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl) -5-

(methoxycarbonyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxvlatβ A4-Me

A solution of Boc-L-tert-leucine 8 (3.54 g, 15.3 mmol, Shanghai HanHong Chemical Co., Ltd., Shanghai, China), EDC (4.31 g, 22.5 mmol) and HOBT (3.44 g, 25.5 mmol) in CH₂CI₂ (100 mL) was stirred at 0°C for 15 minutes. After (3R, 5S)-5-(methoxycarbonyl) pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate hydrochloride 7 (5.17 g, 15.0 mmol) was added, NMM (4.55 g, 45.0 mmol) was added slowly. The resulting solution was stirred at RT for 16 h. Water (50 mL) was added and the reaction mixture was extracted with CH₂CI₂ (50 mL*3). The combined organic layers were washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =2:1) on silica gel to give the desired product Intermediate A4-Me as a white solid (5.15 g, 65 %). LC-MS: 522 (M + H)⁺.

(2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutaπoyl) -4-(4- fluoroisoindoline^-carbonyloxytøyrrolidine^-carboxylic acid A4.

To a solution of Intermediate A4-Me (5.15 g, 9.9 mmol) in THF (50 mL) was added LiOH (1.51 g, 39.6 mmol) and water (10 mL). The reaction mixture was stirred at RT for 2h and then extracted with Et₂O (30 mL*3). The combined organic layers were washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum to give the desired peptide acid product Intermediate A4 as a white solid (4.92 g, 98 %). LC-MS: 508 (Wl + H)⁺.

Intermediate A5

(2S, 4R)-1 -((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl) -4-(4- fluoroisoindoline-2-carbonyloxy) pyrrolidine-2-carboxylic acid

Intermediate A5-Me was prepared from commercially available starting materials by an analogous process to that used to prepare Intermediate A4, coupling pyrrolidine 7 to alternative amino acid 8a as shown below:

(3R, 5S)-1 -((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl) -5- (methoxycarbonyl)pyrrolidiπ-3-yl 4-fluoroisoindoline-2-carboxylate A5-Me

A solution of Boc-L-2-cyclohexylglycine 8a (15 g, 58.3 mmol, Shanghai HanHong Chemical Co., Ltd., Shanghai, China), EDC (15 g, 78.3 mmol) and HOBT (12 g, 88.9 mmol) in CH₂CI₂ (400 mL) was stirred at 0°C for 15 minutes. After 7 (18 g, 52.2 mmol) was added, NIvIM (10 g, 99 mmol) was added slowly. The resulting solution was stirred at RT for 16 h. Water (200 mL) was added and the reaction mixture was extracted with CH₂CI₂ (100 mL*3). The combined organic layer was washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =2:1) on silica gel to give the desired product as a white solid (24.5 g, 86 %). 1H NMR (300 MHz, CDCI₃): δ 7.19 (s, 1H), 6.86-6.99 (m, 2H), 5.34 (s, 1 H), 5.06-5.09 (d, 1 H), 4.54-4.70 (m, 5H), 4.01-4.15 (m, 2H), 3.80-3.84 (m, 1 H), 3.67 (s, 3H), 2.41-2.48 (m, 1 H), 2.09-2.18 (m, 1H), 1.58-1.78 (m, 8H), 0.89-1.35 (m, 12H). LC-MS: 548 (M + H)⁺. (2S, 4R)-1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl) -4-(4- fluoroisoindoline-2-carbonyloxy) pyrrolidine-2-carboxylic acid AS

To a solution of Intermediate A5-Me (7.0 g, 12.8 mmol) in THF (50 mL) was added LiOH (0.6 g, 25.1 mmol) and water (50 mL). The reaction mixture was stirred at RT for 2h and then extracted with Et₂O (20 mL*3). The combined organic layers was washed with saturated NaCI solution, dried over Na₂Sθ₄ and concentrated under vacuum to give the product as a white solid (6.0 g, 88 %). LC-MS: 534 (M + H)⁺. Intermediate A6

(25,4/?)-1-((S)-2-(3-tert-butylureido)-2-cyclohexylacetyl) -4-(4-fluoroisoindoline-2- carbonyloxy)pyrrolidine-2-carboxylic acid

The methyl ester of Intermediate A6 was prepared from Intermediate A5 in a two step procedure via compound 10a as described below. (3R,5S)-5-(methoxycarbonyl)-1 -((S)- 2-amino-2-cyclohexylacetyl)pyrrolidin-3-yl 4- fluoroisoindoline-2-carboxylate 10a

Acetyl chloride (2Og, 0.25mol) was added dropwise to MeOH (300ml) below 10⁰C. The resulting mixture was stirred at rt for 1h. Then Intermediate A5-Me (24.5g, 44mmol) in 400ml of dichloromethane was added. The mixture was stirred at rt for 2 h and then was concentrated under vacuum to give (3R,5S)-5-(methoxycarbonyl)-1-((S)- 2-amino-2- cyclohexylacetyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate 10a as a while solid (21 g, 99%).

LC-MS: 448 (M + H)⁺.

(SR.δSM-KSJ^-IS-tert-butylureidoJ^-cyclohexylacetyO-δ- (methoxycarbonyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxvlate Aβ-Me

10α

A6-Me

1) To a solution of t-butyl amine (73g, 1mol) in dichloromethane (500ml) was added CDI (162g, 1 mol) and the resulting mixture was stirred at rt over night. The solvent was removed under vacuum and the residue was purified on silica gel chromatography with the eluent ethyl acetate/ petroleum ether = 1:3 to afford the intermediate N-tert-butyl-1H-imidazole-1- carboxamide (88g, 50%).

2) (3R,5S)-5-(methoxycarbonyl)-1-((S)- 2-amino-2-cyclohexylacetyl)pyrrolidin-3-yl 4- fluoroisoindoline-2-carboxyIate (7.5g, 15.5mmol) and the above resulting intermediate N-tert- butyl-1H-imidazole-1-carboxamide (5g, 29.5mmol) were dissolved in 200ml of dichloromethane. Then Et₃N (5ml) was added dropwise below 10⁰C and the resulting mixture was stirred at rt over night. The mixture was washed with water, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether/EtOAc = 5:1) on silica gel to give the desired product (Intermediate A6-Me) as a white solid (6.5 g, 76%). LC-MS: 547 (Wl + H)⁺.

(2S,4R)-1-((S)-2-(3-tert-butylureido)-2-cyclohexylacetyl) -4-(4-fluoroisoiπdoline-2- carbonyloxy)pyrrolidine-2-carboxylic acid A6

To a solution of Intermediate A6-Me (6.5 g, 12 mmol) in THF (50 mL) was added LiOH (1.2 g, 50 mmol) and water (50 mL). The reaction mixture was stirred at rt for 2h and then extracted with Et₂O. The aqueous layer was adjusted to pH=5 with cone. HCI followed by extraction with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂Sθ₄ and concentrated under vacuum to give the desired acid product as a white solid (5.4 g, 84 %). LC-MS: 533 (M + H)⁺.

Intermediate A7 (2S,4R)-1 -((S)-2-(cyclopentyloxycarbonylamino)oct-7-enoyl)-4- (4-f luoroisoindoline-2- carbonyloxy)pyrrolidine-2-carboxylic acid

Intermediate A7 was prepared from commercially available starting mateπals by the process outlined in the following scheme

(S)-1-benzylpyrrolidιne-2-carboxylic acid 13

A solution of (S)-prolιne 12 (23 01 g, 0 20 mol) and KOH (3360 g, 0 60 mol) in /-PrOH (150 mL) was stirred at 4O⁰C After the solution became transparent, benzyl chloride (30 24 g, 0 24mol) was added dropwise with stirring at the same temperature for 1h and the stirring was continued for 14 h more The reaction mixture was neutralized with cone HCI until pH 5- 6, then was added to CH₂CI₂ (200 mL) with stirring The mixture was left for 2h at O⁰C, then filtered and the precipitate was washed with CH₂CI₂ The CH₂CI₂ solution was concentrated, and the residue was treated with acetone (150 mL) and the precipitate was dried to give the desired product as a white solid (30 14 g, 73%) ¹H NMR (300 MHz, DMSO-d₆) δ 11 42 (brs, 1 H), 4 18-423 (d, 1 H), 3 92-3 96 (d, 1H), 3 60- 365 (m, 1 H), 3 15-3 22 (m, 1H), 2 76-2 85 (m, 1H), 2 14-226 (m, 1 H), 1 70-1 96 (m, 3H) LC- MS 206 (M + H)*

(S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide IS

To a solution of 13 (20 53 g, 0 10 mol) in CH₂CI₂ (150 mL) was added SOCI₂ (9 0 mL, 0 125 mol) with stirπng at -2O⁰C for 10mm The stirring was continued at -10°C for 30mιn Then 2- amino benzophenone (13 80 g, 007 mol) was added to the reaction mixture at -30⁰C and the stirring was continued at RT for additional 10 h The reaction mixture was neutralized with Na₂CO₃ at 0 C until pH 8-9 The organic layer was separated and the aqueous layer was extracted with CH₂CI₂ (50 mL*2) The combined organic layers were washed with brine, dried and evaporated The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =30 1) on silica gel to give the product as a light yellow solid (17 4 g, 76 % for two steps) ¹H NMR (300 MHz, DMSO-d₆) δ 11 02 (s, 1 H), 825-8 28 (d, 1 H, J= 84 Hz), 745-7 75 (m, 7H), 7 10-7 31 (m, 6H), 3 72-3 76 (d, 1 H, J= 129 Hz), 3 50-3 54 (d, 1 H, J= 12 9 Hz), 3 14-3 18 (m, 1H), 2 94-2 99 (m, 1H), 2 07-2 18 (m, 1H), 2 30-238 (m, 1 H), 1 57- 1 72 (m, 3H) LC-MS 385 (M + H)⁺

16 A solution of KOH (784 g, 1 4 mol) in CH₃OH (300 mL) was poured into a mechanically stirred mixture of 15 (76 8 g, 0 20 mol), nickel nitrate hexahydrate (116 32 g, 040 mol) and glycine (75 g, 1 0 mol) in CH₃OH (700 mL) under inert gas at 45⁰C The resulting mixture was stirred at 55-65⁰C for 1h Then the mixture was neutralized with AcOH (84 g, 1 4mol) and diluted with water to 3L, extracted with CH₂CI₂ (400 mL*3) The combined organic layers were washed with brine, dried and evaporated The residue was purified by column chromatography (eluting with CH₂CI₂ and CH₃OH =30 1) on silica gel to give the desired product as a dark red solid (69 35 g, 70%)

¹H NMR (300 MHz, CDCI₃) δ 8 27-8 30 (d, 1 H, J= 84 Hz), 8 06-8 09 (of, 2H, J= 7 2 Hz), 7 41-752 (m, 5H), 7 19-7 34 (m, 3H), 7 10-7 12 (d, 1 H, J= 6 6 Hz), 6 98-699 (d, 1H, J= 3 6 Hz), 6 79-6 82 (d, 1 H, J= 8 1 Hz), 669-6 73 (t, 1 H, J= 7 2 Hz), 448-4 52 (d, 1 H, J= 12 6 Hz), 3 66-376 (m, 4H), 3 32-3 51 (m, 2H), 2 20-2 60 (m, 2H), 205-2 20 (m, 2H)

LC-MS 498 (M + H)⁺

IZ Compound 16 (43 10 g, 0 087 mol) and NaOH (34 68 g, 0 87 mol) were added to a flask which was purged two times with N₂ Anhydrous DMF (350 mL) was added by syringe and the mixture was allowed to react for 5min at RT before 6-bromohex-1-ene (13 87 g, 0 085 mol) was added in one portion The resulting mixture was stirred at RT for 5mιn Then the mixture was decanted into an aqueous solution (3500 mL) containing AcOH (174 mL) The suspension was filtered and washed with water (300 mL*2). The red solid was purified by column chromatography (eluting with CH₂CI₂ and CH₃OH =50:1) on silica gel to give the desired product as a dark red solid (49.0 g, 99%).

¹H NMR (300 MHz, CDCI₃): 58.11-8.14 (rf, 1 H, J= 8.7 Hz), 8.03-8.05 (d, 2H, J= 7.5 Hz), 7.45-7.49 (/77, 4H), 7.32-7.37 {/77, 2H), 7.11-7.21 (/77, 3H), 6.90-6.93 (of, 1 H, J= 6.9 Hz), 6.61- 6.69 (m, 2H), 5.71-5.80 (m, 1 H), 4.92-5.00 (m, 2H), 4.43-4.47 (d, 1 H, J= 12.6 Hz), 3.92-3.94 (d, 1H, J= 6.0 Hz), 3.44-3.61 (m, 4H), 2.75-2.77 (m, 1H), 2.49-2.56 (/n, 1 H), 1.89-2.16 (m, 5H), 1.63-1.67 (m, 3H), 1.23-1.32 (m, 2H).

LC-MS: 580 (M + H)⁺.

(S)-2-aminooct-7-enoic acid Ig

Compound 17 (54.0 g, 0.093 mol) was dissolved in CH₃OH (500 mL) and heated to 60⁰C. 2N HCI (280 mL, 0.56 mol) was added. After being stirred for 1h, the reaction solution was turned green and cooled to RT and concentrated under vacuum. The residue was added water (150 mL) and extracted with CH₂CI₂ (200 mL*3). The aqueous layer was neutralized to pH 5-6 with ammonia at O⁰C. The resulting precipitate was filtered, washed with ice-water and dried to give the desired product as a white solid (10.28 g, 70%).

¹H NMR (300 MHz, D₂O): 55.70-5.81 (m, 1 H), 4.86-4.97 {m, 2H), 3.80-3.84 (fc 1 H, J= 6.3 Hz), 1.93-1.97 (/77, 2H), 1.75-1.82 {/77, 2H), 1.28-1.38 (/77, 4H). LC-MS: 158 (M + H)⁺.

(S)-2-(cyclopentyloxycarbonylamino)oct-7-enoic acid 19

To a solution of 18 (4.56 g, 0.029 mol) in CH₃CN (150 mL) was added Me₃SiCN (10.62 g, 0.107 mol) and the resulting solution was stirred at RT for 15min and then heated to 75⁰C for 30 min. Cyclopentyl chloroformate (5.40 g, 0.0363 mol) was added dropwise. After the addition, the reaction solution was stirred at 8O⁰C for 12 h and concentrated in vacuum. The residue was adjusted to pH 8.5, extracted with Et₂O (50 mL*3). The aqueous layer was acidified to pH 3 with 2 N HCI and extracted with CH₂CI₂ (80 mL*3). The combined organic layer was washed with brine, dried and evaporated. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =1:1) on silica gel to give the desired product as a light yellow solid (6.61 g, 85 %).

¹H NMR (300 MHz, CDCI₃): 55.71-5.85 (m, 1 H), 4.92-5.10 (m, 4H), 4.35-4.37 (/77, 1H), 2.05- 2.07 (m, 2H), 1.49-1.85 (m, 11H), 1.18-1.25 (m, 4H).

LC-MS: 268 (M - I)⁺. (3fi,5S)-1-((S)-2-(cyclopentyloxycarbonylamino)oct-7-enoyl)-5- (methoxvcarbonvl)pvrrolidiπ-3-vl 4-fluoroisoindoline-2-carboxvlate A7-Me

A solution of 19 (7.42 g, 24.0 mmol), EDC (6.89 g, 36.0 mmol) and HOBT (5.51 g, 40.8 mmol) in CH₂CI₂ (150 mL) was cooled to 0⁰C and stirred for 15 min. Compound 7 (6.61 g, 24.5 mmol) and NMM (4.86 g, 48.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL), extracted with CH₂CI₂ (100 mL*3). The combined organic layer was washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =5: 1 to 1 : 1 ) on silica gel to give a white solid (10.O g, 73 %).

LC-MS: 560 (M + H)⁺.

(2S,4R)-1-((S)-2-(cyclopentyloxycarbonylamino)oct-7-enoyl)-4- (4-fluoroisoindoline-2- carboπyloxy)pyrrolidine-2-carboxylic acid A7 To a solution of Intermediate A7-Me (9.8 g, 17.5 mmol) in THF (200 mL) was added a solution of LiOH (1.68 g, 70.0 mmol) in water (50 mL). The mixture was stirred at room temperature for 4 h and diluted with water (200 mL). The solution was adjusted to pH 2 with 1 N HCI, extracted with EtOAc (80 mL*3). The combined organic layer was washed with brine (100 mL), dried and concentrated under vacuum to give the product as a white solid (7.0 g, 73%).

¹H NMR (300 MHz, CDCI₃): δ 12.55 (s, 1 H), 7.25-7.36 (m, 2H), 7.06-7.18 (m, 2H), 5.70-5.82 (m, 1 H), 5.22 (s, 1H), 4.88-4.99 (m, 2H), 4.32-4.64 (m, 6H), 4.05-4.16 (m, 2H), 3.65-3.68 (c/, 1 H), 2.35-2.42 (m, 1H), 1.95-2.13 (m, 3H), 1.29-1.47 (m, 14H). LC-MS: 546 (M + H)⁺. Purity on HPLC: 97.5% (214 nm), 97.7% (254 nm).

Intermediate A14

(2S,4/?)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4 -(4-fluoroisoindoline-2- carbonyloxy)pyrrolidin

Intermediate A14 was prepared from Compound 16 as shown in the scheme below

20

Compound 16 (28.65 g, 0.0577 mol) and NaOH (23.08 g, 0.577 mol) were added to a flask which was purged two times with N₂. Anhydrous DMF (150 mL) was added by syringe and the mixture was allowed to react for 5 mm at RT before 7-bromohept-1-ene (10.0 g, 0.0565 mol) was added in one portion. The resulting mixture was stirred at RT for 5min. Then the mixture was decanted into an aqueous solution (1000 mL) containing AcOH (116 mL). The suspension was filtered and washed with water (100 mL*2). The red solid was purified by column chromatography (eluting with CH₂CIz and CH₃OH =50:1) on silica gel to give the product 20 as a dark red solid (32 2 g, 94%). LC-WIS: 594 (M + H)*.

(S)-2-aminonon-8-enoic acid 2J.

Compound 20 (32.2 g, 0.0543 mol) was dissolved in CH₃OH (200 mL) and heated to 60°C.

2N HCI (163 mL, 0.326 mol) was added. After stirring for 1h, the reaction solution was turned green and cooled to RT and concentrated under vacuum. The residue was added water (150 mL), extracted with CH₂CI₂ (100 mL*3) The aqueous layer was neutralized to pH 5-6 with ammonia. The resulting precipitate was filtered, washed with ice-water and dried to give the product 21 as a white solid 5.76 g, 62%).

¹H NMR (300 MHz, D₂O)- 55 94-5.96 (m, 1 H), 5.00-5.13 (m, 2H), 3.84 {brs, 1H), 2.09-2.12 (m, 2H), 1.88-1.91 (m, 2H)₁ 1.42-1.43 (m, 6H).

LC-MS: 172 (M + H)⁺.

(S)-2-(tert-butoxycarbonylamino)non-8-enoic acid 22

To a solution of 21 (5.42 g, 0.0317 mol) in i-PrOH (50 mL) was added NaOH solution (1.27 g in 3 mL water, 0.0317 mol). The resulting solution was stirred at RT for 10 min. Di-tert-butyl dicarbonate (6.91 g, 0.0317 mol) was added dropwise. The reaction solution was stirred at RT for overnight. Water (200 mL) was added, extracted with EtOAc (100 mL*3). The organic layer was washed with brine, dried and evaporated The residue was purified by column chromatography (eluting with petroleum ether and EtOAc = 5 1) on silica gel to give the product 22 as a light yellow oil (6 2 g, 72 %)

¹H NMR (300 MHz, CDCI₃) 55 85-5 95 (m, 1H), 4 97-5 02 (m, 2H), 4 16-4 18 (m, 1 H), 2 00- 2 05 (m, 2H), 1 95 (brs, 1H), 1 65-1 68 (m, 1H), 1 46 (s, 9H), 1 35-1 42 (m, 6H) LC-MS 294 (M + Na)⁺

(3R,5S)-1 -((S)-2-(tert-butoxycarbonylamino)non-8-enoyl) -5- (methoxvcarboπvl)pvrrolidin-3-yl 4-fluoroisoindoline-2-carboxvlate A14-Me A solution of Intermediate 13 (5 15 g, 19 0 mmol), EDC (5 34 g, 27 9 mmol) and HOBT (427 g, 31 6 mmol) in CH₂CI₂ (100 mL) was cooled to O⁰C and stirred for 15 mm Intermediate 7 (642 g, 18 6 mmol) and NMM (563 g, 55 8 mmol) was added The mixture was stirred at room temperature overnight The reaction mixture was diluted with water (100 mL), extracted with CH₂CI₂ (50*3 mL) The combined organic layers were washed with saturated NaCI solution, dried over Na₂Sd and concentrated under vacuum The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =1 1) on silica gel to give the product A14-Me as a white solid (8 24 g, 79 %) LC-MS 562 (M + H)⁺ (2S,4R)-1-((S)-2-(tert-butoxycarboπylamiπo)noπ-8-enoyl)-4 -(4-fluoroisoindoline-2- carbonyloxy)pyrrolidine-2-carboxylic acid A14

To a solution of Intermediate A14-Me (2 3 g, 4 0 mmol) in THF (30 mL) was added a solution of LiOH (394 mg, 164 mmol) in water (10 mL) The mixture was stirred at room temperature for 4 h and diluted with water (50 mL) The solution was adjusted to pH 2 with 1 N HCI, extracted with ethyl acetate (20 mL*3) The combined organic layer was washed with brine (30 mL), dried and concentrated under vacuum to give the product Intermediate A14 as a white solid (2 1 g, 94%)

¹H NMR (300 MHz, CDCI₃) δ 7 21 (m, 1H), 6 97-7 02 (m, 2H), 5 67-5 80 (m, 1H), 5 37 (s, 1 H), 5 17-520 (m, 1 H), 4 87-497 (m, 2H), 4 58-472 (m, 5H), 430-437 (m, 1 H), 4 06-4 15 (m, 1H), 3 75-3 80 {m, 1H), 2 37-2 52 (m, 2H), 1 95-2 05 (m, 3H), 1 50-1 71 (m, 2H), 1 19- 1 37 (m, 14H)

LC-MS 548 (M + H)⁺

Intermediate B1

2-(2-Propen-1 -y loxy)-1 ,2-oxaborolane

To a mixture of sodium borohydride (20 g, 0.529 mol) and allylic alcohol (58 g, 1.0 mol) in a 1-L round bottom flask at O⁰C in an ice bath under N₂ was added acetic acid (28.6 mL) dropwise over 2 h. The ice bath was removed. The reaction mixture was heated to 130 ⁰C for 2 h. The reaction mixture was cooled down, and distilled under vacuum to give a crude product (45-70 °C/15 mmHg). Re-distillation gave the title compound_(48 ⁰C to 58 °C/15 mmHg).

Intermediate B2 2-Butyloxy-1 ,2-oxaborolane

To Intermediate B1 (4.8 g, 38 mmol) was added n-butyl alcohol (4.6 mL, 50 mmol) under nitrogen. The reaction mixture was distilled carefully at 98-102 ⁰C (oil bath 130⁰C to 140 ⁰C) to remove allylic alcohol. Then vacuum distillation gave the title compound (70-80 ⁰C/ 15 mmHg).

Intermediate B3 2-Butyloxy-3-chloro-1,2-oxaborinane

To a solution of dichloromethane (4.06 mL, 63.4 mmol) in THF (72 mL) was added n- butyllithium (2.5 M in hexane, 11 mL, 27.4 mmol) at -85⁰C. The n-butyllithium solution was allowed to run down the cold wall of the flask to be chilled before contacting the dichloromethane solution. After 10 minutes, a solution of Intermediate 2 (3 g, 21.1 mmol) in THF (36 mL) was added to the solution. The solution was allowed to warm up to room temperature and stirred overnight. The mixture was concentrated and vacuum distilled affording the title compound (100-110 °C/10 mmHg).

Intermediate B4 [2-(Butyloxy)-1,2-oxaborinan-3-yl]bis(trimethylsilyl)amine

To a solution of Intermediate B3 (0.5 g, 2.62 mmol) in THF (8 mL) was added lithium bis(trimethylsilyl) amide (1M in THF, 3.15 mL, 3.15 mmol) at -78 ⁰C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and dissolved in hexanes (75 mL). The remaining solid was removed by filtration through a Celite cartridge. The filtrate was concentrated to afford the title compound.

¹H NMR (300 MHz, CDCI₃) 54.08 (1 H, dd), 3.92-3.73 (3H, m), 2.39 (1 H, dd), 1.85 (1 H, t), 1.68-1.38 (7H, m), 0.93 (3H, t), 0.08 (18H, s).

