HK40005991B - Compounds for treating parasitic disease - Google Patents

Description

Compounds for treating parasitic diseases

This application is a divisional application of Chinese patent application No. 201780029103.2 (PCT/IB2017/05 2522), filed on May 1, 2017, and entitled “Oxaborane Esters and Their Uses.”

【Technical field】

The present invention relates to oxaborolane esters and uses thereof.

[Background Technology]

Trypanosomes are a group of kinetoplastid protozoa that are distinguished by having only a single flagellum. Trypanosomes are the cause of diseases such as Chagas disease and African animal trypanosomiasis (AAT).

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is endemic to many countries in Latin America. The World Health Organization (WHO) estimates that 16 to 18 million people are currently infected with Chagas disease and 90 million are at risk of contracting Chagas disease (WHO 2002, Schofield et al., 2006). The global estimated cost of the disease is 649,000 disability-adjusted life years (DALYs) (the number of years of healthy life lost due to premature death and disability). Chagas disease kills approximately 14,000 people annually, killing more Latin Americans than any other parasitic disease, including malaria.

Trypanosoma cruzi (T. cruzi) is transmitted by a variety of insect vectors belonging to the family Reduviidae. Transmission to humans depends on living conditions, as these insects inhabit mud and thatch dwellings, common in low-socioeconomic areas. Infection can also occur through ingestion of contaminated food, congenitally, or through blood transfusions or organ transplants. The acute phase of T. cruzi infection is usually controlled by the immune response and is mild or asymptomatic, thus generally going undetected. However, the vast majority of infected subjects fail to clear the infection and remain chronically infected; 30 to 40% of these infected subjects will eventually develop life-threatening cardiac or gastrointestinal disease. Chronic Chagas disease remains an incurable disease, causing severe long-term disability or death in approximately one-third of infected subjects. Furthermore, the disability caused by chronic Chagas disease has a significant social and economic impact, including unemployment and reduced income. A 2012 WHO report estimated that over 500,000 disability-adjusted life years (DALYs) were attributable to Chagas disease (Moncayo A, Ortiz Yanine M. Ann Trop Med Parasitol. 2006; 100: 663-677). In addition to lost productivity, the medical costs of treating infected individuals who develop severe cardiac or chronic digestive disorders are high.

It has long been established that Trypanosoma cruzi can infect dogs, particularly those kept outdoors in the southern United States and Central and South America. Recent studies in Texas, USA, have shown that shelter dogs can serve as good sentinels for all dogs, finding an estimated 9% of shelter dogs in the state to be infected with Trypanosoma cruzi. In Texas, infection with Trypanosoma cruzi in dogs is considered "notifiable"—meaning any dog found to have the parasite must be reported to the Texas Department of Health. Because there are no approved treatments for Chagas disease in dogs, animals may be euthanized.

African animal trypanosomiasis is endemic in 37 African countries, affecting livestock on 10 million ^km² of arable land and remaining a major constraint to agricultural production, particularly livestock production in this region. Trypanosomiasis is also prevalent in Central and South America. The disease is primarily caused by three protozoan parasites: Trypanosoma congolense, Trypanosoma vivax, and Trypanosoma evansi. They are transmitted by tsetse flies, and in the case of T. evansi, the disease is also mechanically transferred from host to host by gadflies of the genus tabanus. The disease is characterized by progressive anemia, weakness, and fatigue, accompanied by recurrent episodes of fever and parasitemia. The severity of the disease varies depending on the trypanosoma species and the breed, age, and health of the infected animal. In cattle, the infection causes significant mortality and morbidity and has a significant negative impact on growth, lactation, weaning age, and weight. The power, speed, and daily distance traveled by pack animals are also affected. In Africa, trypanosomiasis is a major economic threat to cattle production and, if left untreated, often results in a chronic disease with a high mortality rate. It is estimated that trypanosomiasis causes losses of $2 to $5 billion annually to African livestock producers. In the absence of a vaccine, control of the disease has long focused on chemotherapy and vector control. For decades, only three compounds have been widely used as trypanocide: diminazene, isometamidium, and homidium, and therefore, drug resistance in the target pathogens has become a major concern. There is an urgent need for novel chemical entities with novel mechanisms of action to combat these diseases.

[Summary of the invention]

In certain embodiments, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ^1a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L is as defined and described for the classes and subclasses described herein.

Detailed Description of Certain Embodiments

In certain embodiments, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

^R1 is hydrogen or a _C1-6 aliphatic group;

R ^1a is hydrogen or C _1-6 aliphatic; or

R ¹ and R ^1a , together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocarbocyclic ring;

each R ² is independently hydrogen, -halogen, -OR, -NO ₂ , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) ₂ R, -C(O)N(R) ₂ , -SO ₂ N(R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)SO ₂ R, -OC(O)N(R) ₂ , or an optionally substituted group selected from C _1-6 aliphatic and 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl;

R ³ is hydrogen or an optionally substituted C _1-6 aliphatic group;

R ⁴ is hydrogen, a natural or non-natural amino acid side chain group, or an optionally substituted group selected from a C _1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a phenyl group; or

R ³ and R ⁴ together with the carbon atom to which R ⁴ is attached and the nitrogen atom to which R ³ is attached form an optionally substituted 3- to 6-membered heterocyclyl having 0 to 1 additional heteroatoms selected from O, N or S;

R ⁵ is hydrogen or optionally substituted C _1-6 aliphatic; or

^R4 and ^R5 , together with the carbon atom to which they are attached, form an optionally substituted ring selected from 3- to 6-membered spiroheterocyclyl having 1 to 2 heteroatoms selected from O, N or S and 3- to 6-membered saturated or partially unsaturated monocyclic spirocarbocyclyl;

L is a covalent bond or an optionally substituted divalent C _1-10 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ - or -SO ₂ N(R)-;

wherein each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from O, N, or S, a 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from O, N, or S, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclylene, an 8- to 10-membered bicyclic arylene, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from O, N, or S, and a 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from O, N, or S;

^R6 is hydrogen, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , -OC(O)N(R) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 2 heteroatoms selected from O, N or S, 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from O, N or S, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic group, 8- to 10-membered bicyclic aryl group, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms selected from O, N or S, 7- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms selected from O, N or S, and bridged bicyclic group;

Each R is independently hydrogen or an optionally substituted C _1-6 aliphatic group;

wherein when L is a covalent bond, ^R6 is not -OR, -halogen, _-NO2 , -CN, -SR, -N(R) ₂ , -S(O)R, -S(O) _2R , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ ; and

When L is not a covalent bond, L includes the carbon atom bonded to the carboxyl oxygen represented by O*.

definition

The compounds of the present invention include those generally described above and further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version), Handbook of Chemistry and Physics, 75th edition. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

The abbreviations used herein have their usual meanings in chemistry and biology. The chemical structures and formulae shown herein are constructed according to standard rules of chemical valence commonly used in the field of chemical technology.

As used herein, "aliphatic" or "aliphatic group" refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain or monocyclic or bicyclic hydrocarbon, the hydrocarbon chain being fully saturated or containing one or more unsaturated units, the monocyclic or bicyclic hydrocarbon being fully saturated or containing one or more unsaturated units, but not aromatic (also referred to herein as "carbocyclyl,""cycloaliphatic," or "cycloalkyl"), the "aliphatic" or "aliphatic group" having a single point of attachment to the rest of the molecule. Unless otherwise indicated, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In certain embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In certain embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In certain embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In certain embodiments, a "cycloaliphatic" (or "carbocyclyl" or "cycloalkyl") refers to a _C3 - _C7 monocyclic hydrocarbon that is fully saturated or contains one or more unsaturated units and is non-aromatic and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

As used herein, "bridged bicyclic radical" refers to any bicyclic ring system having at least one bridge, i.e., carbocyclic or heterocyclic and saturated or partially unsaturated. "Bridged" as defined by IUPAC is a non-branched chain or atom or covalent bond connecting multiple atoms of two bridgeheads, wherein a "bridgehead" is any backbone atom of the ring system bonded to 3 or more backbone atoms (excluding hydrogen) of the ring system. In certain embodiments, the bridged bicyclic radical has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from N, O or S. These bridged bicyclic radicals are common in this art and include groups in which the bridge group is connected to the rest of the molecule via any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridged bicyclic radical is optionally substituted with one or more substituents, which are substituents such as those shown in aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic radical is optionally substituted.

"Heteroatom" means one or more of O, S, N, P, or Si (including any oxidized form of N, S, P, or Si; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR ⁺ (as in N-substituted pyrrolidinyl)).

As used herein, "unsaturated" means that a group has one or more units of unsaturation.

As used herein, a "divalent C _1-10 (or C _1-6 etc.) saturated or unsaturated linear or branched hydrocarbon chain" refers to a linear or branched divalent alkylene, alkenylene and alkynylene chain as defined herein.

"Alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group (i.e., -( _CH2 ) _n- ), where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include the substituents for substituted aliphatic groups described below.

"Alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

"Halogen" means F, Cl, Br or I.

"Aryl," used alone or as part of a larger group (e.g., "aralkyl," "aralkyloxy," or "aryloxyalkyl"), refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring of the system is aromatic and wherein each ring of the system contains 3 to 7 ring members. "Aryl" can be used interchangeably with "aryl ring." In certain embodiments, the 8- to 10-membered bicyclic aryl group is optionally substituted with a naphthyl ring. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may contain one or more substituents. As used herein, the scope of "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimide, naphthamido, phenanthridinyl, or tetrahydronaphthyl, and the like.

"Heteroaryl" and "heteroar-" used alone or as part of a larger group (e.g., "heteroaralkyl" or "heteroaralkoxy") refer to groups having 5 to 10 ring atoms (preferably 5, 6, or 9 ring atoms), 6, 10, or 14 pi electrons shared by the rings, and 1 to 5 heteroatoms other than carbon atoms. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl groups, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. "Heteroaryl" is used interchangeably with "heteroaryl ring," "heteroaryl," or "heteroaromatic," any of which includes optionally substituted rings. "Heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

As used herein, "heterocyclyl,""heterocyclicgroup," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (preferably 1 to 4) heteroatoms as defined above in addition to carbon atoms. When used herein to refer to a ring atom, "nitrogen (N)" includes substituted nitrogen. In a saturated or partially unsaturated ring containing 0 to 3 heteroatoms selected from O, S, or N, examples of nitrogen include N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺ NR (as in N-substituted pyrrolidinyl).

The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any ring atom is optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. These "heterocyclyl," "heterocycle," "heterocyclic group," "heterocyclic moiety," and "heterocyclic ring" are used interchangeably herein and also include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocycle. A heterocyclyl group may be monocyclic or bicyclic. "Heterocycloalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

As used herein, "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. "Partially unsaturated" is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties as defined herein.

As used herein, "natural amino acid side chain groups" refer to the side chain groups of any of the 20 amino acids naturally occurring in proteins. These natural amino acids include the non-polar or hydrophobic amino acids: glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, and proline. Cysteine is sometimes classified as non-polar or hydrophobic and other times as polar. Natural amino acids also include polar or hydrophilic amino acids, such as tyrosine, serine, threonine, aspartic acid (also known as aspartate when charged), glutamic acid (also known as glutamate when charged), asparagine, and glutamine. Certain polar or hydrophilic amino acids may contain charged side chains. These charged amino acids include lysine, arginine, and histidine. Those skilled in the art will appreciate that protecting the side chains of polar or hydrophilic amino acids can render the amino acid non-polar. For example, by using a hydroxyl protecting group, appropriate protection of the tyrosine hydroxyl group can render the tyrosine non-polar and hydrophobic.

As used herein, "non-natural amino acid side chain radicals" refer to side chain radicals of amino acids that are not included in the 20 amino acids naturally present in proteins as described above. These amino acids include the D isomers of any of the 20 naturally occurring amino acids. Non-natural amino acids also include homoserine, ornithine, norleucine, and thyroxine. Other non-natural amino acid side chains are common to those skilled in the art and include non-natural aliphatic side chains. Other non-natural amino acids include modified amino acids, including those that are N-alkylated, cyclized, phosphorylated, acetylated, amidated, diazotized, labeled, and the like. In certain embodiments, the non-natural amino acids are D isomers. In certain embodiments, the non-natural amino acids are L isomers.

As described herein, the compounds of the present invention may contain "optionally substituted" moieties when specified. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated group are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may contain a suitable substituent at each substitutable position of the group, and when more than one position of any given structure may be substituted with more than one substituent selected from the specified group, the substituents at each position may be the same or different. Combinations of substituents envisioned by the present invention are preferably those that result in stable or chemically feasible compounds. As used herein, "stable" refers to compounds that are not substantially altered when subjected to conditions for their preparation, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently halogen, -( _CH2 ) _0-4Ro , -(CH2) ^0-4ORo , -O( _CH2 ) _0-4Ro , -O-(CH2) _0-4C ( _O ^{) ORo} , -( _CH2 ) _0-4CH (ORo) ² , -( _CH2 ) _0-4SRo , -( _CH2 ) _0-4Ph which may _{be substituted by Ro, -(CH2)0-4O} ⁽ _{CH2 ) 0-1Ph} ^which may be substituted by ^Ro , -CH=CHPh which may be substituted by ^Ro, -( _CH2 ) _0-4O ⁽ _CH2 ) _{0-1 -} pyridyl which may be _substituted by ^Ro , _-NO2 , -CN, _-N3 , _- (CH ₂ ) _0-4 N(R ^o ) ₂ ,

-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o , -N(R ^o )C(S)R ^o ,

-(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ , -N(R ^o )C(S)NR ^o ₂ ,

-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o , -N(R ^o )N(R ^o )C(O)R ^o ,

-N(R ^o )N(R ^o )C(O)NR ^o ₂ , -N(R ^o )N(R ^o )C(O)OR ^o ,

-(CH ₂ ) _0-4 C(O)R ^o , -C(S)R ^o , -(CH ₂ ) _0-4 C(O)OR ^o ,

-(CH ₂ ) _0-4 C(O)SR ^o , -(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ,

-(CH ₂ ) _0-4 OC(O)R ^o , -OC(O)(CH ₂ ) _0-4 SR ^o , -SC(S)SR ^o ,

-(CH ₂ ) _0-4 SC(O)R ^o , -(CH ₂ ) _0-4 C(O)NR ^o ₂ , -C(S)NR ^o ₂ ,

-C(S)SR ^o , -SC(S)SR ^o , -(CH ₂ ) _0-4 OC(O)NR ^o ₂ ,

-C(O)N(OR ^o )R ^o , -C(O)C(O)R ^o , -C(O)CH ₂ C(O)R ^o ,

-C(NOR ^o )R ^o , -(CH ₂ ) _0-4 SSR ^o , -(CH ₂ ) _0-4 S(O) ₂ R ^o ,

-(CH ₂ ) _0-4 S(O) ₂ OR ^o , -(CH ₂ ) _0-4 OS(O) ₂ R ^o , -S(O) ₂ NR ^o ₂ ,

-(CH ₂ ) _0-4 S(O)R ^o , -N(R ^o )S(O) ₂ NR ^o ₂ , -N(R ^o )S(O) ₂ R ^o ,

-N(OR ^o )R ^o , -C(NH)NR ^o ₂ , -P(O) ₂ R ^o , -P(O)R ^o ₂ ,

-OP(O)R ^o ₂ , -OP(O)(OR ^o ) ₂ , SiR ^o ₃ , -(C _1-4 straight or branched alkylene)ON(R ^o ) ₂ , or -(C _1-4 straight or branched alkylene)C(O)ON(R ^o ) ₂ , wherein each R ^o may be substituted as defined below and is independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ -(5- to 6-membered heteroaryl ring) or a 5- to 6-membered saturated, partially unsaturated or aryl ring containing 0 to 4 heteroatoms independently selected from N, O or S, or notwithstanding the above definitions, two independent occurrences of R ^o and their intervening atoms may be taken together to form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring containing 0 to 4 heteroatoms independently selected from N, O or S, which rings may be substituted as defined below.

Suitable monovalent substituents on R ^o (or two independent occurrences of R ^o together with their intervening atoms to form a ring) are independently halogen, -(CH ₂ ) _0-2 R ^· , -(halogen R ^· ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^· ,

-(CH ₂ ) _0-2 CH(OR ^· ) ₂ , -O(halogen R ^· ), -CN, -N ₃ ,

-(CH ₂ ) _0-2 C(O)R ^· , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^· ,

-(CH ₂ ) _0-2 SR ^· , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ ,

-(CH ₂ ) _0-2 NHR ^· , -(CH ₂ ) _0-2 NR ^· ₂ , -NO ₂ , -SiR ^· ₃ ,

-OSiR ^· ₃ , -C(O)SR ^· , -( _C1-4 straight or branched alkylene)C(O)OR ^·, or -SSR ^· , wherein each R ^· is unsubstituted or wherein the preceding "halogen" is substituted only with one or more halogens, and is independently selected from _C1-4 aliphatic, _-CH2Ph , -O( _CH2 ) _0-1Ph , or a 5- to 6-membered saturated, partially unsaturated, or aryl ring containing 0 to 4 heteroatoms independently selected from N, O, or S. Suitable divalent substituents on the saturated carbon atom of R ^· include =O and =S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR ^* ₂ , ═NNHC(O)R ^* , ═NNHC(O)OR ^* , ═NNHS(O) ₂ R ^* , ═NR ^* , ═NOR ^* , —O(C(R ^* ₂ )) _2-3 O—, or —S(C(R ^* ₂ )) _2-3 S—, wherein R ^* at each independent occurrence is selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring containing 0 to 4 heteroatoms independently selected from N, O, or S. Suitable divalent substituents bonded to a substitutable carbon atom adjacent to an "optionally substituted" group include: -O(CR ^* ₂ ) _2-3 O-, wherein R ^* at each independent occurrence is selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring containing 0 to 4 heteroatoms independently selected from N, O, or S.

Suitable substituents on the aliphatic group of R ^* include halogen, -R ^· , -(halogenR ^· ), -OH, -OR ^· , -O(halogenR ^· ), -CN, -C(O)OH, -C(O)OR ^· , -NH ₂ , -NHR ^· , -NR ^· ₂ or -NO ₂ , wherein each R ^· is unsubstituted or wherein the preceding "halogen" is substituted only with one or more halogens and is independently a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring containing 0 to 4 heteroatoms independently selected from N, O or S.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include

or

wherein each is independently hydrogen, C _1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring containing 0 to 4 heteroatoms independently selected from N, O, or S, or, notwithstanding the above definitions, two independent occurrences thereof may be taken together with their intervening atoms to form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring containing 0 to 4 heteroatoms independently selected from N, O, or S.

Suitable substituents on the aliphatic group are independently halogen, -R ^· , -(halogen R ^· ), -OH, -OR ^· , -O(halogen R ^· ), -CN, -C(O)OH, -C(O)OR ^· , -NH ₂ , -NHR ^· , -NR ^· ₂ or -NO ₂ , wherein each R ^· is unsubstituted or wherein the preceding "halogen" is substituted only with one or more halogens and is independently a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring containing 0 to 4 heteroatoms independently selected from N, O or S.

As used herein, "pharmaceutically acceptable salts" refer to salts that, within the scope of normal medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, or the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are commonly used in this art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

In certain embodiments, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. In certain embodiments, the prototype of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents).

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or configurational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E configurational isomers. Therefore, single stereochemical isomers as well as mixtures of enantiomers, diastereoisomers, and geometric (or configurational) isomers of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures of the invention that include the replacement of a hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the invention. According to the invention, these compounds are useful, for example, as analytical tools, biological detection probes, or therapeutic agents.

As used herein, "oxo" refers to an oxygen double-bonded to a carbon atom, thereby forming a carbonyl group.

Unless used to indicate a bond of unknown or mixed stereochemistry, the symbol indicates the point of attachment of a chemical group to the rest of a molecule or chemical formula.

Compound

As described above, in certain embodiments, compounds of formula I are provided:

or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ^1a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L, alone or in combination, is as described above and as described in the classes and subclasses described herein.

As used herein, unless otherwise indicated, Formula I also includes all subsets of Formula I defined and described herein (e.g., Formulas II, III, III-a, IV, V, V-a, V-b, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VII-a, VII-b, VII-c, VIII-a, VIII-b, VIII-c, IX-a, and IX-b).

It should be understood that "O*" as used in Formula I is an oxygen atom and "*" as used herein refers to the linkage to the L group.

In certain embodiments, R ¹ and R ^1a are hydrogen. In certain embodiments, R ¹ and R ^1a are methyl.

In certain embodiments, R ¹ and R ^1a , together with the carbon atom to which they are attached, form an optionally substituted 3 to 6 membered spiro carbocyclic ring. In certain embodiments, R ¹ and R ^1a , together with the carbon atom to which they are attached, form a 6 membered spiro carbocyclic ring. In certain embodiments, R ¹ and R ^1a , together with the carbon atom to which they are attached, form a 5 membered spiro carbocyclic ring. In certain embodiments, R 1 and R 1a, together with the carbon atom to which they are attached ^, form a 4 membered spiro carbocyclic ring. In certain embodiments, ^{R 1} and R ^1a , together with the carbon atom to which they are attached, form a 3 membered spiro carbocyclic ring.

In certain embodiments, ^R is hydrogen. In certain embodiments, ^R is optionally substituted C _1-6 aliphatic. In certain embodiments, ^R is C _1-6 aliphatic. In certain embodiments, ^R is methyl. In certain embodiments, ^R is ethyl, propyl, or isopropyl. In certain embodiments, ^R is methoxy or ethoxy.

In certain embodiments, there is 1 R ² . In certain embodiments, there are 2 R ² . In certain embodiments, there are 3 R ² .

In certain embodiments, R ² is an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, R ² is a 3- to 6-membered saturated monocyclic carbocyclyl. In certain embodiments, R ² is a cyclopropyl.

In certain embodiments, R ² is halogen. In certain embodiments, R ² is fluoro.

In certain embodiments, R ² is a C _1-6 aliphatic group substituted with halogen. In certain embodiments, R ² is -CH ₂ F ₂ or -CF _3. In certain embodiments, R ² is a C _1-6 aliphatic group substituted with hydrogen.

In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is optionally substituted C _1-6 aliphatic. In certain embodiments, R ³ is methyl.

In certain embodiments, ^R4 is hydrogen. In certain embodiments, ^R4 is a natural or non-natural amino acid side chain group.

In certain embodiments, ^R4 is an optionally substituted group selected from _C1-6 aliphatic groups. In certain embodiments, ^R4 is methyl, ethyl, isopropyl, tert-butyl, -C(CH3) _2OH , or -( _{CH2 ) 2OH} . In certain embodiments, ^R4 is methyl. In certain embodiments, ^R4 is isopropyl. In certain embodiments, ^R4 is tert-butyl.

In certain embodiments, R ⁴ is -(CH ₂ ) _m SR, -(CH ₂ ) _m OH, -(CH ₂ ) _m F, -(CH ₂ ) _m C(O)N(R) ₂ , or -C(O)OR, wherein m is 1, 2, 3, 4, 5, or 6. In certain embodiments, R ⁴ is -(CH ₂ ) ₂ SCH ₃ . In certain embodiments, R ⁴ is -CH ₂ OH. In certain embodiments, R ⁴ is -CH ₂ C(O)NH ₂ or -(CH ₂ ) ₂ C(O)NH ₂ .

In certain embodiments, m is 0, 1, 2, or 3.

In certain embodiments, R ⁴ is phenyl. In certain embodiments, R ⁴ is phenyl optionally substituted with -OH.

In certain embodiments, ^R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, ^R is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, ^R is a cyclopropyl. In certain embodiments, ^R is a cyclobutyl. In certain embodiments, ^R is a cyclopentyl.

In certain embodiments, R ⁴ is In certain embodiments, R ⁴ is In certain embodiments, R ⁴ is In certain embodiments, R ⁴ is In certain embodiments, R ⁴ is In certain embodiments, R ⁴ is

In certain embodiments, R ⁴ is -(CH ₂ ) _m R ⁷ or -CH(CH ₃ ) OCH ₂ R ⁷ , wherein R ⁷ is an optionally substituted ring selected from phenyl, an 8- to 10-membered bicyclic aryl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from O, N, or S, or a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, or S. In certain embodiments, R ⁴ is -CH ₂ R ⁷ , wherein R ⁷ is optionally substituted phenyl. In certain embodiments, R 4 is -(CH 2 ) 2 R ⁷ , wherein R ⁷ is optionally substituted phenyl. In certain embodiments, R ⁴ is -(CH ₂ ) ₂ R 7 , wherein R 7 is optionally substituted phenyl. In certain embodiments, R ⁴ is -(CH ₂ ) ₃ R ⁷ , wherein R ⁷ is optionally substituted phenyl.

In certain embodiments, ^R is an optionally substituted ring selected from an optionally substituted group selected from a _C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from O, N, or S, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, or S, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, an 8- to 10-membered bicyclic aryl, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms selected from O, N, or S, or a 7- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from O, N, or S.

In certain embodiments, ^R4 is -( _CH2 ) _nSR , -( _CH2 )nOH, -(CH2) _nF , -( _CH2 ) _nC (O) _N (R _{) 2} , -C(O)OR, -( _CH2 ) _nR7 ^, or -CH( _CH3 ) _OCH2R7 ^.

^R is an optionally substituted ring selected from an optionally substituted group selected from a _C1-6 aliphatic group, a phenyl group, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl group having 1 to 2 heteroatoms selected from O, N or S, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from O, N or S, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl group, an 8- to 10-membered bicyclic aryl group, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl group having 1 to 4 heteroatoms selected from O, N or S, or a 7- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms selected from O, N or S, and m is selected from 0, 1, 2 or 3.

In certain embodiments, R ⁷ is optionally substituted C _1-6 aliphatic. In certain embodiments, R ⁷ is isopropyl.

In certain embodiments, R ⁷ is optionally substituted phenyl. In certain embodiments, R ⁷ is phenyl substituted with one or more halogens. In certain embodiments, R ⁷ is phenyl substituted with 1 fluoro.

In certain embodiments, R ⁷ is an optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, R ⁷ is an optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from O, N or S.

In certain embodiments, R ⁷ is an optionally substituted 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, or S. In certain embodiments, R ⁷ is a 6-membered heteroaryl containing 1 nitrogen. In certain embodiments, R ⁷ is pyridinyl.

In certain embodiments, R ⁷ is an optionally substituted 7- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from O, N, or S. In certain embodiments, R ⁷ is an optionally substituted 10-membered bicyclic heteroaryl containing 1 heteroatom selected from nitrogen.

In certain embodiments, ^R3 and ^R4 , together with the carbon atom to which ^R4 is attached and the nitrogen atom to which ^R3 is attached, form an optionally substituted 3- to 6-membered heterocyclic group having 0 to 1 additional heteroatoms selected from O, N, or S. In certain embodiments, ^R3 and ^R4 , together with the carbon atom to which ^R4 is attached and the nitrogen atom to which ^R3 is attached, form a 5-membered monocyclic heterocyclic ring. For example, in the compound of Example 6-012, ^R3 and ^R4 form a 5-membered monocyclic heterocyclic ring containing 1 nitrogen:

In certain embodiments, R ⁵ is hydrogen. In certain embodiments, R ⁵ is optionally substituted C _1-6 aliphatic. In certain embodiments, R ⁵ is methyl.

In certain embodiments, ^R and ^R, together with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered spiroheterocyclic ring having 1 to 2 heteroatoms selected from O, N, or S. In certain embodiments, ^R and ^R, together with the carbon atoms to which they are attached, form a 4-membered spiroheterocyclic ring containing 1 oxygen. For example, in the compounds of Examples 6-224, ^R and ^R form a 4-membered spiroheterocyclic ring containing 1 oxygen:

In certain embodiments, ^R and ^R form together with the carbon atom to which they are connected 3 to 6 yuan of saturated or partially unsaturated monocyclic spiral carbocycles optionally substituted. In certain embodiments, ^R and ^R form together with the carbon atom to which they are connected 3 yuan of saturated or partially unsaturated monocyclic spiral carbocycles. In certain embodiments, ^R and ^R form together with the carbon atom to which they are connected 4 yuan of saturated or partially unsaturated monocyclic spiral carbocycles.

In certain embodiments, L is a covalent bond. In certain embodiments, L is an optionally substituted divalent C _1-10 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of L are optionally and independently replaced by -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ -, or -SO ₂ N(R)-. In certain embodiments, L is an optionally substituted divalent C _1-10 saturated or unsaturated linear chain substituted with one or more halogens, -CF ₃ , or -OH. In certain embodiments, L is an optionally substituted -CH ₂ -. In certain embodiments, L is -CH ₂ -, wherein -CH ₂ - is substituted with 1 or 2 methyl groups. In certain embodiments, L is _-CH2- , wherein _-CH2- is substituted with 2 methyl groups. In certain embodiments, L is _-CH2- , wherein _-CH2- is substituted with methyl groups.

In certain embodiments, L is optionally substituted _-CH2CH2- . In certain embodiments, L is _-CH2CH2- substituted with one or more methyl groups. In certain embodiments, L is _-CH2CH2- substituted with _methyl groups. In certain embodiments, L is _-CH2CH2- substituted with -OH _groups . In certain embodiments, L is _-CH2CH2- substituted with halogen _groups . In certain embodiments, L is _{-CH2CH2- substituted} with _{fluoro groups} .

In certain embodiments, L is optionally _{substituted -CH2CH2CH2-} . In certain _embodiments , _L is _-CH2CH2CH2- substituted with _-OH . In certain embodiments, _L is _{-CH2CH2CH2- substituted} with _-CH2OH .

In certain embodiments, L is an optionally substituted divalent C _1-10 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of L are optionally and independently replaced by -Cy-. In certain embodiments, 1 or 2 methylene units of L are independently replaced by -Cy-, wherein -Cy- is a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 2 heteroatoms selected from O, N, or S. In certain embodiments, L is

In certain embodiments, L is an optionally substituted divalent C _1-6 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ -, or -SO ₂ N(R)-.

In certain embodiments, L is an optionally substituted divalent C _1-5 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ -, or -SO ₂ N(R)-.

In certain embodiments, L is an optionally substituted divalent C _1-4 saturated or unsaturated linear or branched hydrocarbon chain, wherein one or two methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ -, or -SO ₂ N(R)-.

In certain embodiments, L is an optionally substituted divalent C _1-3 saturated or unsaturated linear or branched hydrocarbon chain, wherein one or two methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ -, or -SO ₂ N(R)-.

In certain embodiments, L is an optionally substituted divalent _C2-6 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, _-SO2- , -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R) _SO2- , or _-SO2N (R)-.

In certain embodiments, L is an optionally substituted divalent _C2-4 saturated or unsaturated linear or branched hydrocarbon chain, wherein one or two methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, _-SO2- , -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R) _SO2- , or _-SO2N (R)-.

In certain embodiments, 1 or 2 methylene units of L are replaced by -Cy-. In certain embodiments, -Cy- is selected from:

In certain embodiments, L is selected from:

In certain embodiments, ^R is optionally substituted phenyl. In certain embodiments, ^R is phenyl. In certain embodiments, ^R is phenyl substituted with one or more groups selected from -OR, -NO ₂ , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) ₂ R, -C(O)N(R) ₂ , -S(O) ₂ N(R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)SO ₂ R, or -OC(O)N(R) ₂ . In certain embodiments, ^R is phenyl substituted with -CN. In certain embodiments, ^R is phenyl substituted with -OCF ₃ .

In certain embodiments, ^R is phenyl substituted with -S(O) _CH3 . In certain embodiments, ^R is phenyl substituted with _{-S(O)CH2CH3. In certain embodiments, R is phenyl substituted with -S(O)2CH3. In certain embodiments, R is phenyl substituted with -S(O)2CH2CH3 .} ^In _certain ^embodiments _, ^R is phenyl substituted with -S(O) _{2CH ( CH3 ). In certain embodiments, R is phenyl substituted with -S(O)2CH2CH3. In certain embodiments, R is phenyl substituted with -S(O)2CH(CH3). In certain embodiments, R is phenyl substituted with -S(O)2NH2 .} ^In _{certain embodiments} ^, _{R is} ^phenyl _{substituted with -NHS} (O) _2CH3 . In certain embodiments, ^R is phenyl substituted with _-CH2NH ( _CH3 ). In certain embodiments, R ⁶ is phenyl substituted with —S(O) ₂ CH ₃ and —CH ₂ N(CH ₃ ) ₂ .

In certain embodiments, ^R is phenyl substituted with one or more halogens. In certain embodiments, ^R is phenyl substituted with one or more fluorines. In certain embodiments, ^R is phenyl substituted with one or more chlorines. In certain embodiments, ^R is phenyl substituted with 1 fluorine. In certain embodiments, ^R is phenyl substituted with 1 chlorine. In certain embodiments, ^R is phenyl substituted with 2 fluorines. In certain embodiments, ^R is phenyl substituted with 3 fluorines. In certain embodiments, ^R is phenyl substituted with _-CF3 . In certain embodiments, ^R is phenyl substituted with _-CF3 and 1 fluorine. In certain embodiments, ^R is phenyl substituted with 1 fluorine and 1 chlorine.

In certain embodiments, R ⁶ is phenyl substituted with one or more optionally substituted C _1-6 aliphatic groups. In certain embodiments, R ⁶ is phenyl substituted with one or more methyl groups.

In certain embodiments, ^R6 is an optionally substituted 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, or S. In certain embodiments, ^R6 is an optionally substituted 6-membered heteroaryl having 1 to 2 heteroatoms selected from O, N, or S. In certain embodiments, ^R6 is an optionally substituted 6-membered heteroaryl having 1 to 2 heteroatoms selected from O or N. In certain embodiments, ^R6 is an optionally substituted 6-membered heteroaryl having 1 to 2 heteroatoms selected from N. In certain embodiments, ^R6 is

In certain embodiments, ^R is optionally substituted pyridinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, ^R is pyridinyl. In certain embodiments, ^R is pyridinyl substituted with -CN or -CF _3. In certain embodiments, R is pyridinyl substituted with halogen. In certain embodiments, ^R is pyridinyl substituted with fluorine. In certain embodiments, ^R is ^pyridinyl substituted with fluorine and -CF _3. In certain embodiments, ^R is In certain embodiments, ^R is pyridinyl substituted with morpholinyl. In certain embodiments, ^R is pyridinyl substituted with piperazinyl.

In certain embodiments, R ⁶ is pyrimidinyl substituted with halogen. In certain embodiments, R ⁶ is pyrimidinyl substituted with fluorine. In certain embodiments, R ⁶ is pyrimidinyl substituted with -CF _3. In certain embodiments, R ⁶ is pyrimidinyl substituted with -NH ₂ .

In certain embodiments, R ⁶ is pyrazinyl substituted with morpholinyl. In certain embodiments, R ⁶ is pyrazinyl substituted with piperazinyl. In certain embodiments, R ⁶ is substituted pyrazinyl.

In certain embodiments, R ⁶ is an optionally substituted 5-membered heteroaryl having 1 to 3 heteroatoms selected from O, N, or S. In certain embodiments, R ⁶ is an optionally substituted 5-membered heteroaryl having 2 heteroatoms selected from O, N, or S. In certain embodiments, R ⁶ is an optionally substituted thiazolyl or imidazolyl.

In certain embodiments, ^R is an optionally substituted 7- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 10-membered bicyclic heteroaryl having 2 heteroatoms selected from N. In certain embodiments, ^R is an optionally substituted 10-membered bicyclic heteroaryl having 1 heteroatom selected from N. In certain embodiments, ^R is an optionally substituted 9-membered bicyclic heteroaryl having 1 heteroatom selected from N.

In certain embodiments, ^R is an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 heteroatom selected from S.

In certain embodiments, ^R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from O or N. In certain embodiments, ^R is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 oxygen and 1 nitrogen. In certain embodiments, ^R is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 2 nitrogen groups. In certain embodiments, ^R is optionally substituted morpholinyl. In certain embodiments, ^R is optionally substituted piperazine. In certain embodiments, ^R is morpholinyl substituted with one or more methyl groups. In certain embodiments, R ⁶ is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from O. In certain embodiments, R ⁶ is

In certain embodiments, ^R is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 2 heteroatoms selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 2 heteroatoms selected from O or N. In certain embodiments, ^R is an optionally substituted oxazolidinyl or dioxolanyl. In certain embodiments, ^R is a dioxolanyl substituted with 2 methyl groups.

In certain embodiments, ^R is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from oxygen. In certain embodiments, ^R is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from nitrogen. In certain embodiments, ^R is an optionally substituted pyrrolidinyl or tetrahydrofuranyl. In certain embodiments, ^R is pyrrolidinyl or tetrahydrofuranyl.

In certain embodiments, ^R is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from O, N, or S. In certain embodiments, ^R is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from oxygen. In certain embodiments, ^R is an optionally substituted oxetane. In certain embodiments, ^R is an optionally substituted oxetane.

In certain embodiments, R ⁶ is an optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, R ⁶ is an optionally substituted 6 membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, R ⁶ is an optionally substituted cyclohexyl. In certain embodiments, R ⁶ is a cyclohexyl. In certain embodiments, R ⁶ is a cyclohexyl substituted with one or more halogens. In certain embodiments, R ⁶ is a cyclohexyl substituted with 2 fluorines. In certain embodiments, R ⁶ is

In certain embodiments, R ⁶ is an optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, R ⁶ is an optionally substituted cyclopentyl. In certain embodiments, R ⁶ is a cyclopentyl.

In certain embodiments, R ⁶ is an optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In certain embodiments, R ⁶ is an optionally substituted cyclobutyl. In certain embodiments, R ⁶ is a cyclobutyl.

In certain embodiments, R is ^-OR , _-NO , -CN, -SR, -N(R), -C(O) _R , -C(O)OR, -S(O)R, -S(O)R, _-C (O) _N (R), -S(O) _N (R ₎ , -OC(O)R, -N(R)C(O)R, -N(R)C(O) _OR , -N( _R )S(O)R, or -OC(O) ^N (R). In certain embodiments, ^R is -OH. In certain embodiments, ^R is -CN. In certain embodiments, R is _-OCF3 . In certain embodiments, ^{R is} _-SOCH3 . In certain embodiments, R is _-S (O) _CH2CH3 . In certain embodiments, ^R is _-S (O) _2CH3 . In certain embodiments, ^R6 is -S(O) _2CH2CH3 . In _certain embodiments, ^R6 _is -S(O) _2CH ( _CH3 ) ₂ . In certain embodiments, R6 is -S(O) _2NH2 . In certain embodiments, ^R6 is _-NHS (O) _2CH3 . In certain embodiments, ^{R6 is} _-CH2NH ( _{CH3 )} .

In certain embodiments, ^R6 is halogen. In certain embodiments, ^R6 is fluoro. In certain embodiments, ^R6 is chloro.

In certain embodiments, R ⁶ is hydrogen.

In certain embodiments, R ⁶ is selected from the following optionally substituted groups:

In certain embodiments, ^R6 is substituted with one or more groups selected from -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , -S(O) _2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)S(O) _2R , -OC(O)N(R) ₂ , or _C1-6 aliphatic optionally substituted with halogen. In certain embodiments, ^R6 is substituted with one or more groups selected from methyl, -F, -Cl, -OH _{, -OCH3} , _-NH2 , _-NHCH3 , -N( _CH3 ) _{CH3 , -CF3, -CN, -OCF3, -S(O)2CH3 , or -NHS} (O) _2CH3 .

In certain embodiments, R ⁶ is optionally substituted C _1-6 aliphatic. In certain embodiments, R ⁶ is C _1-6 aliphatic.

In certain embodiments, R ⁶ is -CF ₃ .

In certain embodiments, ^R6 is selected from:

In certain embodiments, L is a covalent bond and R ⁶ is hydrogen.

In certain embodiments, L is a covalent bond and R ⁶ is phenyl. In certain embodiments, L is -CH ₂ - and R ⁶ is phenyl. In certain embodiments, L is -CH ₂ (CH ₃ )- and R ⁶ is phenyl.

In certain embodiments, L is -CH ₂ - and R ⁶ is phenyl substituted with one fluorine. In certain embodiments, L is -CH ₂ - and R ⁶ is phenyl substituted with two fluorines. In certain embodiments, L is -CH ₂ - and R ⁶ is In certain embodiments, L is -CH ₂ - and R ⁶ is In certain embodiments, L is a covalent bond and R ⁶ is cyclohexyl. In certain embodiments, L is a covalent bond and R ⁶ is cyclopentyl. In certain embodiments, L is a covalent bond and R ⁶ is cyclobutyl. In certain embodiments, L is a covalent bond and R ⁶ is

In certain embodiments, L is a covalent bond and R ⁶ is tetrahydropyranyl. In certain embodiments, L is a covalent bond and R ⁶ is tetrahydrofuranyl. In certain embodiments, L is a covalent bond and R ⁶ is propylene oxide.

In certain embodiments, the present invention provides compounds of formula II:

or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ⁴ , R ⁵ , R ⁶ and L, alone or in combination, is as described above and as described by the types and subtypes described herein.

In certain embodiments, the present invention provides compounds of formula III:

or a pharmaceutically acceptable salt thereof, wherein each of R ⁴ , R ⁵ , R ⁶ and L, alone or in combination, is as defined above and described in the classes and subclasses described herein.

In certain embodiments, the present invention provides a compound of formula III-a:

or a pharmaceutically acceptable salt thereof, wherein each of R ⁴ , R ⁵ , R ⁶ and L, alone or in combination, is as defined above and described in the classes and subclasses herein. In certain embodiments of the compound of formula III-a, L is a covalent bond and R ⁶ is

In certain embodiments, the present invention provides compounds of formula IV:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ , R ^1a , R ^b , R ^b1 , ^Ra , R ⁴ , R ⁵ and R ⁶ , alone or in combination, is as described above and as described by the classes and subclasses described herein. In certain embodiments, each ^Ra is independently -hydrogen, -halogen, -OR, -NO ₂ , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) ₂ R, -C(O)N(R) ₂ , -S(O) ₂ N(R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)S(O) ₂ R, or -OC(O)N(R) ₂ . In certain embodiments, each ^Ra is independently hydrogen, methyl, -F, -Cl, _-CF3 , -CN, _-OCF3 , or -S(O) _2CH3 . In certain embodiments, ^Ra is independently fluoro or chloro _.

In certain embodiments, ^R and ^R are hydrogen. In certain embodiments, ^R and ^R are methyl. In certain embodiments, ^R is methyl and ^R is hydrogen. In certain embodiments of the compound of formula IV, ^R is fluorine and 1 ^Ra is fluorine. In certain embodiments of the compound of formula IV, ^R is fluorine and 2 ^Ras are fluorine.

In certain embodiments, the present invention provides compounds of formula V:

or a pharmaceutically acceptable salt thereof, wherein each of R ^b , R ^b1 , ^Ra and R ⁶ , alone or in combination, is as described above and as described by classes and subclasses herein. In certain embodiments of the compound of formula V, R ⁶ is -S(O) ₂ CH ₃ and ^Ra is -CH ₂ N(CH ₃ ) ₂ .

In certain embodiments, the present invention provides compounds of formula V-a and V-b:

or a pharmaceutically acceptable salt thereof, wherein each of ^Ra and ^R6 , alone or in combination, is as described above in the definitions and classes and subclasses described herein.

In certain embodiments, the present invention provides compounds of Formula VI-a, VI-b, VI-c, VI-d, VI-e, or VI-f:

or a pharmaceutically acceptable salt thereof, wherein each n, Ra ^, and R, alone or in combination, is as described above and as described for classes and subclasses herein. In certain embodiments of compounds of Formula VI-af, n is ¹ , 2, and 3. In certain embodiments of compounds of Formula VI-af, ^R is -F, _-CF3 , -CN, -N( _CH3 ) ₂ , -NH( _CH3 ), or _-NH2 , and ^Ra is hydrogen. In certain embodiments of compounds of Formula VI-af, ^R is hydrogen and ^Ra is hydrogen.

In certain embodiments, the present invention provides compounds of Formula VII-a, VII-b, or VII-c:

or a pharmaceutically acceptable salt thereof, wherein each of n, ^Ra and ^R6 , alone or in combination, is as defined above and described for classes and subclasses herein. In certain embodiments of the compound of formula VII-ac, n is 0, 1, 2, and 3.

In certain embodiments, the present invention provides compounds of Formula VIII-a, VIII-b, or VIII-c:

or a pharmaceutically acceptable salt thereof, wherein each of R ² , R ⁶ and L, alone or in combination, is as described above in the definitions and classes and subclasses described herein.

In certain embodiments, the present invention provides compounds of Formula IX-a or IX-b:

or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or methyl and L is as defined above and described in the classes and subclasses herein. In certain embodiments, the present invention provides a compound of formula IX-a or IX-b and L is selected from:

General Methods for Providing Compounds of the Invention

The compounds of the present invention can be synthesized by appropriate combinations of generally common synthetic methods. For those skilled in the art, the techniques for synthesizing the compounds of the present invention are obvious and readily available. The following discussion is provided to illustrate some of the different methods available for synthesizing the compounds of the present invention. However, this discussion is not intended to define the scope of the reactions or reaction sequences used to prepare the compounds of the present invention.

In certain embodiments, the compounds of the present invention are generally prepared according to the following reaction scheme A:

Reaction Figure A

wherein each of R ¹ , R ^1a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L is as defined above and described by the types and subtypes described herein, and PG and LG are as described below.

In Reaction Scheme A, the group "LG" is a suitable leaving group, i.e., a group that is nucleophilically displaced. A "suitable leaving group" is a chemical group that can be readily displaced by a desired incoming chemical group, such as an amine. Suitable leaving groups are commonly known in the art; see, for example, "Advanced Organic Chemistry," Jerry March, ^5th Ed., pp. 351-357, John Wiley and Sons, NY. These leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, acetoxy, methoxy, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, nitrophenylsulfonyloxy, and bromophenylsulfonyloxy.

In reaction scheme A, the group "PG" is a suitable protecting group as defined above and described herein. Those skilled in the art will be familiar with the various protecting groups and protective group strategies that can be used. Suitable hydroxyl and amine protecting groups are conventional in the art and include those described in detail in the document Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ³ edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference.

In step S-1, amino acid A is coupled with compound B under appropriate conditions to produce compound C. In certain embodiments, step S-1 utilizes a suitable base. The suitable base and suitable conditions are conventional for this technique and may vary depending on the selected LG. In certain embodiments, the suitable base is an inorganic base. In certain embodiments, the suitable base is K ₂ CO ₃ .

Those skilled in the art will appreciate that a variety of suitable leaving groups LG of compound B can be used to facilitate the reaction described in step S-1, and the present invention encompasses all such suitable leaving groups. In certain embodiments, LG is a halogen. In certain embodiments, LG is chlorine. In certain embodiments, LG is trichloroacetimidate.

Step S-1 optionally uses a suitable solvent, including, for example, polar aprotic solvents (ie, THF, DMF, dioxane, acetonitrile, and combinations thereof).

In step S-2, compound C is deprotected under appropriate conditions as described in the aforementioned Greene and Wuts reference to produce amine D. The appropriate conditions are typical for this technique and may vary depending on the protecting group selected. In certain embodiments, PG is a Boc group and the appropriate conditions comprise an appropriate acid. In certain embodiments, the appropriate acid is an inorganic acid or a Lewis acid. In certain embodiments, the acid is HCl.

In step S-3, amine D is coupled with carboxylic acid E under appropriate conditions to produce a compound of formula I. A peptide coupling reagent can be used in step S-3. In certain embodiments, the peptide coupling reagent is selected from FDPP, PFPOH, BOP-Cl, EDC, EDCA, DCC, DIC, HOBt, HOAt, HBTU, HATU, HCTU, TBTU, PyBOP, or a combination thereof. In certain embodiments, suitable conditions comprise a suitable coupling reagent selected from EDCI/HOBt, PyBOP, HATU, or BEM in the presence of a base familiar to those skilled in the art and in a suitable solvent (see Carpino, L.A., J. Am. Chem. Soc. 1993, 115, 4397; Carpino, L.A., El-Faham, A., J. Am. Chem. Soc. 1995, 117, 5401; Li, P., Xu, J., C. J. Pept. Res. 2001, 58, 129). In certain embodiments, the suitable base is an amine base. In certain embodiments, the amine base is DIPEA. In certain embodiments, suitable solvents for use in step S-3 include, for example, polar aprotic solvents (i.e., THF, DMF, dioxane, acetonitrile, and combinations thereof).

An exemplary synthesis of useful intermediates, such as carboxylic acid E, is shown in Scheme B. Additional syntheses are shown in the Examples that follow.

Reaction Figure B

In step S-4, acid F is esterified under appropriate conditions to produce ester G, wherein R ^e is a suitable group to form a carboxylic acid ester. In certain embodiments, R ^e is a C _1-6 aliphatic group. Suitable reactants for the esterification of acid F include alcohols. Step S-4 may use a suitable acid. In certain embodiments, the suitable acid is an inorganic acid or a Lewis acid. In certain embodiments, the acid is H ₂ SO ₄ .

In step S-5, ester G is formylated to produce salicylaldehyde H. Suitable conditions for ortho-formylation of phenols are conventional in the art. In certain embodiments, suitable conditions comprise MgCl ₂ , an amine base, and polyoxymethylene. In certain embodiments, the amine base is Et ₃ N. Step S-5 optionally utilizes a suitable solvent. Suitable solvents for use in step S-5 include polar aprotic solvents (i.e., THF, methyl-THF, dioxane, acetonitrile, and combinations thereof).

In step S-6, salicylaldehyde H is reacted to produce compound J. In certain embodiments, ^XJ is -OTf. Suitable conditions for introducing the trifluoromethanesulfonate group are conventional to the art. In certain embodiments, step S-6 includes a base. In certain embodiments, the base is an amine base. In certain embodiments, the amine base is pyridine, DMAP, or a combination thereof.

In step S-7, compound J is boronated under appropriate conditions to produce boronate ester K. Suitable conditions for the boronation of trifluoromethanesulfonates are conventional to this technique. In certain embodiments, suitable conditions comprise bis(1,1,2,2-tetramethyl-ethane-1,2-diol)diboron, a base, and a palladium catalyst. In certain embodiments, the base is potassium acetate. In certain embodiments, the palladium catalyst is [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Step S-7 optionally utilizes a suitable solvent. Suitable solvents for use in step S-7 include aprotic solvents (i.e., THF, methyl-THF, dioxane, acetonitrile, toluene, and combinations thereof).

It will be appreciated that groups other than triflate are suitable for Compound J and borylation chemistry. For example, Compound J may contain a halogen other than an -OTf group (e.g., chlorine, bromine, or iodine). Appropriate conditions for introducing the halogen group from Compound H or other precursors and the subsequent borylation reaction conditions are conventional in the art. See, for example, WO 2015013318 A1 and the subsequent Examples.

In step S-8, the boronate ester K is cyclized under appropriate conditions to generate the oxaborolane L. In certain embodiments, the appropriate conditions include a reducing agent. Suitable reducing agents include metal hydrides, such as borohydride. In certain embodiments, the reducing agent is sodium borohydride. After the reduction reaction, step S-8 optionally uses a suitable acid. In certain embodiments, the suitable acid is an inorganic acid or a Lewis acid. In certain embodiments, the acid is HCl. Step S-8 optionally uses a suitable solvent. Suitable solvents for use in step S-8 include, as non-limiting examples, THF, dioxane, methanol, ethanol, and combinations thereof.

In step S-9, the oxaborolane L is hydrolyzed to produce the carboxylic acid E. Suitable conditions for ester hydrolysis are conventional in the art and include base-catalyzed or acid-catalyzed reactions of the ester with water. Suitable bases include alkali metal hydroxides. In certain embodiments, the suitable base is NaOH. In certain embodiments, step S-9 comprises aqueous NaOH.

In certain embodiments, each of the synthetic steps described above can be performed after sequentially isolating each intermediate product produced in each step. Alternatively, each of Steps S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, and S-9 shown in Reaction Schemes A and B can be performed without isolating one or more intermediate products. Furthermore, one skilled in the art will appreciate that additional steps can be performed to achieve specific protecting group and/or deprotection strategies.

In certain embodiments, all steps of the above synthesis may be performed to produce the desired final product. In other embodiments, 2, 3, 4, 5 or more than 5 sequential steps may be performed to produce an intermediate or the desired final product.

Those skilled in the art will appreciate that certain starting materials shown in reaction schemes A and B can be readily replaced with other starting materials or reactants to produce additional compounds of Formula I. Such replacements can be accomplished using conventional experimental methods. For example, the amide nitrogen of the coupling product of amine D and carboxylic acid E can be modified to provide an R 3  group other than hydrogen. Furthermore, an alkyl group can be introduced at the R 1 position of the intermediate aldehyde via Grignard chemistry. Subsequent oxidation of a ketone and subsequent similar introduction of an R 1a group can also be performed.

How to use

In certain embodiments, the compounds of the present invention are useful in medical treatment. In certain embodiments, the compounds of the present invention are useful in treating parasitic infections. "Parasitic infection" includes diseases or conditions involving parasites. In certain embodiments, "parasitic infection" includes diseases or conditions involving parasites such as Trypanosoma cruzi, Trypanosoma congolense, Trypanosoma vivax, and Trypanosoma ifensii.

In certain embodiments, the compounds of the present invention can be used as anti-trypanosomal therapeutic agents. In certain embodiments, the parasites treatable by the compounds of the present invention are Trypanosoma cruzi, Trypanosoma congolense, Trypanosoma vivax, and Trypanosoma ivansis.

As used herein, "subject" refers to a mammal to which a pharmaceutical composition is administered. Exemplary subjects include humans and veterinary and laboratory animals such as horses, pigs, cows, dogs, cats, rabbits, rats, mice, and aquatic mammals.

In certain embodiments, the present invention provides a method of treating a disease or condition mediated by Trypanosoma congolense in a subject, comprising administering to the subject a provided compound. In certain embodiments, the disease is trypanosomiasis. In certain embodiments, the disease is African animal trypanosomiasis (AAT).

In certain embodiments, the present invention provides a method of treating a disease or condition mediated by viable trypanosomes in a subject, comprising administering to the subject a provided compound. In certain embodiments, the disease is trypanosomiasis. In certain embodiments, the disease is African animal trypanosomiasis (AAT).

In certain embodiments, the present invention provides a method of treating AAT, comprising administering a provided compound to a subject suffering from AAT. In certain embodiments, the subject suffering from AAT is a mammal. In certain embodiments, the subject suffering from AAT is a bovine species. In certain embodiments, the subject suffering from AAT is a cattle species.

In certain embodiments, the present invention provides a method of treating a disease or condition mediated by Trypanosoma cruzi in a subject, comprising administering to the subject a provided compound. In certain embodiments, the disease is Chagas disease. In certain embodiments, the present invention provides a method of treating Chagas disease, comprising administering to a subject suffering from Chagas disease a provided compound. In certain embodiments, the subject suffering from Chagas disease is a mammal. In certain embodiments, the subject suffering from Chagas disease is a human. In certain embodiments, the subject suffering from Chagas disease is a dog.

In certain embodiments, the compound has a half-maximal inhibitory concentration (IC ₅₀ ) against parasites of less than 1 uM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 500 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 100 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 10 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 1 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 0.1 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 0.01 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of less than 0.001 nM. In certain embodiments, the compound has an IC ₅₀ against parasites of from 0.01 nM to 1 uM. In certain embodiments, the compound has an _IC50 of 0.01 nM to 10 uM against parasites. In certain embodiments, the compound has an _IC50 of 0.1 nM to 10 uM against parasites. In certain embodiments, the compound has an _IC50 of 0.1 nM to 1 uM against parasites. In certain embodiments, the compound has an _IC50 of 0.1 nM to 100 nM against parasites. In certain embodiments, the compound has an _IC50 of 0.1 nM to 10 nM against parasites.

As used herein, "treatment" (also referred to as "treatment" or "treatment") refers to any administration of a drug (e.g., a pharmaceutical composition) that partially or completely alleviates, ameliorates, alleviates, inhibits, delays the onset, reduces the severity, and/or reduces the onset of one or more signs, characteristics, and/or causes of a particular disease, disorder, and/or symptom. The treatment may be administered to subjects who do not show symptoms of the relevant disease, disorder, and/or symptom and/or to subjects who only show early signs of the relevant disease, disorder, and/or symptom. Alternatively or in addition, the treatment may be administered to subjects who have shown one or more confirmed symptoms of the relevant disease, disorder, and/or symptom. In certain embodiments, the treatment may be administered to subjects who have been diagnosed with symptoms of the relevant disease, disorder, and/or symptom. In certain embodiments, the treatment may be administered to subjects who are known to show one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, and/or symptom.

Two drugs approved for the treatment of Chagas disease over 40 years ago (benznidazole and nifurtimox) require long treatment periods (60 to 90 days), have serious safety concerns (20% to 30% side effects leading to treatment discontinuation), show varying efficacy in treating chronic infection and Chagas cardiomyopathy, are contraindicated during pregnancy, and are associated with drug resistance. In certain embodiments, the methods provided are used to treat subjects with previously treated parasitic infections. In certain embodiments, the methods provided are used to treat subjects previously treated with benznidazole and/or nifurtimox. In certain embodiments, the methods provided are used to treat parasitic infections that are refractory to treatment with benznidazole and/or nifurtimox.

Pharmaceutical composition

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or a combination of a compound of Formula I and a pharmaceutically acceptable excipient (eg, carrier).

The pharmaceutical composition includes an optical isomer, diastereomer, or pharmaceutically acceptable salt of the disclosed inhibitor. The compound of Formula I included in the pharmaceutical composition can be covalently linked to a carrier moiety as described above. Alternatively, the compound of Formula I included in the pharmaceutical composition is not covalently linked to a carrier moiety.

As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, such as a pharmaceutically and physiologically acceptable organic or inorganic carrier material that does not adversely react with the active agent and is suitable for enteral or parenteral administration. Suitable pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. These preparations can be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and/or aromatic materials, and the like, which do not adversely react with the compounds of the present invention.

The compounds of the present invention can be administered to a subject individually or in combination. Co-administration includes administering the compounds individually or in combination (more than one) simultaneously or sequentially. These formulations can also be combined with other active agents (e.g., agents that reduce metabolic degradation) when desired.

combination

The compounds of the present invention may also be combined with other therapeutic agents. Thus, in another aspect, the present invention provides a combination comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. In an exemplary embodiment, the other therapeutic agent is a compound of the present invention. In an exemplary embodiment, the other therapeutic agent comprises a boron atom.

When a compound of the present invention is combined with a second therapeutic agent active against the same disease state, the dosage of each of these compounds may differ from the dosage of each of them when used alone. One skilled in the art will readily appreciate the appropriate dosage. It will also be understood that the dosage of the compound of the present invention required for treatment will vary depending on the nature of the condition to be treated and the age and condition of the patient and will ultimately be at the discretion of the attending physician or veterinarian.

preparation

The compounds of the present invention can be prepared and administered in a variety of different oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). The compounds of the present invention can also be administered by inhalation (e.g., intranasally). In addition, the compounds of the present invention can be administered transdermally. It is foreseeable that multiple routes of administration (e.g., intramuscularly, orally, transdermally, etc.) can be used to administer the compounds of the present invention. Thus, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

Pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the compounds of the present invention can be solid or liquid. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible particles. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, and the like. The term "preparation" refers to a formulation comprising the active compound and an encapsulating material, such as a carrier providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier, which is then combined with the active ingredient. Likewise, cachet formulations and lozenges are included. Tablets, powders, capsules, pills, cachet formulations, and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low-melting wax (such as a mixture of fatty acid glycerides) or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds, allowed to cool, and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be prepared as solutions in aqueous polyethylene glycol solution.

When parenteral administration is required or parenteral administration is intended, the particularly suitable mixture of the compound of the present invention is an injectable sterile solution, preferably an oil-soluble or water-soluble solution and suspension, emulsion or implant, which includes a suppository. In certain embodiments, a suitable carrier for parenteral administration will be selected for human administration. In certain embodiments, a suitable carrier for parenteral administration will be selected for veterinary administration. Specifically, carriers for parenteral administration include aqueous glucose solution, saline, pure water, ethanol, glycerol, cyclomethylene glycerol ether, polyethylene glycol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, pyrrolidine, N-methyl pyrrolidone and the like. Ampoules are conventional unit doses. The compound of the present invention can also be incorporated into liposomes or administered via a transdermal pump or patch. Suitable pharmaceutical mixtures for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of which are incorporated herein by reference.

Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavorings, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in an aqueous solution of a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other common suspending agents.

Also included are solid form preparations that can be converted immediately before use into liquid form preparations for oral administration. These liquid form preparations include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

Pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation containing multiple subdivided quantities of the formulation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or an appropriate number of any of these dosage forms packaged together.

The amount of active ingredient in a unit dose of the formulation may be varied or adjusted within the range of 0.1 mg to 10,000 mg, more typically 1.0 mg to 1,000 mg, and most typically 10 mg to 500 mg, depending on the particular administration and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents as desired.

Certain compounds may have limited water solubility and therefore may require a surfactant or other suitable cosolvent in the composition. These cosolvents include polysorbates 20, 60, and 80; commercially available Pluronic F-68, F-84, and P-103; cyclodextrins; and polyethylene glycol 35 castor oil. These cosolvents are typically used in amounts ranging from about 0.01% to about 2% by weight.

A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensed formulations, to reduce physical separation of components of suspension or emulsion formulations, and/or to otherwise improve the formulation. Viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. These viscosity building agents are typically used in amounts ranging from about 0.01% to about 2% by weight.

The compositions of the present invention may further include ingredients that provide sustained release and/or comfort. These ingredients include high molecular weight anionic mucosal mimetic polymers, curdlans, and finely divided drug carrier matrices. These ingredients are described in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference for all purposes.

For administration to non-human animals, a composition containing a therapeutic compound can be added to the animal's feed or drinking water. Furthermore, it is convenient to prepare the animal's feed or drinking water so that the animal receives an appropriate amount of the compound in its diet. Even more conveniently, the compound in the composition can be prepared as a premix for easy addition to the feed or drinking water. The composition can also be prepared as a food or beverage supplement for human use.

Effective dose

The pharmaceutical compositions provided herein include compositions comprising a therapeutically effective amount (i.e., an amount effective to achieve the intended purpose) of an active ingredient. The actual effective amount for a particular administration will depend, inter alia, on the condition being treated. For example, when administered in a method for treating a parasitic infection, the composition will contain an effective amount of the active ingredient to achieve the intended result.

The dose and frequency (single or multiple doses) of the compound administered may vary depending on a variety of factors, including the route of administration, the size, age, sex, health, weight, body mass index, and diet of the recipient, the nature and symptomatic state of the disease to be treated, the presence of other diseases or other health-related problems, the type of current treatment, and complications arising from any disease or treatment. Other treatments or therapeutic agents may be used in conjunction with the methods and compounds of the present invention.

For any compound of the invention, the therapeutically effective amount can be initially determined from cell culture assays.The target concentration will be that concentration of active compound that kills the parasite and/or controls the growth or reproduction of the parasite as determined using, for example, the methods described herein.

The therapeutically effective amount for use in humans can be determined by animal models. For example, the dosage for use in humans can be adjusted to achieve a concentration that has been found to be effective in animals. The dosage for use in humans can be adjusted by monitoring kinase inhibition and adjusting the dosage upward or downward as described above. The therapeutically effective amount for use in animals (e.g., cattle) can be determined by animal models (e.g., mouse models).

The dosage may vary depending on the patient's needs and the compound being used. In the present invention, the dose administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient for a period of time. The size of the dose will also be determined by the presence, nature, and extent of any adverse side effects. Generally, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Subsequently, the dose is increased by small increments until the optimal effect for the treatment situation is achieved. In certain embodiments, the dosage range is 0.001% to 10% w/v. In certain embodiments, the dosage range is 0.1% to 5% w/v.

Dosage amount and interval may be adjusted individually to provide a concentration of the administered compound effective for the particular clinical indication being treated. This concentration will provide therapeutic treatment commensurate with the severity of the subject's disease state.

[Implementation Method]

The following examples will illustrate certain embodiments of the present invention but are not intended to limit the scope of the invention.

It will be understood that when an example describes another example by reciting "Example I-XX", the recitation refers to the synthesis of the respective compound 6-XX or the relevant part of the synthesis.

Example A-1: Preparation of Acid-04

To a solution of compound 1 (1.65 kg, 10.8 mol) in EtOH (6.50 L) was added concentrated H ₂ SO ₄ (326 g, 3.25 mol). The reaction mixture was heated to 105° C. for 24 hours. TLC showed complete consumption of compound 1. The mixture was cooled to 15° C. and concentrated to yield the crude product. The residue was poured into 2M aqueous NaHCO ₃ solution (3 L) and the solid was filtered. The filtrate was concentrated to yield compound 2 (1.75 kg, 90%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ )7.41(d,J＝7.9Hz,1H),7.11(t,J＝7.9Hz,1H), 6.94(d,J＝7.9Hz,1H),4.58(br s,1H),4.37(q,J＝7.4Hz, 2H), 2.46 (s, 3H), 1.40 (t, J = 7.1Hz, 3H).

To a solution of compound 2 (800 g, 4.44 mol) in THF (6.50 liters) were added MgCl ₂ (634 g, 6.66 mol, 273 ml), TEA (1.80 kg, 17.8 mol) and (HCHO) n (600 g, 6.66 mol). The mixture was immediately heated to 90° C. for 14 hours. TLC showed that compound 2 was completely consumed. The reaction mixture was cooled to 15° C., ice water (3 liters) was added, and 12M HCl (1.5 liters) was slowly added. The mixture was stirred for half an hour and then extracted with EtOAc (2 liters). The combined organic layers were washed with saturated NaHCO ₃ solution until neutral, dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce compound 3 (880 g, crude product) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ ) δ11.40 (s, 1H), 9.93 (s, 1H), 7.46 (d, J = 7.6Hz, 1H), 7.37 (d, J = 8.0Hz, 1H), 4.40(q,J＝7.4Hz,2H),2.44(s,3H),1.41(t,J＝7.1Hz,3H).

To a solution of compound 3 (900 g, 4.32 mol) in DCM (7.56 L) were added pyridine (1.02 kg, 12.9 mol) and DMAP (27 g, 221 mmol), respectively. The mixture was cooled to 0°C and _Tf2O (1.60 kg, 5.66 mol) was added dropwise. The reaction mixture was warmed to 15°C and stirred for 1 hour. TLC showed complete consumption of compound 3. The mixture was quenched with water (7.65 L) and then extracted with DCM (7.65 L x 2). The combined organic layers were rinsed with water (2 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 4 (685 g, 47%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) 10.27 (s, 1H), 7.99 (d, J = 8.0Hz, 1H), 7.91-7.87 (m, 1H), 4.43 (q, J = 7.0Hz, 2H), 2.64 (s, 3H), 1.43 (t, J = 7.3Hz, 3H).

To a solution of compound 4 (1.00 kg, 2.94 mol), bis(1,1,2,2-tetramethyl-ethane-1,2-diol)diboron (1.12 kg, 4.41 mol), and KOAc (573 g, 5.84 mol) in 1,4-dioxane (6.50 L) was added Pd(dppf) _Cl₂ · _CH₂Cl₂ (150 g, 184 mmol). The mixture was heated at 85° C. under nitrogen for 15 hours. TLC showed complete consumption of compound _4. The mixture was cooled to 15° C., filtered, and concentrated to yield a crude product. The residue was purified by column chromatography ( _SiO₂ ; petroleum ether/ethyl acetate = 40/1 to 4:1) to yield compound 5 (942 g, crude product) as a yellow oil.

To a solution of compound 5 (1.20 kg, 3.77 mol) in MeOH (300 ml) and THF (6.00 liters) was added _NaBH₄ (80 g, 2.11 mol) portionwise at 0°C. The reaction mixture was then stirred at 15°C for 1 hour. HPLC indicated complete consumption of compound 5. The reaction solution was adjusted to pH 4 with 2M HCl, and the organic layer was removed under vacuum. The mixture was filtered. The filter cake was rinsed with petroleum ether (5 liters) and dried under vacuum to yield compound 6 (665 g, 80%) as a white solid. ¹ HNMR (400MHz, DMSO-d ₆ )9.18 (s, 1H), 7.89 (d, J＝8.0Hz, 1H), 7.32 (d, J＝8.0Hz, 1H), 5.00 (s, 2H), 4.30 (q, J=7.0Hz, 2H), 2.68 (s, 3H), 1.33 (t, J=7.0Hz, 3H).

To a mixture of compound 6 (867 g, 3.94 mol) in _H₂O (5.00 L) was added NaOH (394 g, 9.85 mol) in one portion. The solution was heated at 40°C for 3 hours. HPLC indicated complete consumption of compound 6. This batch was treated with other batches and acidified to pH = 2 with 2M HCl. The solid was filtered and rinsed with water (10 L). The filter cake was dried to yield acid-04 (2.00 kg, 87%) as a white solid. ^1H NMR (400 MHz, DMSO- _d₆ ) 9.13 (br s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 2.68 (s, 3H).

Example A-2: Preparation of Acid-05

To a solution of compound 1 (100 g, 465 mmol) in MeOH (1 L) was added concentrated H ₂ SO ₄ (20 ml). The solution was heated at 80° C. for 16 hours. The solvent was removed under reduced pressure and the residue was slowly poured into water (100 ml). The aqueous layer was extracted with EtOAc (3×200 ml). The combined organic layers were washed with aqueous NaHCO ₃ solution and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude compound 2 (102 g) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 8.18 (d, J=1.2 Hz, 1H), 7.85 (d, J=6.0, 1.76 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 2.44 (s, 3H).

To a solution of LiTMP (35.46 g, 251 mmol) in anhydrous THF (200 ml) was added dropwise n-BuLi (2.5 M, 100 ml, 251 mmol) at -10°C under nitrogen. After cooling to -60°C, a solution of compound 2 (50.0 g, 218 mmol) in anhydrous THF (50 ml) was added dropwise under nitrogen, and the reaction mixture was stirred at -60°C for an additional 30 minutes. _I₂ (166.2 g, 654.8 mmol) was added to the mixture in one portion at -60°C. The resulting solution was allowed to warm to 0°C over 1 hour. The reaction mixture was quenched with saturated aqueous _NH₄Cl , and the aqueous phase was extracted with DCM (3 x 100 ml) _. The combined organic phases _were washed with saturated aqueous _{Na₂S₂O₃} (3 x 100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=20/1) to give compound 3 (20 g, 26%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.45 (d, J=7.6 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 3.96 (s, 3H), 2.59 (s, 3H).

A mixture of compound 3 (20.0 g, 56.3 mmol), NBS (10.0 g, 56.3 mmol), and BPO (1.36 g, 5.63 mmol) in CCl ₄ (200 ml) was heated at 80° C. under nitrogen for 12 hours. NBS (10.0 g, 56.3 mmol) and BPO (1.36 g, 5.63 mmol) were then added. After heating at 80° C. for another 6 hours, the solvent was removed under reduced pressure to yield compound 4, which was used in the next step without further purification.

A mixture of compound 4 (24.0 g, 55.3 mmol) and AcOK (10.86 g, 110.6 mmol) in DMF (250 ml) was heated at 80° C. under nitrogen for 4 hours. The solvent was removed under reduced pressure. The residue was diluted with water (100 ml), and the aqueous layer was extracted with MTBE (3×100 ml). The combined organic layers were washed with brine (500 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue, which was purified by column chromatography (SiO ₂ ; petroleum ether/ethyl acetate = 20/1 to 5/1) to yield compound 5 (7.00 g, 31%) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) 7.51 (d, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 5.24 (s, 2H), 3.96 (s, 3H), 2.19 (s, 3H).

To a mixture of compound 5 (1.65 g, 4.00 mmol), trifluoro(vinyl)-4-borane potassium salt (696 mg, 5.20 mmol), and Cs ₂ CO ₃ (2.61 g, 8.00 mmol) in 1,4-dioxane (30 ml) and water (0.4 ml) was added Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (326 mg, 0.400 mmol). The reaction mixture was heated at 100° C. under nitrogen for 18 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative TLC (eluent: petroleum ether:EtOAc = 10:1) to yield compound 6 (0.60 g, 48%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) 7.61 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.93 (q, J = 10.8 Hz, J = 6.8 Hz, 1H), 5.49 (d, J = 10.0 Hz, 1H), 5.27(m,1H),5.23(s,2H),3.84(s,3H),2.17(s,3H).

To a mixture of compound 6 (0.63 g, 2.0 mmol), AcOK (395 mg, 4.00 mmol), and BPD (1.0 g, 4.0 mmol) in dioxane (12 ml) was added Pd(dppf) _Cl₂ · _CH₂Cl₂ (164 mg, 0.2 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 14 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative TLC ( _SiO₂ ; petroleum ether/EtOAc = 10/1) to give compound ₇ (0.40 g, 55.2%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )7.87 (d, J＝7.6Hz, 1H), 7.44 (d,J＝11.2Hz,1H),7.36(d,J＝8.0Hz,1H),5.36(d,J＝11.2Hz,1H),5.30(d,J＝17.6Hz,1H),5.19(s,2H),3.85(s,3H),2.09(s,3H),1.36(s,12H).

To a solution of compound 7 (0.40 g, 1.1 mmol) in MeOH (10 ml) and water (0.3 ml) was added NaOH (133 mg, 3.33 mmol). The solution was stirred at 50°C for 14 hours. The solvent was removed under reduced pressure. The residue was diluted with water (5 ml) and adjusted to pH 2 with 2M HCl. After filtration, compound 8 (160 mg, 71%) was obtained as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) 8.98 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 6.8 Hz, 1H), 5.70 (d, J = 12 Hz, 1H), 5.42 (d, J = 11.6 Hz, 1H), 5.00 (s, 1H).

A mixture of compound 8 (160 mg, 0.73 mmol) and 10% Pd/C (0.2 g) in MeOH (80 ml) was stirred at 20° C. under H ₂ (14 psi) for 14 hours. After filtration, the filtrate was concentrated under reduced pressure to yield acid-05 (150 mg, 99%) as a white solid. MS (ESI) mass: calculated for C ₁₀ H ₁₁ BO ₄ 206.00, m/z found 205.2 [MH] ⁻ . ¹ H NMR (400MHz, DMSO-d ₆ ) 12.74 (s, 1H), 9.06 (s, 1H), 7.83 (d, J = 8.0Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 4.97 (s, 2H), 3.12 (m, 2H), 1.12 (t,J=7.6Hz,1H).

Example A-3: Preparation of Acid-06

To a mixture of compound 1 (from Reference Example 2; 1.65 g, 4.00 mmol), cyclopropylboronic acid (446 mg, 5.20 mmol), and Cs ₂ CO ₃ (2.61 g, 8 mmol) in 1,4-dioxane (30 ml) and water (3 ml) was added Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (326 mg, 0.40 mmol). The reaction mixture was heated at 100° C. under nitrogen for 18 hours. The solvent was removed under reduced pressure. The crude mixture was purified by preparative TLC (eluent: PE:EtOAc = 10:1) to yield compound 2 (0.55 g, 43%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )7.47(d,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),5.22(s,2H),3.92(s,1H),5.27(m,3H),2.16(s,3H),2.03-1.99 (m, 1H), 1.09 (q, J = 5.6Hz, J = 8.4Hz, 1H), 0.49 (q, J = 5.2 Hz, J = 5.6Hz, 1H).

To a mixture of compound 2 (0.50 g, 1.5 mmol), AcOK (300 mg, 3 mmol), and compound 3 (1.38 g, 6.10 mmol) in dioxane (8 ml) was added Pd(dppf) _Cl₂ · _CH₂Cl₂ ( ₅₀₀ mg, 0.60 mmol). The reaction mixture was stirred at 110° C. under nitrogen for 14 hours. The solvent was removed under reduced pressure. The crude mixture was purified by preparative TLC ( _SiO₂ ; PE/EA=20/1) to give compound 4 (0.35 g, 64%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )7.54 (d, J＝7.6Hz, 1H), 7.25 (d, J＝ 7.2Hz,1H),5.18(s,2H),3.88(s,3H),3.79(s,4H),2.40(m,1H),2.07(s,3H),1.26(s,6H),0.88(s,2H),0.50(t,J＝4.4 Hz,2H).

To a solution of compound 4 (0.32 g, 0.90 mmol) in MeOH (12 ml) and water (4 ml) was added NaOH (106 mg, 2.67 mmol). The solution was stirred at 80°C for 14 hours. The solvent was removed under reduced pressure. The residue was diluted with water (5 ml) and adjusted to pH 2 with 2M HCl. After filtration, acid-06 (170 mg, 88%) was obtained as a pale yellow solid. MS (ESI) mass: calculated for C ₁₁ H ₁₁ BO ₄ 218.01, m/z found 219.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )12.82(s,1H),8.93(s,1H),7.59(d,J＝7.6Hz,1H), 7.26(d,J＝8.0Hz,1H),4.97(s,2H),2.27(m,1H),0.89(d, J=7.2Hz, 2H), 0.70 (d, J=8.4Hz, 2H).

Example A-4: Preparation of Acid-07

To a solution of compound 1 (obtained from Reference Example 1; 50 mg, 157 micromol) in THF (4 ml) was added MeMgBr (21 mg, 172 micromol) at -78°C. The mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with saturated NH ₄ Cl solution (20 ml) at 15°C and then extracted with EtOAc (2×5 ml). The combined organic layers were washed with saturated brine (2×5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was dissolved in DCM (5 ml) and then washed with 1M HCl. The organic layer was washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative TLC (PE/EtOAc = 5/1) to yield compound 2 (20 mg, 54%) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) 8.01(d,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),5.30(q,J＝6.4Hz,1H),4.38(q,J＝7.2Hz,2H),2.80(s,3H),1.52 (d, J=6.4Hz, 3H), 1.41 (t, J=7.2Hz, 3H).

A mixture of compound 2 (160 mg, 683 μmol) and NaOH (82 mg, 2.0 mmol) in MeOH (10 mL) and water (10 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 50° C. under nitrogen for 4 hours. The solvent was removed under reduced pressure. The solution was adjusted to pH 2-3 with 1 M HCl. A white solid subsequently precipitated and was filtered to yield acid-07 (100 mg, 71%) as a white solid. MS (ESI) mass: calculated for C ₁₀ H ₁₁ BO ₄ 206.00, m/z found 207.1 [M+H] ⁺ . ¹ HNMR(400MHz, DMSO-d ₆ )12.74(s,1H),9.04(s,1H),7.89(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H), 5.22-5.17(m,1H),2.67(s,3H),1.40(d,J＝6.8Hz,3H).

Example A-5: Preparation of Acid-08

This compound was prepared from compound 1 obtained in Example A-2 and trifluoro(2-propenyl)-4-borane potassium salt in a similar manner to Example A-2. ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.90 (s, 1H), 9.26 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.99 (s, 2H), 3.58 (t, J=7.2 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H).

Example A-6: Preparation of Acid-09

A mixture of compound 1 (from Reference Example 2; 200 mg, 484 μmol), allyl(tributyl)stannane (160 mg, 0.484 mmol), and Pd(PPh ₃ ) ₄ (56 mg, 48 μmol) in dioxane (5 ml) was degassed and purged with nitrogen three times, and then stirred at 80° C. under nitrogen for 12 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc = 5/1) to yield compound 2 (80 mg, 50%) as a yellow liquid. ^1H NMR (400 MHz, CDCl ₃ ) 7.78 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.00-5.91 (m, 1H), 5.24 (s, 2H), 5.08-4.99 (m, 2H), 3.98 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.19 (s, 3H). Acid-09 was obtained by a method similar to Example A-2. MS (ESI) mass: calculated for C ₁₁ H ₁₃ BO ₄ 220.03, m/z found 221 [M+H] ⁺ .

Example A-7: Preparation of Acid-10

A mixture of compound 1 (from Reference Example 2; 300 mg, 726 μmol), CuI (276 mg, 1.5 mmol), compound 2 (139 mg, 726 μmol), and HMPA (651 mg, 4 mmol) in DMF (5 ml) was stirred at 80° C. under nitrogen for 12 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) to yield compound 3 (30 mg, 12%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 7.62 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 3.93 (s, 3H), 2.19 (s, 3H).

A mixture of compound 3 (100 mg, 281 μmol), Pd(dppf)Cl ₂ (82 mg, 0.11 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-5,5-dimethyl-1,3,2-dioxaborolan (127 mg, 0.563 mmol) and AcOK (55 mg, 0.56 mmol) in dioxane (5 ml) was stirred at 100° C. under nitrogen for 12 hours. The mixture was purified by preparative TLC (petroleum ether/EtOAc=5/1) to give crude compound 4 (35 mg) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) 7.80 (d, J = 6.4 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 5.25 (s, 2H), 3.92 (s, 3H), 3.80 (s, 4H), 2.11 (s, 3H), 1.18 (s, 6H).

To a mixture of compound 4 (900 mg, 2.00 mmol) in MeOH (9 ml) and _H₂O (10 ml) was added NaOH (371 mg, 9.00 mmol). The mixture was stirred at 50°C for 12 hours. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH 2-3 with 1M HCl. The solid was collected after filtration. The crude product was purified by preparative TLC (petroleum ether/EtOAc = 1/1) and then by preparative HPLC (TFA conditions) to yield a mixture of acids 10 (150 mg) as _a white solid. MS (ESI) mass: calculated for _{C₆H₆BF₃O₄ 245.95} , m/ _z found 247 [M+H] ^⁺ .