Intermediate B5 3-Amino-1,2-oxaborinan-2-ol hydrochloride

OH

XJ .HC,

To a solution of Intermediate B4 (0.12 g, 0.38 mmol) in hexanes (3 mL) was added HCI (4M in dioxane, 0.4 mL, 1.6 mmol) at -78 ⁰C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The resulting mixture was filtrated and washed with hexanes. The solid was collected and dry to afford the title compound.

MS calcd for (C₁₄H₁₀BNO₂+ H)⁺ : 116. MS found (ESI positive): (M+H)⁺ = 116. ¹H NMR (300 MHz, DMSO-c/6) δ 8.61 (1 H, bs), 7.64 (3H, bs), 3.87 (2H, m), 2.58 (1 H, m), 1.98 (1 H, m), 1.76-1.48 (3H₁ m).

Intermediate Bβ

(1,1 -Dimethylethyl)(dimethyi){[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)butyl]oxy}silane

To a solution of trans-4-(tert-butyldimethylsiloxy)-1-buten-1-ylboronic acid pinacol ester (Tetrahedron Letters, 2005, 46, 8777-8780) (10.0 g, 32.0 mmol, 1.00 eq) in methanol (60 ml) under a nitrogen atmosphere was added 5% palladium on carbon (1.4 g, 0.64 mmol, 0.02 eq). The reaction flask was evacuated and then charged with a balloon of hydrogen. The reaction mixture was stirred at room temperature for 2 h before being filtered through celite. The filtrate was then concentrated under reduced pressure to give the title compound. ¹H NMR (500MHz, CDCI₃) δ 3.59 (2H, t, J = 6.3 Hz), 1.58-1.48 (2H, m), 1.48-1.38 (2H, m), 1.24 (12H, s), 0.89 (9H, s), 0.78 (2H, t, J = 7.4 Hz), 0.04 (6H, s).

Intermediate B7

{[5-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl]oxy}(1,1- dimethylethyl)dimethylsilaπe

To a solution of DCM (4.0 mL, 61.7 mmol, 2.0 eq) in THF (62 mL) at -100°C was added n- butyl lithium (21.2 mL, 1.6 Wl in hexane, 33.9 mmol, 1.1 eq) slowly under nitrogen and down the inside wall of the flask whilst maintaining the temperature below -90°C. The resulting white precipitate was stirred for 15 minutes before the addition of Intermediate B6 (9.7 g, 30.9 mmol, 1.0 eq) in THF (62 mL) at -90°C. Zinc chloride (30.9 mL, 1.0 M in diethyl ether, 30.9 mmol, 1.0 eq) was then added to the reaction mixture at -90°C and then the reaction was allowed to warm to room temperature where it was stirred for 3 h. The reaction was quenched with a saturated solution of ammonium chloride and the phases were separated. The aqueous phase was then extracted with diethyl ether three times and the combined organic extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. The concentrated material was then diluted in diethyl ether and washed twice with saturated solution of ammonium chloride. The organic layer was then dried over MgSO₄, filtered and concentrated under reduced pressure to give the title compound.

¹H NMR (500MHz, CDCI₃) δ 3.61 (2H, t, J = 5.8 Hz), 3.41 (1 H, t, J = 7.7 Hz), 1.90-1.78 (2H, m), 1.58-1.49 (4H, m), 1.28 (12H, s), 0.89 (9H, s), 0.04 (6H, s). Intermediate B8

[5-{[(1 ,1 -dimethylethyl)(dimethyl)silyl]oxy}-1 -(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pentyl]bis(trimethylsilyl)amine

lntermediate B7 (6.0 g, 16.5 mmol, 1.0 eq) in THF (40 mL) was cooled to -78°C under nitrogen. A solution of LHMDS (16.5 mL, 1.0 M in THF, 16.5 mmol, 1.0 eq) was added slowly and the reaction flask was then allowed to warm to room temperature where it was stirred for 2 h. The yellow solution was concentrated under reduced pressure to give an oil. After hexane was added to the oil, a precipitate formed. This was then filtered through Celite and the filtrate concentrated under reduced pressure to give the title compound. 1H NMR (500MHz, CDCI₃) δ 3.60 (2H, t, J = 6.2 Hz), 2.49 (1 H, t, J = 7.4 Hz), 1.72-1.58 (2H, m), 1.56-1.34 (4H, m), 1.23 (6H, s), 1.22 (6H, s), 0.89 (9H, s), 0.10 (12H, s), 0.05 (6H, s). Intermediate B9

3-Amiπo-1 ,2-oxaborepan-2-ol hydrochloride

OH

O ^HCI

To a solution of Intermediate B8 (3.0 g, 6.15 mmol, 1.0 eq) in hexane (100 mL) was added a solution of HCI (7.7 mL, 4.0 M in dioxane, 37.8 mmol, 5.0 eq). A white precipitate formed instantly and the reaction mixture was stirred for a future 15 minutes before being concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile (120 mL) and HCI (12.0 mL, 1.0 Wl in H₂O) followed by the addition of polymer supported benzene boronic acid (11.8 g, 2.6 mmol/g, 30.8 mmol, 5.0 eq). The reaction mixture was stirred for 1 h before being filtered. The filtrate was concentrated under reduced pressure to give a sticky solid. The sticky solid had acetonitrile added and was again concentrated under reduced pressure to give a solid. Diethyl ether (15 mL) was added to the beige solid under nitrogen and then decanted off. This process was repeated twice more before removing the last traces of diethyl ether under reduced pressure to give the title compound. 1H NMR (after 24 hours) (500MHz, CD₃OD) δ 3.58 (2H, t), 2.93 (1H, q), 1.72-1.65 (2H, m), 1.62-1.54 (2H, m), 1.51-1.42 (2H, m); ¹³C NMR (after 24 hours) (500MHz, CD₃OD) δ 62.46, 40.50 (t), 32.92, 28.30, 23.87. HRMS (ESI): calcd. for C₅H₁₃BNO₂ [M]⁺ 130.1039, found 130.1036.

Intermediate B10 (1S,2S,6R,8S)-2,9,9-Trimethyl-4-[2-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-3,5-dioxa- 4-boratricyclo[6.1.1.0^z'⁶]decane

To a solution of Intermediate B16 (3.80 g, 11.5 mmol) and CH₂ICI (1.00 mL, 13.8 mmol) in anhydrous THF (40 mL) under N₂ at -78 °C was added n-butyllithium (2.5M in THF, 5.06 mL, 12.7 mmol) slowly along the side of the flask resulting in a light solution. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature and heated at 28 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 6:1) to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, 2H), 6.86 (d, 2H), 4.44 (s, 2H), 4.27^1.23 (m, 1 H), 3.80 (s, 3H), 3.61 (t, 2H), 2.36-2.27 (m, 1 H), 2.23-2.14 (m, 1 H), 2.03 (t, 1H), 1.92-1.80 (m, 2H), 1.38 (s, 3H), 1.28 (s, 3H), 1.25 (t, 2H), 1.12 (d, 1H), 0.83 (s, 3H). Intermediate B11

(¹I S,2S,6R,8S)-4-[(1 S)-1 -bromo-3-({[4-(rnethyloxy)phenyl]methyl}oxy)propyl]-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2|6]decane

To a solution of Intermediate B10 (3.0 g, 8.71 mmol) and CH₂Br₂ (2.46 mL, 34.9 mmol) in anhydrous THF (20 mL) under N₂ at -50 ⁰C was added freshly prepared LDA (10.4 mmol in 12 mL THF) slowly along the side of the flask resulting a light yellow solution. After 15 min, ZnCI₂ (3.56 g, 26.1 mmol) in THF (25 mL) was added and the cooling bath was removed. The reaction mixture was allowed to warm up to room temperature and stirred overnight.

The reaction mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 6:1) to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, 2H), 6.88 (d, 2H), 4.45 (s, 2H), 4.33-4.31 (m, 1H), 3.80 (s, 3H), 3.61-3.55 (t, 3H), 2.36-2.27 (m, 1 H), 2.25-2.14 (m, 1H), 2.06 (t, 1H), 1.89-1.84 (m, 2H), 1.34 (s, 3H), 1.28 (s, 3H), 1.25 (t, 2H), 1.12 (d, 1H), 0.83 (s, 3H).

Intermediate B12

{{1R)-3-({[4-(Methyloxy)phenyl]methyl}oxy)-1-[(1S,2S,6/^:?,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0^2|6]dec-4-yl]propyl}bis(trimethylsilyl)amine

A solution of Intermediate B37 (663 mg, 1.52 mmol) in THF (5 mL) was treated with LHMDS

(1.82 mL, 1.0M in THF, 1.82 mmol) under N₂ at -78 °C over 15 min. The reaction was warmed to room temperature overnight. The mixture was diluted with hexanes (-100 mL) and the precipitate was formed. The mixture was filtered, and the filtrate was concentrated to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, 2H), 6.88 (d, 2H), 4.43 (s, 2H), 4.25-4.21 (m, 1 H), 3.80

(s, 3H), 3.53 (t, 2H), 2.83 (t, 1 H), 2.36-2.16 (m, 2H), 2.02 (t, 1 H), 1.89-1.84 (m, 2H), 1.37 (s,

3H), 1.27-1.23 (m, 5H), 1.21 (d, 1H), 0.82 (s, 3H), 0.16 (s, 18 H).

Intermediate B13

(3R)-3-Amino-3-[{1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]dec-4- yl]-1-propanol hydrochloride

.HCI

A solution of Intermediate B12 (483 mg, 0.934 mmol) in hexanes (7 mL) was treated with HCI/dioxane (0.9 mL, 4.0 M) under N₂ at -78 °C. After 16 h, the reaction was concentrated to dryness. The residue was triturated with hexanes and CH₂Cb and dried to afford the title compound.

¹H NMR (300 MHz, DMSO-Cf₆) δ 7.81-7.72 (br, 3H), 4.36 (m, 1 H), 3.52 (t, 2H), 2.84-2.81 (m, 1 H), 2.36-2.27 (m, 1H), 2.25-2.14 (m, 1H),1.96 (t, 1H), 1.89-1.76 (m, 2H), 1.36 (s, 3H), 1.26-1.21 (m, 5H), 1.18 (d, 1H), 0.80 (s, 3H). Intermediate B14

Diisopropyl chloromethyl borate

,-B(OiPR)₂ Cl

To a solution of tri-isopropyl borate (112.5g, 0.6mol) in anhydrous THF (400ml) under nitrogen at -78°C with an acetone/dry ice bath was added iodochloromethane (100g, 0.57mol) slowly followed by n-BuLi (1.6M in hexanes, 0.57mol). The reaction allowed to reach room temperature slowly and stirred overnight. To the reaction mixture was added HCI in diethyl ether (2Wl, 200ml). The precipitate was filtered and the solution was distilled under reduced pressure. The title compound was collected at 45-55⁰C/ 20 mmHg. Intermediate B15

(1S,2S,6R,8S)-4-(Chlorornethyl)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6,1.1.0^{2 G}]decane

(1S,2S,3R,5S)-Pinanediol chloromethyl borate)

To a solution of Intermediate B14 (3Og, 168mmol) in anhydrous diethyl ether (250ml) was added (1S,2S,3R,5S)-pinanediol (25g, 147mmol). The reaction was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The residue oil was purified by flash chromatography on silica gel (2% ethyl acetate in hexane) to give the title compound. 1H NMR (300 MHz, CDCI₃) δ 4.19 (1H, dd), 3.05 (2H, s), 2.38 (1H, m), 2.25 (1H, m), 2.08 (1 H, t), 1.96 (2H, m), 1.42 (3H, s), 1.30 (3H, s), 1.18 (1 H, d), 0.82 (3H, s).

Intermediate B16

(1S,2S,6R,8S)-2,9,9-Trimethyl-4-[({[4-(methyloxy)pheny[]methyl}oxy)methyl]-3,5-dioxa- 4-boratricyclo[6.1.1.0²⁶]decane

To a solution of 4-methoxyl benzyl alcohol (8.32 mL, 66.7 mmol) in anhydrous THF (90 mL) at -78⁰C with an acetone/dry ice bath was added n-BuLi (2.5 M in hexanes, 27.67 mL, 66.7 mmol) slowly. The mixture was stirred at -78⁰C for 15 min. DWISO (4.7 mL) was added dropwise followed by Intermediate B15 (12.3 g, 53.8 mmol). The reaction was allowed to reach room temperature slowly and then was heated at 5O⁰C overnight. The reaction mixture was diluted with diethyl ether (200 mL) and washed with aqueous HCI (0.6 N, 200 mL). The aqueous layer was re-extracted with diethyl ether (2 x 100 mL). The organic layers were combined and concentrated in vacuo. Purification of the crude oil by flash chromatography (5% to 10% ethyl acetate in hexane) gave the title compound.

¹H NMR (300, MHz, CDCI₃) δ 7.28 (2H, d), 6.84 (2H, d), 4.42 (2H, dd), 4.36 (1 H, dd), 3.80 (3H, s), 3.28 (2H, s), 2.36 (1H, m), 2.20 (1H, m), 2.05 (1H, m), 1.90 (2H, m), 1.42 (3H, s), 1.28 (3H, s), 1:18 (1 H, d), 0.82 (3H, s). Intermediate B17

(1S,2S,6R,8S)-4-[(1S)-1-Bromo-2-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^{2 G}]decane

Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 17.7 mL, 44.1 mmol) to a solution of di-isopropylamine (6.19 mL, 44.1 mmol) in anhydrous THF (48 mL) under nitrogen at -78⁰C. The mixture was stirred at -78⁰C for 30 min. In a separate flask Intermediate B16 (12.16 g, 36.8 mmol) was mixed with dibromomethane (10.26 mL, 147.2 mmol) in anhydrous THF (58 mL) at -78⁰C. To the borate solution was added the freshly prepared LDA solution through a syringe. The mixture was stirred at -78°C for 1.5 h. To the reaction mixture was added a solution of zinc chloride (15.05 g, 110.4 mmol) in anhydrous THF (77 mL). The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was diluted with diethyl ether (300 mL) and extracted with sulfuric acid (0.5N, 300 mL), saturated sodium bicarbonate (300 mL) and brine (300 mL). The aqueous layers were re-extracted with diethyl ether (2 x 300 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (5% to 10% ethyl acetate in hexane) to give the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (2H, d), 6.85 (2H, d), 4.52 (2H, s), 4.39 (1H, d), 3.81 (2H, m), 3.80 (3H, s), 3.54 (1H, t), 2.38 (1 H, m), 2.24 (1H, m), 2.08 (1H, m), 1.90 (2H, m), 1.41 (3H, s), 1.30 (3H, s), 1.24 (1H, d), 0.82 (3H, s). Intermediate B18

(1 S,2S,6R,8S)-2,9,9-trimethyl-4-{(1 S)-1 -[({[4-(methyloxy)phenyl]methyl}oxy) methyl]propyl}-3,5-dioxa-4-boratricyclo[6.1.1.0^2rG]decane

To a solution of Intermediate B11 (9.4 g, 22.2 mmol) in anhydrous THF (100 mL) under nitrogen at -78⁰C was added ethyl magnesium bromide (1 M in THF, 22.2 mL, 22.2 mmol) dropwise. The reaction mixture was allowed to reach room temperature and was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (300 mL) and extracted with aqueous HCI (0.6 N, 300 mL), saturated sodium bicarbonate (300 mL) and brine (300 mL). The aqueous phases were re-extracted with diethyl ether (2 x 200 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (5% ethyl acetate in hexane) to give the title compound. 1H NMR (300 MHz, CDCI₃) δ 7.24 (2H, d), 6.82 (2H, d), 4.41 (2H, s), 4.24 (1H, d), 3.79 (3H, s), 3.58 (2H, dd), 2.38 (1H, m), 2.18 (1 H, m), 2.05 (1H, t), 1.85 (2H, m), 1.50 (2H, m), 1.39 (3H, s), 1.28 (3H, s), 1.20 (1 H, d), 0.92 (3H, t), 0.82 (3H, s).

Intermediate B19 Isomer 1 of (1 S,2S,6R,SS)-4-{1 -bromo-2-[({[4-(methyloxy)phenyl]methyl}oxy) methyllbutyl^_jθ.θ-trimethyl-S_jS-dioxa^-boratricyclote.i.i.O^ldecane

Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 1.29 mL, 3.23 mmol) to a solution of di-isopropylamine (0.45 mL, 3.23 mmol) in anhydrous THF (1.8 mL) at -78°C and was stirred at -78⁰C under nitrogen for 30 min. To a solution of Intermediate B18 (1 g, 2.69 mmol) and dibromomethane (0.75 mL, 10.75 mmol) in anhydrous THF (7 mL) at -78⁰C was added the freshly prepared LDA solution through a syringe. The mixture was stirred at - 78⁰C for 1 h. Zinc chloride (1.1 g, 8.07 mmol) in anhydrous THF (6.3 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (100 mL) and extracted with saturated ammonium chloride (100 mL). The aqueous layer was re-extracted with diethyl ether (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by fresh chromatography on silica gel (5% ethyl acetate in hexane) to give the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.24 (2H, d), 6.82 (2H, d), 4.42 (2H, dd), 4.31 (1 H, d), 3.80 (3H, s), 3.59 (1H, d), 3.54 (1H, m), 3.38 (1 H, t), 2.38 (1H, m), 2.20 (1 H, m), 2.05 (1H, m), 1.90 (2H, m), 1.65 (1H, m), 1.40 (1H, m), 1.36 (3H, s), 1.28 (3H, s), 1.25 (1 H, d), 0.90 (3H, t), 0.82 (3H, s).

Intermediate B20

Isomer 1 of {2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²'⁶]dec-4-yl]butyl}bis(trimethylsilyl)amine

To a solution of Intermediate B19 (0.6 g, 1.29 mmol) in anhydrous THF (2.5 mL) under nitrogen at -78⁰C was added LHMDS (1 M in THF, 1.5 mL, 1.5 mmol). The reaction mixture was allowed to reach room temperature and stirred at room temperature overnight. The solvent was removed in vacuo to give the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.20 (2H, d), 6.82 (2H, d), 4.38 (2H, dd), 4.20 (1H, d), 3.78 (3H, s), 3.56 (1 H, dd), 3.36 (1 H, t), 2.58 (1 H, d), 2.25 (1 H, m), 2.16 (1 H, m), 1.98 - 1.60 (4H, m), 1.42 (1H, m), 1.32 (3H, s), 1.24 (3H, s), 1.16 (1 H, d), 0.85 (3H, t), 0.80 (3H, s), 0.08 (18H, s).

Intermediate B21

(1 S,2S,6R,8S)-2,9,9-Trimethyl-4-{(1 S)-1 -[{{[4-(methyloxy)phenyl]methyl}oxy) methyl]-2- propen-1 -yl}-3,5-dioxa-4-boratricyclo[6.1.1.0^2>6]decane

To a solution of Intermediate B11 (2.82 g, 6.68 mmol) in anhydrous THF (30 mL) under N₂ at -78 ⁰C was added vinylmagnesium bromide (6.68 mL, 1.0M in THF) slowly. After 2 h, the reaction mixture was washed with ammonium chloride and diluted with ethyl acetate. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 5:1) to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.25 (d, 2H), 6.84 (d, 2H), 5.90-5.78 (m, 1H), 5.12-5.02 (m, 2H), 4.43 (s, 2H), 4.25^.21 (m, 1 H), 3.80 (s, 3H), 3.62 (d, 2H), 2.38-2.26 (m, 2H), 2.20-2.14 (m, 1H), 2.06 (t, 1 H), 1.89-1.78 (m, 2H), 1.38 (s, 3H), 1.26 (s, 3H), 1.18 (d, 1 H), 0.82 (s, 3H).

Intermediate B22 (1 S,2S,6R,8S)-4-{1 -Bromo-2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-3-buten-1 -yl}- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2|6]decane

To a solution Intermediate B21 (555 mg, 1.50 mmol) and CH₂Br₂ (0.282 mL, 6.00 mmol) in anhydrous THF (4 mL) under N₂ at -50 °C was added a freshly prepared LDA (1.80 mmol in 1 mL THF) slowly along the side of the flask resulting in a solution. After 15 min, ZnCI₂ (613 mg, 4.5 mmol) in THF (4 mL) was added and the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 6:1) to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, 2H), 6.88 (d, 2H), 5.77-5.65 (m, 1H), 5.19-5.12 (m, 2H), 4.46 (dd, 2H), 4.33^1.29 (m, 1 H), 3.80 (s, 3H), 3.56-3.48 (m, 2H), 3.41 (t, 1 H), 2.91- 2.84 (m, 1H), 2.36-2.28 (m, 1H), 2.20-2.14 (m, 1H), 2.06 (t, 1H), 1.92-1.84 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 1.18 (d, 1H), 0.82 (s, 3H).

Intermediate B23

{2-[({[4-(Methyloxy)pheπyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-boratricyclo[6.1.1.0²'⁶]dec-4-yl]-3-buten-1-yI}bis(trimethylsilyl)amine

A solution of Intermediate B22 (230 mg, 0.500 mmol) in THF (3 ml_) was treated with LHMDS (0.5 mL, 0.5 mmoi, 1.0 M in THF) under N₂ at -78 ⁰C over 15 min. The reaction was warmed to room temperature and stirred overnight. The mixture was diluted with hexanes (-70 mL). The mixture was filtered and the filtrate was concentrated to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (d, 2H), 6.88 (d, 2H), 5.77-5.65 (m, 1H), 5.19-5.12 (m, 2H), 4.46 (dd, 2H), 4.33-4.29 (m, 1 H), 3.80 (s, 3H), 3.56-3.48 (m, 2H), 3.01-2.94 (m, 1H), 2.91-2.84 (m, 1 H), 2.36-2.28 (m, 1H), 2.20-2.14 (m, 1 H), 2.06 (t, 1 H), 1.92-1.84 (m, 2H), 1.32 (s, 3H), 1.18 (d, 1 H), 1.26 (s, 3H), 0.82 (s, 3H), 0.18 (s, 18H).

Intermediate B24 4,4,5,5-Tetramethyl-2-(2-{[(methyloxy)methyl]oxy}phenyl)-1,3,2-dioxaborolane

To a mixture of 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (10 g, 45.4 mmol, Aldrich) in 50 mL of DMF at 0⁰C was added sodium hydride (2.18 g, 60% in mineral oil, 54.5 mmol) in portion. Subsequently, MOM-CI (4.14 mL, 54.5 mmol) was added dropwise. The reaction mixture was warmed up to room temperature, and stirred for 2 hours. After 50 mL of water was added, the mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by ISCO CombiFlash Rf silica chromatography eluted with 0-10% ethyl acetate in hexane to give the title compound.

¹H NMR (300 MHz, CDCI₃) S 7.70 (1H, d), 7.37 (1H, t), 6.98-7.04 (2H, m), 5.21 (2H, s), 3.60 (3H₁ S), 1.35 (12H, s) Intermediate B25

2-[ChIoro(2-{[(methyloxy)methyl]oxy}phenyl)methyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolaπe

To a solution of dichloromethane (1.1 mL, 17.3 mmol) in 15 mL of anhydrous THF at -100°C under nitrogen was added π-butyl lithium (4.8 mL, 2.5 M in hexane, 11.9 mmol) dropwise and down the inside wall of the flask. The white precipitate was formed toward the end of BuLi addition. After the addition was completed, Intermediate B24 (2.85 g, 10.8 mmol) in 5 mL of THF was added to the reaction mixture. The reaction was allowed to warm to room temperature and stirred for 12 h. The resulting mixture was concentrated in vacuo to give a yellow residue. Subsequently, hexane was added to the yellow residue and a precipitate formed. After this precipitate was filtered through a glass filter funnel, the filtrate was concentrated under reduced pressure to give the title compound. 1H NMR (300 MHz, CDCI₃) δ 7.44 (1 H, d), 7.22 (1H, t), 7.10 (1H, d), 7.01 (1 H, t), 5.22 (2H, d), 4.76 (1 H, s), 3.52 (3H, s), 1.30 (12H, s)

Intermediate B26

[(2-{[(Methyloxy)methyl]oxy}phenyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl]bis(trimethylsilyl)amine

To a solution of Intermediate B25 (0.68 g, 2.18 mmol) in 15 mL of anhydrous THF at -78°C under nitrogen was added a solution of LHMDS (2.18 mL, 1.0 M solution in THF, 2.18 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting yellow solution was concentrated under reduced pressure to give a yellow oil. Subsequently, hexane was added to the yellow residue and a precipitate formed. After this precipitate was filtered through a glass filter funnel, the filtrate was concentrated under reduced pressure to give the title compound.