Example A-8: Preparation of Acid-11

To a solution of compound 1 (15 g, 55 mmol) in DCM (100 ml) was added DAST (89.0 g, 553 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 16 hours. The reaction mixture was slowly poured into saturated NaHCO ₃ (200 ml) at 0°C and then extracted with DCM (2×100 ml). The combined organic layers were washed with brine (2×50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2 (11 g, 68% yield) as a light yellow oil. ¹ H NMR (400MHz, CDCl ₃ )7.53(d,J＝8.0Hz, 1H),7.39(d,J＝8.0Hz,1H),7.26(t,J＝35.6Hz,1H),4.38 (q, J=8.0Hz, 6.0Hz, 2H), 2.49 (s, 3H), 1.38 (t, J=7.2Hz, 3H).

A mixture of compound 2 (9.0 g, 31 mmol), NBS (6.0 g, 34 mmol), and BPO (744 mg, 3.00 mmol) in CCl ₄ (100 ml) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 80° C. under nitrogen for 16 hours. The solvent was removed under reduced pressure to yield compound 3 (11 g, crude product) as a pale yellow solid, which was used in the next step without further purification.

A mixture of compound 3 (11 g, crude product) and AcOK (3.0 g, 33 mmol) in DMF (30 ml) was stirred at 60° C. under nitrogen for 2 hours. The reaction mixture was diluted with H ₂ O (100 ml) and then extracted with MTBE (2×100 ml). The combined organic layers were washed with brine (100 ml; 2×50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to produce compound 4 (4.0 g, 39%) as a light yellow oil. ¹ H NMR (400MHz, CDCl ₃ )7.65(d,J＝8.0Hz, 1H),7.57(d,J＝8.0Hz,1H),7.26(t,J＝54Hz,1H),5.25 (s, 2H), 4.40 (q, J = 7.2Hz, 2.8Hz, 2H), 2.18 (s, 3H), 1.39 (t, J = 7.2Hz, 3H).

A mixture of compound 4 (50.0 mg, 142 μmol), BPD (145 mg, 0.569 mmol), AcOK (56.0 mg, 0.569 mmol), and Pd(dppf) _Cl₂ (21 mg, 0.028 mmol) in dioxane (2 ml) was degassed and purged with nitrogen three times. The mixture was stirred at 90° C. under nitrogen for 12 hours. The reaction mixture was directly purified by preparative TLC (petroleum ether/EtOAc = 5/1) to give compound 5 (5.0 mg, 8.8% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) 7.96 (d, J = 8.0 Hz, 1H), 7.72-7.37 (m, 2H), 5.23 (s, 2H), 4.39 (d, J = 7.2 Hz, 2H), 2.12 (s, 3H), 1.42 (s, 12H).

A mixture of compound 5 (240 mg, 0.603 mmol) and NaOH (96 mg, 2.0 mmol) in MeOH (2 ml) and _H₂O (2 ml) was stirred at 50°C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH 4 with 1 M HCl. The mixture was concentrated under reduced pressure to yield acid-11 (100 mg) as a _white solid. MS (ESI) mass: calculated for _{C₆H₁₇BF₂O₄ 227.96} , m/ _z found 229 [M+H] ^⁺ .

Example A-9: Preparation of Acid-12

Step 1: To a stirred solution of compound 1 (10 g, 60.2 mmol) in DCM (100 ml) was added _TiCl₄ (1 M solution in DCM, 150 ml, 150 mmol) dropwise at room temperature (RT). _Br₂ (3.09 ml, 60.2 mmol) was then added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. Reaction progress was monitored by TLC. TLC indicated the formation of two closely spaced polar spots and complete consumption of compound 1. The reaction was quenched with ice-cold water and extracted with petroleum ether (3 x 500 ml). The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield the crude product. The crude compound was purified by silica gel column chromatography (100-200 mesh; 100% petroleum ether) to isolate 2.5 g of compound 2 (2.5 g, 12%), compound 2A (8 g), and a mixture of compound 2 and compound 2A (5.4 g).

Step 2: To a stirred solution of compound 2 (2.4 g, 9.836 mmol) in DMF (48 ml) at room temperature was added _{K₂CO₃ (} 2.0 g, 14.75 mmol) and stirred at room temperature for 30 minutes. Mel (0.735 ml, 11.8 mmol) was then added at room temperature and stirred at the same temperature for 2 hours. Reaction progress was monitored by TLC. TLC indicated the formation of a nonpolar spot and complete consumption of compound 2. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield the crude product. The crude compound was purified by silica gel column chromatography (100-200 mesh; 2% EtOAc in petroleum ether) to yield compound 3 (2.5 g, 99%).

Step 3: AIBN (317 mg, 1.937 mmol) and NBS (2.06 g, 11.627 mmol) were added to a stirred solution of compound 3 (2.5 g, 9.689 mmol) in CCl ₄ (25 ml) at room temperature. The reaction mixture was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure to produce a crude residue. The residue was diluted with water and EtOAc. The organic layer was separated and rinsed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to produce a crude product. The crude compound was purified by column chromatography (normal phase; 3% EtOAc in petroleum ether) to produce compound 4 (1.5 g, 46%) as a yellow syrup.

Step 4: To a stirred solution of compound 4 (1.3 g, 3.869 mmol) in CH ₃ CN (26 ml) was added KOAc (1.13 g, 11.607 mmol) at room temperature. The reaction mixture was stirred at reflux for 18 hours. The reaction progress was monitored by TLC, which showed the formation of polar spots and complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to produce a crude residue. The crude residue was diluted with water and EtOAc. The organic layer was separated and washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to produce compound 5 (1.2 g, 98%) as an off-white solid.

Step 5: To a stirred solution of compound 5 (1.7 g, 5.379 mmol) in 1,4-dioxane (20 volumes) was added KOAc (1.58 g, 16.13 mmol) and bis(neopentyl glycol)diborane (2.43 g, 10.759 mmol) at room temperature. The reaction mixture was degassed and filled with argon for 20 minutes. Pd(dppf)Cl ₂ was then added at room temperature. DCM (0.219 g, 0.268 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for 3 hours. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to produce the crude product. The crude compound was purified by silica gel column chromatography (100-200 mesh; 15%-20% EtOAc:petroleum ether) to produce compound 6 (1.5 g, 80%) as a yellow syrup.

Step 6: To a stirred solution of compound 6 (1.5 g, semipure, 4.285 mmol) in MeOH (10 volumes) at 0°C was added 1N NaOH (0.514 g, 12.857 mmol). The reaction mixture was stirred at room temperature for 5 hours. Reaction progress was monitored by TLC, which showed the formation of polar spots and complete consumption of the starting material. The reaction mixture was acidified to pH 3.0 with 2N HCl and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with brine solution and dried over sodium sulfate. The solvent was removed under reduced pressure to yield the crude compound. The crude compound was purified by reverse phase HPLC to yield compound 7 (400 mg, 42%) as a pale yellow solid.

Step 7: To a stirred solution of compound 7 (400 mg, 1.8 mmol) in _H₂O (20 volumes) at 0°C was added NaOH (216 mg, 5.404 mmol). The reaction mixture was allowed to warm to room temperature for 5 hours. Reaction progress was monitored by TLC, which showed the formation of polar spots and complete consumption of the starting material. The reaction mixture was acidified to pH 4.0 with 2N HCl at 0°C and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield compound 8 (303 mg, 80%) as a white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.6(s,1H),9.34(s,1H), 7.76(d,1H),7.10(d,1H),5.02(s,2H),4.0(s,3H); LC-MS: m/z 209.01[M+H] ⁺ .

Example A-10: Preparation of Acid-13

Acid-13 was prepared from the reaction of iodoethane with compound 2 and then by the same procedure as for the synthesis of acid-12.

Step 1: To a stirred solution of compound 2 (3 g, 12.3 mmol) in DMF (30 ml) was added K ₂ CO ₃ (2.54 g, 18.4 mmol) at room temperature and stirred for 30 minutes. EtI (2.92 ml, 36.9 mmol) was then added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. Reaction progress was monitored by TLC. TLC showed the formation of a nonpolar spot and complete consumption of the starting material. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield the crude product. The crude compound was purified by silica gel column chromatography (100-200 mesh; 2% to 4% EtOAc in petroleum ether) to yield compound 3 (2.2 g, 66%) as a colorless liquid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.6(s,1H),9.25(s,1H), 7.72(d,1H),7.10(d,1H),5.02(s,2H),4.32(qt,2H),1.28 (t,3H); LC-MS: m/z 223.33[M+H] ⁺ .

Example A-11: Preparation of Acid-14

This compound was prepared from 5-hydroxy-2-methylbenzoic acid in a similar manner to Example A-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.22 (s, 1H), 7.29 (s, 1H), 4.96 (s, 2H), 2.54 (s, 3H).

Example B-1: Preparation of 4-fluorobenzyl-L-valine ester

To a solution of N-BOC-(S)-valine (500.00 g, 2.30 mol, 1.00 equiv) and 4-fluorobenzyl alcohol (290 g, 2.30 mol, 248.10 mL) in dry DCM (6.0 L) was added DCC (854 g, 4.14 mol, 838 mL) and DMAP (39.36 g, 322.19 mmol). The reaction mixture was stirred at 25° C. for 15 hours. The mixture was filtered, rinsed with DCM (2 L), and concentrated to yield the crude product. The residue was purified by column chromatography (SiO ₂ ; petroleum ether/EtOAc = 50/1 to 10/1) to yield (tert-butoxycarbonyl)-L-valine 4-fluorobenzyl ester (708 g, 95% yield) as a white solid. ¹ H NMR (400MHz CDCl ₃ ) δ7.35 (dd, J＝8.2, 5.5Hz, 2H), 7.05 (t, J＝8.6Hz, 2H), 5.19-5.08 (m, 2H), 5.01 (d, J＝8.4Hz, 1H), 4.25 (dd, J＝8.4, 4.4Hz, 1H), 2.13 (dd, J=6.2, 11.9Hz, 1H), 1.44 (s, 9H), 0.93 (d, J=7.1Hz, 3H), 0.84 (d, J=7.1Hz, 3H).

A mixture of (tert-butoxycarbonyl)-L-valine 4-fluorobenzyl ester (1.06 kg, 3.26 mol) in EtOAc/HCl (6.0 L) was stirred at 25° C. for 14 hours. The solvent was removed under reduced pressure to yield L-valine 4-fluorobenzyl ester hydrochloride (780 g, 91%) as a white solid. ^1H NMR (400 MHz CDCl ₃ ) δ 8.90 (br s, 3H), 7.37 (dd, J=8.2, 5.5 Hz, 2H), 7.03 (t, J=8.4 Hz, 2H), 5.29-5.10 (m, 2H), 3.95 (br s, 1H), 2.44 (dd, J=11.0, 6.6 Hz, 1H), 1.08 (dd, J=10.1, 7.1 Hz, 6H).

Example 1. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine 2,6-dimethylphenyl ester (6-001)

To a solution of compound 1 (1.22 g, 10.0 mmol), compound 2 (1.98 g, 10.5 mmol), and DMAP (122 mg, 1.00 mmol) in dichloromethane (50 ml) was slowly added DCC (2.26 g, 11.0 mmol) at 0°C. The mixture was stirred overnight at 10°C. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to produce compound 3 (2.0 g, 68% yield) as a white solid, which was used in the subsequent step and confirmed at the final stage.

To a solution of compound 3 (1.0 g, 3.4 mmol) in ethyl acetate (20 ml) was slowly added a 4 M HCl solution in ethyl acetate (20 ml) at 0°C. The mixture was stirred at 10°C for 1 hour. TLC (PE/EA = 10/1) indicated complete consumption of the starting material. The reaction mixture was concentrated to dryness to yield compound 4 (750 mg, 95% yield) as a white solid.

To a solution of acid-01 (ACS Med. Chem. Lett., 2010, 1(4), 165-169, 178 mg, 1.00 mmol), compound 4 (230 mg, 1.00 mmol), EDC (384 mg, 2.00 mmol) and HOBt (270 mg, 2.00 mmol) in DMF (5 ml) was added DIPEA (387 mg, 3.00 mmol). The reaction mixture was stirred at 10° C. overnight and then concentrated and purified by preparative HPLC to give compound 6-001 (270 mg, 76% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 9.02 (d, J = 6.62Hz, 1H), 8.30 (s, 1H), 8.00 (dd, J = 7.94Hz, 1.32Hz, 1H),7.51(d,J＝8.38Hz,1H),7.13-6.99(m,3H),5.04(s,2H), 4.74(t,J＝6.84Hz,1H),2.10(s,6H),1.63(d,J＝7.06Hz, 3H); ESI-MS: m/z 354[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 2. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine tert-butyl ester (6-002)

This compound was prepared from (S)-alanine tert-butyl ester and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.68 (t, J = 6.2 Hz, 1H), 8.22 (s, 1H), 7.96-7.92 (m, 2H), 5.01 (s, 2H), 4.30 (quintet, J = 6.1 Hz, 1H), 1.37 (s, 9H), 1.35 (d, J = 6.1 Hz, 3H); ESI-MS: m/z 364 [M+OAc] ⁻ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 3. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-003)

Compound 6-003 was prepared from acid-04 and L-valine tert-butyl ester in analogy to the last step of Example 1, followed by addition of HCl and purification by preparative HPLC (column: Luna C8 100×30 mm; liquid phase: 0.1% TFA-ACN; B%: 10% to 35%, 12 minutes). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 9.00 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.43-7.13 (m, 2H), 4.95 (s, 2H), 4.27 (dd, J=8.2 Hz, 6.4 Hz, 1H), 2.46 (s, 3H), 2.22-1.99 (m, 1H), 0.94 (t, J=6.8 Hz, 6H); ESI-MS: m/z 292 [M+H] ⁺ ; HPLC purity: 99.18% (220 nm), 100% (254 nm).

Example 4. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)glycine benzyl ester (6-004)

This compound was prepared from glycine benzyl ester and acid-01 in a manner analogous to Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.93 (dd, J = 7.9, 1.32 Hz, 1H), 7.49 (d, J = 7.94 Hz, 1H), 7.41-7.21 (m, 5H), 5.14 (s, 2H), 5.03 (s, 2H), 4.06 (d, J = 5.7 Hz, 2H); ESI-MS: m/z 326 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 5. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-005)

This compound was prepared from (S)-valine benzyl ester and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (br s, 1H), 8.66 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 7.95 (dd, J=7.9, 1.76 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.38-7.31 (m, 4H), 5.24-5.09 (m, 2H), 5.04 (s, 2H), 4.33 (t, J=7.5 Hz, 1H), 2.29-2.11 (m, 1H), 0.95 (dd, J=18.96, 6.62 Hz, 6H). ESI-MS: m/z 368 [M+H] ⁺ ; HPLC purity: 98.3% (220 nm), 100% (254 nm).

Example 6. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-leucine ester (6-006)

This compound was prepared analogously to the last step of Example 1 from (S)-leucine benzyl ester and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.32 (s, 1H), 8.79 (d, J = 7.94Hz, 1H), 8.23 (s, 1H), 7.93 (d, J = 7.9Hz, 1H), 7.48 (d,J＝7.9Hz,1H),7.38-7.25(m,5H),5.12(s,2H),5.03(s,2H),4.52(dd,J＝6.8,3.31Hz,1H),1.90-1.42(m,3H),0.90 (d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H),6.39Hz,6H); ESI-MS: m/z 382[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 7. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-serine benzyl ester (6-007)

This compound was prepared from (S)-serine benzyl ester and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.34 (s, 1H), 8.67 (d, 1H), 7.87 (s, 1H), 7.80 (d, 2H), 7.41-7.26 (m, 4H), 5.14 (s, 2H), 5.03 (s, 2H), 4.58 (m, 1H), 3.88-3.77 (m, 2H); ESI-MS: m/z 356 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 8. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-methionine benzyl ester (6-008)

This compound was prepared analogously to the last step of Example 1 from (S)-methionine benzyl ester and acid-01. ¹ HNMR (400MHz, DMSO-d ₆ )9.32 (br s, 1H) 8.84 (d, J＝7.5Hz, 1H), 8.23 (s, 1H), 7.94 (d, J＝7.9Hz, 1H), 7.49 (d,J＝7.9Hz,1H),7.38-7.22(m,5H),5.14(d,J＝4.0Hz, 2H),5.03(s,2H),4.68-4.51(m,1H),2.68-2.51(m,2H), 2.12-2.04 (m, 2H), 2.01 (s, 3H); ESI-MS: m/z400[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 9. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-phenylalanine benzyl ester (6-009)

This compound was prepared from (S)-phenylalanine benzyl ester and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.31 (s, 1H), 8.92 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.36-7.14 (m, 9H), 5.11 (d, J=4.41 Hz, 2H), 5.02 (s, 2H), 4.65-4.77 (m, 1H), 3.22-3.07 (m, 2H); ESI-MS m/z 416 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 10. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-aspartamide benzyl ester (6-010)

This compound was prepared analogously to the last step of Example 1 from (S)-glutamine benzyl ester and acid-01. ¹ HNMR (400MHz, DMSO-d ₆ )8.90(d,J＝7.06Hz, 1H),8.25(s,1H),7.96(dd,J＝8.0,1.76Hz,1H),7.50(d,J＝8.4Hz,1H),7.36-7.31(m,5H),6.82(br s,1H),5.19-5.10 (m,2H),5.04(s,2H),4.47(br s,1H),2.28-2.19(m,2H), 2.16-2.04(m,1H),2.03-1.90(m,1H); ESI-MSm/z 397[M+H] ⁺ ; HPLC purity: 99.39% (220nm), 100% (254nm).

Example 11. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-glutamine benzyl ester (6-011)

This compound was prepared analogously to the last step of Example 1 from (S)-glutamine benzyl ester and acid-01. ¹ HNMR (400MHz, DMSO-d ₆ )8.82(d,J＝7.5Hz,1H), 8.21(s,1H),7.91(dd,J＝8.2,1.54Hz,1H),7.49(d,J＝7.9Hz,1H),7.42(br s,1H),7.38-7.23(m,5H),6.97(br s,1H), 5.13(s,2H),5.04(s,2H),4.78-4.90(m,1H),2.58-2.81(m, 2H); ESI-MS m/z 383[M+H]; HPLC purity: 98.69% (220nm), 97.33% (254nm).

Example 12. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-proline benzyl ester (6-012)

This compound was prepared from (S)-proline benzyl ester and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.92 (s, 1H), 7.66-7.53 (m, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.41-7.13 (m, 5H), 5.16 (s, 2H), 5.05-4.95 (m, 2H), 4.55 (dd, J=7.9, 4.41 Hz, 1H), 3.61-3.47 (m, 2H), 2.36-2.24 (m, 1H), 1.99-1.76 (m, 3H); ESI-MS: m/z 366 [M+H]; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 13. Benzyl 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-2-methylpropanoate (6-013)

This compound was prepared from benzyl 2-amino-2-methylpropanoate and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.31 (s, 1H), 8.71 (s, 1H), 8.20 (s, 1H), 7.90 (dd, J=7.94, 1.32 Hz, 1H), 7.47 (d, J=7.94 Hz, 1H), 7.34-7.18 (m, 5H), 5.04 (d, J=13.67 Hz, 4H), 1.48 (s, 6H); ESI-MS m/z 354 [M+H]; HPLC purity: 99.78% (220 nm), 100% (254 nm).

Example 14. 2,6-Dimethylbenzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine ester (6-014)

A mixture of compound 5 (775 mg, 5.00 mmol), compound 2 (1.00 g, 5.25 mmol), and K ₂ CO ₃ (1.38 g, 10.0 mmol) in DMF (20 ml) was stirred overnight at 10° C. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA=10:1 to 5:1) to give compound 6 (1.3 g, 89% yield) as a white solid. Compound 6-014 was obtained from compound 6 via two additional steps, similar to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.30 (s, 1H), 8.82 (d, J = 6.6Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 7.9Hz, 1H), 7.47 (d, J＝7.9Hz,1H),7.15-7.07(m,1H),7.01(d,J＝7.5Hz,2H), 5.21-5.08(m,2H),5.05-4.96(m,2H),4.43(q,J＝7.2Hz,1H), 2.29(s,6H),1.37(d,J＝7.1Hz,3H); ESI-MS: m/z 390[M+Na] ⁺ ; HPLC purity: 98.83% (220nm), 100% (254nm).

Example 15. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine 2-phenylpropan-2-yl ester (6-015)

To a solution of compound 7 (1.36 g, 10 mmol) in dry THF (20 ml) was slowly added NaH (60% in mineral oil, 240 mg, 10 mmol) at 0°C. The mixture was stirred at 10°C for 0.5 h. Subsequently, _CCl₃CN (1.43 g, 10 mmol) was added dropwise at 0°C, and the resulting mixture was stirred at 10°C for 1 h. The organic solvent was removed under vacuum, and the residue was suspended in hexane (20 ml) and MeOH (1 ml). The solid was removed by filtration and rinsed with hexane (3 x 5 ml). The filtrate was concentrated to dryness to yield compound 8 (2.4 g, 86% yield) as a yellow oil.

A solution of compound 8 (837 mg, 3 mmol) and compound 9 (622 mg, 2 mmol) in DCM (30 ml) was stirred at 10° C. for 1 hour. TLC (PE:EA=5:1) showed complete consumption of the starting material. The suspension was filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (PE:EA=10:1 to 5:1) to produce compound 10 (850 mg, 98% yield) as a yellow oil.

To a solution of compound 10 (429 mg, 1 mmol) in DMF (5 ml) was slowly added piperidine (85 mg, 1 mmol), and the reaction mixture was stirred at 10° C. for 1 hour. TLC (PE:EA=5:1) indicated complete consumption of the starting material. The suspension was filtered. The filtrate was concentrated in vacuo to dryness to produce compound 11 (200 mg, 97% yield) as a yellow oil.

To a solution of acid-1 (178 mg, 1 mmol), compound 11 (207 mg, 1 mmol), EDCI (384 mg, 2 mmol) and HOBT (270 mg, 2 mmol) in DMF (5 ml) was added DIPEA (387 mg, 3 mmol). The mixture was stirred overnight at 10° C. and then purified by preparative HPLC to give compound 6-015 (50 mg, 14% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.28 (s, 1H), 8.73 (d, J = 7.1Hz, 1H,), 8.24 (s, 1H), 7.95 (d, J = 8.8Hz, 1H), 7.48 (d,J＝7.9Hz,1H),7.39-7.34(m,2H),7.29(t,J＝7.5Hz, 2H),7.24-7.18(m,1H),5.03(s,2H),4.46(q,J＝7.3Hz,1H,), 1.69(d,J=8.4Hz,6H), 1.42(d,J=7.50Hz,3H). ESI-MS m/z 390 [M+Na] ⁺ ; HPLC purity: 98.55% (220 nm), 98.90% (254 nm).

Example 16. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine methyl ester (6-016)

This compound was prepared from (S)-alanine methyl ester and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.30 (s, 1H), 8.80 (d, J = 6.8 Hz, 1H), 8.22 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H), 4.45 (quintet, J = 7.2 Hz, 1H), 3.61 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H); ESI-MS m/z 264 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 17. (S)-2-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3,3-dimethylbutanoate (6-017)

This compound was prepared analogously to the last step of Example 1 from (S)-benzyl 2-amino-3,3-dimethylbutanoate and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.34(s,1H), 8.44(d,J＝8.4Hz,1H),7.83(s,1H),7.79(d,J＝7.6Hz, 1H),7.76(d,J＝8.0Hz,1H),7.40-7.29(m,5H),5.18(d,J＝12.5Hz,1H),5.11(d,J＝12.5Hz,1H),5.03(s,2H),4.44 (d, J=8.4Hz, 1H), 1.02 (s, 9H); ESI-MS m/z382[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 18. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-D-phenylalanine methyl ester (6-018)

This compound was prepared analogously to the last step of Example 1 from (S)-phenylalanine methylbenzyl ester and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.31(s,1H),8.87 (d,J＝7.9Hz,1H),8.18(s,1H),7.89(dd,J＝7.9,1.32Hz, 1H),7.48(d,J＝7.9Hz,1H),7.25-7.32(m,4H),7.16-7.22(m, 1H),5.03(s,2H),4.68(ddd,J＝9.7,7.7,5.5Hz,1H),3.64 (s, 3H), 3.05-3.22 (m, 2H); ESI-MS m/z340[M+H] ⁺ ; HPLC purity: 96.83% (220nm), 95.71% (254nm).

Example 19. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine (R)-1-phenylethyl ester (6-019)

This compound was prepared from (R)-1-phenylethan-1-ol, compound 2, and acid-01 in a manner analogous to Example 1. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.28 (s 1H), 8.80 (d, J = 6.4 Hz, 1H), 8.22 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.37-7.30 (m, 5H), 5.80 (m, 1H), 5.02 (s, 2H), 4.48 (t, J = 6.8 Hz, 1H), 1.43-1.41 (m, 6H); ESI-MS m/z 376 [M+Na] ⁺ ; HPLC purity: 99.63% (220 nm), 100% (254 nm).

Example 20. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (R)-1-phenylethyl ester (6-020)

This compound was prepared in analogy to the method of Example 1 from (R)-1-phenylethan-1-ol, N-BOC-(S)-valine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.28(s,1H), 8.60(d,J＝7.6Hz,1H),8.20(s,1H),7.91(d,J＝7.6Hz, 1H),7.46(d,J＝8.0Hz,1H),7.38-7.26(m,5H),5.83(m,1H), 5.01(s,2H),4.29(t,J＝8.0Hz,1H),2.23-2.18(m,3H),0.98 (d, J=7.2Hz, 3H), 0.93 (d, J=6.4Hz, 3H); ESI-MS m/z 404 [M+Na] ⁺ ; HPLC purity: 99.80% (220nm), 100% (254nm).

Example 21. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-phenylalanine (R)-1-phenylethyl ester (6-021)

This compound was prepared in analogy to the method of Example 1 from (R)-1-phenylethan-1-ol, N-BOC-(S)-phenylalanine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.28(s,1H), 8.86(d,J＝7.6Hz,1H),8.16(s,1H),7.85(d,J＝8.0Hz, 1H),7.45(d,J＝8.0Hz,1H),7.31-7.24(m,10H),5.75(m,1H), 5.00(s,2H),4.68(m,1H),3.14(d,J＝7.6Hz,3H),1.30(d,J＝6.8Hz,3H); ESI-MS m/z 452[M+Na] ⁺ ; HPLC purity: 99.22% (220 nm), 98.01% (254nm).

Example 22. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine (S)-1-phenylethyl ester (6-022)

This compound was prepared in analogy to the method of Example 1 from (S)-1-phenylethan-1-ol, N-BOC-(S)-alanine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.28(s,1H), 8.78(d,J＝6.8Hz,1H),8.22(s,1H),7.93(m,1H),7.47(d, J＝8.4Hz,1H),7.32-7.26(m,5H),5.79(m,1H),5.02(s,2H), 4.49(t,J＝6.8Hz,1H),1.45(d,J＝6.8Hz,3H),1.36(d, J＝7.6Hz,3H); ESI-MS m/z 376[M+Na] ⁺ ; HPLC purity: 94.63% (220 nm), 91.44% (254nm).

Example 23. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (S)-1-phenylethyl ester (6-023)

This compound was prepared in analogy to the method of Example 1 from (S)-1-phenylethan-1-ol, N-BOC-(S)-valine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.33(s,1H), 8.60(d,J＝8.0Hz,1H),8.25(s,1H),7.96(d,J＝8.4Hz, 1H),7.50(d,J＝8.0Hz,1H),7.40-7.30(m,5H),5.87(m,1H), 5.06(s,2H),4.35(m,1H),2.21(m,1H),1.51(d,J＝6.8Hz, 3H), 0.91-0.89 (m, 6H); ESI-MS m/z 404[M+Na] ⁺ ; HPLC purity: 98.86% (220nm), 98.19% (254nm).

Example 24. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-phenylalanine (S)-1-phenylethyl ester (6-024)

This compound was prepared in analogy to the method of Example 1 from (S)-1-phenylethan-1-ol, N-BOC-(S)-phenylalanine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.02(s,1H), 8.54(d,J＝8.0Hz,1H),8.17(s,1H),7.85(d,J＝7.6Hz,1H), 7.46(d,J＝8.0Hz,1H),7.31-7.17(m,10H),5.85(m,1H),5.02 (s,2H),4.76(m,1H),3.18(m,1H),3.17(m,1H),1.49(d,J＝6.8Hz,3H); ESI-MS m/z 452[M+Na] ⁺ ; HPLC purity: 98.92% (220 nm), 98.77% (254nm).

Example 25. (R)-2-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-4-phenylbutyric acid methyl ester (6-025)

A solution of compound 12 (1 g, 5.6 mmol) in MeOH (40 ml) was bubbled with HCl gas at 0° C. for 30 minutes. The mixture was then concentrated to dryness at 35° C. The residue was rinsed with MTBE and filtered to yield compound 13 (0.80 g, 73%), which was used in the next step without further purification.

Compound 6-025 was prepared from compound 13 and acid-01 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.33 (br s, 1H), 8.86 (d, J = 7.5Hz, 1H), 8.28 (s, 1H), 7.99 (dd, J = 7.9, 1.76Hz, 1H), 7.52(d,J＝7.9Hz,1H),7.26-7.33(m,2H),7.16-7.25(m,3H), 5.06(s,2H),4.36-4.47(m,1H),3.64(s,3H),2.62-2.83(m, 2H), 2.03-2.18(m,2H); ESI-MS m/z 354[M+H]; HPLC purity: 99.62% (220nm), 100% (254nm).

Example 26. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-phenylalanine methyl ester (6-026)

This compound was prepared analogously to the last step of Example 1 from (S)-phenylalanine methyl ester and acid-01. ¹ HNMR (400MHz, DMSO-d ₆ )9.31 (s, 1H), 8.87 (d, J＝7.8Hz, 1H), 8.18 (s, 1H), 7.84-7.92 (m, 1H), 7.48 (d, J =8.0Hz,1H),7.25-7.31(m,4H),7.16-7.22(m,1H),5.03(s, 2H),4.62-4.74(m,1H),3.64(s,3H),3.05-3.22(m,2H); ESI-MS m/z 340[M+H] ⁺ ; HPLC purity: 99.08% (220nm), 99.48% (254nm).

Example 27. Methyl (S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-4-phenylbutyrate (6-027)

This compound was prepared in analogy to the method of Example 25 from (S)-2-amino-4-phenylbutyric acid and acid-01. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.33 (s, 1H), 8.86 (d, J =7.3 Hz, 1H), 8.28 (s, 1H), 7.99 (d, J =7.8 Hz, 1H), 7.52 (d, J =7.78 Hz, 1H), 7.26-7.32 (m, 2H), 7.17-7.25 (m, 3H), 5.06 (s, 2H), 4.35-4.47 (m, 1H), 3.64 (s, 3H), 2.61-2.83 (m, 2H), 2.03-2.17 (m, 2H); ESI-MS m/z 354 [M+H] ⁺ ; HPLC purity: 99.39% (220 nm).

Example 28. (S)-2-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-5-phenylpentanoic acid methyl ester (6-028)

This compound was prepared from (S)-2-amino-5-phenylpentanoic acid and acid-01 in analogy to the method of Example 25 followed by chiral separation by chiral HPLC. ¹ H NMR (400MHz, DMSO-d ₆ )9.32(s,1H),8.78(d,J＝7.3Hz,1H),8.25(s,1H), 7.96(dd,J＝7.9,1.13Hz,1H),7.50(d,J＝8.0Hz,1H), 7.24-7.31(m,2H),7.13-7.22(m,3H),5.05(s,2H),4.48(q, J＝7.3Hz,1H),3.64(s,3H),2.61(t,J＝6.65Hz,2H),1.83 (q,J＝7.53Hz,2H),1.60-1.75(m,2H); ESI-MS m/z 389[M+Na] ⁺ ; HPLC purity: 98.89% (220nm), 98.87% (254nm).

Example 29. (R)-2-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-5-phenylpentanoic acid methyl ester (6-029)

This compound was prepared from (R)-2-amino-5-phenylpentanoic acid and acid-01 in analogy to the method of Example 25 followed by chiral separation by chiral HPLC. ¹ H NMR (400MHz, DMSO-d ₆ )9.31(s,1H),8.78(d,J＝7.3Hz,1H),8.24(s,1H), 7.96(dd,J＝7.9,1.38Hz,1H),7.50(d,J＝7.8Hz,1H), 7.24-7.30(m,2H),7.14-7.21(m,3H),5.05(s,2H),4.48(q, J＝7.2Hz,1H),3.64(s,3H),2.61(t,J＝6.7Hz,2H),1.82 (q,J=7.7Hz,2H),1.60-1.76(m,2H); ESI-MS m/z 368[M+H] ⁺ ; HPLC purity: 98.74% (220nm), 98.50% (254nm).

Example 30. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-030)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.34 (s, 1H), 8.67 (d, J＝7.6Hz, 1H), 8.24 (s, 1H), 7.96 (d, J＝8.0Hz, 1H), 7.51 (d,J＝8.0Hz,1H),7.45(dd,J＝8.4,5.6Hz,2H),7.21(t,J＝9.6Hz,2H),5.19(d,J＝12.4Hz,1H),5.13(d,J＝12.4 Hz,1H),5.06(s,2H),4.33(t,J＝7.7Hz,1H),2.21(m,1H), 0.98(d,J＝6.8Hz,3H),0.96(d,J＝6.8Hz,3H); ESI-MS m/z 386 [M+H] ⁺ ; HPLC purity: 99.85% (220 nm), 100% (254 nm).

Example 31. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2,4-difluorobenzyl ester (6-031)

This compound was prepared in analogy to the method of Example 1 from 2,4-difluorobenzyl alcohol, N-BOC-(S)-valine and acid-01. ¹ H NMR (400MHz, DMSO-d ₆ )9.34(s,1H),8.63 (d,J＝7.6Hz,1H),8.20(s,1H),7.91(d,J＝8.0Hz,1H), 7.55-7.46(m,4H),5.18(d,J＝12.4Hz,1H),5.11(d,J＝12.4Hz,1H),5.02(s,2H),4.28(t,J＝7.7Hz,1H),2.15(m,1H), 0.93 (d, J=6.8Hz, 3H), 0.88 (d, J=6.8Hz, 3H); ESI-MS m/z 404[M+H] ⁺ ; HPLC purity: 99.32% (220nm), 100% (254nm).

Example 32. (1-Hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-032)

This compound was prepared similarly to the last step of Example 1 from acid-02 (WO 2012109164 A1) and (S)-valine benzyl ester. ¹ H NMR (400MHz, DMSO-d ₆ )8.62(d, J＝7.6Hz,1H),8.17(s,1H),7.94(d,J＝8.0Hz,1H),7.52 (d,J＝8.0Hz,1H),7.53-7.30(m,5H),5.19(d,J＝12.4Hz, 1H),5.15(d,J＝12.4Hz,1H),2.22(m,1H),0.98(d,J＝6.8Hz,3H),0.94(d,J＝6.8Hz,3H); ESI-MS m/z396[M+H]; HPLC Purity: 98.56% (220nm), 100% (254nm).

Example 33. (1-Hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-033)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and hydroxyethyl-02. ¹ H NMR (400MHz, DMSO-d ₆ )8.62(d,J＝7.6Hz,1H), 8.16(s,1H),7.93(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz, 1H),7.45(m,2H),7.20(t,J＝8.8Hz,2H),5.20(d,J＝12.4Hz,1H),5.10(d,J＝12.4Hz,1H),4.34(t,J＝7.6Hz,1H), 2.20(t,J＝5.6Hz,1H),1.47(s,6H),0.99(d,J＝5.6Hz, 3H),0.90(d,J＝5.6Hz,3H); ESI-MS m/z 414[M+H] ⁺ ; HPLC purity: 97.59% (220nm), 100% (254nm).

Example 34. (1-Hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2,4-difluorobenzyl ester (6-034)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and hydroxyethyl-02. ¹ H NMR (400MHz, DMSO-d ₆ )8.61(d,J＝8.0Hz,1H), 8.14(s,1H),7.90(d,J＝8.0Hz,1H),7.56(q,J＝8.0Hz, 1H),7.50(d,J＝8.0Hz,1H),7.29(t,J＝8.0Hz,1H),7.29 (t,J＝8.0Hz,1H),5.16(q,J＝12.4,26.8Hz,2H),4.31(t, J＝7.6Hz,1H),2.17(m,1H),1.46(s,6H 0.98(d,J＝7.2Hz, 3H),0.88(d,J＝7.2Hz,3H); ESI-MS m/z 432[M+H] ⁺ ; HPLC purity: 98.84% (220nm), 100% (254nm).

Example 35. (7-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-035)

This compound was prepared from benzyl alcohol, N-BOC-(S)-valine and acid-03 in a manner similar to Example 1. ESI-MS m/z 386 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 36. (7-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-036)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-03. ¹ H NMR (400MHz, DMSO-d ₆ )9.38 (s, 1H), 8.58 (d, J＝7.6Hz, 1H), 7.65-7.47 (m, 1H), 7.45-7.43 (m, 2H), 7.30 (d, J＝7.6Hz,1H),7.23-7.19(m,2H),5.20-5.11(m,2H),5.04(s,2H),4.38-4.35(m,1H),2.19-2.12(m,1H),0.94-.091(m,6H); ESI-MS m/z 404[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 37. (7-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2,4-difluorobenzyl ester (6-037)

This compound was prepared from 2,4-difluorobenzyl alcohol, N-BOC-(S)-valine, and acid-03 by the method of Example 1. ^1H NMR (400 MHz, DMSO-d ₆ ) 8.57 (d, J=7.6 Hz, 1H), 7.66-7.57 (m, 2H), 7.32-7.29 (m, 2H), 7.28-7.12 (m, 1H), 5.24-5.13 (m, 2H), 5.04 (s, 2H), 4.36-4.32 (m, 1H), 2.18-2.09 (m, 1H), 0.93-0.90 (m, 6H); ESI-MS m/z 422 [M+H] ⁺ ; HPLC purity: 95.88% (220 nm), 97.81% (254 nm).

Example 38. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-038)

This compound was prepared from acid-04 and (S)-valine benzyl ester in a manner analogous to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.03 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 7.41-7.23 (m, 7H), 5.16 (dd, J = 12.4 Hz, J = 20.0 Hz, 2H), 4.96 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 2.43 (s, 3H), 2.18-2.13 (m, 1H), 0.94 (d, J = 5.6 Hz, 6H); ESI-MS m/z 382 [M+H]; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 39. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2,4-difluorobenzyl ester (6-039)

This compound was prepared from 2,4-difluorobenzyl alcohol, N-BOC-(S)-valine, and acid-04 by the method of Example 1. ^1H NMR (400 MHz, DMSO-d ₆ ) 8.57 (d, J=7.6 Hz, 1H), 7.66-7.57 (m, 2H), 7.32-7.29 (m, 2H), 7.28-7.12 (m, 1H), 5.24-5.13 (m, 2H), 5.04 (s, 2H), 4.36-4.32 (m, 1H), 2.18-2.09 (m, 1H), 0.93-0.90 (m, 6H); ESI-MS m/z 418 [M+H] ⁺ ; HPLC purity: 95.88% (220 nm), 97.81% (254 nm).

Example 40. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-chlorobenzyl ester (6-040)

This compound was prepared in analogy to the method of Example 1 from 4-chlorobenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.56 (d, J＝7.5Hz, 1H), 7.43 (s, 4H), 7.32 (d, J＝7.9Hz, 1H), 7.22 (d,J＝7.9Hz,1H),5.15(d,J＝4.0Hz,2H),4.95(s,2H), 4.33(t,J＝7.3Hz,1H),2.42(s,3H),2.19-1.99(m,1H), 0.92(d,J＝6.6Hz,6H); ESI-MS m/z 416[M+H] ⁺ ; HPLC purity: 97.85% (220nm), 98.66% (254nm).

Example 41. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-trifluoromethylbenzyl ester (6-041)

This compound was prepared in analogy to the method of Example 1 from 4-trifluoromethylbenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01(s,1H),8.59 (d,J＝7.5Hz,1H),7.74(d,J＝7.9Hz,2H),7.62(d,J＝8.4 Hz,2H),7.33(d,J＝7.5Hz,1H),7.21(d,J＝7.5Hz,1H), 5.27(s,2H),4.95(s,2H),4.36(t,J＝7.3Hz,1H),2.41(s, 3H),2.16(dq,J＝13.56,6.65Hz,1H),1.00-0.88(m,6H); ESI-MS m/z 450[M+H] ⁺ ; HPLC purity: 98.98% (220nm), 100% (254nm).