¹H NMR (300 MHz, CDCI₃) 57.36 (1 H, d), 7.00-7.10 (2H, m), 6.98 (1 H, t), 5.15 (2H, dd), 4.24 (1H, s), 3.50 (3H, s), 1.28 (12H, s), 0.10 (18H, s) Intermediate B27

3-Aminobenzo[d][1 ,2]oxaborol-2(3H) hydrochloride

To a solution of Intermediate B26 (1.93 g, 4.42 mmol) in hexaπe at -78 ⁰C was added HCI in dioxane (6.6 mL, 4M in dioxane, 26.5 mmol) dropwise. A white precipitate formed instantly. The reaction mixture was warmed up to room temperature, and stirred for overnight. Ater the solvent was decanted, the remaining gummy material was dried in vacuo to give a yellow residue. The residue was triturated with diethyl ether and hexane to give the title compound.

MS calcd for (C₇H₈BNO₂ - H)^" : 148.1. MS found (ESI negative): (M-H)^" = 148.1. Intermediate B28

{2-Cyclopropyl-3-({[4-(methyloxy)phenyl]methyl}oxy)-1-[(1S,2S,6R,8S)-2,9,9-trimethyl- 3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]dec-4-yl]propyl}bis(trimethylsilyl)amine

Similarly prepared according to the procedures of Intermediates B21-B23, replacing vinyl magnesium bromide by cyclopropyl magnesium bromide in Intermediate B21.

Intermediate B29

(1S,2S,6R,8S)-2,9,9-Trimethyl-4-{(1S)-1-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1- cyclopropyl-methyl}-3,5-dioxa-4-boratricyclo[6.1.1.0^2|B]decane

To a solution of (1 S,2S,6R,8S)-4-[(1 S)-1-Bromo-2-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]- 2,9,9-trimethyl-3,5-dioxa-4-boratricycIo[6.1.1.0²⁶]decane (1.5g, 3.5mmol), which was prepared from Intermediate B16 by an insertion reaction with CH₂Br₂ in a similar method described for the preparation of Intermediate 5, in anhydrous THF (1 OmI) under nitrogen at - 40^cC was added cyclopropyl magnesium bromide (0.5M in THF, 7ml, 3.5mmol) dropwise. 15 minutes later, the reaction mixture was allowed to warm up to room temperature and was stirred overnight The reaction mixture was diluted with EtOAc (100 ml) and washed with NH₄CI (saturated aqueous solution) and brine, dried over Na₂SO₄, and concentrated in vacuo The resulting oil was purified by flash chromatography on silica gel (5% ethyl acetate in hexane) to give the title compound 1H NMR (300 MHz, CDCI₃) δ 7 24 (d, 2H), 6 82 (d, 2H), 441 (s, 2H), 425 (d, 1H), 3 80 (s, 3H), 3 58 (d, 2H), 2 36 (m, 1 H), 2 18 (m, 1 H), 2 05 (t, 1 H), 1 85 (m, 2H), 1 39 (s, 3H), 1 26 (s, 3H), 1 20 (d, 1 H), 0 83 (m, 5H), 044 (m, 2H), 0 16 (s, 2H)

Intermediate B30 (1 S,2S,6R,8S)-4-{1 S-Bromo-2-[({[4-(methyloxy)phenyI]methyl}oxy)methyl]-2S- cyclopropyl-ethyl}-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²'⁶]decane

Fresh LDA solution was prepared by adding n-BuLι (1 6M in hexanes, 2 75ml, 44mmol) to a solution of diisopropylamine (445mg, 4 4mmol) in anhydrous THF (3ml) at -78⁰C under nitrogen, and stirred for 30 min To a solution of Intermediate B29 (1 4g, 3 δmmol) and dibromomethane (2 5g, 144mmol) in anhydrous THF (5ml) at -78⁰C was added the freshly prepared LDA solution slowly The reaction solution was stirred at -78⁰C for 1 h, then Zinc chloride (1 36g, lOmmol) in anhydrous THF (5ml) was added The reaction mixture was allowed to warm up to room temperature and stirred overnight The reaction mixture was diluted with diethyl ether (100ml) and washed with saturated ammonium chloride (100ml) The aqueous layer was re-extracted with diethyl ether (2 x 50 ml) The organic layers were combined and concentrated in vacuo The resulting oil was purified by fresh chromatography on silica gel (5% ethyl acetate in hexane) to give the title compound

¹H NMR (300 MHz, CDCI₃) 67 26 (d, 2H), 6 84 (d, 2H), 442 (dd, 2H), 4 31 (d, 1 H), 3 80 (s, 3H), 3 72 (d, 1 H), 362-338 (m, 2H), 237 (m, 1H), 220 (m, 1 H), 2 04 (m, 1H), 1 90 (m, 2H), 1 36 (s, 3H), 1 26 (s, 3H), 1 22 (d, 1 H), 0 83 (m, 5H), 045 (m, 2H), 0 22 (m, 2H) Intermediate B31

{2-[({[4-(Wlethyloxy)phenyl]methyl}oxy)methyl]-2R-cyclopropyl-1R-[(1S,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]dec-4-yl]ethyl}bis(trimethylsilyl)amine

To a solution of Intermediate B30 (0 5g, 1 1mmol) in anhydrous THF (5ml) under nitrogen at -78⁰C was added LHMDS (1 M in THF, 1 1ml, 1 1 mmol) The reaction solution was allowed to warm up to room temperature and stirred at room temperature overnight The solvent was removed in vacuo, then diluted with hexanes (50ml) filtered through celite, concentrated to give the title compounds as an oil

MS calcd for (C₃₀H₅₂BNO₄H-H)⁺ = 558, MS found (ESI positive) (M-2TMS+3H)* = 414 3

Intermediate B32

(1R,2R,8R)-4-[(E)-4-(teιt-Butyl-dimethyl-silanyloxy)-but-1-enyl]-2,9,9-trimethyl-3,5-

To a vigorously stirred solution of 2-[(E)-4-(fert-butyl-dimethyI-silanyloxy)-but-1-enyl]-4,4,5,5- tetramethyl-1,3,2-dιoxaborolane **** (20 O g, 106 8 mmol, 1 0 eq) in hexane (190 mL), diethyl ether (10 mL) and water (200 mL) was added (-)-pιnanedιol (20 O g, 117 5 mmol, 1 1 eq) The reaction mixture was stirred for 16 hours The phases were separated and the organic phase was washed with water (2 x 100 mL) followed by brine (100 mL) The organic layer was then dried over IVIgSO₄, filtered and concentrated under reduced pressure The residue was purified by flash column chromatography (100% petrol to 95 5 petrol diethyl ether) to give the product as an oil TLC, (5% Et₂O petrol) R, = 060

¹H NWIR (500WIHz, CDCI₃) δ 6 61 (td, J = 18 0, 66 Hz, 1 H), 5 52 (d, J = 18 0 Hz, 1 H), 430 (dd, J = 8 7, 1 7 Hz, 1 H), 370 (t, J = 6 9 Hz, 2H), 244-2 31 (m, 3H), 2 21 (ddd, J = 10 8, 6 1 , 3 1 Hz, 1 H), 2 06 (t, J = 5 5 Hz, 1 H), 1 95-1 84 (m, 2H), 1 40 (s, 3H), 1 29 (s, 3H), 1 15 (d, J = 10 8 Hz, 1 H), 0 89 (s, 9H), 0 85 (s, 3H), 0 05 (s, 6H)

**** Tetrahedron Lett, 2005, 8777-8780 Intermediate B33

(1R,2R,8R)-4-[4-(tert-Butyl-dimethyl-silanyloxy)-butyl]-2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.0^2>6]decane

To a solution of Intermediate B32 (36 6 g, 100 mmol, 1 00 eq) in MeOH (200 mL) was added 5% Pd/C (4 2 g, 2 mmol, 0 02 eq) under a N₂ atmosphere The flask was evacuated and filled with a hydrogen atmosphere The reaction was stirred for 16 hours before being filtered through Celite The filtrate was then concentrated under reduced pressure and passed through a short pad of flash silica (10% diethyl ether petrol) to give the product as an oil TLC, (5% Et₂O petrol) R_f = 049 ¹H NMR (500MHz, CDCI₃) δ 4.24 (dd, J = 8.7, 1.3 Hz, 1 H), 3.60 (t, J = 6.6 Hz, 2H), 2.33 (ddd, J = 11.6, 7.7, 2.0 Hz, 1 H), 2.21 (ddd, J = 8.0, 6.1 , 3.0 Hz, 1H), 2.04 (t, J = 5.5 Hz, 1H), 1.94- 1.87 (m, 1H), 1.84 (d, J = 14.8 Hz, 1 H), 1.55 (td, J = 13.5, 6.6 Hz, 2H), 1.46 (td, J = 14.6, 7.4 Hz, 2H), 1.37 (s, 3H), 1.29 (s, 3H), 1.12 (d, J = 10.9 Hz, 1H), 0.89 (s, 9H), 0.86-0.82 (m, 5H), 0.03 (s, 6H).

Intermediate B34

(1R,2R,8R)-4-[(R)-5-((ert-Butyl-dimethyl-silanyloxy)-1-chloro-pentyl]-2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1

To a solution of DCM (2.8 ml_, 43.7 mmol, 2.0 eq) in THF (40 mL) at -95°C, under a N₂ atmosphere, was added nBuLi (17.2 mL, 24.0 mmol, 1.4 M in hexane, 1.1 eq) by running it slowly down the inside of the round bottom flask. The temperature was kept below -9O⁰C throughout the addition. The reaction mixture, with white precipitate, was stirred for 30 minutes at -95°C before the addition of Intermediate B33 in THF (40 mL). After the addition was complete at -95°C the reaction mixture was allowed to warm to room temperature over 2 hours where it was stirred for a further 19 hours. The reaction mixture was then diluted with petrol (400 mL) and washed with water (5 x 200 mL) before being concentrated under reduced pressure. The residue was dissolved in petrol (250 mL) before being washed again with water (2 x 125 mL). The organic phase was then dried over MgSO₄ filtered and concentrated under reduced pressure. The residue was then passed through a short pad of flash silica (5% diethyl etheπpetrol) to give the title compound as an oil.

TLC, (5% Et₂O : petrol) R, = 0.45.

¹H NMR (500MHz, CDCI₃) δ 4.36 (d, J = 8.9 Hz, 1H), 3.62 (t, J = 5.7 Hz, 2H), 3.51-3.42 (m, 1 H), 2.41-2.31 (m, 1 H), 2.30-2.20 (m, 1H), 2.09 (t, J = 5.4 Hz, 1 H), 1.97-1.79 (m, 4H), 1.62- 1.4-1 (m, 4H)₁ 1.42 (s, 3H), 1.30 (s, 3H), 1.18 (d, J = 11.1 Hz, 1H), 0.89 (s, 9H), 0.85 (s, 3H), 0.04 (s, 6H).

Intermediate B35 (1 R,2R,8R)-4-[(S)-5-(tert-Butyl-dimethyl-silanyloxy)-1 -(1,3-di-tert-butyM ,1 ,3,3- tetramethyl-disiIazan-2-yl)-pentyl]-2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.0²'⁶]decane

To a solution of Intermediate B34 (7.5 g, 18.1 mmol, 1.0 eq) in THF (60 mL) at -78°C and under a N₂ atmosphere was added LHMDS (18.1 mL, 18.1 mmol, 1.0M in THF, 1.0 eq). The reaction mixture was allowed to warm to room temperature where it was stirred for 6 hours. The solution was concentrated under reduced pressure and the residue was diluted with hexane (300 mL). The white suspension was filtered through Celite under N₂ and the filtrate was concentrated under reduced pressure to give the title compound as an oil. 1H NMR (500MHz, CDCI₃) δ 4.28 (dd, J = 8.7, 1.7 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 2.54 (t, J = 7.3 Hz, 1H), 2.37-2.28 (m, 1H), 2.25-2.15 (m, 1H), 2.03 (t, J = 5.5 Hz, 1H), 1.89 (td, J = 8.2, 4.2 Hz, 1H), 1.87-1.80 (m, 1H), 1.77-1.66 (m, 1H), 1.57-1.40 (m, 4H), 1.40-1.26 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H), 1.13 (d, J = 10.9 Hz, 1 H), 0.90 (s, 9H), 0.84 (s, 3H), 0.10 (s, 18H), 0.05 (s, 6H).

¹³C NMR (500MHz, CDCI₃) δ 85.3, 78.2, 63.3, 51.4, 39.5, 38.1 , 35.5, 35.4, 33.4, 28.4, 27.1 , 26.3, 26.0, 24.4, 24.0, 18.3, 3.0, -5.3. HRMS (ESI): calcd. for : C₂₇H₅₈BNO₃Si [M+3H - 2 x TMS]⁺ 396.3027, found 396.3104.

Intermediate B36

(S)-5-Amino-5-((1 R,2R,8R)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²'⁶]dec-4-yl)- pentan-1-ol; hydrochloride

To a solution of Intermediate B35 (4.0 g, 7.41 mmol, 1.0 eq) in diethyl ether (50 mL) under a N₂ atmosphere was added a solution of HCI (9.2 mL, 37.05 mmol, 4.0M in dioxane, 5.0 eq) and the reaction mixture was stired for 15 minutes before being concentrated under reduced pressure. The thick residue had diethyl ether added (100 mL) and concentrated under reduced pressure to give the tilte compound as a foam.

¹H NMR (500MHz, DMSO) δ 8.02 (bs, 3H), 4.41 (d, J = 7.2 Hz, 1 H), 3.35 (t, J = 6.1 Hz, 2H), 2.75 - 2.63 (m, 1 H), 2.31 (dd, J = 10.3, 12.9 Hz, 1H), 2.16 (dd, J = 5.5, 9.9 Hz, 1H), 1.98 (t, J = 5.5 Hz, 1 H), 1.86 (bs, 1 H), 1.75 (d, J = 14.4 Hz, 1 H), 1.62 (bs, 2H), 1.43 - 1.28 (m, 3H), 1.35 (s, 3H), 1.24 (s, 3H), 1.13 (d, J = 10.9 Hz, 1 H), 0.80 (s, 3H). 1³C NMR (500MHz, DMSO) δ 87.1, 78.0, 60.8, 51.2, 39.3, 38.3, 35.1, 32.7, 29.6, 28.7, 27.3, 26.4, 24.1 , 23.0. [α]_D ²⁷ = -12.7° (c 2.4, CHCI3) HRMS (ESI): calcd. for : C₁₆H₂₉BCINO₃ [M-Cl]⁺ 282.2240, found 282.2233. Intermediate B37

(1S, 2S, 3R, 5S)-Pinanediol 1S-chloro-3-(4-methoxybenzyloxy)-propyl borate

To a solution of CH₂CI₂ (0.62ml, 9.6mmol) in anhydrous THF (20ml) under N₂ at -100 "C with ethanol and liquid N₂ bath was added πBuLi (1.6M in hexane, 4.13ml, 6.6mmol) dropwise against the wall of flask; 30 minutes after addition, added Intermediate B10 (2.07g, 6mmol) in anhydrous THF (10ml) slowly; the reaction solution was stirred for 30 minutes after addition then added zinc chloride (2.29g, 16.8mmol) in anhydrous THF (10ml), cooling bath was removed after addition and warmed up to room temperature. Stirring was kept overnight. The reaction mixture was diluted with diethyl ether and washed with NH₄CI (saturated aqueous solution) and brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 9:1) to afford the title compound.

¹H NMR (300, MHz, CDCI₃) δ 7.27 (2H, d), 6.87 (2H, d), 4.44 (2H, s), 4.31 (1H, d), 3.81 (3H, s), 3.68 (1 H, t), 3.60 (2H, t), 2.33 (1 H, m), 2.20 (2H, m), 2.05 (2H, m), 2.00-1.80 (2H, m), 1.34 (3H, s), 1.28 (3H, s), 1.17 (1 H, d), 0.82 (3H, s).

Intermediate B38

(4R)-4-Amino-4-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]dec-4- y l]-1 -butanol hydrochloride

To a solution of {(4R)-4-amino-4-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0^{z e}]dec-4-yl]}butyl benzyl ether (purchased from SpeedChemical, Shanghai, China. 460 mg, 1.17 mmol) in 8 mL of MeOH was added Pd/C (5 wt.% on activated carbon, 46 mg). A hydrogen balloon was then placed on the reaction flask. The flask was evacuated quickly and filled with hydrogen three times. The reaction mixture was allowed to stir at room temperature under hydrogen for 16 hours. The reaction mixture was then filtered through a pad of Celite to remove the Pd/C and the solute was concentrated in vacuo to give a yellow oil. Subsequently, 10 mL of hexane was added and followed by 1 mL of 4N HCI in dioxane. After stirred at room temperature for 30 min, the mixture was filtered through a glass filter funnel to give the title compound. 1H NMR (300 MHz, CDCI₃) δ 8.00 (3H, bs), 4.38 (1H, d), 3.73 (2H, t), 3.07 (1 H, m), 2.40-1.60 (10H, m), 1.40 (3H, s), 1.27 (3H, s), 0.82 (3H, s)

Intermediate B39

(1R, 2R,

To a solution of Intermediate B2 (1g, 7.65 mmol) in THF (35 mL) was added (S)-(-)- pinanediol (1.43 g, 8.43 mmol). The resulting solution was heated to 7O⁰C for 1 hr. The solution was cooled down and the solvent was removed. The crude mixture was purified by column chromatography (Hexane/EtOAc, 3:1) to afford the pure title compound. 1H NMR (300 MHz, CDCI₃) δ 4.26 (d, 1 H), 3.62 (t, 2H), 2.37 (m, 1 H), 2.22 (m, 1H), 2.01 (t, 1 H), 1.93-1.78 (m, 2H), 1.62-1.56 (m, 2H), 1.40 (s, 3H), 1.25 (s, 3H), 1.10 (d, 1H), 0.98-0.84 (m, 2H), 0.82 (s, 3H). Intermediate B40

To a solution of Intermediate B39 (1 70 g, 7 14 mmol) in DMF (6 mL) was added TBSCI (1 61 g, 10 7 mmol) and imidazole (1 46 g, 21 4 mmol) The mixture was stirred overnight The resulting solution was diluted with Et₂O and washed with brine The organic phase was separated, dried (Na₂SO₄), and concentrated The residue was purified by flash column chromatograph (Hexane/ EtOAc, 20 1) to give the title compound 1H NMR (300 MHz, CDCI₃) δ 424 (d, 1H), 3 60 (t, 2H), 2 37 (m, 1H), 221 (m, 1 H), 2 01 (t, 1H), 1 92-1 78 (m, 2H), 1 64-1 56 (tt, 2H), 1 39 (s, 3H), 1 22 (s, 3H), 1 10 (d, 1H), 098-0 78 (m, 14H), 0 05 (s, 6H)

Intermediate B41 (1R, 2R, 3S, borate

To a solution of CH₂CI₂ (0 385 mL, 6 0 mmol) in anhydrous THF (7 5 mL) under N₂ at -100 °C was added n-BuLι (2 5 M in hexanes, 1 20 mL, 3 mmol) slowly through the cold wall of the flask Affer 30 mm at -100 "C, a solution of Intermediate B40 (0 704 g, 2 00 mmol) in THF (2 mL) was added in slowly The resulting mixture was stirred at -100 ⁰C for another 20 minutes ZnCI₂ (0 93 g, 6 8 mmol) in THF (5 mL) was added to the solution Following 15 minutes stirring at 100 ⁰C, the cooling bath was removed The reaction mixture was allowed to warm up to room temperature and stirred overnight The reaction mixture was diluted with diethyl ether and washed with saturated aqueous NH₄CI, dried over sodium sulfate, and concentrated The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 20 1) to afford the title compound as an oil

¹H NMR (300 MHz, CDCI₃) δ 439 (d, 1 H), 3 62 (t, 2H), 346 (t, 1H), 2 35 (m, 1H), 2 22 (m, 1 H), 2 05 (t, 1 H), 1 94-1 82 (m, 4H), 1 76-1 62 (tt, 2H), 1 41 (s, 3H), 1 28 (s, 3H), 1 10 (d, 1 H), 0 90 (s, 9H), 0 82 (s, 3H), 0 05 (s, 6H)

Intermediate B42

(1R, 2R, 3S, 5fi)-Pinanediol-1-bis(trimethylsilyl)amino-4-(f-butyl-dimethylsilyloxy)-butyl borate

A solution of Intermediate B41 (600 mg, 1 50 mmol) in THF (5 mL) was treated with LHMDS (1 OM in THF, 1 65 mL, 1 65 mmol) dropwise under N₂ at -78 °C The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed. The residue was redissolved with hexanes (50 mL) and the precipitate was formed. The mixture was filtered, and the filtrate was concentrated to afford the title compound as an oil. 1H NMR (300 MHz, CDCI₃) δ 4.22 (d, 1H), 3.58 (t, 2H), 2.46 (t, 1H), 2.26 (m, 1 H), 2.08 (m, 1H), 1.95 (t, 1 H), 1.82-1.79 (m, 2H), 1.62-1.52 (m, 2H), 1.42-1.34 (m, 2H), 1.30 (s, 3H), 1.25 (S, 3H), 1.06 (d, 1H), 0.92 (s, 9H), 0.88 (s, 3H), 0.05 (s, 6H), 0.00 (s, 18H).

Intermediate B43

(1R, 2R, 3S, 5R)-Pinanediol-1-ami borate hydrochloride

A solution of Intermediate B42 (0.750 g, 1.43 mmol) in hexanes (12 mL) was treated with HCI (4.0 M in dioxane, 1.5 mL) under N₂ at -78 °C. After 16 hr, the reaction was concentrated to dryness. The residue was triturated with hexanes and Et₂O, and dried to afford the title compound as a solid.

Intermediate B44

(1R, 2R₁ 3S, 5R)-Pinanediol 4-methoxybeπzyloxymethyl borate

To a solution of 4-methoxyl benzyl alcohol (14.7ml, 118mmol) in anhydrous THF (90ml) at - 78⁰C with an acetone/dry ice bath was added n-BuLi (1.6M in hexanes, 74ml) slowly. The mixture was stirred at -78⁰C for 15 minutes. DMSO (8.4ml) was added dropwise followed by (I R^R.SS.SRJ^.e.θ-trimethylbicycloJS-i-IJheptane^rS-diol chloromethyl borate, also called (1 R,2R,3S,5R)-pinanediol chloromethyl borate, (16.3g, 118mmol). The reaction was allowed to reach room temperature slowly and then was heated at 5O⁰C overnight. The reaction mixture was diluted with diethyl ether (400ml) and washed with aqueous HCI (1 N, 200ml). The aqueous layer was re-extracted with diethyl ether (2 x 100ml). The organic layers were combined and concentrated in vacuo. Purification of the crude oil by flash chromatography (5% to 10% ethyl acetate in hexane) gave the title compound.

¹H NMR (300, MHz, CDCI₃) δ 7.28 (2H, d), 6.84 (2H, d), 4.42 (2H, dd), 4.36 (1H, dd), 3.80 (3H, s), 3.28 (2H, s), 2.36 (1 H, m), 2.20 (1 H, m), 2.05 (1 H, m), 1.90 (2H, m), 1.42 (3H, s), 1.28 (3H, s), 1.18 (1H, d), 0.82 (3H, s).

Intermediate B45

[1R, 2R, 3S, 5R)-Pinanediol 4-(p-methoxybenzyloxy)ethyl borate

To a solution of Intermediate B44 (4.95g, 15mmo!) and CH₂ICI (1.3ml, 18mmol) in anhydrous THF (50ml) under N₂ at -78 ⁰C was added n-butyllithium (1.6M in THF, 10.4ml, 16.5mmol) slowly along the side of the flask during 30 minutes. The cooling bath was then removed and the reaction mixture was allowed to warm up to room temperature and heated at 28 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 6:1) to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (2H, d), 6.86 (2H, d), 4.44 (2H, s), Λ.Z7-A.2Z (1H, m), 3.80 (3H, s), 3.61 (2H, t), 2.36-2.27 (1H, m), 2.23-2.14 (1H, m), 2.03 (1 H, t), 1.92-1.80 (2H, m), 1.38 (3H, s), 1.28 (3H, s), 1.25 (2H, t), 1.12 (1H, d), 0.83 (3H, s).

Intermediate B46

(1R, 2R₁ ZS, borate

To a solution of CH₂Cl₂ (0.62ml,9.6mmol) in anhydrous THF (20ml) under N₂ at -100 °C with ethanol and liquid N₂ bath was added nBuLi (1.6M in hexane, 4.13ml, 6.6mmol) dropwise against the wall of flask; 30 minutes after addition, added Intermediate B45 (2.07g, 6mmol) in anhydrous THF (10ml) slowly; the reaction solution was stirred for 30 minutes after addition then added zinc chloride (2.29g, 16.8mmol) in anhydrous THF (10ml), cooling bath was removed after addition and warmed up to room temperature. Stirring was kept overnight. The reaction mixture was diluted with diethyl ether and washed with NH₄CI (saturated aqueous solution) and brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 9:1) to afford the title compound.