Example 42. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-fluorobenzyl ester (6-042)

This compound was prepared in analogy to the method of Example 1 from 3-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.06 (s, 1H), 8.63 (d, J＝7.8Hz, 1H), 7.44 (q, J＝7.36Hz, 1H), 7.35 (d, J＝7.8 Hz,1H),7.26(d,J＝6.8Hz,3H),7.21-7.13(m,1H),5.21(s,2H),4.98(s,2H),4.37(t,J＝7.2Hz,1H),2.44(s,3H), 2.23-2.13(m,1H),0.97-0.94(m,6H); ESI-MS m/z 400[M+H] ⁺ ; HPLC purity: 96.98% (220nm), 100% (254nm).

Example 43. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-chlorobenzyl ester (6-043)

This compound was prepared in analogy to the method of Example 1 from 3-chlorobenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.59 (d, J＝7.50Hz, 1H), 7.47 (s, 1H), 7.43-7.30 (m, 4H), 7.22 (d, J ＝7.5Hz,1H),5.17(d,J＝1.8Hz,2H),4.95(s,2H),4.35(t,J＝7.3Hz,1H),2.42(s,3H),2.21-2.09(m,1H),0.93(d,J＝6.62); ESI-MS m/z 416[M+H] ⁺ ; HPLC purity: 99.67% (220nm), 100% (254nm).

Example 44. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-cyanobenzyl ester (6-044)

This compound was prepared in analogy to the method of Example 1 from 4-cyanobenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.06 (s, 1H), 8.65 (d,J＝7.5Hz,1H),7.88(d,J＝8.28Hz,2H),7.62(d,J＝8.0Hz,2H),7.36(d,J＝7.8Hz,1H),7.25(d,J＝7.8Hz,1H), 5.29(s,2H),4.98(s,2H),4.38(t,J＝7.2Hz,1H),2.44(s,3H),2.24-2.12(m,1H),0.96(dd,J＝6.7,1.63Hz,6H); ESI-MS m/z 407[M+H] ⁺ ; HPLC purity: 97.14% (220nm), 98.60% (254nm).

Example 45. (S)-4-Fluorobenzyl 2-(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-2-phenylacetate (6-045)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-phenylglycine, and acid-04 in a manner analogous to Example 1. ^1H NMR (400 MHz, DMSO- _d6 ) 9.13 (d, J = 7.1 Hz, 1H), 9.01 (s, 1H), 7.45 (d, J = 6.2 Hz, 2H), 7.39-7.29 (m, 6H), 7.20 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 8.8 Hz, 2H), 5.67 (d, J = 7.5 Hz, 1H), 5.15 (s, 2H), 4.95 (s, 2H), 2.43 (s, 3H); ESI-MS m/z 434 [M+H] ⁺ ; HPLC purity: 99.70% (220 nm), 100% (254 nm).

Example 46. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-trifluoromethylbenzyl ester (6-046)

This compound was prepared in analogy to the method of Example 1 from 3-trifluoromethylbenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.59 (d, J = 7.5Hz, 1H), 7.56-7.83 (m, 4H), 7.15-7.39 (m, 2H), 5.27 (d,J＝1.8Hz,2H),4.95(s,2H),4.35(t,J＝7.1Hz,1H), 2.41(s,3H),2.15(dd,J＝13.5,6.8Hz,1H),0.93(d,J＝6.17Hz,6H); ESI-MS m/z 450[M+H] ⁺ ; HPLC purity: 99.75% (220nm), 100% (254nm).

Example 47. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-cyanobenzyl ester (6-047)

This compound was prepared in analogy to the method of Example 1 from 3-cyanobenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.60 (d, J = 7.9Hz, 1H), 7.87 (s, 1H), 7.82-7.70 (m, 2H), 7.63-7.56 (m,1H),7.33(d,J＝7.9Hz,1H),7.22(d,J＝7.9Hz,1H), 5.22(s,2H),4.95(s,2H),4.35(t,J＝7.3Hz,1H),2.41(s, 3H), 2.16 (dq, J＝13.45, 6.69Hz, 1H), 0.94 (d, J＝6.6Hz, 6H); ESI-MS m/z 407[M+H] ⁺ ; HPLC purity: 96.71% (220nm), 94.02% (254nm).

Example 48. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3,5-difluorobenzyl ester (6-048)

This compound was prepared in analogy to the method of Example 1 from 3,5-difluorobenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.02(s,1H),8.62 (d,J＝7.9Hz,1H),7.34(d,J＝7.9Hz,1H),7.27-7.03(m, 4H),5.19(s,2H),4.95(s,2H),4.36(t,J＝7.3Hz,1H),2.42 (s,3H),2.16(d,J＝6.6Hz,1H),0.95(dd,J＝6.84,2.4Hz, 6H); ESI-MS m/z 418[M+H] ⁺ ; HPLC purity: 99.91% (220nm), 100% (254 nm).

Example 49. 4-Fluoro-3-(trifluoromethyl)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-049)

This compound was prepared in analogy to the method of Example 1 from 4-fluoro-3-trifluoromethylbenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.58 (d, J＝7.5Hz, 1H), 7.93-7.76 (m, 2H), 7.68-7.49 (m, 1H),7.38-7.16(m,2H),5.24(s,2H),4.95(s,2H),4.33(t, J＝7.3Hz,1H),2.40(s,3H),2.14(d,J＝6.6Hz,1H),0.93 (d,J＝7.1Hz,6H); ESI-MS m/z 468[M+H] ⁺ ; HPLC purity: 96.57% (220nm), 97.23% (254nm).

Example 50. (S)-4-Fluorobenzyl-2-cyclopropyl-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)acetate (6-050)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-cyclopropylglycine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03(d,J＝5.3 Hz,1H),8.83(s,1H),7.45(s,2H),7.36(d,J＝7.1Hz,1H), 7.28-7.14(m,3H),5.24-5.09(m,2H),4.97(d,J＝4.4Hz,2H), 3.79(s,1H),2.44(d,J＝4.9Hz,3H),1.19(s,1H),0.60-0.35 (m,4H); ESI-MS m/z 398[M+H] ⁺ ; HPLC purity: 99.52% (220nm), 100% (254nm).

Example 51. 3-Chloro-4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-051)

This compound was prepared in analogy to the method of Example 1 from 3-chloro-4-fluorobenzyl alcohol, N-BOC-(S)-cyclopropylglycine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.58 (d, J = 7.5Hz, 1H), 7.64 (d, J = 7.5Hz, 1H), 7.43 (d, J = 7.5Hz, 2H), 7.33 (d, J = 7.9Hz, 1H), 7.22 (d, J = 7.9 Hz,1H),5.16(s,2H),4.96(s,2H),4.33(t,J＝7.3Hz,1H), 2.42(s,3H),2.23-2.07(m,1H),0.97-0.86(m,6H); ESI-MS m/z 434[M+H] ⁺ ; HPLC purity: 95.56% (220nm), 98.25% (254nm).

Example 52. (7-Ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-052)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-05. ¹ H NMR (400MHz, DMSO-d ₆ )8.98 (s, 1H), 8.58 (d, J＝8.0Hz, 1H), 7.47-7.43 (m, 2H), 7.29 (d, J＝8.0Hz, 1H), 7.23-7.18(m,3H),5.14(s,2H),4.96(s,2H),4.34(t,J＝7.6 Hz,1H),2.86-2.80(m,2H),2.13(t,J＝6.8Hz,1H),1.06(t, J＝6.8Hz, 3H), 0.92 (d, J＝4.4Hz, 6H); ESI-MS m/z 414[M+H] ⁺ ; HPLC purity: 96.93% (220nm), 95.38% (254nm).

Example 53. (7-Ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-053)

This compound was prepared analogously to the last step of Example 1 from (S)-valine benzyl ester and acid-05. ¹ H NMR (400MHz, DMSO-d ₆ )8.98 (s, 1H), 8.58 (d, J = 8.0Hz, 1H), 7.40-7.30 (m, 5H), 7.21 (d, J = 7.6Hz, 1H), 5.16 (s,2H),4.96(s,2H),4.36(t,J＝7.6Hz,1H),2.84(q,J＝7.2Hz,J＝7.6Hz,2H),2.16(t,J＝6.8Hz,1H),1.07(t,J =7.2Hz, 3H), 0.92 (d, J = 6.8Hz, 6H); ESI-MSm/z 396[M+H] ⁺ ; HPLC purity: 97.21% (220nm), 95.72% (254nm).

Example 54. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-trifluoromethoxybenzyl ester (6-054)

This compound was prepared in analogy to the method of Example 1 from 4-trifluoromethoxybenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01(s,1H), 8.57(d,J＝7.9Hz,1H),7.53(d,J＝8.4Hz,2H),7.44-7.30 (m,3H),7.21(d,J＝7.5Hz,1H),5.36-5.08(m,2H),4.96(s, 2H),4.34(t,J＝7.3Hz,1H),2.41(s,3H),2.22-2.07(m,1H), 0.93 (d, J=6.17Hz, 6H); ESI-MS m/z 466[M+H] ⁺ ; HPLC purity: 99.63% (220nm), 95.53% (254nm).

Example 55. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-trifluoromethoxybenzyl ester (6-055)

This compound was prepared in analogy to the method of Example 1 from 3-trifluoromethoxybenzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.59 (d, J＝7.50Hz, 1H), 7.54-7.49 (m, 1H), 7.46-7.38 (m, 2H), 7.36-7.31(m,2H),7.33(d,J＝7.50Hz,2H),7.21(d,J＝7.9 Hz,1H),5.29-5.17(m,2H),4.96(s,2H),4.35(t,J＝7.3Hz, 1H),2.42(s,3H),2.15(dq,J＝13.51,6.82Hz,1H),0.94(d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); ESI-MS m/z 466 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 56. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(methylsulfonyl)benzyl ester (6-056)

This compound was prepared in analogy to the method of Example 1 from 4-(methylsulfonyl)benzyl alcohol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03(s,1H), 8.61(d,J＝7.5Hz,1H),7.93(d,J＝7.9Hz,2H),7.67(d, J＝7.5Hz,2H),7.43-7.19(m,2H),5.29(s,2H),4.96(s,2H), 4.38(t,J＝7.1Hz,1H),3.21(s,3H),2.43(s,3H),2.25-2.09 (m, 1H), 0.96 (d, J = 6.2Hz, 6H); ESI-MS m/z 460 [M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 57. (7-Cyclopropyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-057)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-06. ¹ H NMR (400MHz, DMSO-d ₆ ) 8.90 (s, 1H), 8.62 (d, J = 7.2Hz, 1H), 7.47 (t, J = 6.0Hz, 2H), 7.23 (d, J = 8.0Hz, 4H),5.19(s,2H),4.96(s,2H),4.34(t,J＝7.2Hz,1H), 2.15-2.13(m,2H),0.94(d,J＝4.4Hz,6H),0.77(d,J＝5.2 Hz,4H); ESI-MS m/z 426[M+H] ⁺ ; HPLC purity: 98.89% (220nm), 99.55% (254nm).

Example 58. (7-Cyclopropyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-058)

This compound was prepared from (S)-valine benzyl ester and acid-06 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.90 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.41-7.35 (m, 5H), 7.22 (t, J = 5.2 Hz, 2H), 5.21-5.14 (m, 2H), 4.96 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 2.16-2.14 (m, 2H), 0.96-0.94 (m, 6H), 0.79-0.76 (m, 4H); ESI-MS m/z 408 [M+H] ⁺ ; HPLC purity: 99.97% (220 nm), 100% (254 nm).

Example 59. (S)-4-Fluorobenzyl-2-cyclobutyl-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)acetate (6-059)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclobutaneacetic acid and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.55 (d, J＝7.5Hz, 1H), 7.42 (dd, J＝8.38, 5.7 Hz, 2H), 7.32 (d, J＝7.9Hz, 1H), 7.26-7.14 (m, 3H), 5.23-5.02 (m,2H),4.95(s,2H),4.39(dd,J＝9.3,7.5Hz,1H),2.73-2.61 (m,1H),2.42(s,3H),2.04-1.71(m,6H); ESI-MS m/z 412[M+H] ⁺ ; HPLC purity: 98.85% (220nm), 94.70% (254nm).

Example 60. (S)-4-Fluorobenzyl-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)acetate (6-060)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.01 (s, 1H), 8.64 (d, J＝7.5Hz, 1H), 7.44 (dd, J＝8.6, 5.51 Hz, 2H), 7.31 (d, J＝7.9Hz, 1H), 7.24-7.15 (m, 3H), 5.19-5.07 (m,2H),4.95(s,2H),4.29(t,J＝8.2Hz,1H),2.41(s,3H), 2.29-2.19(m,1H),1.80-1.38(m,8H); ESI-MS m/z 426[M+H] ⁺ ; HPLC purity: 98.85% (220nm), 94.70% (254nm).

Example 61. (3,7-Dimethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-061)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-07. ¹ H NMR (400MHz, DMSO-d ₆ )8.98 (s, 1H), 8.60 (d, J＝8.0Hz, 1H), 7.48-7.44 (m, 2H), 7.33 (d, J＝6.0Hz, 1H), 7.23-7.20(m,3H),5.20-5.11(m,3H),4.32(s,1H),2.50(s,3H),2.16-2.11(m,1H),1.39(d,J＝6.0Hz,3H),0.93(d,J＝6.4Hz,6H); ESI-MS m/z 414[M+H] ⁺ ; HPLC purity: 99.31% (220nm), 99.01% (254nm).

Example 62. (1-Hydroxy-7-isopropyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-062)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-08. ¹ H NMR (400MHz, DMSO-d ₆ )9.15 (s, 1H), 8.58 (d, J＝8.0Hz, 1H), 7.46-7.43 (m, 2H), 7.22-7.16 (m, 4H), 5.17-5.10 (m,2H),4.96(s,2H),4.34(t,J＝7.2Hz,1H),3.19(t,J＝6.4Hz,1H),2.15-2.10(m,1H),1.29-1.24(m,6H),0.87(t,J＝3.2Hz,6H); ESI-MS m/z 428[M+H] ⁺ ; HPLC purity: 99.85% (220nm), 100% (254nm).

Example 63. (1-Hydroxy-7-isopropyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-063)

This compound was prepared analogously to the last step of Example 1 from (S)-valine benzyl ester and acid-08. ¹ H NMR (400MHz, DMSO-d ₆ )9.15 (s, 1H), 8.58 (d, J = 7.6Hz, 1H), 7.40-7.34 (m, 5H), 7.19 (t, J = 1.6Hz, 2H), 5.12 (d,J＝2.4Hz,1H),4.96(s,2H),4.35(t,J＝6.8Hz,1H), 3.24-3.17(m,1H),2.17-2.12(m,1H),1.29-1.23(m,6H),0.91 (d,J＝6.8Hz,6H); ESI-MS m/z 410[M+H] ⁺ ; HPLC purity: 99.91% (220nm), 100% (254nm).

Example 64. (1-Hydroxy-7-propyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-064)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-09. ¹ H NMR (400MHz, DMSO-d ₆ )8.97 (s, 1H), 8.59 (d, J＝8.0Hz, 1H), 7.48-7.45 (m, 2H), 7.31 (d, J＝8.0Hz, 1H), 7.24-7.21(m,3H),5.12(s,2H),4.97(s,2H),4.35(t,J＝7.2 Hz,1H),2.86-2.80(m,2H),2.18-2.12(m,1H),1.50(s,2H), 0.93(d,J＝3.2Hz,6H),0.81(t,J＝7.2Hz,3H); ESI-MS m/z 428[M+H] ⁺ ; HPLC purity: 96.59% (220nm), 93.52% (254nm).

Example 65. (1-Hydroxy-7-propyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-065)

This compound was prepared analogously to the last step of Example 1 from (S)-valine benzyl ester and acid-09. ¹ H NMR (400MHz, DMSO-d ₆ )8.97(s,1H),8.59(d,J =7.6Hz,1H),7.41-7.24(m,7H),5.17(s,2H),4.97(s,2H), 4.36(t,J＝6.8Hz,1H),2.85(t,J＝8.0Hz,2H),2.18-2.13 (m,1H),1.50(s,2H),0.93(d,J＝3.2Hz,6H),0.81(t,J＝7.6Hz,3H); ESI-MS m/z 410[M+H] ⁺ ; HPLC purity: 96.53% (220nm), 94.89% (254nm).

Example 66. 4-Fluorobenzyl 1-(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)cyclobutane-1-carboxylate (6-066)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.02 (d, J＝5.7Hz, 2H), 7.43 (dd, J＝8.4, 5.7Hz, 2H), 7.33 (d, J＝7.5Hz, 1H), 7.26-7.14 (m, 3H), 5.14 (s, 2H), 4.96 (s, 2H), 2.60-2.54(m,2H), 2.40(s,3H), 2.35-2.22(m,2H), 2.04-1.78 (m,2H); ESI-MS m/z 398[M+H] ⁺ ; HPLC purity: 98.46% (220nm), 97.78% (254nm).

Example 67. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (5-fluoropyridin-2-yl)methyl ester (6-067)

A mixture of compound 14 (500 mg, 4 mmol) and LiAlH ₄ (202 mg, 5 mmol) in THF (10 ml) was degassed and purged with nitrogen three times, and then the mixture was stirred at 0° C. under nitrogen for 12 hours. The reaction mixture was quenched with saturated potassium sodium tartrate solution (0.8 ml) at 15° C. and then filtered. The mixture was diluted with water (5 ml) and extracted with EtOAc (3×5 ml). The combined organic layers were washed with brine (2×5 ml) and dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 15 (236 mg, 52%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) 8.43 (d, J = 2.8 Hz, 1H), 7.45-7.41 (m, 1H), 7.31-7.27 (m, 1H), 4.76 (s, 2H). A mixture of compound 15 (1 g, 8 mmol), DCC (3 g, 16 mmol), DMAP (96 mg, 786 μmol), and N-BOC-(S)-valine (2 g, 9 mmol) in DCM (5 ml) was degassed and purged with nitrogen three times, and then the mixture was stirred at 25° C. under nitrogen for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; PE/EtOAc = 5/1) to give compound 16 (1.3 g, 51%) as a yellow liquid. ¹ H NMR (400MHz, DMSO-d ₆ ) 8.55 (s, 1H), 7.71-7.83 (m, 1H), 7.54-7.51 (m, 1H), 7.25 (d, J = 8.0Hz, 1H), 5.22-5.13 (m, 2H), 3.91 (t, J＝7.2Hz,1H),2.06-2.02(m,1H),1.38(s,9H),0.87(d,J＝6.4Hz,6H).

To a mixture of compound 16 (1.3 g, 4 mmol) in EtOAc (20 ml) was added HCl/EtOAc (6 M, 10 ml). The mixture was stirred at 15° C. under nitrogen for 2 hours. The reaction mixture was concentrated under reduced pressure to yield compound 17 (800 mg, 77%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) 8.58 (d, J=2.4 Hz, 1H), 8.51 (s, 2H), 7.84-7.80 (m, 1H), 7.65-7.61 (m, 1H), 5.36-5.27 (m, 2H), 4.04-4.00 (m, 1H), 2.23-2.19 (m, 1H), 0.99-0.94 (m, 6H).

Compound 6-067 was prepared from compound 17 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ) 8.96 (s, 1H), 8.60 (d, J = 7.6Hz, 1H), 8.55 (d, J = 2.4Hz, 1H), 7.78 (td, J = 8.8, 3.6 Hz,1H),7.56(dd,J＝8.4,4.0Hz,1H),7.34(d,J＝7.6Hz,1H),7.22(d,J＝8.0Hz,1H),5.22(s,2H),4.95(s,2H),4.37 (t, J＝7.2Hz, 1H), 2.42 (s, 3H), 2.21-2.12 (m, 1H), 0.96 (dd, J＝6.8, 2.4Hz, 6H); ESI-MS m/z 401[M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 68. 4-Fluorobenzyl 1-(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)cyclopropane-1-carboxylate (6-068)

This compound was prepared from 4-fluorobenzyl alcohol, 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid, and acid-04 by analogy with the method of Example 1. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.83 (s, 1H), 7.47-7.38 (m, 2H), 7.31 (d, J=7.5 Hz, 1H), 7.20 (t, J=7.7 Hz, 3H), 5.12 (s, 2H), 4.95 (s, 2H), 2.39 (s, 3H), 1.45 (s, 2H), 1.17 (s, 2H); ESI-MS m/z 384 [M+H] ⁺ ; HPLC purity: 97.30% (220 nm), 98.64% (254 nm).

Example 69. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine methyl ester (6-069)

This compound was prepared analogously to the last step of Example 1 from (S)-valine methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.52 (d, J = 7.5Hz, 1H), 7.35 (d, J = 7.5Hz, 1H), 7.23 (d, J = 7.5Hz, 1H), 4.96 (s, 2H), 4.29 (t, J = 7.3Hz, 1H), 3.66 (s, 3H), 2.45 (s, 3H), 2.11 (d, J = 7.1Hz, 1H), 0.94 (d, J = 4.2Hz, 3H), 0.92 (d, J = 4.2Hz, 3H); ESI-MS m/z 306[M+H] ⁺ ; HPLC purity: 99.96% (220nm), 100% (254nm).

Example 70. (1-Hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-070)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-10. ¹ H NMR (400MHz, DMSO-d ₆ )9.23 (s, 1H), 8.88 (d, J＝8.0Hz, 1H), 7.70 (d, J＝8.0Hz, 1H), 7.47 (dd, J＝8.4, 6.4Hz,2H),7.41(d,J＝8.0Hz,1H),7.22(t,J＝8.8Hz,2H), 5.23-5.21(m,2H),5.08(s,2H),4.35(t,J＝7.2Hz,1H), 2.18-2.09 (m, 1H), 0.98-0.81 (m, 6H); ESI-MS m/z 454[M+H] ⁺ ; HPLC purity: 98.51% (220nm), 98.43% (254nm).

Example 71. (1-Hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-071)

This compound was prepared from (S)-valine benzyl ester and acid-10 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.21 (br s, 1H), 8.87 (d, J=7.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.40 (s, 6H), 5.25-5.13 (m, 2H), 5.08 (s, 2H), 4.37 (t, J=6.8 Hz, 1H), 2.16-2.14 (m, 1H), 0.92 (d, J=3.6 Hz, 6H); ESI-MS m/z 436 [M+H] ⁺ ; HPLC purity: 98.07% (220 nm), 93.03% (254 nm).

Example 72. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-(4-methylpiperazin-1-yl) ester (6-072)

A mixture of compound 18 (5.00 g, 19.1 mmol), N-methylpiperazine (5.73 g, 57.2 mmol), Pd ₂ (dba) ₃ (3.49 g, 3.82 mmol), Cs ₂ CO ₃ (12.4 g, 38.2 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.56 g, 5.72 mmol) in 1,4-dioxane (5 ml) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80° C. under nitrogen for 18 hours. The mixture was then cooled to 15° C., filtered, and concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH=20/1) to give compound 19 (1.40 g, 31%) as a brown oil. ^1H NMR (400 MHz, DMSO-d ₆ ) 7.60 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.34-7.30 (m, 1H), 7.12 (dd, J = 7.7, 2.4 Hz, 1H), 3.91 (s, 3H), 3.29-3.25 (m, 4H), 2.62-2.65 (m, 4H), 2.37 (s, 3H). To a solution of compound 19 (1.40 g, 5.98 mmol) in THF (10 mL) was added LiAlH ₄ (454 mg, 12.0 mmol) at 0°C. The mixture was stirred at 70°C for 2 hours. The mixture was cooled to 0°C and quenched with a saturated solution of potassium sodium tartrate (3 mL). The resulting precipitate was collected and removed by filtration. The organic phase was concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH = 20/1) to produce Compound 20 (530 mg, 43%) as a brown solid. ^1H NMR (400 MHz, DMSO-d ₆ ) 7.26 (s, 1H), 6.96 (s, 1H), 6.91-6.80 (m, 2H), 4.66 (s, 2H), 3.32-3.05 (m, 4H), 2.66-2.48 (m, 4H), 2.36 (s, 3H). To a solution of Compound 20 (530 mg, 2.57 mmol) in DCM (10 ml) were added N-Boc-(S)-valine (670 mg, 3.08 mmol), DCC (795 mg, 3.86 mmol), and DMAP (62.8 mg, 0.514 mmol). The mixture was stirred at 15° C. for 24 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH=20/1) to produce compound 21 (600 mg, 58%) as a brown solid. HCl/EtOAc (4 M, 2 ml) was added to a solution of compound 21 (200 mg, 0.493 mmol) in EtOAc (5 ml). The mixture was stirred at 15 ° C for 15 hours. The mixture was then concentrated under vacuum and the formed precipitate was collected by filtration to produce compound 22 (120 mg, 71%) as a yellow solid.

Compound 6-072 was prepared from compound 22 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.05(s,1H),8.59(d,J＝7.8Hz,1H),7.36(d,J＝7.8Hz,1H),7.27-7.15(m,2H),6.94 (s,1H),6.90(d,J＝8.3Hz,1H),6.79(d,J＝7.3Hz,1H), 5.11(d,J＝7.3Hz,2H),4.98(s,2H),4.35(t,J＝7.3Hz, 1H),3.16-3.07(m,4H),2.45(s,3H),2.43-2.38(m,4H),2.21 (s,3H)2.17(br s, 1H), 1.00-0.92 (m, 6H); ESI-MS m/z 480 [M+H]; HPLC purity: 98.26% (220 nm), 99.95% (254 nm).

Example 73. (7-(Difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-073)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-11. ¹ H NMR (400MHz, DMSO-d ₆ )9.18 (s, 1H), 8.83 (d, J＝7.6Hz, 1H), 7.62 (d, J＝7.6Hz, 1H), 7.54-7.39 (m, 3H), 7.22(t,J＝8.8Hz,2H),7.04(t,J＝54.8Hz,1H),5.22-5.12 (m,2H),5.07(s,2H),4.39-4.31(m,1H),2.15(td,J＝13.6, 6.4Hz, 1H), 0.97-0.83 (m, 6H); ESI-MSm/z 436[M+H] ⁺ ; HPLC purity: 98.74% (220nm), 100% (254nm).

Example 74. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-threonine 4-fluorobenzyl ester (6-074)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(L)-threonine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.06 (s, 1H), 8.16 (d, J＝8.3Hz, 1H), 7.52-7.38 (m, 3H), 7.30-7.15 (m, 3H), 5.25-5.10 (m,2H),4.98(s,2H),4.84(d,J＝6.5Hz,1H),4.52(dd,J＝3.6,8.2Hz,1H),4.20(br s,1H),2.46(s,3H),1.16(d,J＝6.3Hz,3H); ESI-MS m/z 402[M+H] ⁺ ; HPLC purity: 98.36% (220nm), 97.90% (254nm).

Example 75. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(methylsulfonamido)benzyl ester (6-075)

To a solution of compound 23 (5.0 g, 30 mmol) and pyridine (7.0 g, 91 mmol) in DCM (20 ml) was added MsCl (4.0 g, 36 mmol) dropwise at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 0.4 h. The reaction mixture was quenched with water (50 ml) at 0°C and then extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine (2 x 50 ml) and dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 24 (7.0 g, 95%) as a red solid. ^1H NMR (400 MHz, DMSO-d ₆ ) 8.03 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 6.0 Hz, 2H), 4.37 (m, 2H), 3.08 (s, 3H), 1.39 (t, J = 6.4 Hz, 3H). To a mixture of compound 24 (2.0 g, 8.0 mmol) in THF (30 ml) was slowly added LiAlH ₄ (468 mg, 12.0 mmol) at 0°C, and the reaction mixture was subsequently stirred at 15°C under nitrogen for 12 hours. The reaction mixture was quenched with saturated potassium sodium tartrate solution (0.5 ml). After filtration, the filtrate was concentrated under reduced pressure to yield compound 25 (300 mg, 18%) as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.62 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 5.12 (s, 1H), 4.44 (d, J = 4.4 Hz, 2H), 2.94 (s, 3H). A mixture of compound 25 (500 mg, 2.50 mmol), N-Boc-(S)-valine (1.2 g, 5.5 mmol), DCC (1 g, 5 mmol), and DMAP (30 mg, 0.25 mmol) in DCM (10 ml) was stirred at 15° C. under nitrogen for 12 hours. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/EtOAc = 2/1) to give compound 26 (600 mg, crude product) as a white solid. To a solution of compound 26 (600 mg) in EtOAc (100 ml) was added HCl/EtOAc (6 M, 2 ml) dropwise, and the mixture was stirred at 15° C. under nitrogen for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 27 (400 mg, crude product) as a white solid.

Compound 6-075 was prepared from compound 27 and acid-04 in analogy to the last step of Example 1. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.80 (s, 1H), 9.03 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 7.41-7.30 (m, 3H), 7.26-7.14 (m, 3H), 5.19-5.05 (m, 2H), 4.97 (s, 2H), 4.33 (t, J=7.2 Hz, 1H), 3.01-2.94 (m, 3H), 2.43 (s, 3H), 2.14 (q, J=13.6, 6.8 Hz, 1H), 1.00-0.89 (m, 6H); ESI-MS m/z 475 [M+H]; HPLC purity: 97.85% (220 nm), 92.14% (254 nm).

Example 76. 4-(Methylsulfonyl)benzyl (7-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-076)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(S)-valine and acid-05. ¹ H NMR (400MHz, DMSO-d ₆ ) 8.99 (s, 1H), 8.64 (d, J = 8.0Hz, 1H), 7.91 (d, J = 8.0Hz, 2H), 7.65 (d, J = 8.4Hz, 2H),7.31(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),5.32-5.25 (m,2H),4.96(s,2H),4.38(t,J＝7.2Hz,1H),3.20(s,3H), 2.86-2.81(m,2H),2.20-2.15(s,1H),1.06(t,J＝7.2Hz,3H), 1.00 (d, J = 7.2 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H); ESI-MS m/z 474 [M+H] ⁺ ; HPLC purity: 98.27% (220 nm), 98.06% (254 nm).

Example 77. O-Benzyl-N-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-threonine 4-fluorobenzyl ester (6-077)

To a solution of (tert-butyloxycarbonyl)-L-threonine (1.00 g, 4.56 mmol) in DMF (15 ml) was added NaH (401 mg, 10.0 mmol) at -15°C. Bromomethylbenzene (858 mg, 5.02 mmol) was then added. The mixture was stirred at 15°C for 10 hours. LCMS indicated the detection of the desired substance. The reaction mixture was quenched by adding 1M aqueous HCl to pH = 4 and extracted with 15 ml (3 x 5 ml) of EtOAc. The combined organic layers were washed with brine (5 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (column: Luna C8 100 x 305 u; liquid phase: [A-TFA/ _H2O = 0.075% v/v; B-ACN] B%: 35%-55%; 12 minutes). After purification by preparative HPLC, the eluent was concentrated to remove the organic solvent. The residual aqueous solution was freeze-dried to produce compound 29 (1.00 g, 71%) as a white solid. Cs ₂ CO ₃ (1.16 g, 3.55 mmol) was added to a solution of compound 29 (1.00 g, 3.23 mmol) in DMF (15 ml) at 0°C. 1-(Bromomethyl)-4-fluoro-benzene (672 mg, 3.55 mmol) was then added. The mixture was stirred at 15°C for 8 hours. HPLC indicated the reaction was complete, and the desired substance was detected by LCMS. The reaction mixture was quenched by the addition of water (15 ml) and extracted with 45 ml (3 x 15 ml) of EtOAc. The combined organic layers were rinsed with brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 5u; liquid phase: [A—10 mM NH ₄ HCO ₃ aqueous solution; B—ACN] B%: 45%-75%; 20 minutes). After purification by preparative HPLC, the eluent was concentrated to remove the organic solvent. The residual aqueous solution was freeze-dried to produce compound 30 (610 mg, 45%) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) 7.32-7.25 (m, 5H), 7.18 (d, J = 7.5 Hz, 2H), 6.97 (t, J = 8.6 Hz, 2H), 5.30 (d, J = 9.7 Hz, 1H), 5.08 (s, 2H), 4.50 (d, J = 11.9 Hz, 1H), 4.34 (dd, J = 1.8, 9.7 Hz, 1H), 4.26 (d, J = 11.9 Hz, 1H), 4.18-4.10 (m, 1H), 1.45 (s, 9H), 1.26 (d, J = 6.2 Hz, 3H). A mixture of compound 30 (501 mg, 1.20 mmol) and HCl/EtOAc (4 M, 3.00 ml) was stirred at 15°C for 5 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound 31 (410 mg, 97% yield) as a yellow solid.

Compound 6-077 was prepared from compound 31 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.02 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 7.45-7.35 (m, 3H), 7.32-7.20 (m, 6H), 7.13 (t, J =8.8Hz,2H),5.16(s,2H),4.97(s,2H),4.75(dd,J＝7.09, 4.0Hz,1H),4.53(d,J＝11.9Hz,1H),4.37(d,J＝11.9Hz, 1H),4.17-4.09(m,1H),2.45(s,3H),1.23(d,J＝6.2Hz,3H); ESI-MS m/z 492 [M+H]; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 78. O-Benzyl-N-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-threonine methyl ester (6-078)

To a solution of compound 29 (600 mg, 1.94 mmol) in DMF (3 ml) at 0°C was added _{Cs₂CO₃ (} 695 mg, 2.13 mmol). Methyl iodide (303 mg, 2.13 mmol) was subsequently added. The mixture was stirred at 15°C for 10 hours. HPLC indicated the reaction was complete, and the desired substance was detected by LCMS. The reaction mixture was quenched by the addition of water (15 ml) and extracted with EtOAc (3 x 15 ml). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 x 25 5u; liquid phase: [A - 10 mM _{aqueous NH₄HCO₃} ; B - ACN] B%: 30%-60%; 20 minutes). After preparative HPLC purification, the eluate was concentrated to remove the organic solvent. The residual aqueous solution was freeze-dried to give compound 32 (520 mg, 83%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.36-7.24 (m, 5H), 5.31 (d, J=9.3 Hz, 1H), 4.57 (d, J=11.9 Hz, 1H), 4.41-4.28 (m, 2H), 4.16-4.09 (m, 1H), 3.68 (s, 3H), 1.46 (s, 9H), 1.27 (d, J=6.2 Hz, 3H).

Compound 6-078 was prepared from compound 32 and acid-04 in analogy to the last two steps of Example 77. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.03 (br s, 1H), 8.47 (d, J=8.4 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.36-7.18 (m, 6H), 4.97 (s, 2H), 4.69 (dd, J=4.2, 8.2 Hz, 1H), 4.59-4.53 (m, 1H), 4.43 (d, J=11.9 Hz, 1H), 4.09 (dd, J=4.4, 6.2 Hz, 1H), 3.66 (s, 3H), 2.48 (br s, 3H), 1.23 (d, J=6.2 Hz, 3H); ESI-MS m/z 398 [M+H]; HPLC purity: 99.60% (220 nm), 97.96% (254 nm).

Example 79. (7-(Difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-079)

This compound was prepared analogously to the last step of Example 1 from (S)-valine benzyl ester and acid-11. ¹ H NMR (400MHz, DMSO-d ₆ )9.18 (s, 1H), 8.84 (d, J = 8.0Hz, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.50 (d, J = 8.0Hz, 1H),7.44-7.31(m,5H),7.05(t,J＝54.8Hz,1H),5.23-5.14 (m,2H),5.07(s,2H),4.37(t,J＝7.2Hz,1H),2.17(dq,J =13.6, 6.6Hz, 1H), 0.94 (d, J = 6.4Hz, 6H); ESI-MSm/z 418 [M+H] ⁺ ; HPLC purity: 99.93% (220nm), 100% (254nm).

Example 80. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-(methylsulfonyl)benzyl ester (6-080)

To a solution of compound 34 (2.00 g, 9.99 mmol) in THF (10 ml) was added LiAlH ₄ (758 mg, 20.0 mmol) at 0°C. The mixture was stirred at 15°C for 14 hours. The mixture was cooled to 0°C and quenched with a saturated solution of potassium sodium tartrate (2 ml). The resulting precipitate was collected and removed by filtration. The organic phase was concentrated under vacuum to yield compound 35 (1.40 g, 63%). ¹ H NMR (400 MHz, CDCl ₃ ) 7.97 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.63-7.53 (m, 1H), 4.82 (d, J = 5.7 Hz, 2H), 3.07 (s, 3H).

To a solution of compound 35 (1.03 g, 5.52 mmol) in DCM (10 ml) were added N-Boc-(S)-valine (1.00 g, 4.60 mmol), DCC (1.42 g, 6.90 mmol), and DMAP (56.2 mg, 0.460 mmol). The mixture was stirred at 15° C. for 14 hours. The reaction mixture was filtered and concentrated under reduced pressure (40° C.) to yield a residue. The residue was purified by column chromatography (SiO ₂ ; petroleum ether/ethyl acetate = 2/1) to yield compound 36 (1.20 g, 68%) as a yellow oil.

To a solution of compound 36 (400 mg, 1.04 mmol) in EtOAc (10 ml) was added HCl/EtOAc (4 M, 5.2 ml). The mixture was stirred at 15°C for 1.5 hours. The reaction mixture was then concentrated under reduced pressure (40°C) to remove the solvent. The resulting precipitate was collected and filtered to yield compound 37 (280 mg, 84%) as a white solid. ¹ HNMR (400MHz, DMSO-d ₆ )8.64(s,3H),8.00(s,1H),7.91(d,J＝7.9 Hz,1H),7.80(d,J＝7.9Hz,1H),7.72-7.65(m,1H),5.35(s, 2H), 3.94 (d, J = 4.4Hz, 1H), 3.22 (s, 3H), 2.20 (m, 1H), 0.97 (d, J = 7.2Hz, 3H), 0.93 (d, J = 7.2Hz, 3H).

Compound 6-080 was prepared from compound 37 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H),8.61(d,J＝7.5Hz,1H),7.98(s,1H),7.90(d,J＝7.9Hz,1H),7.77(d, J＝7.9Hz,1H),7.71-7.65(m,1H),7.34(d,J＝7.5Hz,1H), 7.23(d,J＝7.9Hz,1H),5.30(s,2H),4.97(s,2H),4.37(t, J＝7.1Hz,1H),3.21(s,3H),2.43(s,3H),2.17(dd,J＝13.5, 6.84Hz,1H),0.95(d,J＝6.6Hz,6H); ESI-MS m/z 460 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 81. Benzyl 3-((dimethylamino)methyl)(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-081)

To a solution of compound 38 (4.58 g, 20.0 mmol) and Me ₂ NH.HCl (2.45 g, 30.0 mmol) in CH ₃ CN (50 ml) was added K ₂ CO ₃ (11.1 g, 80.0 mmol). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was filtered, the residue was rinsed with EtOAc (20 ml), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to give compound 39 (1.6 g, 41%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) 7.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.45 (s, 2H), 2.23 (s, 6H). To a solution of compound 39 (1.60 g, 8.28 mmol) in THF (30 mL) was added portionwise LiAlH ₄ (471 mg, 12.0 mmol) at 0°C. The mixture was stirred at 15°C for 12 hours. The reaction mixture was quenched with saturated potassium sodium tartrate solution (1.8 mL) at 0°C and then filtered. The filtrate was concentrated under reduced pressure to give compound 40 (1.32 g, 96%) as a yellow oil.

Compound 6-081 was prepared similarly to the procedure of Example 1 from compound 40 and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.81 (s, 1H), 9.02 (s, 1H), 8.56 (d, J＝7.6Hz, 1H), 7.52 (s, 1H), 7.48 (s, 2H), 7.32 (d, J＝7.2 Hz,1H),7.21(d,J＝8.0Hz,1H),5.20(s,2H),4.95(s,2H), 4.33(t,J＝7.6Hz,1H),4.25(d,J＝4.0Hz,3H),2.69(s, 6H),2.41(s,3H),2.18-2.12(m,1H),0.94-0.92(m,6H); ESI-MS m/z 439[M+H] ⁺ ; HPLC purity: 97.97% (220nm), 98.89% (254nm).

Example 82. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-((4-methylpiperazin-1-yl)methyl)benzyl ester (6-082)

This compound was prepared in analogy to the method of Example 81 from compound 38, 1-methylpiperazine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.57 (d, J = 8.0Hz, 1H), 7.44 (s, 2H), 7.49 (s, 2H), 7.32 (d, J = 8.0Hz, 1H),7.22(d,J＝7.6Hz,1H),5.18(s,2H),4.95(s,2H),4.33 (t,J＝7.2Hz,1H),3.16(d,J＝8.8Hz,2H),2.78(s,3H), 2.31(s,3H),2.18-2.12(m,1H),0.95-0.92(m,6H); ESI-MS m/z 494[M+H] ⁺ ; HPLC purity: 98.25% (220nm), 100% (254nm).