¹H NMR (300 MHz, CDCI₃) δ 7.26 (2H, d), 6.86 (2H, d), 4.44 (2H, s), 4.32^1.28 (1H, m), 3.79 (3H, s), 3.69-3.65 (1 H, m), 3.59 (2H, t), 2.38-2.28 (1H, m), 2.25-2.15 (2H, m), 2.13-2.01 (2H, m), 1.89-1.84 (2H, m), 1.32 (3H, s), 1.28 (3H, s), 1.17 (1 H, s), 0.83 (3H, s). Intermediate B47

(1R, 2R, 3S, borate hydrochloride

The solution of Intermediate B46 (1.1g, 2.8mmol) in anhydrous THF (10ml) was treated with LHMDS (2.8ml, 1M in THF, 2.8mmol) under N₂ slowly at -78 °C over 15 minutes. The reaction solution was then warmed to room temperature and stirred overnight. The mixture was diluted with hexanes (60ml) and the precipitate was formed. The mixture was filtered through celite, and the filtrate was concentrated. To the solution of concentrated filtrate (610mg) in hexane (5ml), added HCI (1.2ml, 4N in dioxaπe, 4.72mmol) dropwise. Stirring was kept at room temperature for 30 hours. Concentrated to dryness, the residue was triturated with hexane and dichloromethane then dried to afford the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 7.8-7.72 (br, 3H), 4.35 (m, 1H), 3.52 (t, 2H), 2.84-2.81 (m, 1 H), 2.36-2.27 (m, 1 H), 2.25-2.14 (m, 1 H), 1.96 (t, 1 H), 1.89-1.76 (m, 2H), 1.36 (s, 3H), 1.26-1.21 (m, 5H), 1.17 (d, 1H), 0.80 (s, 3H). Intermediate B48

2-(2-((Wlethoxymethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 1-bromo-2-((methoxymethoxy)methyl)benzene (1.0 g, 4.33 mmol) in 20 mL of dioxaπe was added bis(pinacolato)diborane (1.2 g, 4.76 mmol) and potassium acetate (1.27 g, 13.0 mmol). The mixture was degassed three times with nitrogen. Subsequently,

PdCI₂(dppf) (0.097 g, 2.5 mol%) was added. The reaction mixture was heated up to 80°C and stirred for 8 hours under nitrogen. After cooled down to room temperature, the mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by ISCO Companion silica chromatography eluted with 0-10% ethyl acetate in hexane to give 1.07 g of the title compound.

¹H NMR (300 MHz, CDCI₃) 7.81 (1H, d), 7.40-7.50 (2H, m), 7.28 (1H, t), 4.85 (2H, s), 4.77 (2H, s), 3.42 (3H, s), 1.36 (12H, s) Intermediate B49

2-(Chloro(2-((methoxymethoxy)methyl)phenyl)methyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

To a stirred solution of dichloromethane (0.395 mL, 6.15 mmol) in 5 mL of anhydrous THF at -100°C under nitrogen was added n-butyl lithium (2.64 mL, 1.6 M in hexane, 4.23 mmol) dropwise and down the inside wall of the flask. The white precipitate was formed toward the end of BuLi addition. Subsequently, Intermediate B48 (1.07 g, 3.85 mmol) in 4 mL of THF was added to the reaction mixture. After the reaction was allowed to warm up to room temperature, the resulting solution was concentrated in vacuo to give a yellow residue. Hexane was added to the residue, and the mixture was allowed to stir for 10 min. After the precipitate was filtered through a sintered glass funnel, the filtrate was concentrated in vacuo to give 1.0 g of the title compound. ¹H NMR (300 MHz, CDCI₃) 7.20-7.70 (4H, m), 4.85 (1 H, s), 4.50-4.80 (4H, m), 3.41 (3H, s), 1.28 (12H₁ S)

Intermediate B50

2-(Bis(trimethylsilyl)amino(2-((methoxymethoxy)methyl)pheπyl)methyl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane

To a stirred solution of Intermediate B49 (1.0 g, 3.06 mmol) in 10 mL of anhydrous THF at -

78°C under nitrogen was added a solution of LHMDS (3.37 mL, 1.0 M solution in THF, 3.37 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting solution was concentrated in vacuo to give a yellow residue.

Hexane was added to the residue, and the mixture was allowed to stir for 20 min. After the precipitate was filtered through a sintered glass funnel, the filtrate was concentrated in vacuo to give 0.94 g of the title compound. 1H NMR (300 MHz, CDCI₃) 7.10-7.50 (4H, m), 4.50-4.90 (4H, m), 4.28 (1H, s), 3.41 (3H, s),

1.29, 1.26 (12H, ds), 0.10 (18H, s)

Intermediate B51

Diisopropyl bromomethyiboronate

P

Br

To a solution of CH₂Br₂ (35 g, 0.201 mol) and triisopropylborate (35 g, 0.186 mol) in THF (150 mL) was added n-butyllithium (77 mL, 0.193 mol) dropwise at -78°C. Then the reaction mixture was warmed to room temperature and stirred for 1h. Then it was re-cooled to 0°C and ethereal HCI was added dropwise until pH=5. Then it was concentrated to give yellow oil (40 g, 95%) and used directly for the next step.

Intermediate B52

(1S,2S,3R,5S)-(+)-Pinanediol bromomethyl Borate

H

To a solution of Intermediate B51 (40 g, 0.179 mol) in ether (180 mL) was added

(1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1 1]heptane-2,3-diol (20 g, 0.118 mol) at room temperature. The reaction mixture was stirred for 2 h and then was concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether) on silica gel to give the desired product (28 g, 87%). ¹H NMR (300 MHz, CDCI₃): δ 4.36-4.39 (d, J=87 Hz, 1H), 2 64 (s, 2H), 222-240 (m, 2H), 207-2 10 (t, J=4 8 Hz, 1H), 1 88-1 93 (m, 2H), 1 42 (s, 3H), 1 30 (s, 3H), 1 18-1 22 (m, 1H), 0 85 (s, 3H) GC-MS 272, 274 (M)

Intermediate B53 (1S,2S,3R,5S)-(+)-Pinanediol 1(R)-chloro-2-(p-Methoxybenzyloxy)-ethyl Borate

To a solution of CH₂CI₂ (3 2 ml, 50 90 mmol) in THF (126 mL) was added n-BuLi (19 mL, 47 51 mmol) dropwise at -100°C under nitrogen After 30 mm of stirring at -10O⁰C, a solution of Intermediate B16 (14 g, 4242 mmol) in THF (28 mL) was added dropwise After being stirred for 30 mm, ZnCI₂ (11666 mL, 116 66 mmol, 1 N in ether) was added directly at -100⁰C, then the reaction mixture was warmed to room temperature and stirred overnight The reaction mixture was diluted with ether and washed with saturated ammonium chloride, concentrated, purified by column chromatography to give a pale yellow oil (5 5 g, 34%) ¹H NWIR (300 MHz, CDCI₃) 57 26-7 29 (d, J=8 1 Hz, 2H), 6 86-6 89 (d, J=84 Hz, 2H), 4 53(s, 2H), 435-4 38 (d, J=8 4 Hz, 1 H), 376-3 81 (m, 5H), 363-3 67 (t, J=6 3 Hz, 1 H), 2 18-2 38 (m, 2H), 2 06-2 10 (t, J=5 1 Hz, 1 H), 1 86-1 92 (t, J=42 Hz, 2H), 1 41 (s, 3H), 1 29 (s, 3H), 1 18-1 22 (d, J=11 1 Hz, 1 H), 0 84 (s, 3H) ppm

Intermediate B54 (1S,2S,3R,5S)-(+)Pinanediol (1S)-1-(4-methoxybenzyloxy)-3 methylbutan-2-yl Borate

To a solution of Intermediate B53 (1 g, 2 6 mmol) in THF (11 mL) was added isopropylmagnesium chloride (1 6 mL, 3 17 mmol) dropwise at -78⁰C under nitrogen Then the reaction mixture was warmed to room temperature naturally until the reaction was complete as shown by TLC It was diluted with ether (50 mL) and washed with saturated ammonium chloride The aqueous layer was extracted with ether (10 mL *2) and the combined organic phase was washed with brine, dried, purified by column chromatography over silica gel to give the desired compound as a colorless oil (0 5 g, 50%) ¹H NMR (300 MHz, CDCI₃) δ 7 23-7 26 (d, J=8 7 Hz, 2H), 6 84-6 86 (d, J=84 Hz, 2H), 442 (s, 2H), 4 25- 4 28 (d, J=9 Hz, 1 H), 380 (s, 3H), 3 54-3 58 (m, 2H), 229-2 34 (m, 1 H), 2 02-2 15 (m, 2H), 1 79-1 92 (m, 3H), 1 21-1 36 (m, 8H), 0 92-0 97(m, 6H), 0 84 (s, 3H)

Intermediate B55

(1S,2S,3R,5S)-(+)-Pinaπediol (1S,2S)-1-chloro-2-((4-methoxybeπzyloxy)methyl)-3- methylbutyl Borate

To a solution of CH₂CI₂ (0.39 ml, 6.22 mmol) in THF (18 mL) was added n-BuLi (2.32 mL, 5.8 mmol) dropwise at -100⁰C under nitrogen. After 30 min of stirring at -100⁰C, a solution of Intermediate B54 (2 g, 5.18 mmol) in THF (4 mL) was added dropwise. After being stirred for 30 min, ZnCI₂ (14.25 mL, 14.25 mmol, 1 N in ether) was added directly at -100⁰C, then the reaction mixture was warmed to room temperature and stirred over night. The reaction mixture was diluted with ether and washed with saturated ammonium chloride, concentrated, purified by column chromatography to give a pale yellow oil (1.3 g, 57%). ¹H NMR (300 MHz, CDCI₃): δ 7.17-7.19 (d, J=6.6 Hz, 2H), 6.78-6.81 (d, J=8.4 Hz, 2H), 4.30-4.44 (m, 2H), 4.18- 4.20 (d, J=8.7 Hz, 1H), 3.73 (s, 3H), 3.47-3.59 (m, 2H), 3.25-3.31 (t, J=8.4Hz, 1H), 2.12-2.25 (m, 1 H), 1.81-2.10 (m, 6H), 1.11-1.28 (m, 7H), 0.87-0.92 (m, 3H), 0.70-0.82 (m, 6H). Intermediate B56

(1S,2S,3R,5SH+)Pinanediol (1R,2R)-2-(benzyloxymethyl)-1-[bis(trimethylsilyl)amino]-3- methylbutyl Borate

To a solution of Intermediate B55 (0.8 g, 1.84 mmol) in THF (5 mL) was added LiHMDS (2.03 mL, 2.03 mmol, 1 N in THF) dropwise at -78⁰C under nitrogen. Then the reaction mixture was warmed to room temperature naturally and stirred overnight. It was diluted with ether (50 mL), filtered, concentrated to give the desired product as yellow oil (0.8g, 77%). LC- MS: 416 (M-TMS₂ + H)⁺. Intermediate B57

((3-Chloropropoxy)methyl)benzene

To a stirred solution of t-BuONa (2.1 g, 22 mmol) in dry THF (20 mL) under nitrogen was added BnBr (2.5 mL, 21 mmol) and 3-chioropropan-1-ol (1.75 mL, 21 mmol) below 15°C. After addition the mixture was stirred overnight at rt, the solution was acidified to pH=2 with 2N HCI followed by extraction with ether. The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under vacuum to give the product as a light yellow oil (3.7g, 92%). ¹H NMR (300 MHz, CDCI₃): 57.33-7.25 (m, 5H), 4.51 (s, 2H), 3.68-3.59 (m, 4H), 2.07-2.03 (f, 2H) ppm.

Intermediate B58 (3-(Benzyloxy)propyl)magnesium chloride

BnO'^{^}^^^'^Mg Cl

A mixture of magnesium turnings (1 78 g, 73 mmol) and iodine (0 01 g, 0 04 mmol) in dry THF (12 mL) was heated to reflux under nitrogen Then 6 0 mL of a solution of Intermediate B57 (11 2 g, 60 8 mmol) in dry THF (19 mL) was added dropwise to the mixture above at reflux After the initial exothermal ceases, gentle reflux was maintained until all the magnesium was consumed Then the mixture was cooled to r t and used directly in the next step Intermediate B59

3-(Benzyloxy)propylboronic acid

Bπθ'^{^x}-^/^^" B(OH)₂

The mixture with Intermediate B58 was added dropwise to a solution of tπmethylborate (6 40 g, 62 mmol) in dry THF (20 mL) at -65°C Then the reaction was allowed to warm to 0°C slowly and stirred at rt overnight The mixture was added dropwise to a stirred solution of sulfuric acid (2 2 mL cone sulfuric acid in 40 mL of water) below 20°C The layers were allowed to settle and the phases were separated The aqueous layer was extracted with ether, and the combined organic layer was dried over Na₂SO₄ filtered and concentrated under vacuum to dryness The residue was taken in THF and filtered The filtrate was concentrated to give the desired boronic acid as a light yellow oil (8 1g 61%) LC-MS 217 (M + Na)⁺

Intermediate B60

(1S,2S,3R,5S)-(+)-Pinanediol 3-(benzyloxy)-propyl Borate

_ H

Q i ^ L — Me Me Me

To a stirred solution of Intermediate B59 (3 5 g, 18 mmol) in dry THF (40 mL) was added (+)-pιnanedιol (1 4 g, 8 2 mmol) at r t, and the mixture was stirred overnight at r t The mixture was concentrated under vacuum The residue was dissolved in hexane, and washed with saturated NaHCO₃ bπne, dried over Na₂SO₄ and concentrated under vacuum The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =100 1 to 50 1) on silica gel to give the desired product as a light yellow oil (1 7 g 30%) ¹H NMR (300 MHz, CDCI₃) 57 39-7 31 (m, 5H), 4 55 (s, 2H),'429-426 (d, 1H)₁ 3 53-348 (f, 2H), 2 09 -1 78 (m, 7H), 1 39 (s, 3H), 1 32 (s, 3H), 1 16-1 12 (of, 1H), 0 94 -0 88 (m, 5H) LC- MS 351 (M + Na)⁺

Intermediate B61 (1S,2S,3R,5S)-(+)-Pinanediol (1S)-1-Chloro-3-(benzyloxy)butyl Borate

To a stirred solution Of CH₂CI₂ (1.1 mL, 16.2 mmol) in dry THF (40 mL) at -100°C under nitrogen was added dropwise n-BuLi (3.0 mL, 7.5 mmol). The mixture was stirred for 30 min before the addition of Intermediate B60 (0.900 g, 2.7 mmol) in dry THF (10 mL) dropwise. The mixture was stirred for 30 min at -100°C and was added dropwise the solution of ZnCI₂ (14.0 mL, 13.5 mmol). Then the mixture was stirred for 10 min, and warmed to rt and stirred overnight. The reaction mixture was quenched with saturated NH₄CI, and the organic layer was washed with brine, dried (Na₂SO₄) and concentrated under vacuum. The residue was purified by column chromatography (eluting with P. E and E.A=75:1) on silica gel to give the desired product as a colorless oil (260 mg, 26 %). ¹H NIvIR (300 MHz, CDCI₃): 57.34-7.26 (m, 5H)₁ 4.50 (s, 2H), 4.37-4.34 (cf, 1H), 3.53-3.48 (m, 3H), 2.34 -1.78 (m, 8H), 1.41 (s, 3H), 1.29 (s, 3H), 1.19-1.15 (d, 1H), 0.84 (s, 4H). LC-MS: 399 (M + Na)*

Intermediate B62

(1 S,2S,3R,5S)-(+)-Pinanediol Borate

To a stirred solution of Intermediate B61 (110 mg, 0.3 mmol) in dry THF (14 mL) at -78°C under nitrogen was added dropwise EtWIgBr (0.3 mL, 0.9 mmol), and stirred for 10 min. Then the mixture was slowly warmed to r.t. and stirred overnight. The reaction mixture was quenched with saturated NH₄CI, and the organic layer was washed with brine, dried (Na₂SO₄) and concentrated under vacuum. Purification with preparative-TLC (eluting with P.E and E.A=15:1) gave the desired product as a colorless oil (68 mg, 61 %). ¹H NMR (300 MHz, CDCI₃): 67.35-7.27 (m, 5H), 4.50 (s, 2H), 4.28-4.25 (ςf, 1H), 3.49-3.45 (f, 2H), 2.08 -0.85 (m, 25H). LC-MS: 393 (M + Na)⁺. Intermediate B63

(1S,2S,3R,5SH+)-Pinanediol (1S,2S)-1-Chloro-2-Ethyl-5-(benzyloxy)peπtyl Borate

Cl

Me Me

To a stirred solution of CH₂CI₂ (0.39 mL, 6 mmol) in dry THF (30 mL) at -100°C under nitrogen was added dropwise n-BuLi (1.12 mL, 2.8 mmol), and stirred for 30 min. Then the solution of Intermediate B62 (0.370 g, 1.0 mmol) in dry THF (8 mL) was added dropwise at - 100°C and stirred for 30 min. Then the solution of ZnCI₂ (5.5 mL, 5.5 mmol) was subsequently added dropwise, and the resulting mixture was stirred for 10 min before being warmed to r.t. and stirred overnight. The reaction mixture was quenched with saturated NH₄CI, and the organic layer was washed with brine, dried (Na₂SO₄) and concentrated under vacuum. The residue was purified by column chromatography (eluting with P.E and

E.A=100:1 to 75:1) on silica gel to give the desired product as a colorless oil (270 mg, 65 %). ¹H NMR (300 MHz, CDCI₃) δ 7 35-726 (m, 5H), 4 50 (s, 2H), 4 37-4 34 (of, 1H), 360-3 58 (cf, 1 H), 3 53-342 (m, 2H), 239 -0 84 (m, 25H) LC-MS 441 (M + Na)⁺

Intermediate B64

(1S,2S,3R,5S)-(+)-Pinanediol (1R,2S)- 1-(Bis(trimethylsilyl)amino)-2-Ethyl -5-

(benzyloxy)pentyl Borate

To a stirred solution of Intermediate B63 (270 mg, 064 mmol) in dry THF (15 mL) at -78°C under nitrogen was added dropwise LiHMDS (1 8 mL, 1 8 mmol), and the resulting mixture was stirred for 30 mm Then the mixture was slowly warmed to r t and stirred overnight The mixture was evaporated to dryness and the residue was taken in hexane (15 mL) The mixture was filtered and the filtrate was concentrated under vacuum to give the product as light yellow needles (372 mg, 100 %) LC-MS 400 (M -TMS₂ + H)⁺ Intermediate B65

(1S, 2S, 6R, 8S)-4-[(1S)-1-methyl-3-({[4-(methyIoxy)phenyl]methyl}oxy)propyl]-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]decaπe

To a solution of Intermediate B37 in anhydrous THF (5ml) at -40 ⁰C under N₂, was added methyl magnesium bromide solution (1ml, 3M in ethyl ether) dropwise during 5 minutes Stirring was kept for 30 minutes, then warmed up to r t , 2 hours later, diluted with EtOAc (100ml), washed with NH4CI (20mlx3, saturated aqueous solution) and brine (20mlx2), dried over sodium sulfate, and concentrated The residue was purified by flash chromatography (silica gel, ethyl acetate/hexanes = 1 9) to give the title compound as colorless oil

¹H NMR (300 MHz, CDCI₃) δ 7 26 (d, 2H), 6 86 (d, 2H), 442 (s, 2H), 4 22 (d, 1H), 379 (s, 3H), 3 6 (t, 2H), 2 38-228 (m, 1 H), 2 22-2 15 (m, 1 H), 2 05 (t, 1H), 1 92-1 75 (m, 2H), 1 58 (s, 3H), 1 29 (d, 3H), 1 28 (s, 3H), 1 18 (d, 1 H), 0 96 (d, 3H), 083 (s, 3H)

Intermediate B66

(1S, 2S, 6R, 8S)-4-[(1S)-1-chloro-(2S)-2-methyl-4-({[4- (methyloxy)phenyl]methyl}oxy)butyl]-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0^Zl6]decane

To a solution of CH₂CI₂ (310mg, 3 65mmol) in anhydrous THF (10ml) under N₂ at -100 °C with ethanol and liquid N₂ bath, was added nBuLi (1 6Wl in hexane, 1 56ml, 2 5mmol) dropwise against the wall of the flask, 30 minutes after addition, slowly added Intermediate B65 (850mg, 2 28mmol) in anhydrous THF (5ml), the reaction solution was stirred for 30 minutes after addition, then added zinc chloride (870mg, 64mmol) in anhydrous THF (10ml), cooling bath was removed after addition and warmed up to room temperature Stirring was kept overnight The reaction mixture was diluted with diethyl ether (100ml) and washed with NH₄CI (20mIx2, saturated aqueous solution) and brine, dried over sodium sulfate, and concentrated The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate = 9 1) to afford the title compound

¹H NMR (300 MHz, CDCI₃) δ 7 24 (d, 2H), 6 84 (d, 2H), 442 (d, 2H), 436 (dd, 1 H), 4 2 (d, 1 H), 3 80 (s, 3H), 3 54 (d, 1 H), 348 (m, 2H), 2 38 (m, 1H), 2 20 (m, 1H), 2 05 (m, 1H), 1 95- 1 7 (m, 3H), 1 55 (s, 3H), 1 40 (s, 1H), 1 28 (s, 3H), 1 25 (d, 1 H), 1 06 (m, 3H), 0 83 (s, 3H)

Intermediate B67

{2-[({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-2S-methyl-1R-[(1S, 2S, 6R, 8S)-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]ethyl}bis(trimethylsilyl)amine

To a solution of Intermediate B66 (04g, 0 95mmol) in anhydrous THF (5ml) under nitrogen at -78°C was added LHMDS (1M in hexane, 0 95ml, 0 95mmol) The reaction solution was allowed to warm up to room temperature after addition and stirred at room temperature overnight The solvent was removed in vacuo, then diluted with hexanes (50ml) filtered through celite, concentrated to give the title compounds as colorless oil Used as crude for next step

MS calcd for (CsoHs_∑BNCU+H)* = 545 3, MS found (ESI positive) (M-2TMS+3H)* = 402 3 Intermediate B68

(1 S,2S,6R,8S)-2,9,9-trimethyl-4-{(1 S)-1 -[({[4-(methyloxy)phenyl]methyl}oxy) methyl] -3- buten-1 -yl}-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]decane

A solution of Intermediate B17 (1 89 g, 5 00 mmol) in anhydrous THF (25 mL) under nitrogen at -78⁰C was treated with allyl magnesium bromide (1 0 M in THF, 5 50 mL, 5 50 mmol) dropwise The reaction mixture was warmed to room temperature and stirred 4h The reaction mixture was diluted with ethyl acetate and washed with brine The organic layers were separated, dried (Na₂SO₄), and concentrated The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate = 6 1), affording the title compound (1 56 g, 81%) as a colorless oil

¹H NMR (CDCI₃) δ 0 80 (s, 3H), 1 21 (d, 1H), 1 30-1 32 (m, 4H), 1 37 (s, 3H), 1 84-1 86 (m, 2H), 2 00-2 03 (m, 1 H), 2 11-2 13 (m, 1 H)₁ 2 32-2 35 (m, 3H), 3 66-3 69 (m, 2H), 3 80 (s, 3H), 423 (d, 1H), 442 (s, 2H), 490-508 (m, 2H), 576-583 (m, 1H), 690 (d, 2H), 724 (d, 2H)

Intermediate B69

(1 S,2S,6/?,8S)-4-{(1 S), (ZS)A -chloro-2-[({[4-(methyloxy)phenyl]methyl}oxy) methyl]-4-

(10 mL) was treated with n-BuLι (2 5 M, 2 11 mL, 5 28 mmol) at -100 °C over 30 mm The solution was kept at -100 °C for the additional 30 mm Then, a solution of Intermediate B68 (1 56g, 4 06 mmol) in THF (5 mL) was added slowly The reaction was stirred at -100⁰C for 30 mm ZnCI₂ (1 66 g, 12 2 mmol) in THF (10 mL) was added directly to the above reaction The suspension was warmed to room temperature and stirred overnight The reaction mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, and concentrated The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate = 7 1) to afford the title compound as a colorless oil (1 24 g, 79%) 1H NMR (CDCI₃) δ 0 80 (s, 3H), 1 21 (d, 1 H), 1 30-1 32 (m, 4H), 1 37 (s, 3H), 1 84-1 86 (m, 2H), 2 00-2 03 (m, 1 H), 2 11-2 13 (m, 1H), 2 32-2 35 (m, 3H), 3 56-3 59 (m, 2H), 3 62 (d, 1H), 3 80 (s, 3H), 4 23 (d, 1H), 442 (s, 2H), 4 90-5 08 (m, 2H), 5 76-5 83 (m, 1 H), 6 90 (d, 2H), 7 24 (d, 2H) Intermediate B70