Example 83. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-(N-morpholinylmethyl)benzyl ester (6-083)

This compound was prepared in analogy to the method of Example 81 from compound 38, 1-methylpiperazine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01(s,1H),8.57(d,J＝7.2Hz,1H),7.56(s,2H),7.49(s,2H),7.31(d,J＝7.2Hz, 1H),7.21(d,J＝7.6Hz,1H),5.19(s,2H),4.95(s,2H), 4.35-4.31(m,3H),3.88(d,J＝12.8Hz,2H),3.66(s,2H),3.18 (s,2H),3.04(s,2H),2.31(s,3H),2.18-2.13(m,1H),0.93-0.92 (m,6H); ESI-MS m/z 481[M+H] ⁺ ; HPLC purity: 96.43% (220nm), 94.91% (254nm).

Example 84. 4-(Methylsulfonyl)benzyl (1-hydroxy-7-isopropyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-084)

This compound was prepared in analogy to the method of Example 1 from 4-(methylsulfonyl)benzyl alcohol, N-BOC-(S)-valine and acid-08. ¹ H NMR (400MHz, DMSO-d ₆ )9.15(s,1H), 8.64(d,J＝8.0Hz,1H),7.92(d,J＝8.4Hz,2H),7.66(d, J＝8.0Hz,2H),7.21-7.18(m,2H),5.28(s,2H),4.96(s,2H), 4.38(t,J＝7.6Hz,1H),3.20-3.18(m,4H),2.19-2.14(m,1H), 1.27(t,J＝6.4Hz,6H),0.94(d,J＝6.8Hz,6H); ESI-MS m/z 488[M+H] ⁺ ; HPLC purity: 98.60% (220nm), 97.23% (254nm).

Example 85. 4-((4-methylpiperazin-1-yl)sulfonyl)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-085)

To a solution of compound 41 (1.0 g, 4.0 mmol) and Et ₃ N (1.3 g, 13 mmol) in DCM (10 ml) was added 1-methylpiperazine (1.1 g, 11 mmol) at 0° C. The reaction mixture was stirred for 1 hour and then rinsed with water (4×10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 42 (700 mg, 55%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.19 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 3.97 (s, 3H), 3.07 (br s, 4H), 2.48 (t, J=4.8 Hz, 4H), 2.27 (s, 3H). To a solution of compound 42 (700 mg, 2.40 mmol) in THF (20 ml) was added LiAlH ₄ (134 mg, 3.60 mmol). The mixture was stirred at 0° C. for 12 hours. Saturated potassium sodium tartrate solution (0.5 ml) was added to the reaction mixture and stirred for 10 minutes. The mixture was then filtered and concentrated under reduced pressure to yield compound 43 (300 mg, 48%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 7.74 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 4.78 (s, 2H), 3.04 (br s, 4H), 2.48 (t, J=4.4 Hz, 4H), 2.27 (s, 3H).

Compound 6-085 was prepared from compound 43 and acid-04 in a manner similar to that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.05 (s, 1H), 8.65 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 5.39-5.27 (m, 2H), 4.98 (s, 2H), 4.38 (t, J=7.2 Hz, 1H), 3.79 (d, J=12.4 Hz, 4H), 3.15 (d, J=9.2 Hz, 4H), 2.76 (s, 3H), 2.45 (s, 1H), 2.22-2.15 (m, 1H), 0.98 (d, J=6.4, 3.6 Hz, 6H); ESI-MS m/z 544 [M+H] ⁺ ; HPLC purity: 92.93% (220 nm), 88.77% (254 nm).

Example 86. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(N-morpholinylsulfonyl)benzyl ester (6-086)

Compound 6-086 was prepared similarly to the method of Example 85 using morpholine instead of 1-methylpiperazine. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.60 (d, J = 7.6Hz, 1H), 7.73 (d, J = 7.6Hz, 2H), 7.67 (d, J = 8.0Hz, 2H),7.32(d,J＝7.6Hz,1H),7.21(d,J＝8.0Hz,1H),5.29 (s,2H),4.95(s,2H),4.36(t,J＝7.2Hz,1H),3.60(s,4H), 2.83(s,4H),2.42(s,3H),2.19-2.14(m,1H),0.93(d,J＝6.4 Hz,6H); ESI-MS m/z 531[M+H] ⁺ ; HPLC purity: 99.94% (220nm), 100% (254nm).

Example 87. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-D-valine 4-fluorobenzyl ester (6-087)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(R)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03 (s, 1H), 8.56 (d, J＝7.5Hz, 1H), 7.46 (dd, J＝8.4, 5.73Hz, 2H), 7.33 (d, J ＝7.5Hz,1H),7.27-7.15(m,3H),5.16(d,J＝7.5Hz,2H),4.97 (s,2H),4.34(t,J＝7.1Hz,1H),2.45-2.41(m,3H),2.14(dd, J=13.5, 6.8Hz, 1H), 1.02-0.82 (m, 6H); ESI-MS m/z 400[M+H] ⁺ ; HPLC purity: 98.94% (220nm), 99.52% (254nm).

Example 88. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-allothreonine 4-fluorobenzyl ester (6-088)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-BOC-(L)-allothreonine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.02(s,1H),8.46 (d,J＝7.6Hz,1H),7.44(t,J＝6.0Hz,2H),7.33(d,J＝8.0 Hz,1H),7.23-7.16(m,3H),5.13(d,J＝3.2Hz,2H),5.04(d,J＝5.6Hz,1H),4.95(s,2H),4.38(t,J＝6.8Hz,1H),4.00 (t,J＝6.0Hz,1H),2.41(s,3H),1.16(d,J＝6.0Hz,3H); ESI-MS m/z 402[M+H] ⁺ ; HPLC purity: 96.86% (220 nm), 95.47% (254 nm).

Example 89. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(isopropylsulfinyl)benzyl ester (6-089)

To a solution of compound 43 (5.00 g, 40.3 mmol) in DMSO (25 ml) were added propane-2-thiol (3.38 g, 44.3 mmol) and K ₂ CO ₃ (11.1 g, 80.6 mmol). The mixture was stirred at 100° C. for 16 hours. The mixture was cooled to 15° C. and poured into ice water (30 ml) and stirred for 20 minutes. The aqueous phase was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine (2×15 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to yield compound 44 (6.3 g, 87%) as a colorless oil. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.93 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 3.79-3.72 (s, 1H), 1.31 (d, J = 7.6 Hz, 6H). To a solution of compound 44 (3.00 g, 16.6 mmol) in THF (20 ml) and MeOH (4 ml) at 0°C was added portionwise NaBH ₄ (755 mg, 20.0 mmol), and the mixture was then stirred at 15°C for 2 hours. The reaction mixture was quenched with water (20 ml) at 0°C and then extracted with DCM (3×20 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 45 (2.99 g, 99%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.38 (d, J = 8.0 Hz, 2H), 7.295 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H), 3.39-3.32 (m, 1H), 1.28 (d, J = 6.4 Hz, 6H).

A mixture of compound 45 (2.9 g, 15.9 mmol), DCC (5.91 g, 28.6 mmol), DMAP (194 mg, 1.6 μmol), and N-Boc-(S)-valine (3.46 g, 15.9 mmol) in DCM (20 ml) was stirred at 15° C. for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc=5:1) to give compound 46 (4.73 g, 78%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )7.36(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz, 2H),5.13(q,J＝17.2,12.0Hz,2H),4.25(dd,J＝4.0Hz,1H), 3.43-3.35(m,1H),2.16-2.11(m,1H),1.43(s,9H),1.29(d, J＝6.8Hz,6H),0.93(d,J＝7.2Hz,3H),0.84(d,J＝6.4Hz, 3H). To a solution of compound 46 (1.00 g, 2.62 mmol) in DCM (20 ml) was added mCPBA (1.13 g, 6.55 mmol) portionwise, and the mixture was then stirred at 15° C. for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc=2:1) to give compound 47 (0.82 g, 78.73% yield) as a colorless oil.

Compound 6-089 was prepared from compound 47 and acid-04 in analogy to the last two steps of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.06(s,1H),8.62(d,J＝7.2Hz,1H),7.62(s,4H),7.34(d,J＝7.6Hz,1H),7.23(d, J＝7.2Hz,1H),5.26(d,J＝7.2Hz,2H),4.98(s,2H),4.36 (t,J＝6.8Hz,1H),2.98-2.92(m,1H),2.42(s,3H),2.20-2.15 (m,1H),1.17(d,J＝6.8Hz,3H),0.95-0.91(m,9H); ESI-MS m/z 472[M+H] ⁺ ; HPLC purity: 99.29% (220nm), 99.18% (254nm).

Example 90. 4-(Methylsulfinyl)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-090)

Compound 6-090 was prepared analogously to the last 2 steps of Example 89 from 4-(methylthio)benzyl alcohol and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.01 (s, 1H), 8.58 (d, J = 7.5Hz, 1H), 7.68 (d, J = 8.4Hz, 2H), 7.62-7.55 (m, 2H),7.32(d,J＝7.5Hz,1H),7.21(d,J＝7.9Hz,1H),5.23(s,2H),4.95(s,2H),4.35(s,1H),2.72(s,3H),2.41(s,3H), 2.19-2.12 (m, 1H), 0.94 (d, J=6.6Hz, 6H); ESI-MS m/z 444[M+H] ⁺ ; HPLC purity: 99.44% (220nm), 100% (254nm).

Example 91. 4-Fluorobenzyl 3-fluoro-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-091)

This compound was prepared in analogy to the method of Example 1 from 2-((tert-butoxycarbonyl)amino)-3-fluoro-3-methylbutanoic acid, 4-fluorobenzyl alcohol and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03 (s,1H),8.82(d,J＝7.9Hz,1H),7.46(dd,J＝8.2,6.0Hz, 2H),7.33(d,J＝7.9Hz,1H),7.26-7.16(m,3H),5.20(d,J ＝6.2Hz,2H),4.97(s,2H),4.76(dd,J＝16.1,8.2Hz,1H), 2.42(s,3H),1.54-1.38(m,6H); ESI-MSm/z 418[M+H] ⁺ ;HPLC Purity: 98.90% (220nm), 95.67% (254nm).

Example 92. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(isopropylsulfonyl)benzyl ester (6-092)

To a solution of compound 46 (1.00 g, 2.62 mmol) in DCM (20 ml) was added mCPBA (2.13 g, 10.5 mmol) portionwise, and the mixture was then stirred at 15° C. for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc=5:1) to yield compound 48 (0.95 g, 88%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )7.87(d,J＝8.4Hz,2H),7.54 (d,J＝8.0Hz,2H),5.29(s,2H),4.14-4.09(m,1H),3.22-3.13 (m,1H),2.20-2.13(m,1H),1.43(s,9H),1.28(d,J＝6.4Hz,6H),0.96(d,J＝6.8Hz,3H),0.87(d,J＝6.4Hz,3H).

Compound 6-092 was prepared from compound 48 and acid-04 in analogy to the last 2 steps of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.01(s,1H),8.60(d,J＝6.8Hz,1H),7.84(d,J＝6.4Hz,2H),7.67(d,J＝6.4Hz,2H), 7.32(d,J＝6.4Hz,1H),7.21(d,J＝7.2Hz,1H),5.29(s,2H),4.95(s,2H),4.38-4.35(m,1H),3.43-3.37(m,1H),2.40 (s,3H),2.19-2.14(m,1H),1.12(d,J＝5.6Hz,6H),0.93(d,J＝6.4Hz,6H); ESI-MS m/z 488[M+H] ⁺ ; HPLC purity: 99.98% (220 nm), 100% (254 nm).

Example 93. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(ethylsulfonyl)benzyl ester (6-093)

Compound 6-093 was prepared similarly to the procedures of Examples 89 and 92, using ethanethiol instead of 2-propanethiol. ¹ HNMR (400MHz, DMSO-d ₆ )9.03 (s, 1H), 8.62 (d, J＝7.2Hz, 1H), 7.89 (d, J＝7.2Hz, 2H), 7.68 (d, J＝7.6Hz, 2H),7.35(d,J＝7.6Hz,1H),7.23(d,J＝7.2Hz,1H),5.30 (s,2H),4.97(s,2H),4.38(m,1H),3.30(t,J＝6.8Hz,2H), 2.42(s,3H),2.19-2.07(m,1H),1.08(t,J＝6.4Hz,3H),0.96 (d,J＝6.0Hz,6H); ESI-MS m/z 474[M+H] ⁺ ; HPLC purity: 99.86% (220nm), 100% (254nm).

Example 94. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(ethylsulfinyl)benzyl ester (6-094)

Compound 6-093 was prepared similarly to the method of Example 89, using ethanethiol instead of 2-propanethiol. ¹ H NMR (400MHz, DMSO-d ₆ )9.04 (s, 1H), 8.60 (d, J = 8.0Hz, 1H), 7.68-7.59 (m, 4H), 7.33 (d, J = 7.2Hz, 1H), 7.22 (d,J＝7.6Hz,1H),5.28-5.21(m,2H),4.97(s,2H),4.38-4.34 (m,1H),3.04-2.99(m,1H),2.78-2.74(m,1H),2.42(s,3H), 2.18-2.16(m,1H),1.05(t,J＝7.6Hz,3H),0.95-0.93(m,6H); ESI-MS m/z 458[M+H] ⁺ ; HPLC purity: 99.56% (220nm), 100% (254nm).

Example 95. 2-(Pyrrolidin-1-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valine ester (6-095)

This compound was prepared in analogy to the method of Example 1 from 2-pyrrolidineethanol, N-BOC-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.07(s,1H),8.67 (br s,1H),7.40(br s,1H),7.26(br s,1H),4.97(s,2H),4.48 (m,1H),4.40(m,2H),3.65-3.52(m,4H),3.07(m,2H),2.47 (s,3H),2.21(m,1H),2.02-1.81(m,4H),0.97(s,6H); ESI-MS m/z 389[M+H] ⁺ ; HPLC purity: 94.65% (220nm), 94.92% (254nm).

Example 96. 2-(4-methylpiperazin-1-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-096)

This compound was prepared in analogy to the method of Example 1 from 2-(4-methylpiperazin-1-yl)ethan-1-ol, N-BOC-(S)-valine and acid-04. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 8.64 (d, J=7.2 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 4.97 (s, 2H), 4.48 (s, 1H), 4.41 (d, J=7.2 Hz, 2H), 3.37 (s, 8H), 2.80 (s, 3H), 2.47 (s, 3H), 2.22-2.18 (m, 1H), 0.97 (d, J=6.0 Hz, 6H); ESI-MS m/z 418 [M+H] ⁺ ; HPLC purity: 99.13% (220 nm), 99.60% (254 nm).

Example 97. 4-Fluorobenzyl O-(4-Fluorobenzyl)-N-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-allothreonine ester (6-097)

To a solution of N-BOC-(L)-allothreonine (300 mg, 1.37 mmol) in DMF (5 ml) was added NaHCO ₃ (345 mg, 4.10 mmol) at 0° C. 4-Fluorobenzyl bromide (310 mg, 1.64 mmol) was then added dropwise and the reaction mixture was stirred at 15° C. for 12 hours. The reaction mixture was diluted with water (20 ml) and then extracted with MTBE (2×15 ml). The combined organic layers were washed with brine (2×10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 49 (400 mg, 89%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.34 (t, J = 4.8 Hz, 2H), 7.04 (t, J = 8.8 Hz, 2H), 5.45 (s, 1H), 5.20-5.12 (m, 2H), 4.39 (s, 1H), 4.13 (s, 1H), 1.43 (s, 9H), 1.14 (s, 3H). To a solution of compound 49 (600 mg, 1.83 mmol) in toluene (15 ml) were added Ag ₂ O (1.27 g, 5.50 mmol) and 4-fluorobenzyl bromide (415 mg, 2.20 mmol). The mixture was stirred at 120° C. for 12 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) to give compound 50 (50 mg, 5.2%) as a yellow oil.

Compound 6-097 was prepared from compound 50 and acid-04 in analogy to the last 2 steps of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.02(s,1H),8.66(d,J＝8.4Hz,1H),7.40(d,J＝7.6Hz,2H),7.32-7.29(m,3H),7.22 (d,J＝7.6Hz,1H),7.17-7.12(m,4H),5.14(d,J＝2.8Hz, 2H),4.95(s,2H),4.74(t,J＝7.6Hz,1H),4.53-4.43(m,2H), 3.95(t,J＝6.0Hz,1H),2.40(s,3H),1.19(d,J＝6.4Hz, 3H); ESI-MS m/z 510[M+H] ⁺ ; HPLC purity: 99.37% (220 nm), 100% (254 nm).

Example 98. (S)-3-Hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-098)

This compound was prepared in analogy to the method of Example 1 from 3,4-difluorobenzyl alcohol, (S)-2-((tert-butyloxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.07(s,1H),8.29(d,J＝8.0Hz,1H),7.56-7.41(m,2H),7.37(d,J＝7.2Hz,1H),7.29(s,1H),7.25(d,J＝7.2 Hz,1H),5.17(s,2H),4.97(s,2H),4.87(s,1H),4.47(d,J =8.0Hz,1H),2.43(s,3H),1.25(s,3H),1.24(s,3H); ESI-MS m/z 434[M+H] ⁺ ; HPLC purity: 96.90% (220nm), 95.33% (254nm).

Example 99. (S)-3-Hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-099)

This compound was prepared in analogy to the method of Example 1 from 3,5-difluorobenzyl alcohol, (S)-2-((tert-butyloxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.07(s,1H),8.34(d,J＝8.0Hz,1H),7.39(d,J＝7.2Hz,1H),7.26(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,3H), 5.23(s,2H),5.00(s,2H),4.92(s,1H),4.51(d,J＝8.0Hz, 1H),2.45(s,3H),1.27(d,J＝5.6Hz,6H); ESI-MS m/z 434[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 100. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3,4,5-trifluorobenzyl ester (6-100)

To a mixture of N-Boc-(S)-valine (300 mg, 1.38 mmol) and _NaHCO₃ (347 mg, 4.14 mmol) in DMF (3 ml) at 0°C was added compound 51 (341 mg, 1.52 mmol). The mixture was stirred at 15°C for 14 hours. Water (5 ml) was then added and the mixture was extracted with MTBE (3 x 5 ml). The combined organic phases were washed with brine (3 x 2 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to give crude compound 52 (1.4 g) as a brown oil.

Compound 6-100 was prepared from compound 52 and acid-04 in analogy to the last two steps of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.04 (s, 1H), 8.64-8.63 (m, 1H), 7.42-7.36 (m, 3H), 7.34-7.23 (m, 1H), 5.21-5.14 (m, 2H), 4.97 (s, 2H), 4.38-4.36 (m, 1H), 2.20-2.15 (m, 1H), 2.43 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H); ESI-MS m/z 436 [M+H] ⁺ ; HPLC purity: 99.52% (220 nm), 100% (254 nm).

Example 101. (S)-3-Hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-101)

This compound was prepared in analogy to the method of Example 100 from 3,4,5-trifluorobenzyl alcohol, (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid and acid-04. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.05 (s, 1H), 8.32-8.30 (m, 1H), 7.43-7.37 (m, 3H), 7.26-7.24 (m, 1H), 5.19 (s, 2H), 4.98 (s, 2H), 4.90 (s, 1H), 4.50-4.48 (m, 1H), 2.33 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H); ESI-MS m/z 434 [M+H] ⁺ ; HPLC purity: 96.90% (220 nm), 95.33% (254 nm).

Example 102. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(piperazine-1-carbonyl)benzyl ester (6-102)

To a solution of N-Boc-(S)-valine (5.0 g, 23 mmol) in DMF (100 ml) was added NaHCO ₃ (5.8 g, 69 mmol) at 0° C. Compound 53 (5.27 g, 23 mmol) was then added dropwise at 0° C., and the reaction mixture was stirred at 15° C. for 12 hours. The reaction mixture was diluted with water (200 ml) and then extracted with MTBE (3×100 ml). The combined organic layers were washed with water (2×100 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 54 (7.5 g, 88.7% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 8.02 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.26-5.16 (m, 2H), 5.01-4.99 (m, 1H), 4.28-4.26 (m, 1H), 3.92 (s, 3H), 2.16-2.14 (m, 1H), 1.43 (s, 9H), 0.94 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H). HCl/EtOAc (4 M, 12.5 ml) was added to a solution of Compound 54 (1.83 g, 5.00 mmol) in EtOAc (25 ml). The reaction solution was stirred at 15° C. for 12 hours. The solvent was removed under reduced pressure to give compound 55 (1.4 g, 93%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) 8.97 (s, 2H), 8.00 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.31-5.21 (m, 2H), 3.95 (s, 1H), 3.90 (s, 3H), 2.45-2.44 (m, 1H), 1.11 (s, J = 7.2 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). To a solution of compound 55 (0.50 g, 2.6 mmol) in DMF (1 ml) were added HATU (1.49 g, 3.9 mmol), TEA (1 g, 10.4 mmol), and acetic acid-04 (0.78 g, 2.6 mmol). The reaction mixture was stirred at 15°C for 2 hours. The mixture was poured into water (30 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (2 x 30 ml), dried over sodium sulfate, and concentrated under reduced pressure to yield compound 56 (1.14 g, 79%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.59 (d, J = 8.0Hz, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.33 (d, J = 7.6Hz, 1H), 7.21 (d,J＝8.0Hz,1H),5.25-5.22(m,2H),4.95(s,2H),3.84(s,4H),2.42(s,3H),2.16-2.15(m,1H),0.94(d,J＝6.4Hz,6H).

To a solution of compound 56 (440 mg, 1.00 mmol) in DMF (10 ml) was added LiCl (424 mg, 10.0 mmol). The mixture was stirred at 140°C for 12 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water (20 ml) and acidified to pH = 5 with 3M HCl. The aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by preparative HPLC (under acidic conditions) to yield compound 57 (30 mg, 7.1%) as a white solid. To a solution of compound 57 (30 mg, 0.07 mmol) in DMF (1 ml) were added HATU (40 mg, 0.10 mmol), TEA (21 mg, 0.21 mmol), and N-Boc-piperazine (14 mg, 0.077 mmol), and the reaction mixture was stirred at 15°C for 2 hours. The mixture was poured into water (5 ml) and extracted with EtOAc (3 x 5 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield Compound 88 (40 mg, 96%) as a white solid. MS (ESI) mass: calculated for C ₃₁ H ₄₀ BN ₃ O ₈ 593.29, m/z found 594.4 [M+H] ⁺ . A solution of Compound 58 (40 mg, 0.067 mmol) and HCl/EtOAc (4 M, 0.84 ml) in EtOAc (1 ml) was stirred at 15° C. for 30 minutes. After filtration, the residue was purified by preparative HPLC (under acidic conditions) to yield Compound 6-102 (11 mg, 29%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.95 (s, 2H), 8.58 (d, J = 7.6Hz, 1H), 7.47 (s, 4H), 7.33 (d, J = 7.6Hz, 1H), 7.22 (d, J = 7.6Hz, 1H), 5.22 (s,2H),4.96(s,2H),4.35(t,J＝7.2Hz,1H),3.62(s,4H), 3.14(s,4H),2.43(s,3H),2.17-2.13(m,1H),0.95(d,J＝6.4 Hz, 3H), 0.94 (d, J = 6.8Hz, 3H); ESI-MS m/z 494[M+H] ⁺ ; HPLC Purity: 95.40% (220nm), 96.27% (254nm).

Example 103. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-((2-(dimethylamino)ethyl)carbamoyl)benzyl ester (6-103)

Compound 6-103 was prepared similarly to step 5 of Example 102 using N ¹ ,N ¹ -dimethylethane-1,2-diamine instead of N-Boc-piperazine. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.56 (d, J = 7.6Hz, 1H), 8.37 (t, J = 5.6Hz, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 7.31 (d,J＝7.6Hz,1H),7.20(d,J＝7.6Hz,1H),5.23-5.16(m, 2H),4.94(s,2H),4.34(t,J＝7.2Hz,1H),3.35-3.30(m,2H), 2.46-2.38(m,5H),2.19(s,6H),2.17-2.13(m,1H),0.94-0.88 (m, 6H); ESI-MS m/z 496 [M+H] ⁺ ; HPLC purity: 96.95% (220 nm), 98.33% (254 nm).

Example 104. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(1,1-dioxo-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)methyl ester (6-104)

To a solution of compound 59 (5.0 g, 28 mmol) in DMF (20 ml) was added MeSNa (13 g, 36 mmol). The mixture was stirred at 80°C for 14 hours. The mixture was cooled to 15°C, poured into ice water (50 ml), and stirred for 30 minutes. The resulting precipitate was collected and filtered to yield compound 60 (3.6 g, 62%) as an off-white solid. ^1H NMR (400 MHz, CDCl ₃ ) 8.24 (s, 1H), 8.17-8.14 (m, 1H), 7.33-7.30 (m, 1H), 3.94 (s, 3H), 2.61 (s, 3H). To a solution of compound 60 (3.00 g, 14.5 mmol) in DCM (20 ml) was added mCPBA (7.4 g, 36 mmol). The mixture was stirred at 15°C for 24 hours. Water (40 ml) was added to the mixture and stirred for 20 minutes. The organic phase was separated and washed with ₅ % NaOH (20 ml). The combined organic phases were washed with saturated _Na₂SO₃ solution (3 x 20 ml) and brine (2 x 20 ml), dried over sodium sulfate, filtered, and concentrated under vacuum to yield compound 61 (2.9 g, 84%) as a white solid. ^1H NMR (400 MHz, DMSO- _d₆ ) 8.58 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.46 (s, 3H). To a solution of compound 61 (2.00 g, 8.36 mmol) in THF (20 ml) at 0°C was added _LiAlH₄ (634 mg, 16.7 mmol). The mixture was stirred at 15° C. for 14 hours. The mixture was quenched with saturated potassium sodium tartrate solution (2 ml) and filtered. The filtrate was concentrated under vacuum to give crude compound 62 (1.2 g) as a yellow oil. ^1H NMR (400 MHz, DMSO-d ₆ ) 8.10 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.3 (s, 1H), 5.64 (s, 1H), 4.65 (s, 2H), 4.58 (s, 2H).

Compound 6-104 was prepared from compound 62, N-Boc-(S)-valine and acid-04 in analogy to the procedure of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.03 (s, 1H), 8.64 (d, J = 7.6Hz, 1H), 8.19 (d, J = 8.0Hz, 1H), 8.08 (d, J = 8.0 Hz,1H),8.04(s,1H),7.35(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),5.39(s,2H),4.97(s,2H),4.63(s,2H),4.44-4.38 (m,1H),2.44(s,3H),2.21-2.16(m,1H),0.96(d,J＝6.8Hz, 6H); ESI-MS m/z 484[M+H] ⁺ ; HPLC purity: 98.53% (220nm), 99.73% (254nm).

Example 105. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(4-methylpiperazine-1-carbonyl) ester (6-105)

Compound 6-105 was prepared similarly to the method of Example 103, using N-methylpiperazine instead of N-Boc-piperazine. ¹ HNMR (400MHz, DMSO-d ₆ )9.03 (s, 1H), 8.57 (d, J = 7.2Hz, 1H), 7.48-7.43 (m, 4H), 7.31 (d, J = 7.6Hz, 1H),7.20(d,J＝8.0Hz,1H),5.20(s,2H),4.94(s,2H),4.33 (t,J＝6.8Hz,1H),3.52(s,4H),3.05(m,4H),2.74(d,J＝ 4.0Hz,3H),2.29(s,3H),2.13(m,1H),0.94-0.92(m,6H); ESI-MS m/z 508[M+H] ⁺ ; HPLC purity: 95.08% (220 nm), 95.49% (254 nm).

Example 106. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)benzyl ester (6-106)

Compound 6-106 was prepared similarly to the method of Example 103, using N ¹ ,N ¹ ,N ² -trimethylethane-1,2-diamine instead of N-Boc-piperazine. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.00 (s, 1H), 8.55 (d, J = 8.0Hz, 1H), 7.42 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 7.30 (d, J = 8.0Hz, 1H), 7.19 (d, J＝8.0Hz,1H),5.22-5.13(m,2H),4.93(s,2H),4.33(t, J＝7.2Hz,1H),3.49(s,1H),3.22(s,1H),2.92-2.86(m,3H), 2.62(s,1H),2.42(s,3H),2.29(s,1H),2.17-2.14(m,4H), 1.92 (s, 3H), 0.90 (d, J=6.0 Hz, 6H); ESI-MS m/z 510 [M+H] ⁺ ; HPLC purity: 97.33% (220 nm), 97.78% (254 nm).

Example 107. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2-methoxyethyl ester (6-107)

To a solution of compound 6-003 (300 mg, 1.03 mmol) in DMF (4 ml) were added 2-chloroethyl methyl ether (116 mg, 1.24 mmol) and Cs ₂ CO ₃ (671 mg, 2.06 mmol). The mixture was stirred at 15° C. for 6 hours. The mixture was purified by preparative HPLC (TFA conditions) to yield compound 6-107 (32 mg, 8.8%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H),8.53-8.51(m,1H),7.37(d,J＝8.0 Hz,1H),7.24(d,J＝8.0Hz,1H),4.97(s,2H),4.33-4.26(m, 1H),4.25-4.14(m,2H),3.54(s,2H),3.28(s,3H),2.47(s,3H),2.16-2.11(m,1H),0.96(d,J＝8.0Hz,6H); ESI-MS m/z 350[M+H] ⁺ ; HPLC purity: 98.34% (220nm), 96.76% (254nm).

Example 108. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-sulfonylaminobenzyl ester (6-108)

To a solution of compound 63 (5.0 g, 25 mmol) in THF (100 ml) was added BH ₃ -Me ₂ S (7.55 g, 100 mmol) dropwise at 0° C. over 10 minutes. After addition, the mixture was stirred at 10° C. for 12 hours. The mixture was quenched with dropwise MeOH (100 ml) at 0° C. and then concentrated under reduced pressure to produce compound 64 (3 g, 64.47% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.78 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.29 (s, 2H), 5.37 (s, 1H), 4.57 (s, 2H). A mixture of compound 64 (1.5 g, 8.0 mmol) and NaH (705 mg, 32 mmol) in DMF (7 ml) was degassed and purged with nitrogen three times, stirred for 12 minutes, and then SEM-Cl (2.54 g, 15 mmol) was added to the mixture and stirred at 20° C. under nitrogen for 1 hour. After quenching at 10° C. by the addition of 50 ml of NH ₄ Cl, the mixture was extracted with MTBE (2×50 ml), and the combined organic layers were washed with brine (2×50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc=2:1) to give compound 65 (2.2 g, 61%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )7.80(d,J＝8.0Hz,2H),7.49(d,J＝8.0 Hz, 2H), 5.43 (t, J = 5.2Hz, 1H), 4.71 (s, 4H), 4.57 (d, J = 4.8Hz, 2H), 3.34 (t, J = 8.4Hz, 4H), 0.74 (t, J = 8.0Hz, 4H), -0.07 (s, 18H).

A mixture of compound 65 (1 g, 2.23 mmol), N-Boc-(S)-valine (533 mg, 2.45 mmol), DCC (920 mg, 4.46 mmol), and DMAP (27 mg, 223 μmol) in DCM (20 ml) was degassed and purged with nitrogen three times, and then the mixture was stirred at 15° C. under nitrogen for 12 hours. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether:EtOAc=10:1) to give compound 66 (1.2 g, 83%) as a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) 8.24 (s, 1H), 7.90 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.4Hz, 2H), 5.26 (d, J = 7.6Hz, 1H), 5.15 (d, J = 7.6Hz, 1H), 4.77 (s, 4H), 4.29 (dd, J＝8.4, 4.4Hz, 1H), 3.48 (t, J＝8.4Hz, 4H), 2.18-2.14 (m, 1H), 1.45 (s, 9H), 0.88-0.83 (m, 10H), -0.02 (s, 18H). To a mixture of compound 66 (200 mg, 0.301 mmol) in MeOH (10 ml) was added dropwise AcCl (49 mg, 0.62 mmol), and the mixture was subsequently stirred at 0° C. under nitrogen for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 67 (30 mg, 34%) as a colorless oil, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.52 (s, 2H), 7.89-7.82 (m, 2H), 7.62 (d, J=7.6 Hz, 2H), 5.34 (s, 2H), 3.99 (s, 1H), 2.21 (s, 1H), 0.97 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H).

Compound 6-108 was prepared from compound 67 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.06 (br s, 1H), 8.62 (d, J = 6.8Hz, 1H), 7.84 (d, J = 7.6Hz, 2H), 7.60 (d, J = 7.6Hz, 2H),7.38-7.26(m,3H),7.25(d,J＝6.8Hz,1H),5.27(s,2H), 4.99(s,2H),4.41-4.40(m,1H),2.48(s,3H),2.22-2.18(m, 1H), 0.97 (d, J=6.0Hz, 6H); ESI-MS m/z461[M+H] ⁺ ; HPLC purity: 97.53% (220nm), 93.64% (254nm).

Example 109. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(N,N-bis(methoxymethyl)sulfamoyl)benzyl ester (6-109)

To a mixture of compound 66 (100 mg, 154 μmol) in MeOH (10 ml) was added AcCl (24 mg, 0.31 mmol) dropwise, and the mixture was then stirred at 0° C. under nitrogen for 1 hour. After being quenched by the addition of water (1 ml) at 10° C., the reaction mixture was concentrated under reduced pressure to give compound 68 (20 mg, 35%) as a colorless oil, which was used in the next step without further purification. ¹ H NMR (400MHz, DMSO-d ₆ )7.85(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),5.24-5.17(m,2H),4.69 (s,4H),3.60(t,J＝6.0Hz,1H),3.13(s,6H),1.91-1.81(m,1H),0.89-0.79(m,6H).

Compound 6-109 was prepared from compound 68 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.02(s,1H),8.62(d,J＝7.2Hz,1H),7.86(d,J＝8.4Hz,2H),7.61(d,J＝8.0Hz,2H), 7.35(d,J＝8.0Hz,1H),7.23(d,J＝7.6Hz,1H),5.27(s, 2H),4.97(s,2H),4.69(s,4H),4.37(t,J＝7.2Hz,1H),3.12 (s,6H),2.44(s,3H),2.20-2.13(m,1H),0.96-0.95(m,6H); ESI-MS m/z 547[M+H] ⁺ ; HPLC purity: 83.51% (220 nm), 83.99% (254 nm).

Example 110. 3-((dimethylamino)methyl)-4-(methylsulfonyl)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-110)

To a solution of compound 61 (2.39 g, 9.99 mmol) in THF (40 ml) was added BH ₃ -Me ₂ S (10 M, 5 ml) dropwise at 0°C under nitrogen. The mixture was stirred at 50°C for 12 hours. The reaction was slowly quenched with water (30 ml) at 0°C. The mixture was then concentrated under vacuum to remove the THF. The aqueous phase was rinsed with EtOAc (2 x 15 ml) and DCM:i-PrOH = 3:1 (3 x 20 ml) to remove impurities and then concentrated under vacuum to yield crude compound 69 (2.7 g) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.42 (br s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 4.62 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 3.30 (s, 3H). A 37% aqueous HCHO solution (4.8 ml) was added to a solution of compound 69 (1.4 g, 6.5 mmol) in MeOH (20 ml). The mixture was stirred at 15° C. for 12 hours. Subsequently, NaBH ₃ CN (1.23 g, 19.5 mmol) was added portionwise at 0° C. The mixture was stirred at 15° C. for 12 hours. The reaction was slowly quenched with water (5 ml) at 0° C., then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 70 (2 g, crude product) as a yellow oil. ¹ H NMR (400 MHz, MeOH-d ₄ ) 8.02 (d, J=8.0 Hz, 1H), 7.53-7.51 (m, 2H), 4.67 (s, 2H), 3.85 (s, 2H), 3.36 (s, 3H), 2.25 (s, 6H).

Compound 6-110 was prepared similarly to the method of Example 1 from compound 70, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.28(s,1H),8.66 (d,J＝7.6Hz,1H),8.09(d,J＝8.4Hz,1H),7.86(s,1H), 7.81(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),5.39-5.29(m,2H),4.98(s,2H),4.61(s,2H), 4.40(t,J＝7.2Hz,1H),3.36(s,3H),2.79(s,6H),2.44(s,3H), 2.23-2.18(m,1H),0.96(d,J＝6.0Hz,6H); ESI-MS m/z 517 [M+H] ⁺ ; HPLC purity: 95.11% (220 nm), 95.87% (254 nm).

Example 111. 4-((4-methylpiperazin-1-yl)methyl)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-111)

To a solution of compound 71 (1.8 g, 10 mmol) in DMF (15 ml) were added HATU (5.7 g, 15 mmol), TEA (3.04 g, 30 mmol), and 1-methylpiperazine (1.0 g, 10 mmol). The mixture was stirred at 15° C. for 2 hours. The reaction mixture was partitioned between water (30 ml) and EtOAc (60 ml). The organic phase was separated and washed with brine (2×20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 72 (2.1 g, 80%) as a brown oil. ^1H NMR (400 MHz, DMSO-d ₆ ) 7.99 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.61 (s, 2H), 3.25 (s, 2H), 2.37 (s, 2H), 2.19 (s, 2H), 1.97 (s, 3H). To a mixture of compound 72 (1.54 g, 5.87 mmol) in THF (20 ml) was added LiAlH ₄ (334 mg, 8.81 mmol) at 0° C., and the mixture was stirred at 0° C. under nitrogen for 1 hour. The reaction mixture was quenched with saturated potassium sodium tartrate solution (1.2 ml), filtered, and concentrated under reduced pressure to give compound 73 (1.2 g, crude product) as a pale yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) 7.26-7.21 (m, 4H), 5.10 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.41 (s, 2H), 2.32 (s, 8H), 2.13 (s, 3H).

Compound 6-111 was prepared from compound 73, N-Boc-(S)-valine and acid-04 in analogy to the method of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.05(s,1H),8.61 (d,J＝7.2Hz,1H),7.49(s,4H),7.36(d,J＝7.6Hz,1H), 7.24(d,J＝7.6Hz,1H),5.22(s,2H),4.98(s,2H),4.35(s,1H),4.18(s,2H),3.20(s,8H),2.83(s,3H),2.44(s,3H), 2.17 (d, J=6.0Hz, 1H), 0.96 (s, 6H); ESI-MSm/z 517[M+H] ⁺ ; HPLC purity: 95.11% (220nm), 95.87% (254nm).

Example 112. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine isopropyl ester (6-112)

Compound 6-112 was prepared similarly to the method of Example 107 using 2-bromopropane instead of 2-chloroethyl methyl ether. ¹ HNMR (400MHz, DMSO-d ₆ )9.03(s,1H),8.47 (d,J＝7.6Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(d,J＝8.0 Hz,1H),4.97-4.93(m,3H),4.25(t,J＝7.2Hz,1H),2.47(s,3H),2.12-2.11(m,1H),1.22(t,J＝5.6Hz,6H),0.95(d,J＝6.4Hz,6H); ESI-MS m/z 334[M+H] ⁺ ; HPLC purity: 95.58% (220nm), 94.84% (254nm).

Example 113. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-(pyrrolidin-1-ylmethyl) ester (6-113)

Compound 6-113 was prepared similarly to the method of Example 81 using pyrrolidine instead of dimethylamine. ¹ H NMR (400MHz, DMSO-d ₆ )9.05(s,1H),8.60(d,J＝7.6 Hz,1H),7.55(s,1H),7.50(s,3H),7.34(d,J＝7.6Hz,1H), 7.24(d,J＝8.0Hz,1H),5.22(s,2H),4.97(s,2H),4.38-4.32 (m,3H),3.33-3.23(m,2H),3.09(d,J＝6.8Hz,2H),2.43(s, 3H),2.22-2.12(m,1H),1.99(d,J＝4.4Hz,2H),1.88-1.77(m, 2H), 0.95 (dd, J=6.4 Hz, 4.0 Hz, 6H); ESI-MS m/z 465 [M+H] ⁺ ; HPLC purity: 99.95% (220 nm), 99.05% (254 nm).

Example 114. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (1-methylpiperidin-4-yl)methyl ester (6-114)

This compound was prepared in analogy to the method of Example 1 from (1-methylpiperidin-4-yl)methanol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 10.41 (s, 1H), 9.11 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.32 (t, J = 7.2Hz,1H),4.01-3.97(m,2H),3.40(d,J＝11.6Hz,2H), 2.97-2.88(m,2H),2.70(d,J＝4.4Hz,3H),2.48(s,3H), 2.19-2.14(m,1H),1.88(d,J＝11.6Hz,3H),1.56-1.50(m,2H), 0.98 (d, J=4.8 Hz, 6H); ESI-MS m/z 416 [M+H] ⁺ ; HPLC purity: 99.67% (220 nm), 100% (254 nm).

Example 115. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine cyclopentylmethyl ester (6-115)

Compound 6-115 was prepared similarly to the method of Example 107 using bromomethylcyclopentane instead of 2-chloroethyl methyl ether. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H),8.51 (d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.24(d,J＝8.0 Hz,1H),4.97(s,2H),4.30(t,J＝7.2Hz,1H),4.01-3.95(m,2H),2.47(s,3H),2.45-2.18(m,2H),1.70-1.58(m,2H) 1.56-1.51(m,4H),1.30-1.25(m,2H),0.96(d,J＝8.0Hz,6H); ESI-MS m/z 374[M+H] ⁺ ; HPLC purity: 99.95% (220nm), 100% (254nm).

Example 116. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine isobutyl ester (6-116)

Compound 6-116 was prepared similarly to the method of Example 107 using isobutyl bromide instead of 2-chloroethyl methyl ether. ¹ HNMR(400MHz, DMSO-d ₆ )9.06(s,1H),8.55(d,J＝7.6Hz,1H),7.38(d,J＝8.0Hz,1H),7.26(d,J＝7.6 Hz,1H),4.99(s,2H),4.33(d,J＝7.6Hz,1H),3.89(q,J＝3.6,2.4Hz,2H),2.50(d,J＝9.6Hz,3H),2.19-2.14(m,1H), 1.95-1.88(m,1H),0.97(d,J＝5.2Hz,6H),0.92(d,J＝6.8Hz,6H); ESI-MS m/z 348[M+H] ⁺ ; HPLC purity: 99.98% (220nm), 100% (254nm).

Example 117. Benzyl 3-(piperazin-1-ylmethyl) (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-117)

A mixture of compound 74 (1.50 g, 4.90 mmol), N-Fmoc-(S)-valine (1.83 g, 5.39 mmol), DCC (2.02 g, 9.79 mmol), and DMAP (60 mg, 0.49 mmol) in DCM (30 ml) was degassed and purged with nitrogen three times, and then the mixture was stirred at 15° C. for 12 hours. After filtration and concentration under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether:EtOAc=2:1) to give compound 75 (1.0 g, 33%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )7.77(d,J＝7.6 Hz,2H),7.61(d,J＝7.2Hz,2H),7.44-7.37(m,2H),735-7.27 (m,6H),5.19(q,J＝12.4Hz,2H),4.41(d,J＝7.2Hz,2H), 4.23(d,J＝4.8Hz,1H),4.03(s,1H),3.50(s,2H),3.43(s, 4H), 2.38 (s, 4H), 2.20 (d, J = 6.0Hz, 1H), 1.50-1.44 (m, 9H), 0.97-0.92 (m, 3H), 0.88 (d, J = 6.4Hz, 3H). To a solution of compound 75 (1.00 g, 1.59 mmol) in THF (10 ml) was added piperidine (1.36 g, 15.9 mmol). The mixture was stirred at 15° C. for 12 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2×50 ml). The combined organic layers were rinsed with brine (2×50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=10/1) to produce compound 76 (250 mg, 39%) as a light yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ )7.38-7.22(m,4H),5.20-5.02(m,2H), 3.47(s,2H),3.30(br s,4H),3.19-3.13(m,1H),2.29(t,J =4.4Hz,4H),1.88-1.80(m,1H),1.38(s,9H),0.86-0.78(m,6H). A mixture of acid-04 (120 mg, 0.625 mmol), HATU (357 mg, 938 μmol), and TEA (253 mg, 3.00 mmol) in DMF (2 ml) was stirred at 15°C for 10 minutes, followed by the addition of compound 76 (253 mg, 0.625 mmol) and stirred at 15°C under nitrogen for 1 hour. The reaction mixture was diluted with _H₂O (10 ml) and extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 77 ₍ 250 mg, crude product, pale _yellow oil), which was used in the next step without further purification. MS (ESI) mass: calculated for _{C₃₁H₄₂BN₃Oₐ 579.31} , m/z found 580.1 [M+H] ^⁺ . To a solution of compound 77 (250 mg, 0.431 mmol) in EtOAc (10 ml) was added HCl/EtOAc (6 M, 1 ml). The mixture was stirred at 15°C for 2 hours. Some white solid subsequently precipitated. After filtration, the white solid was purified by preparative HPLC (column: Luna C18 100×30 5u; liquid phase: [A-HCl/H ₂ O=0.040% v/v; B-ACN] B%: 5%-45%; 12 minutes) to yield compound 6-117 (93 mg, 45%) as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) 9.07 (s, 1H), 8.59 (d, J=6.0 Hz, 1H), 7.67 (s, 2H), 7.49 (s, 2H), 7.33 (s, 1H), 7.24 (s, 1H), 5.19 (s, 2H), 4.97 (s, 2H), 4.38 (s, 3H), 3.42-3.01 (m, 8H), 2.43 (s, 3H), 2.19 (s, 1H), 0.95 (s, 6H); ESI-MS m/z 480 [M+H] ⁺ ; HPLC purity: 99.91% (220 nm), 100% (254 nm).

Example 118. N-(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-N-methyl-L-valine 4-fluorobenzyl ester (6-118)

To a mixture of compound 78 (2.00 g, 6.15 mmol) and NaH (492 mg, 12.30 mmol) in THF (30 ml) was added MeI (1.75 g, 12.30 mmol), and the mixture was stirred at 10° C. under nitrogen for 12 hours. The reaction mixture was quenched at 10° C. by the addition of saturated NH ₄ Cl solution (60 ml) and extracted with EtOAc (2×40 ml). The combined organic layers were washed with brine (2×20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 79 (400 mg, 19%) as a pale yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) 7.41 (br s, 2H), 7.20 (t, J = 8.8 Hz, 2H), 5.18-5.08 (m, 2H), 4.28 (d, J = 10.8 Hz, 1H), 2.73 (d, J = 9.2 Hz, 3H), 2.15 (m, 1H), 1.38 (s, 9H), 0.91 (br s, 3H), 0.81 (br s, 3H). To a solution of compound 79 (400 mg, 1.18 mmol) in EtOAc (10 mL) was added HCl/EtOAc (6 M, 1.97 mL). The mixture was stirred at 15°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to yield compound 80 (300 mg, 92%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) 9.63 (br s, 1H), 7.44 (dd, J＝8.4, 5.6Hz, 2H), 7.07 (t, J＝8.4Hz, 2H), 5.32-5.19 (m, 2H), 3.58 (d, J=4.0Hz, 1H), 2.72 (s, 3H), 2.60 (m, 1H), 1.13-1.06 (m, 6H).

Compound 6-118 was prepared from compound 80 and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.04 (s, 1H), 7.47 (dd, J = 8.4, 5.6Hz, 2H), 7.30-7.19 (m, 3H), 7.06 (brs, 1H), 5.26-5.12 (m, 2H), 4.97 (s, 2H), 4.86 (br s, 1H), 3.00 (d, J = 8.4Hz, 1H), 2.61 (s, 2H), 2.34-2.14 (m, 4H), 1.02 (d, J = 6.0Hz, 3H), 0.93 (d, J = 6.4Hz, 3H); ESI-MS m/z 414 [M+H] ⁺ ; HPLC purity: 99.60% (220nm), 95.53% (254nm).

Example 119. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine cyclohexylmethyl ester (6-119)

This compound was prepared in analogy to the method of Example 1 from cyclohexylmethanol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H),8.52 (d,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),7.24(d,J＝7.6 Hz,1H),4.97(s,2H),4.31(t,J＝7.0Hz,1H),3.90(br s, 2H),2.47(s,3H),2.14(dd,J＝12.8,6.0Hz,1H),1.78-1.56 (m, 6H), 1.29-1.01 (m, 4H), 0.95 (d, J = 5.2Hz, 6H); ESI-MS m/z 388 [M+H] ⁺ ; HPLC purity: 99.38% (220nm), 100% (254nm).

Example 120. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine thiazol-5-ylmethyl ester (6-120)

Compound 6-120 was prepared similarly to the method of Example 107 using 5-(chloromethyl)thiazole instead of 2-chloroethyl methyl ether. ¹ H NMR (400MHz, DMSO-d ₆ )9.13(s,1H), 9.02(s,1H),8.57(d,J＝7.6Hz,1H),8.00(s,1H),7.35(d, J＝7.2Hz,1H),7.24(d,J＝7.6Hz,1H),5.45(q,J＝13.2, 16.0Hz,2H),4.98(s,2H),4.32(t,J＝7.2Hz,1H),2.44(s, 3H), 2.16-2.11(m,1H), 0.94-0.91(m,6H); ESI-MSm/z 389[M+H] ⁺ ; HPLC purity: 95.91% (220nm), 94.63% (254nm).

Example 121. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorophenethyl ester (6-121)

Compound 6-121 was prepared similarly to the method of Example 107, using 1-(2-bromoethyl)-4-fluorobenzene instead of 2-chloroethyl methyl ether. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.03 (s, 1H), 8.48 (d, J=7.2 Hz, 1H), 7.35-7.33 (m, 3H), 7.25 (d, J=8.0 Hz, 1H), 7.11 (t, J=8.4 Hz, 2H), 4.99 (s, 2H), 4.37-4.28 (m, 3H), 2.95-2.92 (m, 2H), 2.47 (s, 3H), 2.11-2.06 (m, 1H), 0.89 (d, J=6.4 Hz, 6H); ESI-MS m/z 414 [M+H] ⁺ ; HPLC purity: 99.48% (220 nm), 99.10% (254 nm).

Example 122. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-((methylamino)methyl)benzyl ester (6-122)

To a solution of tert-butyl-N-methylcarbamate (3.00 g, 22.9 mmol) in THF (50 ml) was added NaH (1.37 g, 34.3 mmol) in portions at 0°C. The reaction mixture was stirred at 15°C for 1 hour. A solution of compound 81 (5.24 g, 22.9 mmol) in THF (20 ml) was then added dropwise. The reaction mixture was stirred at 15°C for 13 hours. The reaction was slowly quenched with ice water (10 ml) and then extracted with EtOAc (3 x 20 ml). The combined organic phases were rinsed with brine (2 x 10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 4/1) to produce compound 82 (2.9 g, 45%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.95-7.91 (m, 2H), 7.42-7.38 (m, 2H), 4.45 (s, 2H), 3.91 (s, 3H), 2.85 (s, 3H), 1.48 (s, 9H). To a solution of compound 82 (2.8 g, 10 mmol) in THF (20 ml) was added portionwise LiAlH ₄ (456 mg, 12.0 mmol) at 0°C. The mixture was stirred at 15°C for 2 hours. The mixture was cooled to 0°C and quenched with a saturated solution of potassium sodium tartrate (0.5 ml). The mixture was concentrated under vacuum (40°C) to give compound 83 (1.8 g, 71%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.32-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7.15-7.14 (m, 1H), 4.68 (s, 2H), 4.42 (s, 2H), 2.82 (s, 3H), 1.48 (s, 9H). To a solution of compound 83 (1.5 g, 6.0 mmol) in DCM (20 mL) was added N-Fmoc-(S)-valine (2.23 g, 6.57 mmol), DCC (1.6 g, 7.8 mmol), and DMAP (73 mg, 0.60 mmol). The mixture was stirred at 15° C. for 12 hours. DCM (10 mL) was then added, and the organic layer was washed with brine (3×10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc=4/1) to give compound 84 (1.8 g, 53%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )7.70-7.80(m,2H), 7.54-7.62(m,2H),7.35-7.42(m,2H),7.23-7.33(m,4H),7.19 (br s,2H),5.34-5.32(m,1H),5.29-5.14(m,2H),4.43-4.41(m, 4H),4.40-4.14(m,4H),2.83(s,3H),2.12-2.23(m,1H),1.47 (s, 9H), 0.86 (dd, J = 6.84, 2.87Hz, 6H). To a solution of compound 84 (1.00 g, 1.75 mmol) in THF (6 ml) was added piperidine (298 mg, 3.50 mmol). The mixture was stirred at 15° C. for 12 hours. The mixture was concentrated under reduced pressure at 40° C. The residue was purified by column chromatography (petroleum ether/EtOAc = 1/4) to produce compound 85 (400 mg, 65%) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ )7.37-7.35(m,1H), 7.34-7.29(m,1H),7.27-7.22(m,1H),7.18-7.17(m,1H), 5.16-5.06(m,2H),4.37(s,2H),3.15(d,J＝4.0Hz,1H),2.74(s,3H),1.99-1.84(m,1H),1.42-1.39(m,9H),0.85(d,J＝6.8 Hz, 3H), 0.79 (s, J = 6.4Hz, 3H). To a solution of acid-04 (164 mg, 0.856 mmol) in DMF (3 ml) were added HATU (390 mg, 1.03 mmol) and TEA (260 mg, 2.57 mmol). The mixture was stirred at 20°C for 1 hour. Compound 85 (300 mg, 0.856 mmol) was then added in one portion. The mixture was stirred at 20°C for 11 hours. The reaction was slowly quenched with water (10 ml) at 0°C and then extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine (1 x 10 ml), dried over anhydrous sodium sulfate, filtered, and HCl/EtOAc (4 M, 4 ml) was then added. The mixture was stirred at 20°C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Luna C18 100×30 mm; liquid phase: 0.1% TFA-ACN; B%: 10%-40%; 12 min). After preparative HPLC purification, 3N HCl (2 ml) was added before freeze-drying. Compound 6-122 (137 mg, 33%) was obtained as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ )9.21(br s,2H),9.03(s,1H),8.59(d,J＝8.0Hz,1H), 7.55-7.51(m,2H),7.46-7.45(m,2H),7.35(d,J＝8.0Hz,1H), 7.24(d,J＝8.0Hz,1H),5.19(s,2H),4.97(s,2H),4.37(t,J＝8.0Hz,1H),4.10(s,2H),2.39(s,3H),2.21-2.16(m,1H), 0.96 (d, J=6.0Hz, 6H); ESI-MSm/z 425[M+H] ⁺ ; HPLC purity: 94.93% (220nm), 87.86% (254nm).

Example 123. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valinequinoxaline-2-ylmethyl ester (6-123)

Compound 6-123 was prepared similarly to the method of Example 107 using 2-(bromomethyl)quinoxaline instead of 2-chloroethyl methyl ether. ¹ H NMR (400MHz, DMSO-d ₆ )9.05 (s, 1H), 9.01 (s, 1H), 8.63 (d, J = 8.0Hz, 2H), 8.14-8.12 (m, 1H), 8.08-8.06(m,1H),7.90-7.88(m,2H),7.36(d,J＝8.0Hz,1H), 7.22(d,J＝8.0Hz,1H),5.57-5.49(m,2H),4.96(s,2H),4.46 (t, J＝4.5Hz, 1H), 2.45 (s, 3H), 2.44-2.24 (m, 1H), 1.00 (d, J＝6.0Hz, 6H); ESI-MS m/z 434[M+H] ⁺ ; HPLC purity: 98.71% (220nm), 96.67% (254nm).

Example 124. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine thiazol-2-ylmethyl ester (6-124)

Compound 6-124 was prepared similarly to the method of Example 107 using 2-(chloromethyl)thiazole instead of 2-chloroethyl methyl ether. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H), 8.62(d,J＝8.0Hz,1H),7.84(d,J＝4.0Hz,1H),7.81(d,J＝4.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz, 1H),5.52-5.41(m,2H),4.97(s,2H),4.38(t,J＝8.0Hz,1H), 2.44(s,3H),2.32-2.15(m,1H),0.96(d,J＝6.0Hz,6H); ESI-MS m/z 389[M+H] ⁺ ; HPLC purity: 99.65% (220nm), 100% (254nm).

Example 125. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valinequinolin-2-ylmethyl ester (6-125)

Compound 6-125 was prepared similarly to the method of Example 107 using 2-(chloromethyl)quinoline instead of 2-chloroethyl methyl ether. ¹ H NMR (400MHz, DMSO-d ₆ )8.69(d,J＝8.0Hz,1H),8.64(d,J＝8.4Hz,1H),8.14-8.10(m,2H),7.90 (t,J＝8.0Hz,1H),7.78-7.72(m,2H),7.39(d,J＝7.6Hz, 1H),7.24(d,J＝7.6Hz,1H),5.54(s,2H),4.98(s,2H),4.48 (t, J＝7.2Hz, 1H), 2.45 (s, 3H), 2.29-2.24 (m, 1H), 1.02 (d, J＝6.8Hz, 6H); ESI-MS m/z 433[M+H] ⁺ ; HPLC purity: 97.79% (220 nm), 97.66% (254 nm).

Example 126. Benzyl 3-(piperazin-1-yl)-L-valine (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-126)

A mixture of compound 86 (3.00 g, 14.0 mmol), N-Boc-piperazine (2.73 g, 14.7 mmol), Pd(OAc) ₂ (313 mg, 1.40 mmol), Cs ₂ CO ₃ (9.09 g, 27.9 mmol) and BINAP (869 mg, 1.40 mmol) in toluene (20 ml) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. under nitrogen for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give compound 87 (3.80 g, 85%) as a pale yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) 7.60 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.60 (t, J = 4.4 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). To a solution of compound 87 (1.00 g, 3.12 mmol) in THF (20 ml) was added LiAlH ₄ (118 mg, 3.12 mmol). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with sodium potassium tartrate solution (0.5 ml) at 15° C., then filtered and concentrated under reduced pressure to yield compound 88 (700 mg, 77%) as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.28-7.25 (m, 1H), 6.96 (s, 1H), 6.89-6.84 (m, 2H), 4.66 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). To a solution of compound 88 (293 mg, 1.00 mmol) and Et ₃ N (304 mg, 3.00 mmol) in DCM (10 mL) was added MsCl (229 mg, 2.00 mmol). The mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched at 15° C. by the addition of water (20 mL) and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield crude compound 89 (200 _mg , _yellow solid), which was used in the next step without further purification. MS (ESI) mass: calculated for _{Ci7H26N2O5S 370.16} , m/z found 371.2 [M+H] ⁺ . A mixture of compound 89 (300 mg, 810 μmol), compound 6-003 (236 mg, 0.810 mmol), and _K2CO3 (336 _mg , 2.43 mmol) in DMF (5 ml) was stirred at 60°C under nitrogen for 1 hour. The reaction mixture was quenched with water (10 ml) at 15°C and then extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield crude compound 90 (400 mg, pale yellow oil), which was used in the next step without further purification. MS (ESI) mass: calculated for C ₃₀ H ₄₀ BN ₃ O ₇ 565.30, m/z found 566.3 [M+H] ⁺ . To a solution of compound 90 (400 mg, 0.707 mmol) in EtOAc (10 ml) was added HCl/EtOAc (6 M, 1.18 ml). The mixture was stirred at 15° C. for 1 hour. After concentration under reduced pressure, the reaction mixture was purified by preparative HPLC (column: Luna C18 100×30 mm; liquid phase: [A-HCl/H ₂ O=0.040% v/v; B-ACN] B%: 13%-43%, 12 minutes) to give compound 6-126 (102 mg, 28%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )9.17(s,2H),8.58(d,J＝7.2Hz,1H),7.34 (d,J＝7.2Hz,1H),7.28-7.22(m,2H),7.01(s,1H),6.95(d, J＝8.0Hz,1H),6.88(d,J＝7.2Hz,1H),5.13(s,2H),4.97 (s,2H),4.34(t,J＝7.2Hz,1H),3.36(d,J＝5.2Hz,4H), 3.17(d,J＝2.8Hz,4H),2.44(s,3H),2.20-2.11(m,6.8Hz, 1H), 0.958-0.942 (m, 6H); ESI-MS m/z 466 [M+H] ⁺ ; HPLC purity: 97.27% (220 nm), 96.92% (254 nm).

Example 127. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valinequinolin-6-ylmethyl ester (6-127)

Compound 6-127 was prepared by using 6-(chloromethyl)quinoline instead of 2-chloroethyl methyl ether in a similar manner to Example 107. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.00 (s, 1H), 8.88 (d, J=3.2 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.32 (d, J=3.2 Hz, 1H), 8.02-8.00 (m, 2H), 7.55-7.52 (m, 1H), 7.33-7.31 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 5.37-5.36 (m, 2H), 4.94 (s, 2H), 4.38 (t, J=7.2 Hz, 1H), 2.41 (s, 3H), 2.18-2.14 (m, 1H), 0.93 (d, J=6.4 Hz, 6H); ESI-MS m/z 433 [M+H] ⁺ ; HPLC purity: 99.81% (220 nm), 100% (254 nm).

Example 128. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine thiazol-4-ylmethyl ester (6-128)

Compound 6-128 was prepared similarly to the method of Example 107 using 4-(chloromethyl)thiazole instead of 2-chloroethyl methyl ether. ¹ H NMR (400MHz, DMSO-d ₆ )9.09(s,1H), 9.02(s,1H),8.55(d,J＝8.0Hz,1H),7.75(d,J＝1.2Hz, 1H),7.32(d,J＝8.0Hz,1H),7.21(d,J＝7.6Hz,1H),5.30-5.21 (m,2H),4.94(s,2H),4.32(t,J＝7.6Hz,1H),2.41(s,3H), 2.14-2.09 (m, 1H), 0.91 (dd, J=4.0Hz, 2.8Hz, 6H); ESI-MS m/z 389[M+H] ⁺ ; HPLC purity: 99.53% (220nm), 100% (254nm).

Example 129. (1-Hydroxy-5-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-129)

This compound was prepared in analogy to the method of Example 1 from 4-fluorobenzyl alcohol, N-Boc-(S)-valine and acid-14. ¹ H NMR (400MHz, DMSO-d ₆ )9.19 (s, 1H), 8.60 (d, J＝7.6Hz, 1H), 7.66 (s, 1H), 7.46-7.42 (m, 2H), 7.24 (s, 1H), 7.19(d,J＝8.8Hz,1H),5.14(q,J＝12.4,5.6Hz,2H),4.95 (s,2H),4.33(t,J＝6.8Hz,1H),2.30(s,3H),2.16-2.11(m, 1H), 0.91 (d, J=6.4Hz, 6H); ESI-MS m/z400[M+H] ⁺ ; HPLC purity: 99.53% (220nm), 100% (254nm).

Example 130. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(N-morpholinylmethyl)benzyl ester (6-130)

This compound was prepared in analogy to the method of Example 1 from (4-(N-morpholinylmethyl)phenyl)methanol, N-Boc-(S)-valine and acid-14. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.06 (br s, 1H), 8.62 (d, J = 6.8Hz, 1H), 7.61 (d, J = 7.2Hz, 2H), 7.50 (d, J = 7.2Hz, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.25 (d,J＝7.2Hz,1H),5.23(s,2H),4.98(s,2H),4.35(s,3H), 3.94(d,J＝11.6Hz,2H),3.75(t,J＝11.2Hz,2H),3.21(d, J＝10.4Hz,2H),3.10(s,2H),2.44(s,3H),2.18(d,J＝6.0 Hz, 1H), 0.97 (s, 6H); ESI-MS m/z 481 [M+H] ⁺ ; HPLC purity: 100% (220 nm), 100% (254 nm).

Example 131. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(pyrrolidin-1-ylmethyl) ester (6-131)

To a solution of compound 91 (3.0 g, 13 mmol) and pyrrolidine (1.21 g, 17.0 mmol) in CH ₃ CN (10 ml) was added K ₂ CO ₃ (5.43 g, 39.0 mmol). The mixture was stirred at 80° C. for 12 hours. After filtration, the residue was rinsed with CH ₃ CN (3 ml), and the combined filtrates were concentrated under reduced pressure to give compound 92 (2.5 g, 87%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.97 (d, J=7.6 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.90 (s, 3H), 3.65 (s, 2H), 2.50 (s, 4H), 1.78 (s, 4H). To a solution of compound 92 (0.80 g, 3.6 mmol) in THF (50 ml) was added portionwise LiAlH ₄ (208 mg, 5.00 mmol) at 0° C., and the mixture was then stirred at 20° C. for 12 hours. The reaction mixture was quenched with saturated potassium sodium tartrate solution (1 ml) at 0° C. and then filtered. The filtrate was concentrated under reduced pressure to give compound 93 (0.51 g, crude product) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 7.39-7.32 (m, 4H), 4.70 (s, 2H), 3.63 (s, 2H), 2.52 (s, 4H), 1.82-1.79 (m, 4H).

Compound 6-131 was prepared from compound 93, N-Boc-(S)-valine and acid-04 in a manner similar to that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 10.05 (s, 1H), 9.07 (s, 1H), 8.62 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 4.38-4.35 (m, 3H), 3.35 (s, 2H), 3.18-3.06 (m, 2H), 2.44 (s, 3H), 2.21-2.15 (m, 1H), 2.04 (m, 2H), 1.89-1.86 (m, 2H), 0.98-0.95 (m, 6H); ESI-MS m/z 465 [M+H] ⁺ ; HPLC purity: 95.74% (220 nm), 92.57% (254 nm).

Example 132. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine cyclopentyl ester (6-132)

Compound 6-132 was prepared similarly to the method of Example 107 using bromocyclopentane instead of 2-chloroethyl methyl ether. ¹ HNMR (400MHz, DMSO-d ₆ ) 8.96 (s, 1H), 8.49 (d, J = 7.2Hz, 1H), 7.38 (d, J = 7.6Hz, 1H), 7.26 (d, J = 7.6 Hz,1H),5.15(s,1H),4.99(s,2H),4.27(t,J＝7.2Hz,1H), 2.51(s,3H),2.18-2.10(m,1H),1.85(d,J＝4.8Hz,2H), 1.68-1.58 (m, 6H), 0.96 (d, J=6.4Hz, 6H); ESI-MS m/z 360[M+H] ⁺ ; HPLC purity: 99.59% (220nm), 97.74% (254nm).

Example 133. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine cyclohexyl ester (6-133)

Compound 6-133 was prepared similarly to the method of Example 107 using bromocyclohexane instead of 2-chloroethyl methyl ether. ¹ HNMR (400MHz, DMSO-d ₆ )9.04(s,1H),8.48 (d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(d,J＝8.0 Hz,1H),4.97(s,2H),4.75(s,1H),4.28(t,J＝6.0Hz,1H), 2.48(s,3H),2.15-2.13(m,1H),1.78(s,2H),1.68(s,2H), 1.45-1.31 (m, 6H), 0.95 (d, J=4.0Hz, 6H); ESI-MSm/z 374[M+H] ⁺ ; HPLC purity: 99.57% (220nm), 100% (254nm).

Example 134. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine tetrahydro-2H-pyran-4-yl ester (6-134)

This compound was prepared in analogy to the method of Example 1 from tetrahydro-2H-pyran-4-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H), 8.53(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(d, J＝8.0Hz,1H),4.97-4.94(m,3H),4.29(t,J＝8.0Hz,1H), 3.82-3.78(m,2H),3.49-3.36(m,2H),2.48(s,3H),2.18-2.13 (m,1H),1.88-1.85(m,2H),1.57-1.53(m,2H),0.96(d,J＝4.0 Hz,6H); ESI-MS m/z 376[M+H] ⁺ ; HPLC purity: 98.56% (220nm), 98.51% (254nm).

Example 135. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valine oxetane-3-yl ester (6-135)

This compound was prepared in analogy to the method of Example 1 from oxetane-3-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.05(s,1H),8.62 (d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.25(d,J＝8.0 Hz,1H),5.46-5.43(m,1H),4.98(s,2H),4.83(t,J＝8.0Hz, 2H),4.52-4.47(m,2H),4.32(t,J＝4.0Hz,1H),2.32(s,3H), 2.20-2.15(m,1H),0.99(dd,J＝4.0Hz,8.0Hz,6H); ESI-MS m/z 348[M+H] ⁺ ; HPLC purity: 95.11% (220nm), 96.76% (254nm).

Example 136. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine cyclobutyl ester (6-136)

This compound was prepared analogously to the method of Example 1 from cyclobutanol, N-Boc-(S)-valine and acid-04. ¹ HNMR(400MHz, DMSO-d ₆ )9.05(br s,1H),8.51(d,J＝7.2Hz,1H),7.36(d,J＝7.6Hz,1H),7.24(d,J＝7.6 Hz,1H),4.97-4.92(m,3H),4.25(t,J＝7.2Hz,1H),2.48(s, 3H),2.30(d,J＝8.8Hz,2H),2.14-2.12(m,1H),2.07-2.00(m, 2H),1.76(q,J＝10.0Hz,1H),1.63-1.58(m,1H),0.95(d,J＝6.4Hz,6H); ESI-MS m/z 346[M+H] ⁺ ; HPLC purity: 99.96% (220nm), 100% (254nm).

Example 137. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valinequinazolin-2-ylmethyl ester (6-137)

A mixture of compound 94 (5.00 g, 26.9 mmol), acetamidine (3.12 g, 53.8 mmol), CuBr (385 mg, 2.69 mmol), and K ₂ CO ₃ (11.1 g, 80.6 mmol) in DMSO (50 ml) was degassed and purged with nitrogen three times, and then stirred at 100° C. under nitrogen for 14 hours and at 25° C. under air for 2 hours. The reaction was slowly quenched with water (50 ml) and then extracted with EtOAc (3×40 ml). The combined organic phases were washed with brine (2×20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1) to give compound 95 (2.5 g, 65%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) 9.33 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90-7.86 (m, 2H), 7.60 (t, J = 8.0 Hz, 1H), 2.91 (s, 3H). To a solution of compound 95 (1.40 g, 9.71 mmol) in CCl ₄ (10 ml) were added NBS (1.56 g, 8.74 mmol) and BPO (470 mg, 1.94 mmol). The mixture was stirred at 80° C. for 2 hours. The reaction was filtered and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/EtOAc = 4/1) to yield compound 96 (150 mg, 6.9%) as a yellow solid. ¹ HNMR (400MHz, CDCl ₃ ) 9.46 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.98-7.95 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 4.80 (s, 2H).

Compound 6-137 was prepared similarly to the method of Example 107, using Compound 96 instead of 2-chloroethyl methyl ether. ¹ HNMR (400MHz, DMSO-d ₆ )9.63(s,1H),8.58 (d,J＝8.0Hz,1H),8.19(d,J＝8.0Hz,1H),8.03(t,J＝4.0 Hz,1H),7.94(d,J＝8.0Hz,1H),7.77(t,J＝8.0Hz,1H), 7.39(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),5.54(d, J＝16.0Hz,1H),5.43(d,J＝16.0Hz,1H),4.97(s,2H),4.53 (t,J＝8.0Hz,1H),2.47(s,3H),2.38-2.33(m,1H),1.08(d, J = 8.0 Hz, 6H); ESI-MS m/z 434 [M+H] ⁺ ; HPLC purity: 97.45% (220 nm), 95.68% (254 nm).

Example 138. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(1H-imidazol-4-yl)methyl ester (6-138)

To a solution of compound 97 (3.00 g, 23.8 mmol) in DMF (5 ml) was added portionwise NaH (1.14 g, 28.6 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour. SEM-Cl (8.44 ml, 47.6 mmol) was then added dropwise at 0°C. The reaction mixture was stirred at 25°C for 13 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (10 ml) at 0°C and then extracted with EtOAc (3×20 ml). The combined organic phases were rinsed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/2) to produce compound 98 (2.00 g, 33% yield) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) 7.73 (s, 1H), 7.62 (s, 1H), 5.31 (s, 2H), 3.91 (s, 3H), 3.50 (t, J = 8.0 Hz, 2H), 0.92 (t, J = 8.0 Hz, 2H), -0.01 (s, 9H). To a solution of compound 98 (2.00 g, 7.80 mmol) in THF (20 mL) was added portionwise LiAlH ₄ (355 mg, 9.36 mmol) at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction was quenched with saturated aqueous potassium sodium tartrate (1 mL) at 0°C, filtered, and concentrated in vacuo to give compound 99 (1.4 g, 79% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) 7.56 (s, 1H), 6.99 (s, 1H), 5.23 (s, 2H), 4.61 (s, 2H), 3.48 (t, J = 8.0 Hz, 2H), 0.91 (t, J = 8.0 Hz, 2H), 0.01 (s, 9H).

Compound 6-138 was prepared from compound 99 and acid-04 in analogy to the procedure of Example 108. ¹ H NMR (400MHz, DMSO-d ₆ )9.15(s,1H),8.60(d,J＝8.0 Hz,1H),7.75(s,1H),7.34(d,J＝8.0Hz,1H),7.23(d,J＝ 8.0Hz, 1H), 5.28 (d, J＝12.0Hz, 1H), 5.18 (d, J＝12.0Hz, 1H), 4.96 (s, 2H), 4.33 (t, J＝8.0Hz 1H), 2.47 (s, 3H), 2.18-2.13(m,1H),0.92(dd,J＝4.0Hz,8.0Hz,6H); ESI-MS m/z 372[M+H] ⁺ ; HPLC purity: 96.31% (220nm), 99.54% (254nm).

Example 139. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 1,3-dimethoxypropan-2-yl ester (6-139)

This compound was prepared in analogy to the method of Example 1 from 1,3-dimethoxypropan-2-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03 (s, 1H), 8.51 (d, J = 8.0Hz, 1H), 7.37 (d, J = 7.6Hz, 1H), 7.24 (d,J＝7.6Hz,1H),5.12-5.09(m,1H),4.97(s,2H),4.35-4.31 (m,1H),3.51-3.46(m,4H),3.25(d,J＝10.0Hz,6H),2.47(s, 3H), 2.17-2.12 (m, 1H), 0.96 (d, J=6.4Hz, 6H); ESI-MS m/z 394[M+H] ⁺ ; HPLC purity: 99.79% (220nm), 100% (254nm).

Example 140. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (S)-tetrahydrofuran-3-yl ester (6-140)

This compound was prepared in analogy to the method of Example 1 from (S)-tetrahydrofuran-3-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(br s,1H), 8.54(d,J＝7.6Hz,1H),7.37(d,J＝7.2Hz,1H),7.25(d, J＝7.6Hz,1H),5.29(s,1H),4.98(s,2H),4.26(t,J＝6.8 Hz,1H),3.84-3.67(m,4H),2.48(s,3H),2.21-2.13(m,2H), 1.94-1.92 (m, 1H), 0.96 (d, J=6.4Hz, 6H); ESI-MS m/z 362 [M+H] ⁺ ; HPLC purity: 99.71% (220nm), 98.22% (254nm).

Example 141. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (R)-tetrahydrofuran-3-yl ester (6-141)

This compound was prepared in analogy to the method of Example 1 from (R)-tetrahydrofuran-3-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.05(br s,1H), 8.54(d,J＝7.6Hz,1H),7.37(d,J＝8.0Hz,1H),7.25(d, J＝8.0Hz,1H),5.29(t,J＝5.2Hz,1H),4.97(s,2H),4.26 (t,J＝7.2Hz,1H),3.81-3.72(m,4H),2.47(s,3H),2.19-2.11 (m, 2H), 1.91-1.88 (m, 1H), 0.96 (d, J = 6.4Hz, 6H); ESI-MS m/z 362 [M+H] ⁺ ; HPLC purity: 99.83% (220nm), 100% (254nm).

Example 142. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 1-methylpiperidin-4-yl ester (6-142)

This compound was prepared from 1-methylpiperidin-4-ol, N-Boc-(S)-valine, and acid-04 in a manner similar to Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 10.85 (s, 1H), 9.10 (s, 1H), 8.59 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.2 Hz, 1H), 7.49 (q, J=2.8 Hz, 4.8 Hz, 1H), 4.99 (s, 2H), 5.10-4.92 (m, 1H), 4.43-4.24 (m, 1H), 3.43 (d, J=12.4 Hz, 1H), 3.34 (s, 1H), 3.11-3.08 (m, 2H), 2.74-2.71 (m, 3H), 2.49 (s, 3H), 2.15-2.14 (m, 1H), 2.12-1.94 (m, 4H), 0.98 (t, J=6.0 Hz, 6H); ESI-MS m/z 389 [M+H] ⁺ ; HPLC purity: 97.80% (220 nm), 96.87% (254 nm).

Example 143. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(1H-imidazol-2-yl)methyl ester (6-143)

This compound was prepared in analogy to the method of Example 138 from 1H-imidazole-2-carboxylic acid methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.00 (br s, 1H), 8.67 (d, J＝6.8Hz, 1H), 7.73 (s, 2H), 7.36 (d, J＝7.6Hz, 1H), 7.24 (d,J＝7.2Hz,1H),5.42(s,2H),4.97(s,2H),4.41(t,J＝6.8Hz,1H),2.42(s,3H),2.23-2.18(m,1H),0.94(d,J＝6.8 Hz,6H); ESI-MS m/z 372[M+H] ⁺ ; HPLC purity: 93.06% (220nm), 90.56% (254nm).

Example 144. ((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-144)

This compound was prepared in analogy to the method of Example 1 from (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03(s,1H),8.54(d,J＝7.6Hz,1H),7.39(d,J＝8.0Hz,1H),7.25(d,J＝7.6Hz,1H),4.99(s,2H),4.34(t, J＝7.6Hz,1H),4.30-4.27(m,1H),4.26-4.20(m,1H),4.11-4.02 (m,2H),3.71(t,J＝7.2Hz,1H),2.49(s,3H),2.19-2.13(m, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 0.98 (d, J = 6.8Hz, 6H); ESI-MS m/z 406 [M+H] ⁺ ; HPLC purity: 98.83% (220 nm), 99.07% (254 nm).

Example 145. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester (6-145)

This compound was prepared in analogy to the method of Example 1 from (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.03(s,1H),8.54(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),4.98(s,2H),4.32-4.29 (m,2H),4.15-4.12(m,2H),4.10-4.02(m,1H),3.71-3.69(m, 1H),2.47(s,3H),2.18-2.13(m,1H),1.34(s,3H),1.28(s, 3H), 0.96 (d, J＝8.0Hz, 6H); ESI-MS m/z 406[M+H] ⁺ ; HPLC purity: 98.83% (220nm), 99.07% (254nm).

Example 146. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine piperidin-4-yl ester (6-146)

This compound was prepared in analogy to the method of Example 117 from tert-butyl 4-hydroxypiperidine-1-carboxylate, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 8.96 (s, 2H), 8.60 (d, J＝8.0Hz, 1H), 7.37 (d, J＝8.0Hz, 1H), 7.25 (d, J＝8.0Hz, 1H), 5.03-4.99 (m, 1H), 4.98 (s, 2H), 4.30(t,J＝8.0Hz,1H),3.20-3.17(m,2H),3.10-3.08(m,2H), 2.48(s,3H),2.17-2.15(m,1H),2.02-2.00(m,2H),1.82-1.80 (m,2H),0.96(d,J＝8.0Hz,6H); ESI-MS m/z 375[M+H] ⁺ ; HPLC purity: 98.56% (220nm), 96.69% (254nm).

Example 147. (R)-2,3-dihydroxypropyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-147)

A mixture of compound 6-144 and 37% HCl (0.5 ml) in DMF (5 ml) was stirred at 25° C. for 12 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Luna C8 100×30 mm; liquid phase: water (0.1% TFA)-ACN; B%: 10% to 35%, 12 minutes) to produce compound 6-147 (206 mg, 3%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.01 (s, 1H), 8.45 (d, J = 8.0Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 7.20 (d, J = 8.0Hz, 1H), 4.94(s,2H),4.83-4.75(m,1H),4.64(s,1H),4.34(t,J＝7.2Hz,1H),4.14-4.10(m,1H),3.95-3.92(m,1H),3.65-3.63(m, 1H),3.47-3.34(m,2H),2.44(s,3H),2.17-2.09(m,1H),0.92 (t,J＝4.4Hz,6H); ESI-MS m/z 366[M+H] ⁺ ; HPLC purity: 98.56% (220 nm), 96.69% (254 nm).

Example 148. (S)-2,3-dihydroxypropyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-148)

This compound was prepared in analogy to the method of Example 147 from compound 6-145. ¹ H NMR (400MHz, DMSO-d ₆ )9.02(s,1H),8.47(d,J＝8.0Hz,1H),7.38 (d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),4.97(s,2H), 4.39-4.36(m,1H),4.23-4.13(m,1H),4.03-3.99(m,1H), 3.69-3.65(m,2H),3.39-3.37(m,2H),2.48(s,3H),2.38-2.33 (m,1H),0.97-0.95(m,6H); ESI-MS m/z 366[M+H] ⁺ ;HPLC purity: 99.66% (220nm), 99.63% (254nm).