(1 S,2S,6R,8S)-4-{(1 R), (2R)-1 -(bis(trimethylsilyl))-2-[({[4-(methyloxy)phenyl]methyl}oxy)

A solution of Intermediate B69 (648 mg, 1 50 mmol) in THF (4 mL) was treated with LHMDS (1 65 mL, 1 OM in THF, 1 65 mmol) under N₂ at -78 °C over 15 mm The reaction was warmed to room temperature overnight The mixture was diluted with hexanes (~100 mL) and the precipitate was formed The mixture was filtered through a pad of Celite The filtrate was concentrated to afford the title compound (780 mg, 93%) 1H NMR (CDCI₃) δ 0 10 (s, 18H), 0 80 (s, 3H), 1 21 (d, 1 H), 1 30-1 32 (m, 4H), 1 37 (s, 3H), 1 84-1 86 (m, 2H), 2 00-2 03 (m, 1H), 2 11-2 13 (m, 1H), 2 32-2 35 (m, 3H), 2 62 (d, 1H),3 58-360 (m, 2H), 3 80 (s, 3H), 423 (d, 1 H), 442 (s, 2H), 4 90-5 08 (m, 2H), 5 76-5 83 (m, 1H), 6 90 (d, 2H), 7 24 (d, 2H)

Intermediate B71 (1 R, 2R, 6S, 8R)-4-(Bromomethyl)-2, 9, 9-trimethyl-3, 5-dioxa-4-boratricyclo [6.1.1.0²' ⁶I decane

To a solution of dibromomethane (4 1 mL, 58 mmol) and trimethyl borate (56 mL, 50 mmol) in anhydrous THF (40 mL) was added n-BuLι (2 5 M in hexanes, 21 mL, 53 mmol) slowly at - 78⁰C The mixture was stirred at -78⁰C for 1 h tπmethylsilyl bromide (7 7 mL, 58 mmol) was added to the mixture at -78⁰C and the reaction mixture was allowed to warm to room temperature and stirred overnight A solution of (1R, 2R, 6S, 8R)-pιnanedιol (9 g, 52 mmol) in anhydrous THF (34 mL) was added and the mixture was stirred at room temperature for 1 h The reaction mixture was diluted with ethyl acetate (200 mL) and extracted with brine (100 mL) The organic layer was collected, dried over Na₂SO₄ and concentrated Flash chromatography on silica gel (2% ethyl acetate in hexane) gave the title compound (84 g)

¹H NMR (300 MHz, CDCI₃) δ 4 19 (1H, dd), 2 82 (2H, s), 2 38 (1H, m), 2 25 (1 H, m), 2 08 (1H, t), 1 96 (2H, m), 1 42 (3H, s), 1 30 (3H, s), 1 18 (1H, d), 0 82 (3H, s)

Intermediate B72 (1 R, 2R, 6S, 8R)- 2, 9, 9-trimethyl-4-[({[4-(methyloxy)phenyl]methyl}oxy)-methyl]-3,5- dioxa-4-boratricyclo [6.1.1.0²' ^G] decane

p-Methoxyl benzyl alcohol (4 8 mL, 382 mmol) was dissolved in anhydrous THF (52 mL) and cooled to -78⁰C with an acetone/dry ice bath To this soluton n-BuLι (2 5 M in hexanes, 15 3 mL, 38 2 mmol) was added slowly The mixture was stirred at -78⁰C for 15 mm DMSO (2 7 mL, 30.8 mmol) was added dropwise followed by Intermediate B71 (8.4 g, 30.8 mmol). The reaction was allowed to reach room temperature slowly and then was heated at 5O⁰C overnight. The reaction mixture was diluted with diethyl ether (200 mL) and extracted with aqueous HCI (0.6 N, 200 mL). The aqueous layer was re-extracted with diethyl ether (2 x 100 mL). The organic layers were combined and concentrated in vacuo. Purification of the crude oil by flash chromatography (5% to 10% ethyl acetate/hexanes) gave the title compound (6.6 g) as a colorless oil.

¹H NMR (300 MHz, CDCI₃) δ 7.28 (2H, d), 6.84 (2H, d), 4.42 (2H, dd), 4.36 (1 H, dd), 3.80 (3H, s), 3.28 (2H, s), 2.36 (1H, m), 2.20 (1 H, m), 2.05 (1H, m), 1.90 (2H, m), 1.42 (3H, s), 1.28 (3H, s), 1.18 (1 H, d), 0.82 (3H, s).

Intermediate B73

(1R, 2R, 6S, 8R)-4-[(1R)-1-Chloro-2-({[4-(methyloxy)phenyl]methyl}oxy)-ethyl]-2, 9, 9- trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.0^{2 6}] decane

MeCk ^f^ Cl.

A solution of dichloromethane (1.7 mL, 26.32 mmol) in anhydrous THF (62 mL) was cooled to -100⁰C. To this n-BuLi (2.5 M solution in hexane, 9.5 mL, 23.8 mmol) was added slowly. The mixture was stirred at -100°C for 30 minutes. A solution of Intermediate B72 (5.6 g, 16.8 mmol) in anhydrous THF (13 mL) was added slowly and the reaction mixture was stirred at -100⁰C for 30 minutes. A solution of ZnCI₂ (7.84 g, 57.68 mmol) in anhydrous THF (47 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with Et₂O (200 mL) and extracted with saturated NH₄CI (200 mL). The aqueous layer was re-extracted with 2x100 mL Et₂O. The combined organic layer was dried over Na₂SO₄ and concentrated under high vacuum to give the title compound (6 g) as a colorless oil. 1H NMR (300 MHz, CDCI₃) δ 7.27 (2H, d), 6.84 (2H, d), 4.58 (2H, s), 4.36 (1 H, dd), 3.78 (3H, s), 3.72 (2H, m), 3.62 (1H, m), 2.38 (1H, m), 2.20 (1H, m), 2.05 (1H, t), 1.86 (2H, m), 1.39 (3H, s), 1.28 (3H, s), 1.20 (1H, d), 0.8 (3H, s).

Intermediate B74

(1R, 2R, 6S, 8R)- 2, 9, 9-trirnethyl-4-{[(1S)- 1 [({[4-(methyloxy)phenyl]methyl}- oxy)methyl]-3-buten-1 -yl-S.δ-dioxa^-boratricycIo [6.1.1.0²' ^δ] decane

O ΛPMBT

To a solution of Intermediate B73 (2 g, 5 mmol) in anhydrous THF (24 mL) at -78°C was added allyl magnesium chloride (2 Wl in THF, 3 mL, 6 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight under nitrogen. The reaction mixture was diluted with diethyl ether (100 mL) and washed with aqueous HCI (0.6 N, 100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL). The aqueous phases were re-extracted with diethyl ether (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by flash chromatography (5% ethyl acetate/hexanes) to give the title compound (1.2 g) as a colorless oil.

¹H NMR (300 MHz, CDCI₃) δ 7.28 (2H, d), 6.84 (2H, d), 5.80 (1H, m), 5.00 (2H, m), 4.42 (2H, s), 4.28 (1H, dd), 3.78 (3H, s), 3.56 (2H, m), 2.30 (2H, m), 2.18 (1H, m), 2.02 (1H, m), 1.88 (2H, m), 1.56 (1H, m), 1.38 (3H, s), 1.22 (3H, s), 1.20 (1H, d), 0.80 (3H, s).

Intermediate B75

(1R, 2R, 6S, 8R)- 4-{(1R)-1-Chloro-2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-4- penten-1 -yl-2, 9, 9-trimethyl-3, [6.1.1.O²'⁶] decane

Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 0.33 mL, 0.82 mmol) to a solution of di-isopropyllamine (0.11 mL, 0.82 mmol) in anhydrous THF (0.17 mL) at - 78^DC and was stirred at -78°C under nitrogen for 30 min. In a separate flask Intermediate B74 (0.27 g, 0.63 mmol) was mixed with dichloromethane (0.24 mL, 3.76 mmol) in anhydrous THF (1.7 mL) at -78⁰C. To the solution, the fresh prepared LDA solution was added through a syringe. The mixture was stirred at -78°C for 1 h and zinc chloride (0.36 g, 2.6 mmol) in anhydrous THF (2.22 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (50 mL) and extracted with sulfuric acid (0.5N, 50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL). The aqueous layers were re- extracted with diethyl ether (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by fresh chromatography (5% to 10% ethyl acetate/hexanes) to give the title compound (0.25 g) as a colorless oil.

¹H NMR (300 MHz, CDCI₃) δ 7.24 (2H, d), 6.82 (2H, d), 5.78 (1 H, m), 5.10 (2H, m), 4.48 (2H, dd), 4.28 (1 H, dd), 3.80 (3H, s), 3.68 (1 H, d); 3.52 (2H, m), 2.35 (2H₁ m), 2.18 (2H, m), 2.02 (1 H, m), 1.88 (2H, m), 1.38 (3H, s), 1.22 (3H, s), 1.20 (1H, d), 0.80 (3H, s).

Intermediate B76

{2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1R, 2 R, 6S, 8R)-2, 9, 9-trimethyl-3,5- dioxa-4-boratricyclo [6.1.1.0²' ⁶] dec-5-yl]pentenyl}bis(trimethylsilyl)amine

To a solution of Intermediate B75 (0.25 g, 0.53 mmol) in anhydrous THF (1 mL) at -78⁰C was added LHWIDS (1 M in THF, 0.58 mL, 0.58 mmol) and the reaction mixture was allowed to reach room temperature. The reaction was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo to give the title compound (0.28 g) as a yellow oil.

¹H NMR (300 MHz, CDCI₃) δ 7.24 (2H,.d), 6.80 (2H, d), 5.70 (1H, m), 4.88 (2H, m), 4.30 (2H, dd), 4.18 (1 H, dd), 3.68 (3H, s), 3.50 (1H, d); 3.42 (1 H, m), 2.50 (1 H, d), 2.18 (1H, m), 2.06 (1 H, m), 1.95 (1H, m), 1.80 (2H, m), 1.22 (3H, s), 1.20 (3H, s), 1.05 (1 H, d), 0.70 (3H, s), 0.05 (18H, s).

Intermediate B77

(1 R, 2R, 6S, 8R)- 2, 9, 9-trimethyl-4-{[(1S)- 1 [({[4-(methyloxy)phenyl]methyl}

Intermediate B73 (1 g, 2.5 mmol) was dissolved in anhydrous THF (12 mL) and was cooled to -78⁰C. To this vinyl magnesium bromide (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and was stirred at room temperature for 3 h under nitrogen. The reaction mixture was diluted with diethyl ether (50 mL) and extracted with aqueous HCI (0.6 N, 50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL). The aqueous phases were re-extracted with diethyl ether (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by flash chromatography (5% ethyl acetate/hexaπes) to give the title compound (0.6 g) as a colorless oil.

¹H NMR (300 MHz, CDCI₃)δ 7.25 (2H, d), 6.84 (2H, d), 5.84 (1H, m), 5.02 (2H, m), 4.42 (2H, s), 4.25 (1 H, dd), 3.78 (3H, s), 3.60 (2H, m), 2.35 (2H, m), 2.18 (1 H, m), 2.02 (1H, m), 1.88 (2H, m), 1.38 (3H, s), 1.22 (3H, s), 1.20 (1H, d), 0.80 (3H, s).

Intermediate B78

Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 0.77 ml_, 1.92 mmol) to a solution of diisopropylamine (0.27 ml_, 1.92 mmol) in anhydrous THF (0.4mL) at -78⁰C and stirred for 30 min. In a separate flask Intermediate B77 (0.55 g, 1.48 mmol) was mixed with dichloromethane (0.57 mL, 8.88 mmol) in anhydrous THF (4 mL) at -78⁰C. To this solution was added the fresh prepared LDA solution through a syringe. The mixture was stirred at -78⁰C for 1 h and zinc chloride (0.84 g, 6.2 mmol) in anhydrous THF (5.2 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (50 mL) and extracted with sulfuric acid (0.5N, 50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL). The aqueous layers were re-extracted with diethyl ether (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The resulting oil was purified by fresh chromatography (5% to 10% ethyl acetate/hexanes) to give the title compound (0.16 g) as a colorless oil.

¹H NMR (300 MHz, CDCI₃)δ 7.24 (2H, d), 6.82 (2H, d), 5.78 (1H, m), 5.08 (2H, m), 4.42 (2H, dd), 4.28 (1 H, dd), 3.78 (3H, s), 3.66 (1H, d); 3.45 (2H, m), 2.85 (1H, m), 2.30 (1 H, m), 2.18 (2H, m), 2.02 (1H, m), 1.84 (2H, m), 1.35 (3H, s), 1.22 (3H, s), 1.20 (1 H, d), 0.80 (3H, s).

Intermediate B79

{2-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1 R, 2R, 6S, 8R)-2, 9, 9-trimethy 1-3,5-

To a solution of Intermediate B78 (0.14 g, 0.32 mmol) was dissolved in anhydrous THF (0.6 mL) at -78⁰C was added LHMDS (1 M in THF, 0.38 mL, 0.38 mmol) and the reaction mixture was allowed to reach room temperature. The reaction was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo to give the title compound (0.1 g) as a yellow oil. ¹H NMR (300 MHz, CDCI₃) 7.24 (2H, d), 6.80 (2H, d), 5.80 (1 H, m), 5.20 (2H, m), 4.50 (2H, dd), 4.38 (1H, dd), 3.80 (3H, s), 3.70 (1H, dd); 3.30 (1H, t), 2.60 (1H, d), 2.38 (1 H, m), 2.10 (1 H, m), 2.02 (1H, m), 1.85 (2H, m), 1.35 (3H, s), 1.25 (3H, s), 1.10 <1 H, d), 0.85 (3H, s), 0.05 (18H, s).

Intermediate C1

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-W-{(1 R)-3-hydroxy-1 -[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-boratricyclo[6.1.1.

To a solution of Intermediate A3 (81.9 mg, 0.158 mmol) and Intermediate B13 (137 mg, 0.473 mmol) in CH₂CI₂ (8 mL) and DMF (4 mL) was added HATU (90.1 mg, 0.237 mmol) followed by dropwise DIEA (91 μL, 0.553 mmol). The reaction was stirred at room temperature over weekend. The mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by the reverse phase column (C-18, CH₃CN/H₂O = 1 : 1), affording the title compound.

MS calcd for (C₃₉H₅₈BFN₄O₉ + H)⁺: 755 MS found: (M+H)⁺ = 755

Intermediate C2

Isomer 1 of W-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-methyl-Λ/-{2-

[({[4-(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-

4-boratricyclo[6.1.1.0^{2 ε}]dec-4-yl]butyl}-L-prolinamide - 1(2H)-isoquinolinone (1:1)

To a solution of Intermediate B20 (0.25 g, 0.46 mmol), HATU (97 mg, 0.26 mmol), and Intermediate A1 (81.5 mg, 0.17 mmol) in anhydrous DMF (2 mL) and dichloromethane (4 mL) under nitrogen at room temperature was added DIEA (84 uL, 0.51 mmol). The solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 mL), washed with aqueous HCI (1 N, 100 ml_), saturated sodium bicarbonate (100 mL) and brine (100 mL). The aqueous layers were re-extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, dried and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel to give the title compound.

¹H NMR (300 MHz, CDCI₃) δ 8.12 (1H, d), 7.90 (1H, d), 7.62 (1H, d), 7.59 (1 H, t), 7.40 (1 H, t), 7.20 (3H, m), 6.79 (2H, d), 6.48 (1H, d), 5.79 (1H, s), 5.19 (1H, d), 4.56 (1 H, t), 4.39 (2H, S), 4.20 (3H, m), 3.92 (1H, dd), 3.62 (3H, s), 3.62 (1H, overlap with -OCH₃), 3.39 (1 H, m), 3.30 (1H, t), 2.60 (1H, m), 2.47 (1H, m), 2.21 (1 H, m), 2.05 (1H, m), 1.90 (3H, m), 1.70 (2H, m), 1.38 (1 H, m), 1.26 (9H, s), 1.24 (3H, s), 1.21 (3H, s), 1.20 (1 H, overlap with -CH₃), 0.92 (9H, s), 0.84 (3H, t), 0.78 (3H, s).

Intermediate C3 isomer 1 of W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3- dihydro-2H-isoindoi-2-yl)carbonyl]oκy}-W-{2-[({[4-

(methyloxy)phenyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²'⁶]dec-4-yl]butyl}-L-prolinamide

To a solution of Intermediate B20 (0.15 g, 0.28 mmol), HATU (55 mg, 0.14 mmol), and Intermediate A3 (50 mg, 0.096 mmol) in anhydrous DMF (1.1 mL) and dichloromethane (2.3 mL) under nitrogen at room temperature was added DIEA (48 uL, 0.29 mmol). The solution was stirred under nitrogen at room temperature overnight, diluted with dichloromethane (50 mL), extracted with aqueous HCI (1 N, 50 mL), saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layers were re-extracted with dichloromethane (2 x 25 mL) and the organic layers were combined, concentrated in vacuo. The resulting oil was purified from flash chromatography to give the title compound. 1H NMR (300 MHz, CDCI₃) δ 7.25 (3H, m), 7.05 (1 H, d), 6.90 (1 H, m), 6.82 (2H, d), 6.65 (1H, m), 5.38 (1H, s), 5.20 (1 H, d), 4.82 - 4.56 (7H, m), 4.44 (2H, dd), 4.21 (2H, m), 3.79 (1 H, overlap with -OCH₃), 3.76 (3H, s), 3.65 (1H, m), 3.48 (1H, m), 3.39 (1H, m), 2.58 (1 H, m), 2.30 (2H, m), 2.12 (1 H, m), 1.98 (3H, m), 1.79 (2H, m), 1.60 - 1.38 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.27 (1 H, overlap with -CH₃), 0.98 (9H, s), 0.88 (3H, t), 0.82 (3H, s). Intermediate C4

W-{[(1,1-Dimethylethyl)oxy]carboπyl}-3-methyl-L-valyl-(4R)-W-{2-[({[4- (methyloxy)phenyl]methyl}oxy)methyl]-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²'⁶]de linamide

To a solution of Intermediate A1 (65.1 mg, 0.138 mmol) and Intermediate B23 (150 mg, 0.276 mmol) in CH₂CI₂ (4 mL) and DMF (2 mL) was added HATU (78.7 mg, 0.207 mmol) followed by dropwise DIPEiA (57 μL, 0.35 mmol). The reaction was stirred at room temperature over for two days. The mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (silica gel, hexanes/ethyl acetate = 1 : 1) to afford the title compound.

MS calcd for (C₄₈H₆₅BN₄O₉ + H)⁺: 853.5 MS found: (M+H)⁺ = 853.5

Intermediate Cβ

W-{[(1 ,1 -Dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-(1 -isoquinolinyloxy)-W-

{{1R)-3-({[4-(methyloxy)pheπyl]methyl}oxy)-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-

4-boratricyclo[6.1.1.0²'⁶]dec-4-yl]propyl}-L-prolinamide

To a solution of Intermediate A1 (60.0 mg, 0.127 mmol) and Intermediate B12 (131 mg, 0.254 mmol) in CH₂CI₂ (4 mL) and DMF (2 mL) was added HATU (72.6 mg, 0.191 mmol), followed by dropwise DIEiA (52 μL, 0.32 mmol). The reaction was stirred at room temperature for two days. The mixture was diluted with CH₂CI₂ and washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (silica gel, hexanes/ethyl acetate = 1: 2) to give the title compound. MS calcd for (C₄₆H₆₃BN₄O₉ + H)⁺: 827.5 MS found: (M+H)⁺ = 827.5 Intermediate Cβ

W-KCycIopentyloxyJcarbonyll-S-methyl-L-valyl-f^-W-ftiRJ-S-hydroxy-i-

[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0²⁶]dec-4-yl]propyl}-4-(1 - isoquinolinyloxy)-L-prolinamide

The product was prepared according to the procedure of Intermediate C1, using Intermediate A2 (50 mg, 0.103 mmol) and Intermediate B13 (60 mg, 0.207 mmol). 1H NMR (300 MHz, CD₃OD) 6 8.22 (d, 1 H), 7.97 (d, 1 H), 7.81 (d, 1 H), 7.70 (t, 1 H), 7.54 (t, 1H), 7.31 (d, 1 H), 6.94 (d, 1 H), 5.88 (s, 1 H), 4.65 (s, 1H), 4.50 (d, 1 H), 4.27 (t, 1H), 4.17 (d, 1 H), 4.08-4.02 (m, 1H), 3.98-3.93 (m, 1 H), 3.67-3.63 (m, 2H),2.85-2.83 (m, 1 H), 2.80-2.74 (m, 1H), 2.48-2.36 (m, 2H), 2.17-2.13 (m, 2H), 1.96 (t, 2H), 1.92-1.79 (m, 2H), 1.70-1.43 (m, 8H), 1.32 (s, 3H), 1.26 (s, 3H), 1.18 (d, 1 H), 1.06 (s, 9H), 0.82 (s, 3H).

Intermediate C7

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-{2-cyclopropyl-3-({[4- (methyloxy)phenyl]methyl}oxy)-1-[(1S,2S,6R,8S)-2,9,9-trimethyi-3,5-dioxa-4- boratricyclo[6.1.1.0^2>6]dec-4-yl]propyl}-4-(1 -isoquinoliπyloxy)-L-prolinamide

Similarly prepared according to the procedure of Intermediate C5, using Intermediate A2

(49 mg, 0.1 mmol) and Intermediate B28 (100 mg, 0.19 mmol)

MS calcd for (C₅₀H₆₇BN₄O₉ + H)⁺: 879, MS found (ESI positive): (M+H)⁺=879.4

MS calcd for (C₅₀He₇BN₄O₉ - H)^": 877, MS found (ESI negative): (M-H)^" =877.4 Intermediate C8

Λf-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-{2-cyclopropyl-3-({[4- (methyloxy)phenyl]methyl}oxy)-1-[(1S_I2S,6R,8S)-2,9,9-thmethyl-3,5-dioxa-4- boratricyclo[6.1.1.0²'⁶]dec-4-yl]propyl}-4-{t(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-L-prolinamide

The product was prepared according to the procedure of Intermediate C5, using Intermediate B28 and Intermediate A3.

MS calcd for (C₆₀H₆₈BN₄O₁₀ + H)⁺: 915, MS found (ESI positive): (M+H)*=915.4 MS calcd for (C₅₀H₆₈BN₄O₁₀ - H)^": 913, MS found (ESI negative): (M-H)^" =913.5

Intermediate C9

W-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4/?)-W-{3-rιydroxy-1- [(1S,2S,6/?,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0².⁶]dec-4-yl]propyl}-4-(1- isoquinoliπyloxy)-L-prolinamide

To a solution of Intermediate C5 (28.0 mg, 0.034 mmol) in CH₂CI₂ and water (3 mL, 10:1) was added DDQ (9.2 mg, 0.041 mmol). The reaction was stirred at room temperature for two hours. The mixture was diluted with CH₂CI₂ and washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was purified by prep-TLC (silica gel, hexanes/ethyl acetate = 1 : 2) to give the title compound. MS calcd for (C38H55BN4O8 - H)+: 705.4 MS found: (M+H)+ = 705.4

Intermediate C10

(3R, 5S)-1-((S)-2-(tert-butoxycarboπylamiπo)-2-cyclohexylacetyl)-5-((1R, 2S) -1-

(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- carboxylate

To a solution of Intermediate A6 (799 mg, 1.5 mmol) in CH₂CI₂(30 mL), was added EDC (359 mg, 1.88 mmol) and HOBT (203 mg, 1.5 mmol) at O⁰C under nitrogen. After 30 min of stirring, a solution of Intermediate B56 (700 mg, 1.25 mmol) in CH₂CI₂ (5 mL) and NMM (303 mg, 3 mmol) were added sequentially. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (10 mL), extracted with CH₂CI₂ (15*3 mL). The combined organic layer was washed with saturated NaCI solution, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =1 :2) on silica gel to give the desired product as a white solid (600mg, 51 %). LC-MS: 930 (M + H)*

Intermediate C-11

To a stirred solution of Intermediate A6 (245 mg, 0.46 mmol) in CH₂CI₂ (15 mL) at 0⁰C under nitrogen was added dropwise EDC (109 mg, 0.57 mmol) and HOBT (62.1 mg, 0.46 mmol) in CH₂CI₂ (15 mL) and stirred at 0°C for 15 minutes. Then Intermediate B64 (208 mg, 0.38 mmol) in CH₂CI₂ (5 mL) and NMM (92.3 mg, 0.91 mmol) were added sequentially. The resulting mixture was stirred at rt overnight. The mixture was washed with saturated NaHCθ₃, brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =2:1) on silica gel to give the product as/a white solid (150 mg, 43 %). LC-MS: 914 (M + H)⁺. Intermediate C12

To a stirred solution of Intermediate A3 (229.3 mg, 0.442 mmol) in CH₂CI₂ (2OmL) at 0°C under nitrogen was added dropwise EDC (105.8 mg, 0.552 mmol) and HOBT (59.7 mg, 0.442 mmol) in CH₂CI₂ (15 mL) and stirred at O⁰C for 15 minutes. Then Intermediate B64 (200 mg, 0.368 mmol) in CH₂CI₂ (5 mL) and NMM (89.5 mg, 0.884 mmol) were sequentially added. The resulting mixture was stirred at rt overnight. The mixture was washed with saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =2:1) on silica gel to give the desired product as a white solid (104 mg, 31 %). LC-MS: 901 (M + H)⁺.