Example 149. 3-Hydroxy-2-(hydroxymethyl)propyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-149)

To a solution of compound 100 (1.06 g, 12.0 mmol) in DCM (20 ml) were added N-Boc-(S)-valine (2.17 g, 9.99 mmol), DCC (2.68 g, 13.0 mmol), and DMAP (122 mg, 0.999 mmol). The mixture was stirred at 25° C. for 14 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to yield compound 101 (2.1 g, 73%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 4.99-4.83 (m, 1H), 4.81-4.80 (m, 2H), 4.48-4.46 (m, 2H), 4.40-4.37 (m, 2H), 4.14-4.12 (m, 1H), 3.36-3.29 (m, 1H), 2.14-2.11 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 8.0 Hz, 3H), 0.90 (d, J = 8.0 Hz, 3H). To a solution of compound 101 (1.00 g, 3.48 mmol) in DCM (15 mL) was added TFA (5 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under vacuum to yield compound 102 (800 mg, 76%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) 4.40-4.55 (m, 1H), 4.24-4.33 (m, 1H), 3.95-4.03 (m, 1H), 3.73-3.86 (m, 1H), 2.32-2.44 (m, 1H), 1.08 (t, J=7.5 Hz, 6H). To a solution of acid-04 (200 mg, 1.04 mmol) in DMF (3 ml) was added HATU (474 mg, 1.25 mmol) and NMM (315 mg, 3.12 mmol). The mixture was stirred at 25° C. for 0.5 h. Compound 102 (344 mg, 1.14 mmol) was then added in one portion. The mixture was stirred at 25° C. for 12 hours. The mixture was purified by preparative HPLC (column: Luna C8 100×30 mm; liquid phase: water (0.1% TFA)-ACN; B%: 18% to 48%, 12 minutes) to give compound 6-149 (101 mg, 26%) as a white solid. ¹ HNMR (400MHz, DMSO-d ₆ )9.04(s,1H), 8.51(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),4.97(s,2H),4.51(t,J＝4.0Hz,2H),4.32 (t,J＝8.0Hz,1H),4.10-4.05(m,2H),3.47-3.42(m,4H),2.47 (s,3H),1.88-1.85(m,1H),2.23-2.21(m,1H),0.95(d,J＝8.0 Hz,6H); ESI-MS m/z 380[M+H] ⁺ ; HPLC purity: 99.75% (220nm), 100% (254nm).

Example 150. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valineoxetane-3-ylmethyl ester (6-150)

This compound was prepared in analogy to the method of Example 117 from oxetane-3-ylmethanol, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.05 (s, 1H), 8.55 (d, J＝8.0Hz, 1H), 7.37 (d, J＝8.0Hz, 1H), 7.25 (d,J＝8.0Hz,1H),4.98(s,2H),4.64-4.38(m,2H),4.37-4.30 (m,5H),3.30-3.27(m,1H),2.47(s,3H),2.17-2.12(m,1H), 0.96 (dd, J=4.0Hz, 8.0Hz, 6H); ESI-MSm/z 362[M+H] ⁺ ; HPLC purity: 96.41% (220nm), 97.05% (254nm).

Example 151. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2,2,2-trifluoroethyl ester (6-151)

This compound was prepared in analogy to the method of Example 117 from 2,2,2-trifluoroethan-1-ol, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.05 (s, 1H), 8.55 (d, J＝8.0Hz, 1H), 7.37 (d, J＝8.0Hz, 1H), 7.25 (d,J＝8.0Hz,1H),4.98(s,2H),4.64-4.38(m,2H),4.37-4.30 (m,5H),3.30-3.27(m,1H),2.47(s,3H),2.17-2.12(m,1H), 0.96 (dd, J=4.0Hz, 8.0Hz, 6H); ESI-MSm/z 362[M+H] ⁺ ; HPLC purity: 96.41% (220nm), 97.05% (254nm).

Example 152. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)methyl ester (6-152)

To a solution of compound 103 (5.00 g, 34.7 mmol) in THF (50 ml) was added LDA (2 M, 17.3 ml) at -78°C. The mixture was stirred at 0°C for 0.5 hours. MOMCl (4.19 g, 52.0 mmol) was then added in one portion at -78°C. The mixture was stirred at 25°C for 1 hour. The reaction was slowly quenched with water (20 ml) and then extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield compound 104 (5.6 g, crude product) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) 3.76-3.69 (m, 2H), 3.67 (s, 3H), 3.42-3.40 (m, 2H), 3.39 (s, 2H), 3.24 (s, 3H), 2.01-1.98 (m, 2H), 1.55-1.48 (m, 2H). To a solution of compound 104 (2.00 g, 10.6 mmol) in THF (20 ml) was added LiAlH ₄ (807 mg, 21.3 mmol) in one portion at 0° C. The mixture was stirred at 25° C. for 12 hours. The mixture was cooled to 0° C. and quenched with a saturated solution of potassium sodium tartrate (3 ml). The resulting precipitate was collected, filtered, and concentrated in vacuo to give crude compound 105 (1.2 g) as a colorless oil, which was used in the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ )3.67-3.64(m,6H),3.40(s,2H),3.35(s,3H),1.53-1.48(m,4H).

Compound 6-152 was prepared from compound 105, N-Fmoc-(S)-valine and acid-04 in analogy to the method of Example 117. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.04 (s, 1H), 8.54 (d, J = 8.0Hz, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.25 (d, J = 8.0Hz, 1H), 4.97 (s, 2H), 4.34 (t, J = 8.0Hz, 1H), 4.04 (q,J＝8.0Hz,2H),3.56(t,J＝8.0Hz,4H),3.30(s,2H), 3.24(s,2H),2.47(s,3H),2.16-2.13(m,1H),1.45(s,4H), 0.96(d,J＝8.0Hz,6H); ESI-MS m/z 434[M+H] ⁺ ; HPLC purity: 97.28% (220nm), 97.90% (254nm).

Example 153. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2,2,3,3,3-pentafluoropropyl ester (6-153)

This compound was prepared in analogy to the method of Example 117 from 2,2,3,3,3-pentafluoropropan-1-ol, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.05 (s, 1H), 8.68 (d, J＝7.2Hz, 1H), 7.37 (d, J＝8.0Hz, 1H), 7.25 (d, J＝8.0Hz, 1H), 4.98 (s, 2H), 4.93-4.82 (m, 2H), 4.40(t,J＝7.2Hz,1H),2.47(s,3H),2.20-2.13(m,1H),0.98 (dd,J＝6.4Hz,2.4Hz,6H); ESI-MS m/z 424[M+H] ⁺ ; HPLC purity: 99.71% (220nm), 100% (254nm).

Example 154. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(4,4-difluorocyclohexyl)methyl ester (6-154)

To a solution of compound 106 (4.00 g, 20.8 mmol) in THF (40 ml) was added portionwise LiAlH ₄ (1.18 g, 31.2 mmol) at 0° C. The mixture was stirred at 25° C. for 4 hours. The mixture was cooled to 0° C. and quenched with a saturated solution of potassium sodium tartrate (3 ml). The resulting precipitate was collected, filtered, and concentrated in vacuo to yield compound 107 (2.6 g, 83%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) 3.45 (J=4.0 Hz, 2H), 2.07-2.03 (m, 2H), 2.01-1.83 (m, 2H), 1.82-1.79 (m, 2H), 1.72-1.64 (m, 1H), 1.28-1.24 (m, 2H).

Compound 6-154 was prepared similarly to the method of Example 117 from compound 107, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.03 (s, 1H), 8.53 (d, J = 8.0Hz, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 4.97 (s, 2H), 4.31 (t, J = 8.0Hz, 1H), 3.99 (d,J＝8.0Hz,2H),2.47(s,3H),2.17-2.11(m,1H),2.07-2.01 (m,2H),1.85-1.79(m,5H),1.28-1.25(m,2H),0.98(d,J＝4.0 Hz, 3H), 0.94 (d, J = 4.0Hz, 3H); ESI-MS m/z 424 [M+H] ⁺ ; HPLC purity: 96.95% (220 nm).

Example 155. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4,4-difluorocyclohexyl ester (6-155)

This compound was prepared in analogy to the method of Example 117 from 4,4-difluorocyclohexan-1-ol, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.04 (s, 1H), 8.56 (d, J = 8.0Hz, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.25 (d, J = 8.0Hz, 1H), 4.97 (s, 3H), 4.30 (t, J = 8.0Hz, 1H), 2.47 (s, 3H), 2.16-2.13 (m, 1H), 2.07-1.99 (m, 4H), 1.85-1.76 (m, 4H), 0.96 (d, J = 8.0Hz, 6H); ESI-MSm/z 410 [M+H] ⁺ ; HPLC Purity: 99.28% (220nm), 99.20% (254nm).

Example 156. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 1,1,1,3,3,3-hexafluoropropan-2-yl ester (6-156)

This compound was prepared in analogy to the method of Example 117 from 1,1,1,3,3,3-hexafluoropropan-2-ol, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.06 (s, 1H), 8.84 (d, J＝8.0Hz, 1H), 7.36 (d, J＝8.0Hz, 1H), 7.27 (d, J＝8.0Hz, 1H), 6.93-6.86 (m, 1H), 4.98 (s, 2H), 4.42 (t, J=8.0Hz, 1H), 2.49 (s, 3H), 2.20-2.07 (m, 1H), 1.00 (q, J=8.0Hz, 6H); ESI-MS m/z 442[M+H] ⁺ ; HPLC purity: 96.04% (220nm), 93.40% (254nm).

Example 157. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(1,4-dioxepan-6-yl)methyl ester (6-157)

A mixture of ethylene glycol (6.46 g, 104 mmol) and NaH (10.4 g, 260 mmol, 60% purity) in DMF (50 ml) was stirred at 0°C for 0.5 hours. Compound 108 (13.00 g, 104 mmol) was then added to the mixture and stirred at 15°C for 2.5 hours. The reaction mixture was diluted with water (100 ml) and extracted with MTBE (2 x 50 ml). The combined organic layers were washed with brine (2 x 30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 109 (8.0 g, crude product, yellow oil), which was used in the next step without further purification.

To a solution of compound 109 (8.00 g, 70.1 mmol) in THF (50 ml) was added BH ₃ -Me ₂ S (10 M, 7.7 ml). The mixture was stirred at 0° C. for 1 hour. H ₂ O ₂ (23.8 g, 210 mmol, 30% purity) was then added dropwise to the reaction mixture. Under ice-cooling, aqueous NaOH solution (1 M, 210 ml) was added, and the mixture was stirred at 0° C. for 1 hour. The mixture was extracted with DCM/isopropanol (6/1; 2×50 ml). The organic layer was washed with saturated brine (50 ml) and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to yield compound 110 (1.20 g, crude product) as a pale yellow oil.

Compound 6-157 was prepared from compound 110, N-Fmoc-(S)-valine and acid-04 in analogy to the method of Example 117. ¹ H NMR (400MHz, DMSO-d ₆ )8.53(d,J＝7.6Hz,1H),7.37(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H), 4.97(s,2H),4.30(t,J＝7.2Hz,1H),4.05-4.03(m,2H),3.82 (dd,J＝12.4,5.2Hz,2H),3.64-3.61(m,6H),2.47(s,3H), 2.31-2.28(m,1H),2.18-2.11(m,1H),0.95(dd,J＝6.8,2.4 Hz,6H); ESI-MS m/z 406[M+H] ⁺ ; HPLC purity: 99.36% (220nm), 99.47% (254nm).

Example 158. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (3-(methoxymethyl)oxetane-3-yl)methyl ester (6-158)

A mixture of compound 111 (100 g, 734 mmol), diethyl carbonate (104 g, 881 mmol), and KOH (412 mg, 7.34 mmol) in EtOH (25 ml) was degassed and purged with nitrogen three times, then stirred at 140° C. under nitrogen for 12 hours. After removing EtOH and diethyl carbonate by distillation, the mixture was purified by distillation under reduced pressure (0.019 mbar) to yield compound 112 (20.0 g, 23%) as a white gum. ^1H NMR (400 MHz, DMSO-d ₆ ) 4.76 (br s, 1H), 4.27 (s, 4H), 3.54 (s, 4H). To a solution of compound 112 (5.00 g, 42.3 mmol) and NaOH (1.69 g, 42.3 mmol) in DMF (20 ml) was added dropwise MeI (5.41 g, 38.1 mmol) at 0°C. The mixture was stirred at 15°C for 12 hours. DMF was evaporated under reduced pressure, and the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with brine (2 x 20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 113 (1.00 g, crude product, brown oil), which was used in the next step without further purification.

Compound 6-158 was prepared similarly to the method of Example 117 from compound 113, N-Fmoc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.04(s,1H), 8.56(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.25(d, J＝7.6Hz,1H),4.97(s,2H),4.39-4.33(m,5H),4.28(s,2H), 3.56(s,2H),3.30(s,3H),2.47(s,3H),2.20-2.12(m,1H), 0.96 (d, J=6.4Hz, 6H); ESI-MS m/z 406[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 159. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (2-(trifluoromethyl)pyrimidin-5-yl)methyl ester (6-159)

To a solution of compound 114 (500 mg, 2.84 mmol) in THF (10 ml) was added BH ₃ -Me ₂ S (10 M, 2.84 ml) at 0° C. The mixture was stirred at 0° C. for 5 hours. The reaction mixture was quenched at 0° C. by the addition of MeOH (5 ml) and then concentrated under reduced pressure to yield a residue. The crude product 115 (500 mg, white solid) was further purified and used in the next step.

Compound 6-159 was prepared from compound 115, N-Boc-(S)-valine and acid-04 in analogy to the method of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.14 (s, 2H), 9.05 (br s, 1H), 8.66 (d, J = 7.6Hz, 1H), 7.36 (d, J = 7.2Hz, 1H), 7.25(d,J＝7.6Hz,1H),5.42-5.36(m,2H),4.98(s,2H),4.39 (t,J＝7.0Hz,1H),2.41(s,3H),2.22-2.17(m,1H),0.98(d,J＝6.4Hz,6H); ESI-MS m/z 452[M+H] ⁺ ; HPLC purity: 98.44% (220 nm), 97.67% (254nm).

Example 160. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (2-(trifluoromethyl)pyrimidin-4-yl)methyl ester (6-160)

To a solution of compound 116 (2.00 g, 11.0 mmol) in EtOH (50 ml) was added TEA (4.56 ml, 32.9 mmol) and Pd(dppf) _Cl₂ (802 mg, 1.10 mmol). The suspension was degassed under vacuum and purged with CO₂ several times. The mixture was stirred at 60° C. under a CO₂ atmosphere (50 psi) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 30/1) to yield compound 117 (600 mg, 25%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) 9.16 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 4.0 Hz, 1H), 4.54 (q, J = 8.0 Hz, 2H), 1.47 (t, J = 8.0 Hz, 3H). To a solution of compound 117 (700 mg, 3.18 mmol) in THF (5 mL) and EtOH (0.5 mL) at 0°C was added NaBH ₄ (241 mg, 6.36 mmol). The mixture was stirred at 0°C for 2 hours. The reaction was slowly quenched with water (2 mL) at 0°C and then extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield compound 118 (500 mg, 88% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) 8.90 (d, J=4.0Hz, 1H), 7.63 (d, J=4.0Hz, 1H), 4.90 (s, 2H).

Compound 6-160 was prepared similarly to the method of Example 1 from compound 117, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )9.10(d,J＝8.0 Hz,1H),9.04(s,1H),8.69(d,J＝8.0Hz,1H),7.93(d,J＝ 8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H), 5.40(s,2H),4.97(s,2H),4.44(t,J＝8.0Hz,1H),2.45(s, 3H),2.26-2.07(m,1H),1.01(dd,J＝8.0Hz,4.0Hz,6H); ESI-MS m/z 452[M+H] ⁺ ; HPLC purity: 99.93% (220 nm), 99.54% (254 nm).

Example 161. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(trifluoromethyl)pyrimidin-4-yl)methyl ester (6-161)

This compound was prepared in analogy to Example 160 using 4-chloro-6-(trifluoromethyl)pyrimidine instead of Compound 116. ¹ H NMR (400MHz, DMSO-d ₆ )9.43(s,1H), 9.04(s,1H),8.72(d,J＝7.2Hz,1H),8.12(s,1H),7.39(d, J＝8.0Hz,1H),7.24(d,J＝7.6Hz,1H),5.47-5.37(m,2H), 4.97(s,2H),4.43(t,J＝7.2Hz,1H),2.44(s,3H),2.23-2.19 (m, 1H), 1.01 (dd, J=6.8, 3.2Hz, 6H); ESI-MS m/z 452[M+H] ⁺ ; HPLC purity: 99.09% (220nm), 97.38% (254nm).

Example 162. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 1,4-dioxepan-6-yl ester (6-162)

ESI-MS m/z 392 [M+H] ⁺ ; HPLC purity: 99.78% (220 nm), 100% (254 nm).

Example 163. 4-(2-(pyrrolidin-1-yl)ethoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-163)

To a solution of compound 122 (J. Med. Chem. 1984, 27, 1057; 500 mg, 2.01 mmol) in THF (5.00 ml) was added LiAlH ₄ (153 mg, 4.02 mmol) at 0° C. The mixture was stirred at 60° C. for 2 hours. Saturated potassium sodium tartrate solution (2 ml) was then added to the mixture at 0° C., filtered, and concentrated under reduced pressure to yield compound 123 (390 mg, 1.76 mmol, 88%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) 7.32-7.18(m,2H),6.88(d,J＝8.4Hz,2H),4.60(s,2H),4.08 (t,J＝6.2Hz,2H),2.88(t,J＝6.0Hz,2H),2.61(s,4H), 1.80(dt,J=6.8,3.2Hz,4H).

Compound 6-163 was prepared from compound 123, N-Boc-(S)-valine and acid-04 in a manner similar to Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.03 (s, 1H), 8.52 (d, J=7.9 Hz, 1H), 7.37-7.28 (m, 3H), 7.22 (d, J=7.5 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 5.17-5.01 (m, 2H), 4.96 (s, 2H), 4.31 (t, J=7.3 Hz, 1H), 4.05 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.43 (s, 3H), 2.18-2.05 (m, 1H), 1.67 (dt, J=7. =6.5, 3.1 Hz, 4H), 0.92 (d, J =6.4 Hz, 3H), 0.90 (d, J =6.4 Hz, 3H); ESI-MS m/z 495 [M+H] ⁺ ; HPLC purity: 95.47% (220 nm), 90.82% (254 nm).

Example 164. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine (6-164)

A solution of compound 6-002 (40 mg, 0.11 mmol) obtained in Example 2 in TFA (2 ml) and dichloromethane (2 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give compound 6-164 (27 mg, 100%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.53 (b,1H),9.32(s,1H),8.63(s,1H),8.22(s,1H),7.94(d,J =8.0Hz, 1H), 7.47 (d, J = 7.6Hz, 1H), 5.01 (s, 2H), 4.37 (q, J = 6.8Hz, 2H), 1.36 (d, J = 6.8Hz, 3H); ESI-MS: m/z 248 [MH] ^- ; HPLC purity: 100% (220nm), 100% (254nm).

Example 165. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-165)

To a mixture of acid-04 (150 mg, 0.77 mmol), the compound of Example B-1 (203 mg, 0.77 mmol), and DIEA (0.4 ml, 2.33 mmol) in DMF was added HATU (325 mg, 0.86 mmol). The mixture was stirred at room temperature for 3 hours. The crude product was purified by preparative HPLC and preparative TLC to produce compound 6-165 (125 mg, 40% yield). ¹ H NMR (400MHz, DMSO-d ₆ )9.03(s,1H),8.57(d,J＝7.2 Hz,1H),7.47-7.43(m,2H),7.33(d,J＝7.6Hz,1H),7.23-7.18 (m,3H),5.21(d,J＝12.4Hz,1H),5.11(d,J＝12.4Hz,1H),4.96(s,2H),4.33(t,J＝7.2Hz,1H),2.42(s,3H),2.14-2.13 (m,1H),0.94(d,J＝6.8Hz,3H),0.92(d,J＝6.8Hz,3H); ESI-MS m/z 400[M+H] ⁺ ; HPLC purity: 100% (220nm), 100% (254nm).

Example 166. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3,4-difluorobenzyl ester (6-166)

To a solution of N-Boc-(S)-valine (2.6 g, 12.15 mmol, 1.00 equiv) and (3,4-difluorophenyl)methanol (2.8 g, 19.44 mmol) in dry DCM (65 ml) was added DCC (4.45 g, 21.56 mmol) and DMAP (0.219 g, 1.797 mmol). The reaction mixture was stirred at 25° C. for 18 hours. The mixture was filtered, rinsed with DCM (100 ml), and concentrated to yield the crude product. The residue was purified by column chromatography (SiO ₂ ; petroleum ether/ethyl acetate = 50/1 to 10/1) to yield (tert-butoxycarbonyl)-L-valine 3,4-difluorobenzyl ester (3.7 g, 88% yield) as a yellow gummy solid. The reaction was repeated on the same scale to provide additional amounts for the next step.

To a stirred solution of (tert-butyloxycarbonyl)-L-valine 3,4-difluorobenzyl ester (5 g, 14.57 mmol) in dioxane (25 mL) was added HCl-dioxane (3N, 25 mL). The reaction mixture was stirred at room temperature for 18 hours. After workup, the crude compound was triturated with diethyl ether to yield L-valine 3,4-difluorobenzyl ester hydrochloride (2.65 g, 63% yield) as a white solid.

To a solution of acid-04 (0.7 g, 3.64 mmol) in DMF (20 ml) were added L-valine 3,4-difluorobenzyl ester hydrochloride (1.06 g, 4.37 mmol), EDCI (1.04 g, 5.47 mmol), HOBt (738 mg, 5.47 mmol), and DIPEA (2.01 ml, 10.93 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by flash chromatography (reverse phase) to yield compound 6-166 (350 mg, 23% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.02 (s, 1H), 8.58 (d, J=7.94 Hz, 1H), 7.54-7.39 (m, 2H), 7.35-7.17 (m, 3H), 5.15 (s, 2H), 4.95 (s, 2H), 4.33 (t, J=7.1 Hz, 1H), 2.41 (s, 3H), 2.20-2.08 (m, 1H), 0.94 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H); ESI-MS m/z 418 [M+H] ⁺ ; HPLC purity: 98.35% (220 nm), 98.15% (254 nm).

Example 167. 4-Chloro-3-(2-N-morpholinoethoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-167)

This compound was prepared in analogy to Example 163. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.43 (s, 1H), 9.04 (s, 1H), 8.72 (d, J = 7.2Hz, 1H), 8.12 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.24 (d, J = 7.6Hz, 1H),5.47-5.37(m,2H),4.97(s,2H),4.43(t,J＝7.2Hz,1H), 2.44(s,3H),2.23-2.19(m,1H),1.00(d,J＝6.8Hz,3H),0.99 (d,J＝6.8Hz,3H); ESI-MS m/z 545[M+H] ⁺ ; HPLC purity: 96.16% (220nm),95.23%(254nm).

Example 168. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(trifluoromethyl)pyridin-3-yl)methyl ester (6-168)

This compound was prepared in analogy to the method of Example 1 from (6-(trifluoromethyl)pyridin-3-yl)methanol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.01 (s, 1H), 8.82 (s, 1H), 8.61 (d, J = 7.5Hz, 1H), 8.13 (d, J = 7.9Hz, 1H), 7.95 (d, J = 7.9Hz, 1H), 7.45-7.15 (m, 2H), 5.35(s,2H),4.97(s,2H),4.38(t,J＝7.3Hz,1H),2.42(s,3H),2.27-2.10(m,1H),0.96(d,J＝6.6Hz,6H); ESI-MS m/z 451[M+H] ⁺ ; HPLC purity: 95.79% (220nm), 92.56% (254nm).

Example 169. (S)-4-Fluorobenzyl 3-Hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-169)

To a solution of (3,4-difluorophenyl)methanol (2.43 g, 19.31 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid (3 g, 12.87 mmol, 1.00 equiv) in dry DCM (35 ml) was added DCC (4.77 g, 23.16 mmol) and DMAP (0.471 g, 3.85 mmol). The reaction mixture was stirred at 25° C. for 16 hours. The mixture was filtered, rinsed with DCM (100 ml), and concentrated to yield the crude product. The residue was purified by flash chromatography (reverse phase) to yield 4-fluorobenzyl (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoate (2.8 g, 64% yield) as a yellow syrup.

To a stirred solution of (S)-4-fluorobenzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoate (2.8 g, 5.27 mmol) in DCM (5 ml) was added TFA (2 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The solvent and TFA were then removed by rotary evaporation, and the residue was dissolved in DCM and then adjusted to pH 7, dried over sodium sulfate, and concentrated to give crude (S)-4-fluorobenzyl 2-amino-3-hydroxy-3-methylbutanoate (2.77 g) as a yellow syrup, which was used in the next step without further purification.

To a solution of acid-04 (67.7 mg, 0.352 mmol) in DMF (2 ml) at room temperature were added (S)-4-fluorobenzyl 2-amino-3-hydroxy-3-methylbutanoate (85 mg, 0.352 mmol), EDCI (101 g, 0.529 mmol), HOBt (71.4 mg, 0.529 mmol), and DIPEA (0.25 ml, 1.41 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by flash chromatography (reverse phase) to yield compound 6-169 (52 mg, 35% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) 9.06 (s, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.53-7.44 (m, 2H), 7.37 (d, J = 7.8Hz, 1H), 7.29-7.18 (m, 3H), 5.17 (d, J = 3.8Hz, 2H), 4.98 (s, 2H), 4.82 (s, 1H), 4.47 (d, J = 8.0Hz, 1H), 2.46-2.44 (m, 3H), 1.24 (s, 6H); ESI-MS m/z 416[M+H] ⁺ ; HPLC purity: 96.10% (220nm), 93.44% (254nm).

Example 170. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2-N-morpholinoethyl ester (6-170)

This compound was prepared in analogy to the method of Example 1 from 2-N-morpholinoethan-1-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) 8.63 (d, J = 8.0Hz, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.23 (d, J = 8.0Hz, 1H), 4.96 (s, 2H), 4.57-4.54 (m, 1H), 4.47-4.44 (m, 1H), 4.40-4.36(m,1H),3.89(s,2H),3.80(s,2H),3.43(s,4H), 3.15(s,2H),2.43(s,3H),2.21-2.16(m,1H),0.95(d,J＝6.4 Hz,6H); ESI-MS m/z 405[M+H] ⁺ ; HPLC purity: 99.93% (220nm), 100% (254nm).

Example 171. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (5-(trifluoromethyl)pyridin-2-yl)methyl ester (6-171)

This compound was prepared in analogy to the last step of Example 1 from L-valine (5-(trifluoromethyl)pyridin-2-yl)methyl ester and acid-01. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.96 (s, 1H), 8.64 (d, J = 7.7Hz, 1H), 8.27 (dd, J = 8.20, 2.0Hz, 1H), 7.73 (d, J = 8.0Hz, 1H), 7.37 (d, J = 7.7Hz,1H),7.24(d,J＝8.0Hz,1H),5.35(s,2H),4.97(s,2H),4.43(t,J＝7.3Hz,1H),2.44(s,3H),2.28-2.13(m,1H), 0.99 (d, J=6.6Hz, 6H); LC-MS: m/z 451.37[M+H] ⁺ . HPLC purity: 97.38% (220 nm); chiral HPLC purity: 94.17% (210 nm).

Example 172. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (tetrahydro-2H-pyran-4-yl)methyl ester (6-172)

A mixture of (tert-butoxycarbonyl)-L-valine (3.64 g, 16.75 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (3.00 g, 16.75 mmol), and _NaHCO₃ (2.81 g, 33.50 mmol) in DMF (30 ml) was stirred at 70° C. under nitrogen for 12 hours. The reaction mixture was diluted with water (100 ml) and extracted with MTBE (2×50 ml). The combined organic layers were washed with brine (2×20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (tert-butoxycarbonyl)-L-valine (tetrahydro-2H-pyran-4-yl)methyl ester (5 g, 94.63% yield, light yellow oil), which was used in the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ5.01(d,J＝8.4Hz,1H),4.22(dd,J＝8.8Hz,4.8Hz,1H),4.00-3.97(m,4H),3.40(t,J＝11.2Hz,2H), 2.16-2.11(m,1H),1.96-1.90(m,1H),1.63(d,J＝13.2Hz,2H), 1.45(s,9H),0.97(d,J＝6.4Hz,3H),0.90(d,J＝7.2Hz,3H).

To a solution of (tert-butoxycarbonyl)-L-valine (tetrahydro-2H-pyran-4-yl)methyl ester (5.00 g, 15.85 mmol) in EtOAc (50 ml) was added HCl/EtOAc (6 M, 26.42 ml). After stirring at 15° C. for 2 hours, the mixture was concentrated under reduced pressure to produce L-valine (tetrahydro-2H-pyran-4-yl)methyl ester hydrochloride (3.80 g, 95.23% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.53 (br.s., 2H), 4.04 (d, J＝6.0Hz, 2H), 3.88-3.84 (m, 3H), 3.29 (t, J＝11.2Hz, 2H), 2.21-2.17(m,1H),1.91-1.86(m,1H),1.59(d,J＝13.65Hz, 2H),1.29-1.34(m,2H),0.97(dd,J＝16.4,7.2Hz,6H).

A mixture of acid-04 (2.00 g, 10.42 mmol), TEA (3.16 g, 31.26 mmol) and HATU (4.75 g, 12.50 mmol) in DMF (10 ml) was degassed and purged with nitrogen three times and stirred at 15° C. for 10 minutes. L-valine (tetrahydro-2H-pyran-4-yl)methyl ester hydrochloride (2.75 g, 10.94 mmol) was then added to the reaction mixture and stirred at 15° C. under nitrogen for 20 minutes. After filtration, the mixture was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250×80 10u; liquid phase: [A-TFA/H ₂ O=0.075% v/v; B-ACN] B%: 10% to 40%, 20 min]) to give compound 6-172 (1.300 g, 24.98% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ )9.04(br s,1H),8.54(d,J＝7.6Hz,1H),7.37 (d,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),4.97(s,2H), 4.31(t,J＝7.0Hz,1H),3.96(d,J＝6.0Hz,2H),3.85(d,J＝9.2Hz,2H),3.29(t,J＝11.6Hz,2H),2.47(s,3H),2.14 (dd,J＝13.2,6.4Hz,1H),1.87(brs,1H),1.59(d,J＝12.0 Hz, 2H), 1.31-1.23 (m, 2H), 0.96 (d, J=4.4 Hz, 6H); ESI-MS m/z 390 [M+H] ⁺ ; HPLC purity: 98.49% (220 nm), 89.53% (254 nm).

Example 173. 2-(Pyridin-2-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-173)

This compound was prepared in analogy to the method of Example 1 from 2-(pyridin-2-yl)ethan-1-ol, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ )8.79 (d, J＝5.6Hz, 1H), 8.52-8.47 (m, 2H), 8.05 (d, J＝8.0Hz, 1H), 7.91(t,J＝6.4Hz,1H),7.30-7.28(m,1H),7.24-7.22(m,1H), 4.97(s,2H),4.61-4.51(m,2H),4.24(t,J＝7.2Hz,1H),3.46 (t, J＝6.0Hz, 2H), 2.41 (s, 3H), 2.08-1.99 (m, 1H), 0.83 (t, J＝6.4Hz, 6H); ESI-MS m/z 397[M+H] ⁺ ; HPLC purity: 96.77% (220 nm), 98.73% (254 nm).

Example 174. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alanine benzyl ester (6-174)

This compound was prepared from L-alanine benzyl ester and acid-01 in a manner analogous to Example 1. ESI-MS m/z 340 [M+H] ⁺ ; HPLC purity: 94.51% (220 nm), 97.57% (254 nm).

Example 175. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-D-alanine benzyl ester (6-175)

This compound was prepared from D-alanine benzyl ester and acid-01 in a manner analogous to Example 1. ESI-MS m/z 340 [M+H] ⁺ ; HPLC purity: 91.01% (220 nm), 100% (254 nm).

Example 176. Methyl (S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-(pyridin-4-yl)propanoate (6-176)

This compound was prepared from (S)-methyl 2-amino-3-(pyridin-4-yl)propanoate and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 341 [M+H] ⁺ .

Example 177. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-aspartic acid dimethyl ester (6-177)

This compound was prepared from dimethyl L-aspartate and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 322 [M+H] ⁺ .

Example 178. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-leucine methyl ester (6-178)

This compound was prepared from L-leucine methyl ester and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 306 [M+H] ⁺ .

Example 179. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine methyl ester (6-179)

This compound was prepared from L-valine methyl ester and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 292 [M+H] ⁺ .

Example 180. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-alloisoleucine methyl ester (6-180)

This compound was prepared from L-alloisoleucine methyl ester and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 306 [M+H] ⁺ .

Example 181. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-phenylalanine methyl ester (6-181)

This compound was prepared from L-phenylalanine methyl ester and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 340 [M+H] ⁺ .

Example 182. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-tyrosine methyl ester (6-182)

This compound was prepared from L-tyrosine methyl ester and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 356 [M+H] ⁺ .

Example 183. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-tryptophan methyl ester (6-183)

This compound was prepared from L-tryptophan methyl ester and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 379 [M+H] ⁺ .

Example 184. Methyl (S)-3-cyclopropyl-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)propanoate (6-184)

This compound was prepared from (S)-methyl 2-amino-3-cyclopropylpropanoate and acid-01 in analogy to the last step of Example 1. ESI-MS m/z 304 [M+H] ⁺ .

Example 185. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3,4-difluorobenzyl ester (6-185)

This compound was prepared analogously to the last step of Example 1 from L-valine 3,4-difluorobenzyl ester and acid-01. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 8.69 (d, J = 7.7Hz, 1H), 8.24 (s, 1H), 7.95 (dd, J = 7.9, 1.7Hz, 1H),7.53-7.37(m,3H),7.30-7.20(m,1H),5.15(s,2H),5.05(s,2H),4.34(t,J＝7.5Hz,1H),2.22(qd,J＝13.8Hz,1H), 0.98(d,J＝6.6Hz,3H),0.96(d,J＝6.6Hz,3H); LC-MS: m/z 404.40[M+H] ⁺ HPLC purity: 98.78% (220 nm), 97.43% (254 nm); chiral HPLC purity: 96.73% (232 nm).

Example 186. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine pyrazin-2-ylmethyl ester (6-186)

This compound was prepared analogously to the last step of Example 1 from L-valine pyrazin-2-ylmethyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.77 (d, J = 1.5Hz, 1H), 8.69-8.52 (m, 3H), 7.36 (d, J = 7.3Hz, 1H),7.24(d,J＝7.8Hz,1H),5.41-5.24(m,2H),4.97(s,2H), 4.47-4.30(m,1H),2.43(s,3H),2.19(qd,J＝13.3,6.8Hz, 1H), 0.97 (dd, J=6.8, 2.4Hz, 6H); LC-MS: m/z384.05[M+H] ⁺ . HPLC purity: 95.93% (220 nm), 95.25% (254 nm); chiral HPLC purity: 97.38% (220 nm).

Example 187. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine pyridin-3-ylmethyl ester (6-187)

This compound was prepared analogously to the last step of Example 1 from L-valine pyridin-3-ylmethyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.70-8.46 (m, 3H), 7.82 (br d, J＝7.8Hz, 1H), 7.42 (dd, J＝ 7.8,4.9Hz,1H),7.33(d,J＝7.8Hz,1H),7.23(d,J＝7.3Hz,1H),5.31-5.16(m,2H),4.97(s,2H),4.35(br t,J＝7.3 Hz, 1H), 2.42 (s, 3H), 2.21-2.09 (m, 1H), 0.93 (dd, J=2.0, 6.8Hz, 6H); LC-MS: m/z 383.35[M+H] ⁺ . HPLC purity: 98.95% (220 nm), 98.46% (254 nm); chiral HPLC purity: 95.05% (215 nm).

Example 188. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine tert-butyl ester (6-188)

This compound was prepared from (S)-valine tert-butyl ester and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.39 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 4.97 (s, 2H), 4.18 (dd, J=7.8, 6.8 Hz, 1H), 2.49-2.42 (m, 3H), 2.11 (qd, J=13.7, 6.8 Hz, 1H), 1.44 (s, 9H), 0.95 (d, J=5.9 Hz, 6H); LC-MS: m/z 348.19 [M+H] ⁺ . HPLC purity: 98.79% (220 nm); chiral HPLC purity: 96.91% (211 nm).

Example 189. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-cyanopyridin-2-yl)methyl ester (6-189)

This compound was prepared in analogy to the last step of Example 1 from L-valine (6-cyanopyridin-2-yl)methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.69-8.54 (m, 1H), 8.17-8.08 (m, 1H), 8.01 (d, J = 7.3Hz, 1H),7.83(d,J＝7.8Hz,1H),7.37(d,J＝7.8Hz,1H),7.24 (d,J＝7.8Hz,1H),5.39-5.20(m,2H),4.97(s,2H),4.41(t, J＝7.1Hz,1H),2.44(s,3H),2.28-2.14(m,1H),1.00(d,J＝6.8Hz,3H),0.98(d,J＝6.8Hz,3H); LC-MS: m/z 408.46 [M+H] ⁺ HPLC purity: 98.89% (220 nm), 97.41% (254 nm); chiral HPLC purity: 99.44% (210 nm).

Example 190. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine pyridin-4-ylmethyl ester (6-190)

This compound was prepared analogously to the last step of Example 1 from L-valine pyridin-4-ylmethyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (br s, 1H), 8.65 (br d, J = 7.7Hz, 1H), 8.57 (d, J = 5.9Hz, 2H), 7.46-7.33 (m,3H),7.24(d,J＝7.7Hz,1H),5.24(s,2H),4.97(s,2H), 4.40(t,J＝7.2Hz,1H),2.44(s,3H),2.20(br dd,J＝13.4, 6.8Hz, 1H), 0.99 (d, J = 6.6Hz, 3H), 0.96 (d, J = 6.6Hz, 3H); LC-MS: m/z 383.32 [M+H] ⁺ . HPLC purity: 97.2% (220 nm); chiral HPLC purity: 95.08% (212 nm).

Example 191. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine pyridin-2-ylmethyl ester (6-191)

This compound was prepared analogously to the last step of Example 1 from L-valine pyridin-2-ylmethyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.56 (br d, J = 3.9 Hz, 1H), 7.83 (dt, J ＝7.6,1.5Hz,1H),7.48(d,J＝7.8Hz,1H),7.41-7.31(m,2H), 7.24(d,J＝7.8Hz,1H),5.33-5.13(m,2H),4.97(s,2H),4.41 (t, J＝7.3Hz, 1H), 2.44 (s, 3H), 2.20 (qd, J＝13.5, 6.8Hz, 1H), 0.97 (dd, J＝6.8, 1.5Hz, 6H); LC-MS: m/z 383.45 [M+H] ⁺ HPLC purity: 99.25% (220 nm), 98.10% (254 nm); chiral HPLC purity: 98.92% (210 nm).

Example 192. (7-Ethoxy-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-192)

This compound was prepared from L-valine benzyl ester and acid-13 in analogy to the last step of Example 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.53-7.27 (m, 5H), 7.16 (d, J = 7.7 Hz, 1H), 5.30-5.10 (m, 2H), 5.01 (s, 2H), 4.62-4.30 (m, 3H), 2.31-2.03 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 6H); LC-MS: m/z 412.01 [M+H] ⁺ . HPLC purity: 99.77% (220 nm), 99.36% (254 nm); chiral HPLC purity: 99.73% (210 nm).

Example 193. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(6-N-morpholinylpyrazin-2-yl)methyl ester (6-193)

This compound was prepared analogously to the last step of Example 1 from L-valine (6-N-morpholinylpyrazin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 8.63 (br d, J = 8.1Hz, 1H), 8.28 (s, 1H), 7.96 (s, 1H),7.35(d,J＝7.7Hz,1H),7.24(d,J＝7.7Hz,1H),5.19-5.03 (m,2H),4.97(s,2H),4.39(br t,J＝7.2Hz,1H),3.81-3.63 (m,4H),3.59-3.47(m,4H),2.44(s,3H),2.18(br dd,J＝13.4, 6.4Hz,1H),0.97(br d,J＝6.6Hz,6H); LC-MS: m/z 468.99 [M+H] ⁺ HPLC purity: 97.87% (220 nm), 97.59% (254 nm); chiral HPLC purity: 98.56% (252 nm).

Example 194. (1-Hydroxy-7-methoxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine benzyl ester (6-194)

This compound was prepared analogously to the last step of Example 1 from L-valine benzyl ester and acid-12. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.39 (s, 1H), 8.62 (d, J = 8.1Hz, 1H), 7.87 (d, J = 7.7Hz, 1H), 7.57-7.30 (m, 5H), 7.16 (d,J＝7.7Hz,1H),5.29-5.09(m,2H),5.02(s,2H),4.49(dd, J＝8.1,5.5Hz,1H),4.07(s,3H),2.20(dt,J＝13.0,6.6Hz, 1H), 0.93 (dd, J=4.0, 6.6Hz, 6H); LC-MS: m/z 398.40[M+H] ⁺ . HPLC purity: 99.03% (220 nm); chiral HPLC purity: 99.71% (215 nm).

Example 195. (1-Hydroxy-7-methoxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-195)

This compound was prepared analogously to the last step of Example 1 from L-valine 4-fluorobenzyl ester and acid-12. ¹ HNMR (300MHz, DMSO-d ₆ ) δ9.39 (s, 1H), 8.62 (d, J = 8.1Hz, 1H), 7.87 (d, J = 8.1Hz, 1H), 7.46 (dd, J = 8.6, 5.7Hz,2H),7.30-7.02(m,3H),5.27-5.09(m,2H),5.02(s,2H), 4.48(dd,J＝7.7,5.5Hz,1H),4.07(s,3H),2.30-2.07(m,1H), 0.93 (d, J=6.6Hz, 3H), 0.91 (d, J=6.6Hz, 3H); 0.92 (dd, J=4.0, 6.6Hz, 6H). LC-MS: m/z 416.38 [M+H] ⁺ HPLC purity: 99.3% (220 nm); chiral HPLC purity: 98.89% (217 nm).