Intermediate d 3

A solution of Intermediate B70 (216 mg, 0.48 mmol) and Intermediate A3 (100 mg, 0.19 mmol) in CH₂CI₂ (8 mL) and DMF (4 mL) was added HATU (110 mg, 0.288 mmol) followed by dropwise DIPEA (110 μL, 0.67 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by the reverse phase column (C-18, CH₃CN/H₂O = 1: 1), affording the title compound as a white solid (119 mg, 68%).

MS calcd for (C₆₀H₆₈BFN₄O₁₀ + H)⁺: 915.5 MS found: (M+H)⁺ = 915.5 Intermediate d 4

A solution of Intermediate B70 (412 mg, 0 916 mmol) and Intermediate A7 (200 mg, 0367 mmol) in CH₂CI₂ (20 ml.) and DMF (10 mL) was added HATU (209 mg, 0 551 mmol) followed by dropwise DIPEA (212 μL, 1 28 mmol) The reaction was stirred at room temperature overnight The mixture was diluted with CH₂CI₂ and washed with brine The organic phase was separated, dried over sodium sulfate, and concentrated The residue was purified by the preparative TLC (silica, hexanes/ethyl acetate = 1 1), affording the title compound as a white solid (233 mg, 68%) MS calcd for (C₅₂H₇₀BFN₄O₁₀ + H)⁺ 941 5 MS found (M+H)⁺ = 941 5

and A solution of Intermediate C14 (134 mg, 0 14 mmol) in CH₂CI₂ (245 mL) was degassed 3 times and Zhan 1B catalyst (10 5 mg, 0 014 mmol) (purchased from Zannaπ Pharma, Ltd , Shanghai, P R China) was added The mixture was degassed 3 times again The resulting green solution was stirred at room temperature overnight The reaction mixture was concentrated to dryness The residue was purified by the preparative TLC (silica, hexanes/ethyl acetate = 1 1), affording two major products Intermediate C15 (lower Rf, 27 mg) and Intermediate C16 (higher Rf, 27 mg) The structures of two compounds were arbitrarily assigned

For Intermediate C15

MS calcd for (C₅OH₆₆BFN₄Oi₀ + H)⁺ 913 5 MS found (M+H)⁺ = 913 5 For Intermediate C16

MS calcd for (C₅₀H₆₆BFN₄O₁₀ + H)⁺ 913 5 MS found: (WH-H)⁺ = 913.5

I ntermed iate C 17

(1R, 2R, 3S, 5R)-PinanedioI 1-((2S, 4R)-1-((S)-2-(cyclopentyloxycarbonylamino)-3,3- dimethylbutanoyl)-4-(4-fluoroisoindoline-2-carbonyloxy)pyrrolidine-2-carboxamido)-2-

((4-methoxybenzyloxy)methyl)allylethyl borate

° --

Intermediate B76 (85 mg, 0.16 mmol), HATU (91 mg, 0.24 mmol), Intermediate A3 (100 mg, 0.19 mmol) were mixed in anhydrous DMF (1.8 mL) and dichloromethane (3.6 mL). To this was added DIPEA (80 uL, 0.48 mmol) and the solution was stirred under nitrogen at room temperature for overnight. The reaction mixture was diluted with dichloromethane (100 mL), extracted with aqueous HCI (1 N, 100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The aqueous layers were re-extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, concentrated in vacuo. The resulting oil was purified from flash chromatography (40% ethyl acetate/hexane) to give the title compound (110 mg) as a white powder.

MS calcd for (C₄₀H₅₄BFN₄Og + H)*: 915.9 MS found (electrospray): (M + H)⁺ = 915.4

Intermediate C18

(1 R, 2R, 3S, 5R)-Piπaπediol 1-((2S, 4R)-1-((S)-2-(cyclopentyloxycarboπylamiπo)-3,3- dimethylbutanoyl)-4-(4-fluoroisoindoline-2-carbonyloxy)pyrrolidine-2-carboxamido)-2-

((4-methoxybeπzyloxy)methyl)vinylethyl borate

To a solution of Intermediate B79 (100 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), Intermediate A3 (80 mg, 0.15mmol) in anhydrous DMF (1.8 mL) and dichloromethane (3.5 mL) was added DIPEEA (74 uL, 0.45 mmol). The solution was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 mL), extracted with aqueous HCI (1 N, 100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The aqueous layers were re-extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, concentrated in vacuo. The resulting oil was purified from flash chromatography (40% ethyl acetate/hexane) to give the title compound (50 mg) as a white powder.

MS calcd for (C₄₉H₆₆BFN₄O₁₀+ H)⁺: 901.9 MS found (electrospray): (M + H)⁺ = 901.3

Intermediate d 9

To a solution of Intermediate B76 (174 mg, 0.31 mmol), HATU (212 mg, 0.56 mmol), and Intermediate A7 (270 mg, 0.49 mmol) in anhydrous DMF (3.6 mL) and dichloromethane (7.2 mL) was added DIPEEA (155 uL, 0.93 mmol). The solution was stirred under nitrogen at room temperature overnight, was diluted with dichloromethane (100 mL), extracted with aqueous HCI (1 N, 100 rtiL), saturated sodium bicarbonate (100 mL) and water (100 mL). The aqueous layers were re-extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, concentrated in vacuo. The resulting oil was purified from flash chromatography (40% ethyl acetate/hexane) to give the title compound (210 mg) as a white powder.

MS calcd for (C₅₂H₇₀BFN₄O₁₀+ H)⁺: 942.0 MS found (electrospray): (M + H)* = 942.0

Intermediate C20

Intermediate C19 (210 mg, 0.22 mmol) were mixed with ZhaniB catalyst (16 mg, 0.022 mtnol) (purchased from Zannan Pharma, Ltd., Shanghai, P.R. China) in dichloromethane (385 mL). The solution was degassed for 30 min. The reaction was left overnight at room temperature and another portion of Zhani B catalyst (8 mg, 0.011 mmol) was added. The reaction was stirred for overnight and DMSO (2.34 uL) was added. The solvent was removed. The residue was purified by flash column chromatography (40% ethyl acetate/hexanes) to give the title compound (150 mg) as a colorless oil.

MS calcd for (C₅₀H₆₆BFN₄O_1D + H)⁺: 913.9 MS found (electrospray): (M + H)⁺ = 913.5

Example 1

W-{[(1 ,1 -dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-W-(2-hydroxy-1 ,2- oxaborinan-3-yl)-4-(1-isoquinolinyloxy)-L-prolinamide

Intermediate A1 (0.2 mmol,) was dissolved in THF (2 mL), and /V-methylmorpholine (22 μL, 0.2 mmoi) was added. The solution was cooled to -20 ⁰C, and isobutyl chloroformate (25.9 μL, 0.2 mmol) was added. After 5 minutes, a cold (-20 ⁰C) solution of Intermediate B5 (33.4 mg, 0.22 mmol) in DMF (2 mL) was added followed by the addition of triethylamine (30.7 μL, 0.22 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The oily residue was dissolved in ethyl acetate, washed with 0.2 N HCI, 5% NaHCO₃, and brine. The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified by C-18 coated silica gel column (ACNrH₂O, 2:1). The pure fractions were extracted with ethyl acetate. The organic layers were dried and concentrated to afford the title compound. MS calcd for (C₂₉H₄IBN₄O₇ - H)^" : 567 MS found (ESI negative): (Wl-H)^" = 567

¹H NMR (300 MHz, CD₃OD) 8.24 (1 H, d), 7.96 (1 H, d), 7.80 (1H, d), 7.70 (1 H, t), 7.51 (1H, t), 7.33 (1H, d), 6.48 (1H, dd), 5.89 (1 H, bs), 4.80 (1 H, t), 4.57 (1 H, t), 4.21 (1 H, dd), 4.08 (1H, dd), 3.78 (2H, m), 2.72 (1 H, m), 2.62 (1 H, m), 2.44 (1H, m), 1.73-1.68 (3H, m), 1.42-1.37 (1 H, m), 1.24 (9H, s), 1.05 (9H, s). 2 protons assumed to be exchanged with solvent.

Example 2

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-W-(2-hydroxy-1,2-oxaborinan-3-yl)-L-prolinamide

mg, 0.2 mmol).

MS calcd for (C₃₀H₄₂BFN₄O₈ - H)^" : 615 MS found (ESI negative): (M-H)^" = 615

¹H NMR (300 MHz, CD₃OD) δ 7.28 (1H, dd), 7.05 (1 H, dd), 7.01 (1 H, d), 6.72 (1H, t), 5.18

(1 H, s), 4.81-4.64 (5H, m), 4.44 (2H, d), 4.07 (1H, m), 3.85-3.67 (3H, m), 2.68 (1H, dt), 2.54

(1 H, m), 2.32 (1 H, m), 1.78-1.60 (3H, m), 1.59-1.32 (8H, m), 1.05 (9H, s). 3 protons assumed to be exchanged with solvent.

Example 3

(3ff,5S)-1-[(2S)-2-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)acetyl]-5-{[(2- hydroxy-1 ,2-oxaborinan-3-y l)amino]carbonyl}-3-pyrrolidinyl 1 ,3-dihydro-2H-isoindole-

2-carboxylate

Similarly prepared according procedure of Example 1 , using (2S,4R)-1-((S)-2-(3-terf- butylureido)-2-cyclohexylacetyl)-4-(isoindoline-2-carbonyloxy)pyrrolidine-2-carboxylic acid*(51 mg, 0.1 mmol) and Intermediate B5 (15 mg, 0.1 mmol). MS calcd for (C_3IH₄₆BN₅O₇ - H)^": 610.4 MS found (ESI negative): (M-H)^" = 610.3

¹H NMR (300 MHz, CD₃OD) δ 7.15-7.35 (4H, m), 5.4 (1H, br s), 4.6-4.8 (4H), 4.3 (1 H, d), 4.15 (1 H, t), 3.65-95 (2H, m), 2.2-2.75 (3H, m), 1.55-1.90 (8H, m), 1.2 (9H, s), 0.82-1.55 (1OH, m). *WO2007/089618A2

Example 4

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-vaIyI-(4/?)-W-(2-hydroxy-1,2-oxaborinan-3-yl)-

4-(1-isoquinolinyloxy)-L-prolinamide

The product was prepared according to the procedure of Example 1, using Intermediate A2

(80 mg, 0.166 mmol).

MS calcd for (C₃₀H_4IBN₄O₇ - H)^" : 579

MS found (ESI negative): (M-H)^" = 579 1H NMR (300 MHz, CD₃OD) 8.23 (1H, d), 7.96 (1H, d), 7.80 (1H, d), 7.70 (1H, t), 7.52 (1H, t),

7.33 (1 H, d), 5.89 (1H, bs), 4.82 (1H, t), 4.66 (1H, m), 4.52 (1H, d), 4.28 (1H, m), 4.08 (1 H, m), 3.78 (2H, m), 2.70 (2H, m), 2.44 (1 H, m), 1.78 -1.22 (12H, m) ,1.04 (9H, s). 3 protons assumed to be exchanged with solvent. Example 5

(1S,3aR,6aS)-2-(N-{(2S)-2-Cyclohexyl-2-[(2-pyrazinylcarbonyl)amino]acetyl}-3-methyl-L- valyl)-W-(2-hydroxy-1,2-oxaborinan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

The product was prepared according to the procedure of Example 1 , replacing (2S,4R)-1- ((S)-2-(fert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isoquinolin-1-yIoxy)-pyrrolidine-2- carboxylic acid by (7S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta-[c]pyrrole-1 -carboxylic acid^* (100 mg, 0.195 mmol). MS calcd for (C_3IH₄₇BN₆O₆ - H)^" : 609 MS found (ESI negative): (M-H)^" = 609

¹H NMR (300 MHz, CD₃OD) 9.17 (1H, d), 8.71 (1H, d), 8.60 (1 H, dd), 8.17 (1H, 7), 4.52 (2H, rn), 4.22 (1H, d), 3.84 (2H, m), 3.65 (2H, m), 2.78 (1H, m), 2.59 (2H, m), 1.98 -1.76 (3H, m) ,1.75-1 48 (10H, m), 1.46-1.32 (2H, m), 1.22-1.02 (6H, m), 0.95 (9H, s). 3 protons assumed to be exchanged with solvent. *WO2007/022459A2 Example 6

W-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-W-(2-hydroxy-1,2- oxaborepan-3-yl)-4-(1-isoquϊnolinyloxy)-L-prolinamide

Similarly prepared according to the procedure of Example 1, using Intermediate A1 and Intermediate B9 (50 mg, 0.106 mmol).

MS calcd for (C₃₀H₄₃BN₄O₇ - H)^": 581

MS found (ESI negative): (M-H)^" .= 581

¹H NMR (300 MHz, CD₃OD) 8.26 (1H, t), 7.97 (1H, d), 7.81 (1 H, d), 7.70 (1H, t), 7.52 (1H, t),

7.33 (1H, d), 6.49 (1 H, dd), 5.89 (1H, bs), 4.82 (1H, m), 4.60 (1H, m), 4.23 (1 H, m), 4.09 (1 H, m), 3.43-3.68 (2H, m), 2.75 (2H, m), 2.50 (1 H, m), 1.72 -1.38 (6H, m) ,1.23 (9H, s), 1.05 (9H, s). 2 protons assumed to be exchanged with solvent.

Example 7

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H^r- isoindol-2-yl)carbonyl]oxy}-W-[(3R)-2-hydroxy-1,2-oxaborolan-3-yl]-L-prolinamide

A solution of Intermediate C1 (64.5 mg, 0.085 mmol) in hexanes (5 mL) and MeOH (5 ml.) was treated with isobutyl boronic acid (17.4 mg, 0.171 mmol) and HCI (0.18 mL, 37% aqueous), respectively. The reaction was stirred at room temperature for 3 hr. The mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by the reverse phase column (C-18 coated silica gel, CH₃CN/H₂O = 1 : 1) to afford a mixture of isomers, 90% of which is the title compound.

MS calcd for (C₂₉H₄₀BFN₄OB + H)⁺: 603.3

MS found: (M+H)⁺ = 603.3

¹H NMR (CD₃OD) δ 7.32 (m, 1 H), 7.15 (d, 1H), 7.16-6.98 (m, 1H), 6.78 (d, 1H), 5.37 (s, 1 H),

4.71-4.61 (m, 3H), 4.50-4.40 (m, 2H), 4.13 (d, 1H)₁ 3.88-3.84 (m, 2H), 3.62-3.48 (br, 1H),

2.96 (d, 1H), 2.62-2.55 (m, 1H), 2.34-2.30 (m, 1 H), 1.90-1.84 (m, 1 H), 1.77-1.71 (m, 1 H),

1.55-1.28 (m, 8H), 1.21-1.17 (m, 2H), 1.04 (s, 9H).

Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC.

Example 8

W-{[{1 ,1 -Dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-W-(4-ethyl-2-hydroxy-1 ,2- oxaborolan-3-yl)-4-(1-isoquinolinyloxy)-L-proliπamide

Intermediate C2 (15 mg, 0.018 mol) and 2-methylpropyl boronic acid (3.4 mg, 0.035 mmol) were mixed in a mixture of hexanes (1 mL) and methanol (1 mL). To the mixture was added aqueous HCI (1 N, 0.76 mL). The mixture was stirred at room temperature for 2 days, diluted with dichloromethane (50 mL) and extracted with saturated sodium bicarbonate (50 mL). The aqueous layer was re-extracted with dichloromethane (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The solid was purified by preparative TLC (dichloromethane : methanol 10 : 1) to afford a mixture of isomers, 85% of which is the title compound.

MS calcd for (C₃₀H₄₃BN₄O₇ + H)⁺ : 583.5 MS found (electrospray): (M+H)⁺ = 583.3 1H NMR (CDCI₃) δ 8.28 (1 H, d), 7.99 (1H, d), 7.82 (1H, d), 7.70 (1 H, t), 7.53 (1H, t), 7.36 (1 H, d), 5.88 (1 H, s), 4.61 (1H, d), 4.22 (1 H, s), 4.08 (1 H, dd), 3.81 (1 H, t), 3.62 (1H, s), 3.04 (1 H, t), 2.92 (1H, d), 2.79 (1H, m), 2.40 (1 H, m), 1.90 (1H, m), 1.30 (2H, m), 1.28 (9H, s), 1.10 (9H, s), 0.94 (3H, t). 3 protons assumed to be exchanged with solvent. Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC.

Example 9

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-(4-ethyl-2-hydroxy-1,2- oxaborolan-3-yl)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)carboπyl]oxy}-L-prolinamide

The product of Intermediate C3 (72 mg, 0.08 mmol) and 2-methylpropyl boronic acid (16.26 mg, 0.16 mmol) were mixed in a mixture of hexanes (4.43 ml.) and methanol (4.43 mL). To this was added aqueous HCI (1 N, 3.4 mL) and the mixture was stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (50 mL) and extracted with saturated sodium bicarbonate (50 mL). The aqueous layer was re-extracted with dichloromethane (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The solid was purified by preparative TLC (dichloromethane : methanol, 10 : 1) to afford a mixture of isomers, 85% of which is the title compound (25 mg). MS calcd for (C₃₀H₄₄BFN₄O₈ + H)⁺ : 630/631/632 MS found (electrospray) : (M+H)* = 630/631/632

¹ H NMR (CD₃OD) δ 7.38 (1 H, m), 7.18 - 7.00 (2H, m), 5.39 (1 H, d), 4.85 - 4.72 (5H, m), 4.50 (2H, m), 4.18 (1 H, s), 3.82 (2H, m), 3.04 (1 H, t), 2.98 (1H, d), 2.58 (1H, m), 2.30 (1H, m), 1.92 (1 H, m), 1.60 - 1.20 (1 OH, m), 1.06 (9H, s), 0.98 (3H, t). 3 protons assumed to be exchanged with solvent. Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC. Example 10

Λ/-{[(1,1-diιnethylethyl)oxy]carbonyl}-3-niethyl-L-valyl-(4R)-Λr-[(3R)-4-ethenyl-2-hydroxy-

1,2-oxaborolan-3-yl]-4-(1-isoquinolinyloxy)-L-prolinamide

To a solution of Intermediate C4 (51.6 mg, 0.0605 mmol) in hexane (3 ml_) and methanol (3 ml.) was added isobutyl boronic acid (12.3 mg, 0.121 mmol) and HCI (1 N aqueous, 2 mL). The reaction was stirred at room temperature for 2 days. The mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by preparative TLC (silica, CH₂CI₂ZMeOH = 10: 1) to give the title compound (as a mixture of isomers). MS calcd for (C₃₀H_4IBN₄O₇ + H)⁺: 581.5 MS found: (M+H)⁺ = 581.5

¹H NMR (CD₃OD) δ 8.26 (d, 1H), 7.98 (d, 1 H), 7.81 (d, 1 H), 7.70 (t, 1 H), 7.53 (t, 1H), 7.34 (d, 1 H), 6.50 (d, 1 H), 5.91 (s, 1H), 5.65-5.80 (m, 1H), 5.13 (s, 1 H), 5.07-5.10 (d, 1H), 4.62 (s, 1 H), 4.59 (s, 1H), 4.23 (t, 1H), 4.08^.11 (m, 1H), 3.79 (t, 1 H), 2.95 (d, 2H), 2.68-2.82 (m, 3H), 2.40-2.48 (m, 2H), 1.23 (1s, 9H), 1.06 (s, 9H).

Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC. Example 11

W-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-W-[(3R)-2-hydroxy-1,2- oxaborolan-3-yl]-4-(1-isoquinolinyloxy)-L-prolinamide

A solution of Intermediate C5 (10.0 mg, 0.0193 mmol) in hexanes (1 mL) and MeOH (1 mL) was treated with isobutyl boronic acid (3.9 mg, 0.0386 mmol) and HCI (0.76 mL, 1N aqueous), respectively. The reaction was stirred at room temperature for 2 days. The mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was purified by preparative TLC (silica gel, CH₂CI₂/Me0H = 10: 1) to afford the title compound (as a mixture of isomers). MS calcd for (C_2BH₃₉BN₄O₄ + H)⁺: 555.3 IVIS found: (M+H)⁺ = 555.3

¹H NMR (CD₃OD) δ 8.26 (d, 1 H), 7.98 (d, 1H), 7.81 (d, 1 H), 7.70 (t, 1 H), 7.53 (t, 1H), 7.34 (d, 1 H), 6.70 (d, 1 H), 5.92 (s, 1H), 4.60 (d, 2H), 4.23 (d, 2H), 4.08-4.11 (m, 1H), 3.82 (t, 1H), 3.50 (m, 2H), 2.95 (d, 1H), 2.68-2.82 (m, 2H), 2.40-2.48 (m, 2H), 1.23 (1s, 9H), 1.06 (s, 9H). Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC.

Example 12

N-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4/?)-W-[(3R)-2-hydroxy-1,2-oxaborolan-

3-yl]-4-(1-isoquinolinyloxy)-

Similarly prepared according to the procedure of Example 8, using Intermediate C6 (116 mg, 0.40 mmol) to afford a mixture of isomers, 90% of which is the title compound.

MS calcd for (C₂₉H₃₉BN₄O₇ + H)*: 567.3

MS found: (M+H)⁺ = 567.3 1H NMR (300 MHz, CD₃OD) δ 8.34 (d, 1 H), 7.97 (d, 1 H), 7.81 (d, 1 H), 7.71 (t, 1 H), 7.53 (t,

1H), 7.34 (d, 1 H), 5.91 (s, 1 H), 4.54-4.69 (m, 3H), 4.27 (s, 1H), 4.07-4.12 (m, 1 H), 3.84 (d,

1 H), 3.45-3.49 (m, 1 H), 2.95 (d, 1 H), 2.76-2.79 (m, 1 H), 2.41-2.47 (m, 1H), 1.95 (m, 1H),

1.28-1.75 (m, 10H), 1.05 (s, 9H).

Example 13

W-[(cycIopentyloxy)carbonyl]-3-methyl-L-valyl-(4/?)-W-(4-cyclopropyl-2-hydroxy-1,2- oxaborolaπ-3-yl)-4-(isoquinolin-1-yloxy)-L-proliπamide

Intermediate C7 (81 mg, 0.09 mmol) and 2-methylpropyl boronic acid (19 mg, 0.186 mmol) were mixed in a mixture of hexanes (8 ml) and methanol (8 ml). Aqueous HCI (1 N, 2.2ml) was added to the mixture. The mixture was stirred at room temperature for 2 days, diluted with dichloromethane (50 ml) and extracted with saturated sodium bicarbonate (50 ml). The aqueous layer was re-extracted with dichloromethane (2 x 50 ml). The organic layers were combined and concentrated in vacuo. The solid was purified by preparative TLC (dichloromethane : methanol 10 : 1) to give the title compound (16 mg) (as a mixture of isomers).

MS calcd for (C_3IH₄₃BN₄O₇ + H)⁺: 607, MS found (ESI positive): (M+H)*=607.3 MS calcd for (C₃₁H₄₃BN₄O₇ - H)^': 605, MS found (ESI negative): (M-H)^" =605.3 1H NMR (CD₃OD) δ 8.15 (1H, d), 7.88 (1 H, d), 7.72 (1H, d), 7.61 (1H, t), 7.44 (1H, t), 7.24 (1H, d), 5.82 (1 H, s), 4.52 (1H, d), 4.18 (1H, m), 4.01 (1H, dd), 3.72 (1H, m), 3.53 (1 H, s), 3.04 (6H, m), 2.83 (1 H, d), 2.70 (1 H, m), 2.53 (1H, m), 1.49 (4H, m), 1.18 (4H, m), 0.97 (5H, m), 0.77 (3H, s), 0.38 (2H, s), 0.08 (2H, s). 2 protons assumed to be exchanged with solvent. Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC.

Example 14

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-(4-cyclopropyl-2-hydroxy-1,2- oxaborolan-3-yl)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)carboπyl]oxy}-L-prolinamide

Intermediate C8 (50 mg, 0.055 mmol) and 2-methylpropyl boronic acid (14 mg, 0.137 mmol) were mixed in a mixture of hexanes (5 ml) and methanol (5 ml). Then aqueous HCI (1 N, 1.5ml) was added to the mixture. The mixture was stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (50 ml) and extracted with saturated sodium bicarbonate (50 ml). The aqueous layer was re-extracted with dichloromethane (2 x 50 ml). The organic layers were combined and concentrated in vacuo. The solid was purified by reverse phase chromatography (C-18 silica) with 1:1 mixture of acetonenitrile and water to afford the title compound (as a mixture of isomers). MS calcd for (C₃₂H₄₄BFN₄O₈ + H)⁺: 643, WIS found (ESI positive): (M+H)⁺=643.4 MS calcd for (C₃₂H₄₄BFN₄O₈ - H)-: 641 , MS found (ESI negative): (M-H)^" =641.3

¹H NMR (CD₃OD) δ 7.15 (1H, m), 6.83-6.99 (2H, m), 5.19 (1 H, s), 4.90-4.40 (8H, m), 4.30 (1H, m), 3.97 (1 H, s), 3.72 (2H, m), 3.15 (3H, s), 2.74 (1 H, d), 2.42 (1H, m), 2.16 (1 H, m), 0.7-1.6 (16H, m), 0.35 (2H, s), 0.15 (2H, s). 2 protons assumed to be exchanged with solvent. Individual diastereoisomers can be identified by using separation techniques known to people skilled in the art, for example chiral HPLC.

Example 15

Λ/-[(Cyciopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-(2-hydroxy-2,3-dihydro-1,2- benzoxaborol-3-yl)-4-(1 -isoquinolinyloxy)-L-prolinamide

To a mixture of Intermediate A2 (74 mg, 0.152 mmol), Intermediate B27 (124 mg, 0.283 mmol) and HATU (59.4 mg, 0.156 mmol) was added 4 mL of anhydrous DMF. The reaction was stirred at room temperature for 10 min. Subsequently, DIEA (27 uL, 0.155 mmol) in 2 mL of anhydrous THF was added dropwise to the reaction mixture at 0 ⁰C. After stirred at 0 ⁰C for 10 min, 2 mL of 6N HCI was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate three times. After washed water and brine, the organic layer was dried over Na₂SO₄ and concentrated to give a yellow residue. The crude product was purified by C-18 reversed-phase column eluted with ACN and H₂O. The pure fractions were pooled and ACN was removed in vacuo. The aqueous solution was extracted with ethyl acetate three times. The organic layer was dried over Na₂SO₄ and concentrated to give the title compound. MS calcd for (C₃₃H₃₉BN₄O₇ + H)⁺ : 615.3, MS found (ESI positive): (M+H)* = 615.3 MS calcd for (C₃₃H₃₉BN₄O₇ - H)^' : 613.3, MS found (ESI negative): (M-H)^' = 613.3 1H NMR (300 MHz, CD₃OD) 8.23 (1 H, d), 7.91 (1H, d), 7.83 (1H, d), 7.72 (1H, t), 7.54 (1 H, t), 7.35 (1 H, d), 7.26 (1H, t), 6.96 (1 H, m), 6.62 (2H, m), 5.89 (1H, s), 4.96-3.16 (7H, m), 2.71 (1 H, m), 2.52 (1H, m), 1.76-1.08 (8H, m), 1.00 (9H, s). 2 protons assumed to be exchanged with solvent.

Example 16

W-[(Cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-W-(2-hydroxy-2,3-dihydro-1,2-benzoxaborol-3-yl)-L- prolinamide

To a mixture of Intermediate A3 (48 mg, 0.093 mmol), Intermediate B27 (81 mg, 0.185 mmol) and HATU (38 mg, 0.1 mmol) was added 2 mL of anhydrous DMF. The reaction was stirred at room temperature for 10 min. Subsequently, DIPEA (17.4 uL, 0.1 mmol) in 1 mL of anhydrous THF was added dropwise to the reaction mixture at 0 ⁰C. After stirred at 0 ⁰C for 10 min, 1 mL of 6N HCI was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate three times. After washed water and brine, the organic layer was dried over Na₂SO₄ and concentrated to give a yellow residue. The crude product was purified by C-18 reversed-phase column eluted with ACN and H₂O. The pure fractions were pooled and ACN was removed on rotavap. The aqueous solution was extracted with ethyl acetate three times. The organic layer was dried over Na₂SO₄ and concentrated to give the title compound. MS calcd for (C₃₃H₃₉BFN₄Os + H)⁺: 651.3, MS found (ESI positive): (M+H)⁺ = 651.3 MS calcd for (C₃₃H₃₉BFN₄O₈ - H)^" : 649.3, MS found (ESI negative): (M-H)^" = 649.3 ¹H NMR (300 MHz, CD₃OD) δ 7.35 (1H, m), 7.20 (1H, m), 7.20-6.96 (2H, m), 6.90 (1H, m), 6.54 (2H, m), 5.29 (1 H, s), 4.90-3.88 (1OH, m), 2.50 (1 H, m), 2.32 (1 H, m), 1.60-1.00 (8H, m), 0.95 (9H, s). 2 protons assumed to be exchanged with solvent.

Example 17

W-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-N-(2-hydroxy-1,2-oxaborepan-3-yl)-L-prolinamide

Similarly prepared according to the procedure of Example 1, using Intermediate A4 and Intermediate B9.

Example 20

Cyclopentyl (2S)-1 -((2S,4R)-2-(3-hydroxy-3,4-dihydro-1 H-benzo[d][1 ,2]oxaborinin-4- ylcarbarnoyl)-4-(isoquinolin-1-yloxy)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- ylcarbamate

To a mixture of Intermediate A2 (66 mg, 0.137 mmol), Intermediate B50 (123 mg, 0.273 mmol) and HATU (57 mg, 0.150 mmol) was added 4 mL of anhydrous DMF. The reaction was stirred at room temperature for 60 min. After 1 mL of 6N HCI was added, the reaction mixture was allowed to stirr for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. After washed water and brine, the organic layer was dried over Na₂SO₄ and concentrated to give a yellow residue. The crude product was purified by C-18 reversed-phase column eluted with ACN and H₂O. The pure fractions were pooled and ACN was removed on rotavap. The aqueous solution was extracted with ethyl acetate three times. The organic layer was dried over Na₂SO₄ and concentrated to give 20 mg of the title compound as an off-white solid. MS calcd for (C₃₄H₄₁BN₄O₇ + H)⁺ : 629.5, MS found (ESI positive): (M+H)⁺ = 629.3 MS calcd for (C₃₄H₄₁BN₄O₇ - H)^" : 627.5, MS found (ESI negative): (M-H)^" = 627.3

Example 22

(3R,5S)-1-((S)-2-(3-tert-butylureido)-2-cyclohexylacetyl)-5-((2-hydroxy-4-isopropyl-1₇2- oxaborolan-3-yl)carbamoyl 4-fluoroisoindoline-2-carboxylate

To a solution of Intermediate C10 (250 mg, 0.27 mmol) in MeOH (5 mL) was added 10% HCI (0.5 mL) and 5% Pd/C (10mg). The mixture was stirred at room temperature for 3 h under hydrogen and filtered, concentrated and purified by preparative HPLC to give the desired title compound as a white solid (40 mg, 22%). ¹H NMR (300 MHz, CDCI₃): 5 9.11- 9 15 (d, J=10 8 Hz, 1 H), 7 34-7 37 (d, J=6 9 Hz, 1H), 7 11-7 20 (m, 2H), 6 14-6 19 (m, 1 H), 5 96-5 98 (d, J=66Hz, 1H), 574-576 (d, J=7 5Hz, 1H), 5 28 (s, 1H) 3 78-3 82 (m, 2H), 3 59- 3 61 (m, 1H), 348-3 50 (m, 3H), 2 98-3 19 (m, 2H), 2 01-2 39 (m, 3H), 1 66-1 75 (m, 8H), 1 23-1 40 (m, 2H) 0 78-1 18 (m, 16H), 0 74-0 78 (m, 4H) LC-MS 658 (M + H)⁺

Example 23

(3R,5S)-1-((S)-2-(3-tert-butylureido)-2-cyclohexylacetyl)-5-((3R,4S)-4-ethyl-2-hydroxy- 1,2-oxaborepaπ-3-ylcarbam 4-fluoroisoindoline-2-carboxylate

To a stirred solution of BCI₃ (0 8 mL, 0 82 mmol) in CH₂CI₂ (20 ml.) at -78°C under nitrogen was added dropwise Intermediate C11 (150 mg, 0 164 mmol), and the resulting mixture was stirred for 2 hrs at -78°C Then the mixture was allowed to warm to rt The solvent was evaporated under vacuum and the residue was purified by preparative HPLC to give a white solid (50 mg, 50 %) LC-MS 694 (M + Na)⁺

Example 24

(3R, 5S)-1-((S)-2(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-5-(4-vinyl-2- hydroxy-1,2-oxaborolan-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- car boxy late

Intermediate C18 (50 mg, 0 056 mmol) and 2-methylpropyl boronic acid (11 3 mg, 0 11 mmol) were mixed in a mixture of hexanes (3 mL) and methanol (3 mL) To this was added aqueous HCI (1 N, 24 mL) and the mixture was stirred at room temperature for 2 days The reaction was diluted with dichloromethane (50 mL) and extracted with saturated sodium bicarbonate (50 mL) The aqueous layer was re-extracted with dichloromethane (2 x 50 mL) The organic layers were combined and concentrated in vacuo The solid was purified by preparative TLC (dichloromethane : methanol 10 : 1) to give the title compound (13 mg) as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 7.38 (1H, m), 7.18 - 6.8 (2H, m), 5.90 (1H, m), 5.40 (1H, m), 5.20 (2H, t), 4.90 - 4.70 (4H, m, overlap with water), 4.50 (2H, m), 4.08 (1 H, d), 3.90 (1 H, dd), 3.70 (1 H, m), 3.50 (1 H, t), 2.84 (1 H, m), 2.70 (1 H, m),2.58 (1 H, m), 2.38 (1 H, m), 1.65 - 1.25 (9H, m), 1.08 (9H, s). Three protons were assumed to be exchanged with solvent.

MS calcd for (C₃₁H₄₂BFN₄O₉ H- H)⁺: 629.5 MS found (electrospray): (M + H)⁺ = 629.3 Example 25

(1R,2S,5S)-3-((S)-2-(3-tert-butylureido)-3_I3-dimethylbutanoyi)-N-((R)-2-hydroxy-1,2-

To a mixture of (1 R,2S,5S)-3-((S)-2-(3-tert-butyIureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (purchased from ACME Bioscience, 63 mg, 0.171 mmol), Intermediate B13 (99.3 mg, 0.343 mmol) and HATU (130 mg, 0.343 mmol) was added 5 mL of anhydrous DMF. The reaction was stirred at room temperature for 10 min. Subsequently, DIEA (60 uL, 0.343 mmol) in 1 mL of anhydrous THF was added dropwise to the reaction mixture. After stirred for 16 hours, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated to give a yellow residue. Subsequently, a solution of this residue in 5 mL of hexane and 5 mL of MeOH was treated with isobutyl boronic acid (34 mg, 0.334 mmol) and HCI (0.6 mL, 6N), respectively. The reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude residue was purified by reversed-phase column eluted with ACN and H₂O. The pure fractions were collected and ACN was removed in vacuo. The aqueous solution was extracted with ethyl acetate three times. The organic layer was dried over Na₂SO₄ and concentrated to give 22 mg of the title compound as a white solid.

MS calcd for (C₂₂H₃₉BN₄O₅ + H)⁺: 451.4, MS found (ESI positive): (M+H)⁺ = 451.3 MS calcd for (C₂₂H₃₉BN₄O₆ - H)^" : 449.4, MS found (ESI negative): (M-H)^" = 449.3

Example 31 (3R,5S)-1-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-5-((3R)-4-ethyl- 2-hydroxy-1,2-oxaborepan-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- carboxylate

To a stirred solution of BCI₃ (0.8 mL, 0.82 mmol) in CH₂CI₂ (20 mL) at -78⁰C under nitrogen was added dropwise Intermediate C12 (50 mg, 0.0556 mmol), and the resulting mixture was stirred for 2 hrs at -78°C. Then the mixture was allowed to warm to rt. The solvent was evaporated under vacuum and the residue was purified by prep-HPLC to give the two isomers (22 mg, 60 %) and (17 mg, 40 %) as a white solid respectively. LC-MS: 681 (M + Na)⁺.

Example 33

(3R,5S)-5-((3R,4R)-4-allyl-2-hydroxy-1,2-oxaborolan-3-ylcarbamoyl)-1-((S)-2- (cyclopeπtyloxycarbonylamiπo)-3,3-dimethylbutanoyl)pyrrolidin-3-yl 4- fluoroisoindoline-2-carboxylate

A solution of Intermediate C13 (119 mg, 0.130 mmol) in MeOH/hexanes (7mL/7mL) was treated with isobutyl boronic acid (26.5 mg, 0.260 mmol) and 1N HCI (4 mL). -The resulting mixture was stirred at room temperature for 3 days. Then, the reaction mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried (Na₂SO₄), and concentrated to dryness. The residue was purified by the reverse phase column (MeCN : H₂O = 2:1) to give the title compound (42 mg) as a white solid.

MS calcd for (C₃₂H₄₄BFN₄O₈ + H)⁺ = 643.3 MS found (electrospray): (MH-H)⁺ = 643.3

Example 34

{3R,5S)-5-((3R,4RH-allyl-2-hydroxy-1_!2-oxaborolan-3-ylcarbamoyl)-1-((S)-2- (cyclopeπtyloxycarbonylamino)oct-7-enoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- carboxylate

A solution of Intermediate C14 (83 mg, 0.089 mmol) in MeOH/hexanes (4mL/4mL) was treated with isobutyl boronic acid (18 mg, 0.18 mmol) and 1 N HCI (3 mL). The resulting mixture was stirred at room temperature for 3 days. Then, the reaction mixture was diluted with CH₂CI₂ and washed with brine. The organic phase was separated, dried (Na₂SO₄), and concentrated to dryness. The residue was purified by the reverse phase column (MeCN : H₂O = 2:1) to give the title compound (38 mg) as a white solid.

MS calcd for (C₃₄H₄₆BFN₄O₈ + H)⁺ = 669.3 MS found (electrospray): (M+Hf = 669.3

Example 35

Λf-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-[(3R,4R)-4-methyl-2-hydroxy-1,2- oxaborinan-3-yl]-4-(1-isoquin

To the mixture of Intermediate A2 (49mg, 0.1 mmol) and Intermediate B67 (110mg,

0.2mmol) in DMF (3ml), added HATU (57mg, 0.15mmol) then DIPEA (32mg, 0.25mmol) in CH₂CI₂ (3ml) dropwise. Stirring was kept for 2 hours after addition. Diluted with EtOAc (60ml), washed with water (2x1 OmI) and brine (10ml). The organic phase was separated, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in MeOH/Hexane (1 :1 , 8ml), then added isopropyl boronic acid (36mg, 0.3mmol) followed by HCI (1 N in H₂O, 1ml). Stirring was kept at room temperature overnight. Diluted with CH₂CI₂ (30ml) and washed with brine (2x5ml). The organic phase was separated, dried over sodium sulfate and concentrated. The residue was purified by the reverse phase column (acetonitrile/water, 1:2 to 1:1) to give the title compound as a white solid.

MS calcd for (C₃₂H₄₇BN₄O₈-H)- = 594.3; MS found (ESI negative): (M-H)^' = 593.3

Example 38

(3R, 5S)-1-((S)-2(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-5-(4-allyl-2- hydroxy-1,2-oxaborolan-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- carboxylate

Intermediate C17 (107 mg, 0.12 mmol) and 2-methylpropyl boronic acid (24.5 mg, 0.24 mmol) were mixed in hexanes (7 mL) and methanol (7 mL). To this was added aqueous HCI (1 N, 5.2 mL) and the mixture was stirred at room temperature for 2 days. Additional aqueous HCI (3 N, 3.7 mL) was added and the reaction was stirred at room temperature for another 2 days. The reaction was diluted with dichloromethane (50 mL) and extracted with saturated sodium bicarbonate (50 mL). The aqueous layer was re-extracted with dichloromethane (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The solid was purified by preparative TLC (dichloromethane : methanol, 10 : 1) to give the title compound (10 mg) as a white solid. Example 44

(3aR,11 S,15R,16aS,18afi,Z)-11 -(cyclopentyloxycarbonylaminoH -hydroxy-12,17-dioxo- 3,3a,4J,8,9,10,11,12,14,15,16,16a,17,18,18a-hexadecahydro-1W-[1,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ,4]diazacyclopentadecin-15-yl 4-fluoroisoindoline-2-carboxylate

A solution of Intermediate C15 (27 0 mg, 0 030 mmol) in hexanes/MeOH (2/2 mL) was treated with isobutyl boronic acid (6 03 mg, 0 059 mmol) and HCI (3N, 1 mL) at room temperature The reaction was stirred for 2 days The mixture was diluted with ethyl acetate and washed with brine The organic phase was separated, dried (Na₂SO₄), and concentrated The residue was purified by reverse phase column to afford the title compound (6 9 mg)

MS calcd for (C₃₂H₄₂BFN₄O₈ + H)⁺ 641 3 MS found (M+H)⁺ = 641 3

Example 45 (3aR,11 S,15R,16aS,18aR,£)-11 -(cyclopentyloxycarbonylaminoj-i -hydroxy-12,17-dioxo- 3,3a,4,7,8,9,10,11 ,12,14,15,16,16a,17,18,18a-hexadecahydro-1 H-[1 ,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ,4]diazacyclopeπtadecin-15-yl 4-fluoroisoindoline-2-carboxylate

A solution of Intermediate C16 (27 0 mg, 0 030 mmol) in hexanes/MeOH (1 1, 4 mL) was treated with isobutyl boronic acid (6 03 mg, 0059 mmol) and HCI (3N, 1 mL) at room temperature The reaction was stirred for 2 days The mixture was diluted with ethyl acetate and washed with brine The organic phase was separated, dried (Na₂SO₄), and concentrated The residue was purified by reverse phase column to afford the title compound (5 7 mg)

MS calcd for (C₃₂H₄₂BFN₄O₈ + H)⁺ 641 3 MS found (Mn-H)⁺ = 641 3

¹H NMR (300 MHz, CD₃OD) δ 7 38 (1H, m), 7 18 - 68 (2H, m), 6 10 (1 H, m), 545 (2H, m), 5 15 - 4 75 (4H, m, overlap with water), 4 55 (2H, m), 4 17 (1 H, d), 3 95 (1 H₁ dd), 3 78 (1 H, m), 3 70 (1 H₁ S), 3 55 (1H, m), 260 (1H, m), 2 36 (1 H, m), 2 15 (2H, m), 1 65 - 1 25 (11H, m), 1 10 (9H, s) Three protons were assumed to be exchanged with solvent

MS calcd for (C₃₂H₄₄BFN₄O₈ + H)⁺ 642 5 MS found (electrospray) (M + H)⁺ = 643 3 Example 46

(3aS,11 S,15R,16aS,18aR)-11 -(cyclopentyloxycarbonylaminoj-i -hydroxy-12,17-dioxo- 3,3a,4,7,8,9,10,11 ,12,14,15,16,16a,17,18,18a-hexadecahydro-1 H-[1 ,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ,₄]diazacyclopentadecin-15-yl 4-fluoroisoindoline-2-carboxylate

Intermediate C20 (40 mg, 0.044 mmol) and 2-methylpropyl boronic acid (9 mg, 0.088 mmol) were mixed in a mixture of hexanes (3 ml.) and methanol (3 ml_). To this was added aqueous HCI (3 N, 1.5 mL) and the mixture was stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (50 mL) and extracted with saturated sodium bicarbonate (50 mL). The aqueous layer was re-extracted with dichloromethane (2 x 50 mL). The organic layers were combined and concentrated in vacuo. The solid was purified by preparative TLC (dichloromethane : methanol 10 : 1) to give the title compound (10 mg) as a white solid as a mixture of cis and trans isomers.

¹H NMR (300 MHz, CD₃OD) 57.25 (1H, m), 7.08 (1 H, m), 6.90 (1 H, t), 5.56 (1H, m), 5.25 (1 H, m), 4.80 - 4.60 (5H, m, overlap with water), 4.25 (1H, m), 3.82 (1 H, m), 3.20 (2H, m), 3.10 (1 H, t), 2.75 (1H, m), 2.20 (2H, m), 1.92 (1 H, m), 1.80 (1 H, m), 1.68 (1H, m), 1.40 - 1.10 (15H, m), 0.85 (3H, m). 3 protons assumed to be exchanged with solvent. MS calcd for (C₃₂H₄₂BFN₄O₈ + H)⁺: 641.5 MS found (electrospray): (M + H)⁺ = 641.3

The following compounds were also prepared using the methods described above:

,2-

,2- 4-

Ths following compounds may also be prepared using the methods described above ,2- ,2- ,2-

Intermediates B4, B5, B8, B9, B12, B13, B20, B23, B26, B27, B28, B31, B35, B36, B38, B42, B43, B47, B50, B56, B64, B67, B70, B76 and B79 may be used to prepare further examples of compounds of the invention. Intermediates B5, B9 and B27 are compounds of Formula (III) that may, for example, be coupled to compounds of Formula (II) in the processes described and exemplified above to provide further examples of compounds of Formula (I). Intermediate B4 is a compound of Formula (IV) that may, for example, be coupled to compounds of Formula (II) in the processes described and exemplified above to provide further examples of compounds of Formula (I). Intermediates B13, B36, B38, B43 and B47 are compounds of Formula (IHb) that may, for example, be coupled to compounds of Formula (II) in the processes described and exemplified above to provide further examples of compounds of Formula (Xl), and subsequently Formula (I). Intermediates B8, B12, B20, B23, B26, B28, B31 , B35, B42, B50, B56, B64, B67, B70, B76 and B79 are compounds of Formula (VIb) that may, for example, be coupled to compounds of Formula (II) in the processes described and exemplified above to provide further examples of compounds of Formulae (Xl) and (XIa), and subsequently Formula (I).

For example, Intermediate A4, can be coupled with any one of Intermediates B5, B9 and B27 to provide further example compounds of Formula (I). In another example, Intermediate A14 can be coupled with Intermediate B70 to provide an analogue to Intermediate C14 which in turn can be cyclised to form a analogues of Intermediates C15 and C16 which can in turn be converted into compounds of Formula (I) including a 16-membered hetrocyclic ring using the procedure described for Examples 44 and 45.

The compounds of Formula (I) or salts thereof may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.

The compounds of Formula (I) or salts thereof can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.

Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds of Formula (I) or salts, solvates or esters thereof are formulated in liquid solutions, preferably, in pharmaceutically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Systemic administration can also be by transmucosal or transdermal means. For traπsmucosal 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.

For topical administration, the compounds of Formula (I) or salts thereof can be formulated into ointments, salves, gels, or creams, as is generally known in the art.

The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound (IC₅₀) potency, (EC₅₀) 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.

Suitably 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.

Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(l). A topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I). The active ingredient may be administered from 1 to 6 times per day, for example once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.

Compounds of Formula (I) or salts thereof which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. 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 flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard 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.

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.

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. A typical suppository formulation comprises a compound of Formula (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 dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.

ASSAYS The potential for compounds of Formula (I) or salts thereof to inhibit NS3-4A HCV protease activity may be demonstrated, for example, using the following in vitro assay:

Hepatitis C NS3 Protease FRET Assay using the HCV Genotype 1a NS3-4A Protease Domain Compounds are tested as inhibitors of HCV NS3-4A protease domain in 30 μl reactions which contain 50 mM HEPES pH 7.5, 300 mM NaCI, 20% glycerol or 20% sucrose, 0.1% NP40, 2 mM DTT, 30 μM 4A peptide (KKGSWIVGRIVLSGKPAIIPKK that serves as a cofactor and activates the enzyme in the assay) (prepared by standard synthetic methods), 5 μM FRET substrate (FAM-EDWPPraSMSYK-TAMRA) and typically 100 nM NS3-4A protease domain. The FRET substrate (FAM-EDWPPraSMSYK-TAMRA) was prepared by attaching FAM and TAMRA (obtainable for example from Molecular Probes, or Invitrogen) by standard methods to a peptide EDWPPraSMSYK. Assembly of the EDWPPraSMSYK peptide was carried out using standard methods of solid phase peptide synthesis and incorporating the non-natural amino acid, L-propargylglycine (Pra, used to replace cysteine in the natural sequence) using the commercially available Fmoc derivative of Pra: Fmoc-Pra- OH (Advanced ChemTech, cat # CB6025).

^ Q Fmoc-Pra-OH

The N-termiπal was capped with 5-carboxy fluorescein (5-FAM-, Molecular Probes, or Invitrogen) as the free acid via a hydroxybenzotriazole/carbodiimide mediated coupling and the mono-tagged peptide was cleaved from the resin and purified to homogeneity by 15 preparative HPLC. This was reacted with the /V-hydroxysuccinimide ester of 5-carboxy- tetramethylrhodamine (5-TAMRA-ONSu, Molecular Probes, or Invitrogen) in solution and the resultant bis-tagged molecule purified by HPLC.

Cleavage of the substrate, which is based on the natural 5A/5B junction, is followed by an

20 increase in fluorescence with 485 nm excitation/535 nm emission in a PerkinElmer Victor3V plate reader. Compounds are dissolved in DMSO and tested at 100 μM in duplicate or in dose response curves with usually 100 μM top concentration and doubling dilutions. The maximum level of DMSO is 5%. Standards in the assay are the compound BILN-2061

(Lamarre et a/., (2003) Nature, 426, 186-189) and the translactam compound GW640014X

25 (Andrews ef a/. , (2003) Org Lett. , 5, 4631 -4634).

Table 1 shows the sequence of the HCV 1a NS3-4A protease domain compared to the full length HCV 1a NS3-4A protease. Shaded areas indicate where residues of the NS3-4A protease domain exactly match those of the full length NS3-4A protease. 30

Table 1

Hepatitis C NS3 Protease FRET Assay using the Full Length HCV Genotype 1a NS3-4A Protease

Compounds are tested by the same method as for NS3-4A protease domain, but the buffer contains 50 mM HEPES pH 8.0 and the glycerol level is 10% (or 20% sucrose to replace glycerol) and full length HCV genotype 1a NS3-4A protease replaces the NS3-4A protease domain.

Compounds are considered active as inhibitors of the protease if they have an ICs₀ value of less than 50 μM.

The compounds of Examples 1-16, 18-23, 25-29, 31-34, 36-39 and 44-45 were tested and demonstrate an activity of IC₅₀ < 50 μM in the hepatitis C NS3 protease FRET assay using the HCV genotype 1a NS3-4A protease domain. The compound of Example 46 was also tested and demonstrates and activity of IC₅₀ > 100 μM in the same assay.

Compounds of Examples 1-15, 18-19, 22-23, 25-29, 31 , 33-34, 36-39 and 44-45 demonstrate an activity of IC₅₀ < 15 μM in the hepatitis C NS3 protease FRET assay using the HCV genotype 1a NS3-4A protease domain.

Compounds of Examples 1-9, 11-14, 18-19, 22, 25-28, 33-34, 36-39 and 44-45 demonstrate an activity of IC₅₀ < 10 μM in the hepatitis C NS3 protease FRET assay using the HCV genotype 1a NS3-4A protease domain. Compounds of Examples 2-7, 9, 11 , 12, 14, 18-19, 22, 26, 33, 36 and 39 demonstrated an activity of IC₅₀ < 1 μM in the hepatitis C NS3 protease FRET assay using the HCV genotype 1a NS3-4A protease domain. The pharmaceutical compositions according to the invention 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 a pharmaceutically acceptable salt thereof together with at least one other therapeutic agent. When a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or ester thereof is used in combination with a second therapeutic agent active against the same disease state, 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 Formula (I) or a salt thereof 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 pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies [e.g. interferon, such as interferon alfa-2a (ROFERON®-A; Hoffmann-La Roche), interferon alpha-2b (INTRON(B)-A; Schering-Plough), interferon alfacon-1 (INFERGEN®; Intermune), peginterferon alpha-2b (PEGINTRON™; Schering-Plough) or peginterferon alpha-2a (PEGASYS®; Hoffmann-La Roche)], therapeutic vaccines, antifibrotic agents, antiinflammatory 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 [e.g. N- acetylcysteine], cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial, anti-viral agents [e.g. ribavirin and amantidine], and anti-HCV agents [for example HCV NS3 protease inhibitors, e.g. VX950 (telapravir; Vertex), SCH503034 (Schering Plough) or ITMN191 (Intermune)], or HCV NS5b polymerase inhibitors [for example HCV796 (Wyeth) or R1626 (Roche)], RNAi agents or cyclophilin inhibitors (for example DEBIO-025) . The compositions according to the invention may also be used in combination with gene replacement therapy. Suitable other therapeutic agents include interferon, ribavirin and/or an additional anti-HCV agent The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art. All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

Claims

1. A compound of Formula (I):

(D wherein:

R¹ is selected from H; Ci-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-Ce alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃- C₇ cycioalkyl optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); or R¹, R⁴ and the atoms between them form a 7 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^A, S, and SO₂;

R^A is H or CrC₆ alkyl, optionally substituted with one or more fluoro groups; or R¹ and R⁸ together with the two carbon atoms between them form a C₃-C₇ cycloalkyl group, optionally substituted by one or more groups selected from C_rC₆ alkyl (optionally substituted with one or more fluoro groups), C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups) and fluoro;

R² is a group -X-(CH₂)_m-R¹⁰, where m is 0, 1 or 2;

X is selected from NH, O, O-C(O), S and bond; R¹⁰ is selected from C₆ ioaryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR^B, NR^BR^B, SR^B, SO₂R^B, NHSO₂R⁸, CONHR^B, NHCOR^B, C_{6 10}aryl, 5 to 10-membered heteroaryl and 5 to 10- membered heterocyclyl, which latter C^-maryl, 5 to 10-membered heteroaryl and 5 to 10- membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from C₁-C₆ alkyl, OR^B, NR^BR^B, SR^B, SO₂R⁸, NHSO₂R⁸, CONHR^B and NHCOR^B, each R^B is independently selected from H, C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro, C_{6 10} aryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl), C₂-C₆ alkeπyl optionally substituted with one or more groups selected from fluoro, C_{6 10} aryl (optionally substituted with one or more groups selected from halo and Ci-C₆ alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl), C_{6 10} aryl optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl, and 5 to 10-membered heteroaryl optionally substituted with one or more groups selected from halo and C₁-C₆ alkyl,

R³ is H, or R² and R³ together with the two carbon atoms between them form a C^cycloalkyl group, wherein the cycloalkyl group is optionally substituted by one or more groups selected independently from C^alkyl and halo, when X is bond, R²⁰ is H or OH, otherwise R²⁰ is H,

R⁴ is selected from H, C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups), C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups), or R⁴, R⁸ and the atoms between them form an 8 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₅ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR^A, S, and SO₂;

Z is selected from -NHR⁵, -OR⁵, -R^6a and

R⁵ is selected from C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, CrCe alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups;

R^5a is selected from CrC₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, CrC₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, CrC₆ alkyl and C₂-C₆ alkenyl, the CrC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₆.₁₀ aryl optionally substituted by one, two or three groups selected from C₁- C₆ alkyl (optionally substituted with one or more fluoro groups), OR^A, NR^AR^A, hydroxy and halo; and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), OR* NR^AR^A, hydroxy and halo;

R^4a is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃- C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups);

R⁶ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); and C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; n is 1 , 2 or 3; each Y group is selected from C(H)_PR⁷, O and NR⁹, with the proviso that no two O or NR⁹ groups are adjacent to each other in the ring; p being 1 if the Y group is only single bonded; p being 0 if the Y group is part of an aryl, heteroaryl or heterocyclic ring;

R⁷ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl and C₂-C₆ alkenyl, the Ci-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups;

R⁹ is selected from H; C₁-C₆ alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups); C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, Ci-C₆ alkyl and C₂-C₆ alkenyl, the CrC₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups; C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups; C(O)R⁸; CO₂R⁸; S(O)R⁸; and SO₂R⁸ where R^B is independently as defined above; R⁸ and R³⁰ are independently selected from H, CrC₆alkyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups), C₃-C₇ cycloalkyl optionally substituted with one or more groups selected from fluoro, CrC₆ alkyl and C₂-C₆ alkenyl, the C₁-C₆ alkyl and C₂-C₆ alkenyl groups being optionally substituted with one or more fluoro groups, and C₂-C₆ alkenyl optionally substituted with one or more groups selected from fluoro and C₃-C₇ cycloalkyl, the C₃-C₇ cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and C₂-C₆ alkenyl (optionally substituted with one or more fluoro groups), or R⁸ and R³⁰ together with the carbon atom to which they are attached form a C₃₆membered cyclic ring, for example spirocyclopropane, or R⁸ and an R⁷ together with the atoms between them, or two R⁷ groups together with the atoms between them, form a 5, 6 or 7 membered cyclic group which may be aromatic, which may include one or two heteroatom groups selected from O, NR^A, S, and SO₂, and which may be optionally substituted by one, two or three groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) and fluoro,

R³⁰ is selected from H and C_rC_βalkyl, or salts thereof

2 A compound according to claim 1 wherein R¹ is H

3 A compound according to claim 1 or claim 2 wherein m is 0

4 A compound according to any of claims 1 to 3 wherein R¹⁰ is selected from 5 to 10- membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo, C_rC₆alkyl (optionally substituted with one or more fluoro groups), OR⁸ and NR^aR^B, wherein each R^B is independently selected from H and C₁-C₆ alkyl optionally substituted with one or more fluror groups

5 A compound according to claim 1 or claim 2 wherein R² and R³ together with the two carbon atoms between them form a C₃-C₅ cycloalkyl group, optionally substituted by one or more groups selected from C₁-C₆ alkyl (for example methyl) and fluoro

6 A compound according to any of claims 1 to 5 wherein R²⁰ is H 7. A compound according to any of claims 1 to 6 wherein R⁴ is selected from CrC₆ alkyl, C₂-C₆ alkenyl and C₃-C₇ cycloalkyl.

8. A compound according to any of claims 1 to 6 wherein R⁴, R⁸ and the atoms between them form an 12 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds.

9. A compound according to any of claims 1 to 7 wherein R⁸ is H, C₁-C₆ alkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups, or C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups. to any of claims 1 to 9 wherein Z is selected from -NHR⁵, -OR⁵

11. A compound according to any of claims 1 to 10 wherein R⁵ is selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl.

12. A compound according to any of claims 1 to 11 wherein R^5a is 5 to 10-membered heteroaryl.

13. A compound according to any of claims 1 to 12 wherein R⁶ is H.

14. A compound according to any of claims 1 to 13 wherein Y is C(H)_PR⁷.

15. A compound according to any of claims 1 to 14 wherein R⁷ is H.

16. A compound according to any of claims 1 to 15 wherein R³⁰ is H or CrCβalkyl optionally substituted with one or more fluoro groups.

17. A compound according to any of claims 1 to 16 wherein R¹ is H; either R² is -X-(CH₂)_m- R¹⁰, m is 0, R¹⁰ is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo and C₁-C₆ alkyl (optionally substituted with one or more fluoro groups) or R² and R³ together with the two carbon atoms between them form a C^₅ cycloalkyl group, optionally substituted by one or more groups selected from CrC₆ alkyl (for example methyl) and fluoro; R²⁰ is H; R⁴ is selected from C₁-C₆ alkyl, C₂-C₆ alkenyl and C₃-C₇ cycloalkyl; Z is selected from -NHR⁵, - OR⁵, -R^5a and

; R⁵ is selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl; R^5a is selected from 5 to 10-membered heteroaryl; R^4a is selected from CrC₆ alkyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; R⁶ is H; n is 1 , 2 or 3; Y is C(H)_PR⁷; R⁷ is H; R^B is H, d-Cβalkyl optionally substituted with one or more fluoro groups, C₂-C₆ alkenyl optionally substituted with one or more fluoro groups, or C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; and R³⁰ is H or C_rC₆ alkyl optionally substituted with one or more fluoro groups, or salts thereof.

18. A compound according to claim 17 wherein R¹ is H; either R² is -X-(CH₂)_m-R¹⁰, m is 0, X is -O- or -OC(O)-, R¹⁰ is selected from

and R³ is H or R² and R³ together with the two carbon atoms between them form a cycloalkyl group selected from an unsubstituted cyclopentyl ring and a cyclopropyl

19. A compound according to any of claims 1 to 16 wherein R¹ is H; either R² is -X-(CH₂)_m- R¹⁰, m is 0, R¹⁰ is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo and CrCealkyl (optionally substituted with one or more fluoro groups) or R² and R³ together with the two carbon atoms between them form a C₃.₅ cycloalkyl group, optionally substituted by one or more groups selected from Ci_β alkyl (for example methyl) and fluoro; R²⁰ is H; R⁴, R⁸ and the atoms between them form an 12 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C₁-C₆ alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH₂ group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds; Z is selected from -NHR⁵, -OR⁵, -R^5a and

; R⁵ is selected from C₁-C₆ alky! and C₃-C₇ cycloalkyl; R^5a is selected from 5 to 10-membered heteroaryl; R^4a is selected from C₁-C₆ alkyl optionally substituted with one or more fluoro groups and C₃-C₇ cycloalkyl optionally substituted with one or more fluoro groups; R⁶ is H; n is 1, 2 or 3; Y is C(H)_PR⁷; R⁷ is H; and R³⁰ is H or Ci-C₆alkyl optionally substituted with one or more fluoro groups, or salts thereof.

20. A compound according to claim 19 wherein R¹ is H; either R² is -X-(CH₂)_m-R¹⁰, m is 0, X is -O- or -OC(O)-, R¹⁰ is selected from

and R³ is H or R² and R³ together with the two carbon atoms between them form a cycloalkyl group selected from an unsubstituted cyclopentyl ring and a cyclopropyl ring substituted by two methyl groups; R⁴, R⁸ and the atoms between them form a 15 to 16-membered heterocyclic ring which may be optionally substituted with one or more groups selected from methyl and a CH₂ group bridging two neighbouring carbon atoms

21. A compound of Formula (I) chosen from the group consisting of:

Λ/-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4/^:?)-Λ/-(2-hydroxy-1,2-oxaborinan-3-yl)-

4-(1-isoquinolinyloxy)-L-proliπamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaborinan-3-yl)-L-prolinamide;

(3R,5S)-1-[(2S)-2-cyclohexyl-2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)acetyl]-5-{[(2- hydroxy-1 ,2-oxaborinan-3-yl)amino]carbonyl}-3-pyrrolidinyl 1 ,3-dihydro-2H-isoindole-2- carboxylate;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4f?)-/V-(2-hydroxy-1 ,2-oxaborinan-3-yl)-4-

(isoquinolin-i-yloxy)-L-prolinamide;

(1 S,3a/?,6aS)-2-(/V-{(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3-methyl-L- valyl)-Λ/-(2-hydroxy-1,2-oxaborinaπ-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;

Λ/-(ferf-butoxycarbonyl)-3-methyl-L-valyl-(4/?)-W-(2-hydroxy-1 ,2-oxaborepan-3-yl)-4-

(isoquinoIin-i-yloxy)-L-prolinamide; Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoiπdol-2- yl)carboπyl]oxy}-Λ/-[(3f?)-2-hydroxy-1 ,2-oxaborolan-3-yl]-L-prolinamide;

Λ/-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-Λ/-(4-ethyl-2-hydroxy-1 ,2- oxaborolan-3-yl)-4-methyl-L-prolinamide - 1(2H)-isoquinolinone;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-(4-ethyl-2-hydroxy-1 ,2-oxaborolan-3-yl)-

4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2-yl)carboπyl]oxy}-L-proliπamide

Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-vaIyl-(4R)-/V-[(3R)-4-ethenyl-2-hydroxy-1 ,2- oxaborolan-3-yl]-4-methyl-L-prolinamide - 1(2H)-isoquinolinone;

Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-Λ/-[(3R)-2-hydroxy-1 ,2-oxaborolan-

3-yl]-4-methyl-L-prolinamide - 1(2H)-isoquinolinone;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-[(3R)-2-hydroxy-1 ,2-oxaborolan-3-yl ] -

4-(isoquinolin-1-yloxy)-L-prolinamide

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyI-(4R)-Λ/-(4-cyclopropyl-2-hydroxy-1,2- oxaborolan-3-yl)-4-(isoquinoliπ-1-yloxy)-L-prolinamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-W-(4-cyclopropyl-2-hydroxy-1,2- oxaborolan-3-yl)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-proliπamide;

N-[(cyclopentyloxy)carboπyI]-3-methyl-L-valyl-(4R)-W-(2-hydroxy-2,3-dihydro-1,2- benzoxaborol-3-yl)-4-(1-isoquinolinyloxy)-L-proliπamide;

Λ/-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2/-/-isoiπdol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-2,3-dihydro-1 ,2-benzoxaborol-3-yl)-L-prolinamide;

Λ/-(fert-butoxycarbonyl)-3-methyl-L-vaIyI-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaborepan-3-yl)-L-proIinamide;

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-vaIyl-(4R)-Λ/-(2-hydroxy-1 ,2-oxaborepan-3-yl)-4-

(isoquinolin-i-yloxy)-L-prolinamide;

Λ/-[(cyclopeπtyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-W-(2-hydroxy-1 ,2-oxaborepan-3-yl)-L-prolinamide;

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-(3-hydroxy-3,4-dihydro-1H-2,3- benzoxaborin-4-yl)-4-(1-isoquinolinyloxy)-L-proliπamide;

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-Λ/-(3-hydroxy-3,4-dihydro-1H-2,3-benzoxaborin-4-yl)-L-prolinamide;

(3R,5S)-1 -[(2S)-2-cyclohexyl-2-({[{1 , 1 -dimethylethylJaminolcarbonylJaminoJacetyll-S-KP- hydroxy-4-(1 -methylethyl)-1 ,2-oxaborolan-3-yl]amino}carbonyl)-3-pyrrolidinyl 4-fluoro-1 ,3- dihydro-2H-isoιπdole-2-carboxylate;

(3R,5S)-1 -[(2S)-2-cyclohexyl-2-({[(1 , 1 -dimethylethylJaminolcarbonylJamincOacetyll-S-

({[(3R,4S)-4-ethyl-2-hydroxy-1 ,2-oxaborepan-3-yl]amino}carbonyl)-3-pyrrolidinyI 4-fluoro-1 ,3- dihydro-2H-isoιndole-2-carboxylate;

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-[(3S,4S)-4-ethenyl-2-hydroxy-1 ,2- oxaborolaπ-3-yl]-4-{[(4-fluoro-1,3-dihydro-2/-/-isoindol-2-yl)carbonyl]oxy}-L-prolinamide;

(1 R,2S,5S)-3-(Λ/-{[(1 , 1 -dimethylethyl)amino]carboπyl}-3-methyl-L-valyl)-Λ/-[(3R)-2-hydroxy-

1 ,2-oxaborolan-3-yl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

W-{(1 S)-1 -cyclohexyl-2-[((1 S)-1 -{[{1 S,3aR,6aS)-1 -({[(3R)-2-hydroxy-1 ,2-oxaborolaπ-3- y[]amino}methyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carboπyl}-2,2-dimethylpropyl)amino]-

2-oxoethyl}-2-pyrazinecarboxamide; W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-[(3S)-2-hydroxy-1 ,2-oxaborolan-3-yl]-4-

(i-isoquinolinyloxy)-L-prolinamide;

W-[(cyclopentyloxy)carboπyl]-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaborolaπ-3-yI)-L-prolinamide;

W-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-Λ/-[(3S)-2-hydroxy-1 ,2-oxaborinan-3-yl]-4-

(i-isoquinolinyloxy)-L-proliπamide;

(3R,5S)-1-((S)-2-(cyclopentyloxycarbonylamiπo)-3,3-dimethylbutanoyl)-5-(2-hydroxy-4- isopropyl-i ^-oxaborolan-S-ylcarbamoylJpyrrolidin-S-yU-fluoroisoindoline^-carboxylate;

(3R,5S)-1-((S)-2-(cyclopeπtyloxycarbonylamino)-3,3-dimethylbutanoyl)-5-(4-ethyl-2-hydroxy-

1 ,2-oxaborepan-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate;

(3R,5S)-1-((S)-2-(cyclopentyloxycarbonyIamino)-3,3-dimethylbutanoyl)-5-(4-ethyl-2-hydroxy-

(3R,5S)-5-((3R,4R)-4-allyl-2-hydroxy-1 ,2-oxaborolan-3-ylcarbamoyl)-1-((S)-2-

(cyclopeπtyloxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2- carboxylate;

(3R,5S)-5-((3R,4R)-4-allyl-2-hydroxy-1 ,2-oxaboroIan-3-ylcarbamoyl)-1-((S)-2-

(cyclopeπtyloxycarbonylamino)oct-7-enoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate; cyclopentyl (S)-1 -((2S,4R)-2-((3R,4S)-2-hydroxy-4-methyI-1 ,2-oxaborinan-3-ylcarbamoyl)-4-

(isoquinolin-1-yloxy)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate;

(3R)-1-((S)-2-(cyclopeπtyloxycarbonylamino)-3,3-dimethylbutaπoyl)-5-((S)-2-hydroxy-1 ,2- oxaborepan-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate; cyclopentyl (S)-1-({2S,4R)-2-((R)-2-hydroxy-1 ,2-oxaborinan-3-ylcarbamoyl)-4-(isoquiπoliπ-1- yloxy)pyrrolidiπ-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate;

(3R,5S)-5-((3S,4S)-4-allyl-2-hydroxy-1 ,2-oxaborolan-3-ylcarbamoyl)-1-((S)-2-

(cyclopentyloxycarbonylaminoJ-S.S-dimethylbutanoylJpyrrolidin-S-yl 4-fluoroisoindoliπe-2- carboxylate;

(3R,5S)-1-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutaπoyl)-5-((R)-2-hydroxy-1 ,2- oxaborinaπ-3-ylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate;

W-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carboπyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaboriπan-3-yl)-L-proliπamide;

Λ/-{[(1 ,1-dimethylethyl)amino]carboπyl}-3-methyl-L-valyl-(4/?)-4-{[(4-fluoro-1 ,3-dihydro-2/-/- isoindol-2-yl)carboπyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaboriπaπ-3-yl)-L-prolinamide;

Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valyl-(4/^:?)-4-{[{4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaborolan-3-yl)-L-prolinamide;

Λ/-{[(1 ,1-dimethylethyl)amino]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-fluoro-1 ,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}-Λ/-(2-hydroxy-1 ,2-oxaborolaπ-3-yl)-L-proliπamide;

(3aR,11 S, 15R, 16aS, 18aR,Z)-11 -(cyclopentyloxycarbonylamino)-1-hydroxy-12, 17-dioxo-

3,3a,4,7,8,9,10, 11 , 12, 14,15, 16, 16a, 17, 18, 18a-hexadecahydro-1 H-[1 ,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ^Jdiazacyclopentadecin-15-yl 4-fluoroisoiπdoliπe-2-carboxylate;

(3aR, 11 S, 15R, 16aS, 18aR,E)-11 -(cyclopentyloxycarbonylamino)^ -hydroxy-12, 17-dioxo-

3,3a,4,7,8,9, 10, 11 , 12, 14, 15, 16, 16a,17, 18, 18a-hexadecahydro-1 H-[1 ,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1 ^Idiazacyclopentadecin-15-yl 4-fluoroisoindoliπe-2-carboxylate; PBtJ2b4bVVU

(3aS, 11 S, 15R, 16aS, 18aR)-11 -(cyclopentyloxycarbonylaminoj-i -hydroxy-12, 17-dioxo- 3,3a,4,7,8,9,10,11,12,14,15,16,16a,17,18,18a4iexadecahydro-1H-[1,2]oxaborolo[3,4- e]pyrrolo[1 ,2-a][1,4]diazacyclopentadecin-15-yl 4-fluoroisoindoline-2-carboxylate; and salts thereof.

22. A method of treating or preventing viral infection which comprises administering to a subject in need thereof, an effective amount of a compound of Formula (I) as claimed in any of claims 1 to 21.

23. A method as claimed in claim 22 which involves inhibiting HCV replication.

24. A compound of Formula (I) as claimed in any of claims 1 to 21 for use in medical therapy.

25. A compound as claimed in claim 24 wherein the medical therapy is the treatment of viral infection.

26. A compound as claimed in claim 25 wherein the viral infection is HCV.

27. A pharmaceutical formulation comprising a compound of Formula (I) as claimed in any of claims 1 to 21 or a pharmaceutically acceptable salt thereof in conjunction with at least one pharmaceutically acceptable diluent or carrier.

28. A pharmaceutical formulation as claimed in claim 27, presented in an oral dosage form.

29. Use of a compound of Formula (I) as claimed in any of claims 1 to 21 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection.

30. Use as claimed in claim 29 wherein the viral infection is HCV.

31. A combination comprising a compound of Formula (I) as claimed in any of claims 1 to 21 , together with at least one other therapeutically active agent.

32. A combination as claimed in claim 31 , wherein the other therapeutically active agent is selected from interferon, ribavirin and/or an additional anti-HCV agent.