Example 196. (7-Ethoxy-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester (6-196)

This compound was prepared from L-valine 4-fluorobenzyl ester and acid-13 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.54-7.41 (m, 2H), 7.30-7.07 (m, 3H), 5.27-5.12 (m, 2H), 5.01 (s, 2H), 4.61-4.33 (m, 3H), 2.23-2.08 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 5.9 Hz, 6H); LC-MS: m/z 430.38 [M+H] ⁺ . HPLC purity: 99.23% (220 nm); chiral HPLC purity: 97.74% (218 nm).

Example 197. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(6-N-morpholinylpyridin-2-yl)methyl ester (6-197)

This compound was prepared analogously to the last step of Example 1 from L-valine (6-N-morpholinylpyridin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 8.59 (br d, J = 7.7Hz, 1H), 7.61-7.51 (m, 1H), 7.36 (d, J = 7.7Hz, 1H), 7.24 (d, J = 7.7Hz, 1H), 6.83-6.69 (m, 2H),5.11-5.02(m,2H),4.97(s,2H),4.40(t,J＝7.3Hz,1H), 3.72-3.62(m,4H),3.49-3.38(m,4H),2.45(s,3H),2.24-2.13 (m,1H),0.97(d,J＝6.6Hz,6H); LC-MS: m/z 468.43 [M+H] ⁺ HPLC purity: 97.75% (220 nm), 99.50% (254 nm); chiral HPLC purity: 98.07% (248 nm).

Example 198. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (R)-1-phenylethyl ester (6-198)

This compound was prepared analogously to the last step of Example 1 from (R)-1-phenylethyl L-valine and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.58 (d, J = 8.1Hz, 1H), 7.48-7.28 (m, 6H), 7.28-7.19 (m, 1H), 5.89 (q,J＝6.6Hz,1H),4.97(s,2H),4.33(t,J＝7.5Hz,1H), 2.46(s,3H),2.16(qd,J＝13.6,6.7Hz,1H),1.49(d,J＝6.6 Hz, 3H), 0.96 (d, J = 6.8 Hz, 1H), 0.94 (d, J = 6.8 Hz, 3H); LC-MS: m/z 396.45 [M+H] ⁺ . HPLC purity: 98.07% (220 nm), 96.63% (254 nm); chiral HPLC purity: 97.84% (214 nm).

Example 199. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (S)-1-phenylethyl ester (6-199)

This compound was prepared analogously to the last step of Example 1 from (S)-1-phenylethyl L-valine and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.51 (d, J = 8.1Hz, 1H), 7.52-7.30 (m, 6H), 7.28-7.17 (m, 1H), 5.87 (q,J＝6.6Hz,1H),4.97(s,2H),4.36(dd,J＝7.9,6.4Hz, 1H),2.44(s,3H),2.17(qd,J＝6.7,13.4Hz,1H),1.51(d, J=6.6Hz, 3H), 0.89 (dd, J=13.8, 6.8Hz, 6H); LC-MS: m/z 396[M+H] ⁺ . HPLC purity: 99.08% (220 nm); chiral HPLC purity: 98.31% (210 nm).

Example 200. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(5-cyanopyridin-2-yl)methyl ester (6-200)

This compound was prepared in analogy to the last step of Example 1 from L-valine (5-cyanopyridin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.08-8.94 (m, 2H), 8.66 (d, J = 7.3Hz, 1H), 8.38 (dd, J = 2.2, 8.4Hz, 1H), 7.70 (d, J = 8.1Hz, 1H), 7.37 (d, J = 7.7Hz, 1H), 7.25 (d,J＝7.7Hz,1H),5.50-5.21(m,2H),4.97(s,2H),4.42(t, J＝7.2Hz,1H),2.47(d,J＝13.2Hz,3H),2.21(qd,J＝13.7, 7.0Hz, 1H), 0.99 (dd, J＝6.8, 1.3Hz, 6H); LC-MS: m/z 408.36 [M+H] ⁺ HPLC purity: 97.57% (220 nm); chiral HPLC purity: 98.17% (215 nm).

Example 201. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl ester (6-201)

This compound was prepared in analogy to the last step of Example 1 from L-valine (6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.05 (br s, 1H), 8.61 (br d, J = 7.7Hz, 1H), 7.75-7.57 (m, 1H),7.36(d,J＝7.7Hz,1H),7.29-7.19(m,1H),6.98-6.74(m,2H),5.09(s,2H),4.98(s,2H),4.56-4.29(m,3H),3.50(br d,J＝8.8Hz,2H),3.08(br d,J＝10.6Hz,4H),2.90-2.69(m, 3H), 2.45 (s, 3H), 2.27-2.10 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H); LC-MS: m/z 481.46 [M+H] ⁺ . HPLC purity: 98.11% (220 nm), 98.54% (254 nm); chiral HPLC purity: 98.33% (245 nm).

Example 202. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(5-fluoropyrimidin-2-yl)methyl ester (6-202)

This compound was prepared in analogy to the last step of Example 1 from L-valine (5-fluoropyrimidin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 8.92 (d, J = 0.7Hz, 2H), 8.58 (d, J = 8.1Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.24 (d, J = 7.7Hz, 1H), 5.33 (m, 2H), 4.97 (s, 2H), 4.47 (dd, J = 6.4, 7.9Hz, 1H), 2.45 (s, 3H), 2.25 (qd, J = 6.7, 13.3Hz, 1H), 1.00 (dd, J = 6.6, 2.2Hz, 6H); LC-MS: m/z 402.39 [M+H] ⁺ . HPLC purity: 98.58% (220 nm); chiral HPLC purity: 98.47% (210 nm).

Example 203. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (4-(trifluoromethyl)pyrimidin-2-yl)methyl ester (6-203)

This compound was prepared analogously to the last step of Example 1 from L-valine (4-(trifluoromethyl)pyrimidin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.20 (d, J = 5.1 Hz, 1H), 9.03 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.23 (d,J＝7.7Hz,1H),5.57-5.28(m,2H),4.97(s,2H),4.62-4.38 (m,1H),2.46(s,3H),2.27(qd,J＝6.7,13.3Hz,1H),1.03 (dd, J=2.8, 6.8Hz, 6H); LC-MS: m/z 452.36[M+H] ⁺ . HPLC purity: 96.72% (220 nm); chiral HPLC purity: 95.23% (215 nm).

Example 204. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methyl ester (6-204)

This compound was prepared in analogy to the last step of Example 1 from L-valine (6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.06 (s, 1H), 8.62 (br d, J = 7.7Hz, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.35 (d, J = 7.7Hz, 1H), 7.23 (d, J = 7.7Hz, 1H), 5.22-5.03(m,2H),4.97(s,2H),4.46-4.31(m,1H),3.56(br s,4H),2.50-2.33(m,7H),2.30-1.97(m,4H),0.96(d,J＝6.6 Hz,6H). LC-MS: m/z 482[M+H] ⁺ . HPLC purity: 98.14% (220nm), 99.12% (254nm); chiral HPLC purity: 99.11% (210nm).

Example 205. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(piperazin-1-yl)pyrazin-2-yl)methyl ester (6-205)

To a stirred solution of compound 124 (1.5 g, 8.72 mmol) in NMP (10 volumes) at room temperature were added DIPEA (7.6 ml, 43.60 mmol) and N-Boc-piperazine (3.24 g, 17.44 mmol). The reaction mixture was stirred at 100°C for 16 hours. Reaction progress was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (3 x 100 ml). The combined organic layers were concentrated under reduced pressure to yield the crude product. The crude compound was purified by silica gel column chromatography (100-200 mesh, 15-20% EtOAc:petroleum ether) to yield compound 125 (1 g, 35%) as a colorless liquid. To a stirred solution of compound 125 (1 g, 3.10 mmol) in dry THF (10 ml) was added dropwise a LiAlH solution ( ₂ M in THF, 0.776 ml, 1.55 mmol) at -20°C and stirred at the same temperature for 2 hours. Reaction progress was monitored by TLC. TLC indicated the formation of polar spots and complete consumption of the starting material. The reaction was quenched with saturated sodium sulfate solution and the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure to yield a crude residue. The crude compound was purified by silica gel column chromatography (100-200 mesh, 25-28% EtOAc:petroleum ether) to yield compound 126 (500 mg, 54%) as a pale yellow solid. To a stirred solution of compound 126 (500 mg, 1.70 mmol) in DCM (10 volumes) at 0°C was added TEA (0.715 ml, 5.10 mmol) and methanesulfonyl chloride (0.197 ml, 2.55 mmol) dropwise. The reaction was stirred at room temperature for 2 hours. TLC indicated the formation of a nonpolar spot and complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to yield crude compound 127 (400 mg) as a yellow syrup. This crude compound was used in the next step without further purification. To a stirred solution of compound 6-103 (375.4 mg, 1.29 mmol) in DMF (20 ml) at room temperature was added _K₂CO₃ (355.6 _mg , 2.57 mmol) and stirred at room temperature for 10 minutes. A solution of compound 127 (400 mg, crude product, 1.075 mmol) in DMF was then added dropwise at room temperature. The reaction was heated to 90°C for 16 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to produce a crude product. The crude compound was purified by C-18 column (0.01% aqueous HCOOH and acetonitrile) to produce compound 128 (95 mg, 10%) as a white solid. HCl-dioxane (4 M, 10 ml) was added to a stirred solution of compound 128 (90 mg, 0.158 mmol) in 1,4-dioxane (10 volumes) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to produce a residue, which was triturated with diethyl ether to produce compound 6-205 (85 mg) as the HCl salt. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14 (br s, 3H), 8.61 (br d, J = 7.8Hz, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.40-7.31 (m,1H),7.24(d,J＝7.8Hz,1H),5.24-5.06(m,2H),4.97(s,2H),4.47-4.35(m,1H),3.90-3.76(m,4H),3.17(br s,4H), 2.49-2.37(m,3H),2.22-2.11(m,1H),0.97(br d,J＝6.8Hz, 6H). LC-MS: m/z 468.34[M+H] ⁺ . HPLC purity: 95.10% (220 nm), 96.29% (254 nm); chiral HPLC purity: 95.97% (247 nm).

Example 206. 2-(2,6-dimethyl-N-morpholinyl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-206)

This compound was prepared in analogy to the last step of Example 1 from L-valine 2-(2,6-dimethyl-N-morpholinyl)ethyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.49 (d, J = 7.8Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.25-7.16(m,1H),4.97(s,2H),4.33-4.22(m,2H),4.15(td, J＝11.5,5.5Hz,1H),3.51(br dd,J＝3.7,6.1Hz,2H),2.76 (br d,J＝10.3Hz,2H),2.51(br s,2H),2.47(s,3H),2.14 (qd,J＝13.7,6.8Hz,1H),1.67(br d,J＝8.3Hz,2H),1.07-0.90 (m, 12H). LC-MS: m/z 433.38 [M+H] ⁺ . HPLC purity: 95.98% (220 nm); chiral HPLC purity: 95.04% (211 nm).

Example 207. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2-N-morpholinopropyl ester (6-207)

This compound was prepared analogously to the last step of Example 1 from L-valine 2-(3-methyl-N-morpholinyl)ethyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (br s, 1H), 8.50 (br d, J = 7.7Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.24 (d, J = 8.1Hz, 1H), 4.97 (s, 2H), 4.42-4.13 (m, 2H), 4.06-3.85(m,1H),3.67-3.44(m,4H),2.89-2.69(m,1H), 2.48-2.36(m,7H),2.23-2.06(m,1H),0.96-0.94(m,overlap,9H); LC-MS: m/z 419.32[M+H] ⁺ . HPLC purity: 99.11% (220 nm).

Example 208. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-N-morpholinopropyl ester (6-208)

This compound was prepared analogously to the last step of Example 1 from L-valine 3-N-morpholinopropyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (br s, 1H), 8.51 (br d, J = 7.7Hz, 1H), 7.37 (d, J = 7.7Hz, 1H), 7.28-7.16 (m,1H),4.97(s,2H),4.35-4.25(m,1H),4.19-4.04(m,2H), 3.72-3.49(m,4H),2.48(d,J＝5.5Hz,3H),2.42-2.27(m,6H), 2.21-2.05(m,1H),1.76(q,J＝6.7Hz,2H),0.96(d,J＝6.6Hz,6H). LC-MS: m/z: 419.29[M+H] ⁺ . HPLC purity: 97.20% (220 nm); chiral HPLC purity: 95.25% (218 nm).

Example 209. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3-hydroxy-3-methylbutyl ester (6-209)

This compound was prepared from 3-hydroxy-3-methylbutyl L-valine and acid-04 in analogy to the last step of Example 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.50 (d, J=8.1 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 4.97 (s, 2H), 4.38 (s, 1H), 4.32-4.25 (m, 1H), 4.22-4.14 (m, 2H), 2.50-2.42 (m, 3H), 2.23-2.02 (m, 1H), 1.72 (t, J=7.5 Hz, 2H), 1.12 (s, 6H), 0.95 (d, J=7.0 Hz, 6H). LC-MS: m/z 378.29 [M+H] ⁺ HPLC purity: 97% (220 nm); chiral HPLC purity: 97.9% (219 nm).

Example 210. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(tetrahydrofuran-2-yl)methyl ester (6-210)

This compound was prepared analogously to the last step of Example 1 from L-valine cyclopentylmethyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.61-8.45 (m, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.24 (d, J = 8.1Hz, 1H), 4.97(s,2H),4.32(t,J＝7.2Hz,1H),4.17-3.95(m,3H), 3.83-3.54(m,2H),2.47(s,3H),2.14(qd,J＝13.5,6.9Hz, 1H), 2.00-1.73 (m, 3H), 1.60 (br dd, J＝9.0, 6.1Hz, 1H), 0.96 (d, J＝6.6Hz, 6H); LC-MS: m/z 376.24 [M+H] ⁺ HPLC purity: 96.93% (220 nm).

Example 211. 2-Hydroxy-2-methylpropyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-211)

This compound was prepared analogously to the last step of Example 1 from L-valine 2-hydroxy-2-methylpropyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 8.51 (d, J = 8.1Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.25 (d, J = 7.7Hz, 1H), 4.98 (s, 2H), 4.58 (br s,1H),4.40(dd,J＝6.4,7.9Hz,1H),3.86(s,2H),2.47(s,3H),2.18(qd,J＝6.7, 13.5Hz,1H),1.13(s,6H),0.99(d,J＝7.0Hz,3H),0.98(d, J=7.0Hz, 3H); LC-MS: m/z 364.28[M+H] ⁺ . HPLC purity: 99.4% (220 nm); chiral HPLC purity: 97.03% (212 nm).

Example 212. 2-(2-oxopyrrolidin-1-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-212)

This compound was prepared in analogy to the last step of Example 1 from L-valine 2-(2-oxopyrrolidin-1-yl)ethyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.04 (br s, 1H), 8.50 (d, J = 8.1Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.24 (d, J = 7.7Hz, 1H), 4.97 (s, 2H), 4.36-4.27 (m, 1H), 4.20 (t, J＝5.5Hz, 2H), 3.50-3.33 (m, 4H), 2.48 (d, J＝5.5 Hz, 3H), 2.29-2.06 (m, 3H), 1.89 (quintet, J＝7.4Hz, 2H), 0.94 (d, J＝6.6Hz, 6H); LC-MS: m/z 403.28[M+H] ⁺ . HPLC purity: 96.7% (220 nm); chiral HPLC purity: 98.12% (215 nm).

Example 213. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(piperazin-1-yl)pyridin-2-yl)methyl ester (6-213)

This compound was prepared in analogy to the method of Example 205 from methyl 6-chloropicolinate. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (br s, 2H), 8.60 (br d, J＝7.8 Hz, 1H), 7.72-7.60 (m, 1H), 7.36 (d, J＝7.8Hz, 1H), 7.24 (d, J＝7.8Hz,1H),6.87(d,J＝8.3Hz,1H),6.81(d,J＝7.3Hz,1H),5.09(s,2H),4.97(s,2H),4.57-4.29(m,1H),3.79-3.66 (m,4H),3.15(br s,4H),2.49-2.39(m,3H),2.20(qd,J＝13.6, Hz, 1H), 0.98 (d, J = 6.8 Hz, 6H). LC-MS: m/z 467.35 [M+Na] ⁺ . HPLC purity: 97.48% (220 nm); chiral HPLC purity: 96.58% (246 nm).

Example 214. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2-(1,4-oxazepan-4-yl)ethyl ester (6-214)

To a stirred solution of compound 6-003 (1.00 g, 3.43 mmol) in DMF (10 ml) was added K ₂ CO ₃ (948 mg, 6.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. 1,2-Dibromoethane (2.9 ml, 34.36 mmol) was then added at room temperature. The reaction mixture was microwaved at 80°C for 30 minutes. Reaction progress was monitored by TLC. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield compound 129 (800 mg, 59%) as an off-white solid. To a stirred solution of 1,4-oxazepane hydrochloride (200 mg, 1.98 mmol) in DMF (10 volumes) at room temperature were added compound 129 (786 mg, 1.98 mmol) and potassium carbonate (819 mg, 5.94 mmol). The reaction mixture was stirred at 80°C for 1 hour. Reaction progress was monitored by TLC. TLC showed the formation of nonpolar spots and complete consumption of the two starting materials. The solvent was removed under reduced pressure to yield the crude product. The crude compound was purified by C-18 column (0.1% aqueous HCOOH and acetonitrile) to yield compound 6-214 (181 mg, 22%) as an off-white gummy solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.52 (br d, J = 7.3Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.24 (d, J = 7.8Hz, 1H), 4.97 (s,2H),4.38-4.07(m,3H),3.71-3.47(m,4H),2.97-2.63(m, 6H),2.47(s,3H),2.15(qd,J＝13.3,6.8Hz,1H),1.86-1.76 (m, 2H), 0.97 (d, J = 6.8 Hz, 6H); LC-MS: m/z 419.35 [M+H] ⁺ . HPLC purity: 97.02% (220 nm); chiral HPLC purity: 97.7% (215 nm).

Example 215. ((R)-tetrahydrofuran-2-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-215)

This compound was prepared in analogy to the last step of Example 1 from ((R)-tetrahydrofuran-2-yl)methyl L-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.52 (d, J = 7.8Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.24 (d,J＝7.8Hz,1H),4.97(s,2H),4.36-4.27(m,1H),4.20-4.09 (m,1H),4.06-3.95(m,2H),3.80-3.72(m,1H),3.70-3.60(m, 1H),2.47(s,3H),2.21-2.08(m,1H),2.01-1.74(m,3H),1.61 (ddd, J = 11.9, 8.4, 6.6 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); LC-MS: m/z 376.28 [M+H] ⁺ . HPLC purity: 97.39% (220 nm); chiral HPLC purity: 96.76% (225 nm).

Example 216. 2-(2-oxooxazolidin-3-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-216)

This compound was prepared in analogy to the last step of Example 1 from L-valine 2-(2-oxooxazolidin-3-yl)ethyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.52 (d, J = 7.8Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.24 (d, J = 7.8Hz, 1H), 4.97 (s, 2H), 4.34-4.29 (m, 1H), 4.28-4.17(m,4H),3.60(t,J＝8.1Hz,2H),3.50-3.39(m,2H), 2.47(s,3H),2.14(dd,J＝13.5,6.6Hz,1H),0.95(d,J＝6.8 Hz,6H); LC-MS: m/z 405.26[M+H] ⁺ . HPLC purity: 99.25% (220 nm); chiral HPLC purity: 98.99% (211 nm).

Example 217. 2-(2-oxa-7-aza[3.5]nonan-7-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-217)

This compound was prepared from 2-oxa-7-aza[3.5]nonane in analogy to the last step of Example 214. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.53 (br d, J = 7.3 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.25 (br d, J = 7.7 Hz, 1H), 4.98 (s, 2H), 4.40-4.08 (m, 7H), 2.95-2.51 (m, 6H), 2.47 (br s, 3H), 2.14 (br dd, J = 13.8, 6.8 Hz, 1H), 1.79 (br s, 4H), 0.96 (d, J = 6.6 Hz, 6H). LC-MS: m/z 445.4 [(M+H) ⁺ ]. HPLC purity: 93.46% (220 nm); chiral HPLC purity: 96.16% (211 nm).

Example 218. 2-(2-oxa-6-aza[3.3]hept-6-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-218)

This compound was prepared from 2-oxa-6-aza[3.3]heptane in analogy to the last step of Example 214. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (br s, 1H), 8.52 (br d, J=8.1 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 4.98 (s, 2H), 4.58 (s, 4H), 4.32 (t, J=7.2 Hz, 1H), 4.06 (br t, J=5.3 Hz, 2H), 3.50 (br s, 4H), 2.73 (br s, 2H), 2.48 (br s, 3H), 2.24-2.04 (m, 1H), 0.96 (d, J=7.0 Hz, 6H). LC-MS: 417.31 [M+H] ⁺ HPLC purity: 97.53%; chiral HPLC purity: 99.04% (212 nm).

Example 219. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 2-(3-methyl-N-morpholinyl)ethyl ester (6-219)

This compound was prepared analogously to the last step of Example 1 from L-valine 2-(3-methyl-N-morpholinyl)ethyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.04 (br s, 1H), 8.69-8.41 (m, 1H), 7.38 (d, J = 7.3Hz, 1H), 7.25 (br d,J＝7.8Hz,1H),4.98(s,2H),4.53-3.96(m,4H),3.77-3.34(m,4H),3.12-2.86(m,2H),2.75(br s,1H),2.48(s,3H), 2.41-2.24(m,2H),2.15(br s,1H),1.32-1.11(m,1H),1.03-0.84 (m,7H); LC-MS: m/z 419.35[M+H] ⁺ . HPLC purity: 99.61% (220 nm).

Example 220. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (1-hydroxycyclopentyl)methyl ester (6-220)

This compound was prepared analogously to the last step of Example 1 from L-valine (1-hydroxycyclopentyl)methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.49 (d, J = 8.2Hz, 1H), 7.38 (d, J = 7.6Hz, 1H), 7.25 (d, J＝7.9Hz,1H),4.97(s,2H),4.49(s,1H),4.39(dd,J＝7.9, 6.4Hz,1H),4.09-3.94(m,2H),2.47(s,3H),2.18(qd,J＝13.4, 6.7Hz,1H),1.71(br d,J＝4.0Hz,2H),1.55(br s,6H),0.98 (d,J＝7.0Hz,3H),0.94(d,J＝7.0Hz,3H); LC-MS: m/z 387.82 [M+H] ⁺ HPLC purity: 97.94% (220 nm); chiral HPLC purity: 97.86% (213 nm).

Example 221. 4-Fluorobenzyl 3-(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)oxetane-3-carboxylate (6-221)

This compound was prepared analogously to the last step of Example 1 from 4-fluorobenzyl 3-aminooxetane-3-carboxylate and acid-04. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 9.07 (br s, 1H), 7.57-7.35 (m, 3H), 7.32-7.02 (m, 3H), 5.22 (s, 2H), 5.04-4.84 (m, 4H), 4.67 (d, J=6.6 Hz, 2H), 2.42 (s, 3H); LCMS: m/z 400.27 [M+H] ⁺ . HPLC purity: 95.08% (220 nm).

Example 222. 2-N-Morpholinylethyl 3-(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)oxetane-3-carboxylate (6-222)

This compound was prepared analogously to the last step of Example 1 from 2-N-morpholinoethyl 3-aminooxetane-3-carboxylate and acid-04. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 9.08 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.29 (br d, J = 7.7 Hz, 1H), 5.09-4.87 (m, 4H), 4.67 (br d, J = 6.6 Hz, 2H), 4.31 (br s, 2H), 3.54 (br s, 4H), 2.52 (br s, 6H), 2.47-2.17 (m, 3H); LC-MS: m/z 404.8 [M+H] ⁺ . HPLC purity: 97.2% (220 nm).

Example 223. 2-Pyridin-2-ylmethyl 3-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carboxamido)oxetane-3-carboxylate (6-223)

This compound was prepared from pyridin-2-ylmethyl 3-aminooxetane-3-carboxylate and acid-04 in analogy to the last step of Example 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 9.07 (s, 1H), 8.56 (d, J = 4.0 Hz, 1H), 7.92-7.77 (m, 1H), 7.49-7.42 (m, 2H), 7.35 (dd, J = 7.2, 5.3 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 5.31 (s, 2H), 5.04-4.93 (m, 4H), 4.71 (d, J = 6.6 Hz, 2H), 2.44 (s, 3H); LC-MS: m/z 383.24 [M+H] ⁺ . HPLC purity: 99.27% (220 nm).

Example 224. Cyclopentylmethyl 3-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)oxetane-3-carboxylate (6-224)

This compound was prepared analogously to the last step of Example 1 from cyclopentylmethyl 3-aminooxycyclobutane-3-carboxylate and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.44 (s, 1H), 9.08 (s, 1H), 7.48 (d, J = 7.7Hz, 1H), 7.29 (d, J = 7.7Hz, 1H), 4.99 (s, 2H), 4.91 (d, J = 6.6Hz, 2H), 4.66 (d, J＝6.6Hz,2H),4.06(d,J＝7.0Hz,2H),2.47(br s,3H), 2.26-2.11(m,1H),1.77-1.61(m,2H),1.60-1.40(m,4H),1.25(br dd, J=6.8, 11.9Hz, 2H); LC-MS: m/z 374.3[M+H] ⁺ . HPLC purity: 97.32% (220 nm).

Example 225. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(2-aminopyrimidin-5-yl)methyl ester (6-225)

To a stirred suspension of compound 130 (500 mg, 4 mmol) in DCM (10 ml) was added SOCl ₂ (1 ml) dropwise at 0°C. After the addition was complete, the reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to produce crude compound 131 (290 mg) as the HCl salt. The crude compound was used in the next step without any further purification. To a stirred solution of compound 6-003 (582 mg, 2 mmol) in DMF (10 ml) at room temperature were added compound 131 (290 mg, crude product, 2 mmol) and K ₂ CO ₃ (828 mg, 6 mmol). The reaction mixture was microwaved at 80°C for 1 hour. The reaction progress was monitored by TLC. The solvent was removed under reduced pressure to produce the crude product. The crude compound was purified by a Grace purification system (C-18 column; 0.01% HCOOH aqueous solution and acetonitrile) to produce crude compound 6-225 (500 mg). The crude compound was purified by preparative HPLC to give compound 6-225 (60 mg, 4% over 2 steps) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (br s, 1H), 8.53 (br d, J = 7.8Hz, 1H), 8.31 (s, 2H), 7.35-7.30 (d, J = 7.3Hz, 1H), 7.23 (d, J = 7.3Hz, 1H), 7.09-6.84 (m,2H),5.13-4.85(m,4H),4.37-4.22(m,1H),2.43(s,3H), 2.11(qd,J＝13.3,6.3Hz,1H),0.92(d,J＝6.8Hz,3H),0.90 (d,J＝6.8Hz,3H). LC-MS: m/z 399.22[M+H] ⁺ . HPLC purity: 94.03% (220 nm); chiral HPLC purity: 98.99% (229 nm).

Example 226. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (4-fluorotetrahydro-2H-pyran-4-yl)methyl ester (6-226)

This compound was prepared analogously to the last step of Example 1 from L-valine (4-fluorotetrahydro-2H-pyran-4-yl)methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.58 (d, J = 7.3Hz, 1H), 7.37 (d, J = 7.8Hz, 1H), 7.25 (d, J = 7.3Hz, 1H), 4.97 (s, 2H), 4.35 (t, J = 7.3Hz, 1H),4.29-4.14(m,2H),3.73(td,J＝11.5,3.8Hz,2H),3.56 (dt,J＝3.9,10.8Hz,2H),2.47(s,3H),2.16(qd,J＝13.6, 6.7Hz,1H),1.91-1.69(m,4H),0.97(dd,J=6.8,3.4Hz,6H); LC-MS: m/z 408.23 [M+H] ⁺ , HPLC purity: 99.40% (220 nm), chiral HPLC purity: 98.37% (210 nm).

Example 227. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine(1,4-dioxan-2-yl)methyl ester (6-227)

This compound was prepared analogously to the last step of Example 1 from L-valine (1,4-dioxan-2-yl) methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.54 (d, J = 7.8Hz, 1H), 7.38 (d, J = 7.3Hz, 1H), 7.25 (d,J＝7.8Hz,1H),4.98(s,2H),4.36-4.27(m,1H),4.17-3.98 (m,2H),3.78-3.69(m,3H),3.66-3.52(m,2H),3.51-3.40(m, 1H),3.38-3.33(m,1H),2.47(s,3H),2.21-2.08(m,1H),0.97 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H); LC-MS: m/z 392.22 [M+H] ⁺ . HPLC purity: 99.17% (220 nm).

Example 228. (S)-3-Hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoic acid cyclopentylmethyl ester (228)

This compound was prepared in analogy to the last step of Example 1 from (S)-cyclopentylmethyl 2-amino-3-hydroxy-3-methylbutanoate and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.12 (d, J = 8.3Hz, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.26 (d, J = 7.8Hz, 1H), 4.98 (s, 2H), 4.74 (s, 1H), 4.40 (d, J＝7.8Hz,1H),4.06-3.77(m,2H),2.49(d,J＝5.4Hz,3H), 2.24-2.02(m,1H),1.78-1.65(m,2H),1.62-1.45(m,4H),1.25 (d, J=2.9Hz, 8H); LC-MS: m/z 390.24[M+H] ⁺ . HPLC purity: 98.87% (220 nm); chiral HPLC purity: 99.5% (227 nm).

Example 229. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (1-hydroxycyclohexyl)methyl ester (6-229)

This compound was prepared analogously to the last step of Example 1 from L-valine (1-hydroxycyclohexyl) methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 8.50 (d, J = 8.1Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.25 (d, J＝8.1Hz,1H),4.97(s,2H),4.40(dd,J＝6.6,8.1Hz,1H), 4.32(s,1H),3.87(s,2H),2.47(s,3H),2.18(br dd,J＝13.4, 6.8,Hz,1H),1.67-1.32(m,9H),1.17(br d,J＝11.0Hz,1H), 0.97(d,J＝7.0Hz,3H),0.96(d,J＝7.0Hz,3H); LC-MS: m/z 404.27 [M+H] ⁺ HPLC purity: 99.19% (220 nm); chiral HPLC purity: 96.91% (210 nm).

Example 230. (S)-2-ylmethyl pyridin-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-230)

This compound was prepared in analogy to the last step of Example 1 from (S)-pyridin-2-ylmethyl 2-amino-3-hydroxy-3-methylbutanoate and Acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.05 (br s, 1H), 8.55 (br d, J＝4.4Hz, 1H), 8.29 (d, J＝ 8.1Hz,1H),7.82(dt,J＝7.7,1.8Hz,1H),7.60-7.47(m,1H),7.45-7.32(m,2H),7.25(d,J＝7.7Hz,1H),5.37-5.16(m,2H), 5.04-4.82(m,3H),4.53(d,J＝8.1Hz,1H),2.45(s,3H),1.27(d,J＝4.4Hz,6H). LC-MS: m/z 399.25[M+H] ⁺ . HPLC purity: 93.98% (220 nm); chiral HPLC purity: 96.7% (210 nm).

Example 231. 2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)ethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-231)

This compound was prepared in analogy to the last step of Example 214 from 6-oxa-3-azabicyclo[3.1.1]heptane. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.03 (br s, 1H), 8.51 (d, J = 7.7Hz, 1H), 7.37 (d, J = 8.1Hz, 1H), 7.24 (d, J＝7.7Hz,1H),4.97(s,2H),4.40(d,J＝5.9Hz,2H),4.35-4.28 (m,2H),4.25-4.15(m,1H),3.06(br d,J＝11.0Hz,2H), 2.87-2.76(m,3H),2.74-2.61(m,2H),2.47(s,3H),2.24-2.02 (m,2H),0.96(d,J＝6.6Hz,6H); LC-MS: m/z 417.31 [M+H] ⁺ HPLC purity: 95.6% (220 nm); chiral HPLC purity: 95.17% (215 nm).

Example 232. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-(dimethylamino)pyrazin-2-yl)methyl ester (6-232)

This compound was prepared in analogy to the last step of Example 1 from L-valine (6-(dimethylamino)pyrazin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.64 (br d, J = 7.7Hz, 1H), 8.33 (d, J = 4.8Hz, 1H), 7.37 (d, J = 7.7Hz, 1H), 7.24 (d, J = 7.7Hz, 1H), 6.63 (d,J＝4.8Hz,1H),5.04(s,2H),4.97(s,2H),4.44(t,J＝7.3Hz,1H),3.10(s,6H),2.46(s,3H),2.22(br dd,J＝6.8, 13.4Hz, 1H), 0.99 (d, J=6.6Hz, 6H); LC-MS: m/z 427.27[M+H] ⁺ . HPLC purity: 98.46% (220 nm), 98.32% (254 nm); chiral HPLC purity: 99.61% (244 nm).

Example 233. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (3-methyltetrahydrofuran-3-yl)methyl ester (6-233)

This compound was prepared from L-valine (3-methyltetrahydrofuran-3-yl)methyl ester and acid-04 in analogy to the last step of Example 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.55 (br d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.97 (s, 2H), 4.37-4.27 (m, 1H), 4.05-3.92 (m, 2H), 3.75 (t, J = 7.2 Hz, 2H), 3.57 (dd, J = 8.4, 5.1 Hz, 1H), 3.29-3.22 (m, 1H), 2.48 (s, 3H), 2.22-2.06 (m, 1H), 1.89-1.71 (m, 1H), 1.66-1.50 (m, 1H), 1.10 (s, 3H), 1.01-0.84 (m, 6H); LC-MS: m/z 390.3 [M+H] ⁺ HPLC purity: 96.4% (220 nm).

Example 234. ((R)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-234)

This compound was prepared from ((R)-tetrahydrofuran-2-yl)methyl L-valine and acid-04 in analogy to the last step of Example 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.54 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.98 (s, 2H), 4.30 (t, J = 7.2 Hz, 1H), 4.15-3.91 (m, 2H), 3.82-3.54 (m, 3H), 3.45 (dd, J = 8.6, 5.7 Hz, 1H), 2.57-2.51 (m, 1H), 2.47 (s, 3H), 2.14 (qd, J = 13.5, 6.6 Hz, 1H), 2.01-1.85 (m, 1H), 1.58 (dt, J = 13.1, 6.8 Hz, 1H), 0.96 (dd, J = 6.8, 1.7 Hz, 6H); LC-MS: m/z 376.24 [M+H] ⁺ . HPLC purity: 96.3% (220 nm); chiral HPLC purity: 97.66% (210 nm).

Example 235. ((S)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-235)

This compound was prepared in analogy to the last step of Example 1 from ((S)-tetrahydrofuran-2-yl)methyl L-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 8.53 (d, J = 7.3Hz, 1H), 7.37 (d, J = 7.3Hz, 1H), 7.25 (d,J＝7.8Hz,1H),4.97(s,2H),4.34-4.27(m,1H),4.11-3.95 (m,2H),3.79-3.69(m,2H),3.65-3.58(m,1H),3.44(dd,J＝8.8,5.9Hz,1H),2.57-2.51(m,1H),2.47(s,3H),2.14(qd, J = 13.3, 6.8 Hz, 1H), 2.02-1.90 (m, 1H), 1.64-1.53 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); LC-MS: m/z 376.24 [M+H] ⁺ ; HPLC purity: 99.29% (220 nm); chiral HPLC purity: 97.79% (215 nm).

Example 236. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (5-(trifluoromethyl)pyrimidin-2-yl)methyl ester (6-236)

This compound was prepared in analogy to the last step of Example 1 from L-valine (5-(trifluoromethyl)pyrimidin-2-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.29 (s, 2H), 9.02 (s, 1H), 8.58 (d, J = 7.8Hz, 1H), 7.39 (d, J = 7.8Hz, 1H), 7.24 (d, J = 7.3Hz, 1H), 5.44 (q, J = 15.2 Hz,2H),4.97(s,2H),4.51(dd,J＝7.8,6.4Hz,1H),2.46(s,3H),2.28(qd,J＝13.5,6.8Hz,1H),1.03(dd,J＝6.6,4.6Hz,6H); LC-MS: m/z 452.16[M+H] ⁺ . HPLC purity: 98.97% (220 nm); chiral HPLC purity: 99.74% (215 nm).

Example 237. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (2-aminopyrimidin-4-yl)methyl ester (6-237)

This compound was prepared in analogy to the last step of Example 1 from L-valine (2-aminopyrimidin-4-yl)methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.64 (br d, J = 7.8Hz, 1H), 8.23 (d, J = 5.4Hz, 1H), 7.38 (d, J = 7.3Hz, 1H), 7.25 (br d,J＝7.3Hz,1H),6.76-6.57(m,3H),5.11-4.91(m,4H),4.42(br t,J＝7.1Hz,1H),2.46(s,3H),2.29-2.15(m,1H),0.99(br d, J=6.4Hz, 6H); LC-MS: m/z 399.22[M+H] ⁺ . HPLC purity: 97.35% (220 nm); chiral HPLC purity: 99.97% (222 nm).

Example 238. (S)-2-N-Morpholinylethyl 3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-238)

This compound was prepared from (S)-2-amino-3-hydroxy-3-methylbutanoic acid 2-N-morpholinylethyl ester and acid-04 in analogy to the last step of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.13 (s, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 4.98 (s, 2H), 4.42 (m, 2H), 4.20 (br s, 1H), 4.18 (br s, 1H), 3.54 (s, 4H), 2.60-2.32 (m, 9H), 1.26 (d, J=6.4 Hz, 6H); LC-MS: m/z 421.27 [M+H] ⁺ . HPLC purity: 96.83% (220 nm); chiral HPLC purity: 98.10% (210 nm).

Example 239. (R)-Tetrahydrofuran-2-ylmethyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-239)

This compound was prepared in analogy to the last step of Example 1 from ((R)-tetrahydrofuran-2-yl)methyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 8.13 (d, J = 7.6Hz, 1H), 7.41 (d, J = 7.6Hz, 1H), 7.26 (d, J = 8Hz, 1H), 4.98 (s, 2H), 4.74 (s, 1H),4.42(d,J＝8.4Hz,1H),4.12(m,1H),4.08-3.98(m,2H), 3.76(m,1H),3.65(m,1H),2.50(m,3H),1.95-1.75(m,3H), 1.61(m,1H),1.20(m,6H); LC-MS: m/z 392.22[M+H] ⁺ . HPLC purity: 98.71% (220 nm); chiral HPLC purity: 94.97% (210 nm).

Example 240. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (2-(methylamino)pyrimidin-4-yl)methyl ester (6-240)

This compound was prepared analogously to the last step of Example 1 from L-valine (2-(methylamino)pyrimidin-4-yl)methyl ester and acid-04. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.64 (d, J = 7.8Hz, 1H), 8.27 (brd, J = 4.2Hz, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.25 (d, J = 7.8Hz, 1H), 7.11 (m,1H),6.61(d,J＝4.8Hz,1H),5.01(s,2H),4.97(s,2H), 4.42(t,J＝7.2Hz,1H),2.78(d,J＝4.8Hz,3H),2.46(s, 3H), 2.22 (m, 1H), 0.98 (d, J = 6.6Hz, 6H); LC-MS: m/z 413.18 [M+H] ⁺ . HPLC purity: 98.37% (220 nm); chiral HPLC purity: 96.6% (210 nm).

Example 241. (S)-(Tetrahydro-2H-pyran-4-yl)methyl 3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoate (6-241)

This compound was prepared in analogy to the last step of Example 1 from (S)-(tetrahydro-2H-pyran-4-yl)methyl 2-amino-3-hydroxy-3-methylbutanoate and Acid-04. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 8.17 (d, J = 8.7Hz, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.26 (d, J = 7.8Hz, 1H), 4.98 (s, 2H), 4.75 (s,1H),4.42(d,J＝8.7Hz,1H),3.96(d,J＝6.6Hz,2H), 3.84(m,2H),3.26(d,J＝10.5Hz,2H),2.45(m,3H),1.87(m, 1H), 1.62-1.58(m,2H), 1.33-1.20(m,8H); LC-MS: m/z 406.22 [M+H] ⁺ . HPLC purity: 98.28% (220 nm); chiral HPLC purity: 99.48% (210 nm).

Example 242. 3-Fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-242)

This compound was prepared in analogy to the method of Example 163 from methyl 3-fluoro-4-hydroxybenzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.56 (d, J = 8.0Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.27-7.18 (m, 2H), 7.17-7.16 (m, 2H), 5.10 (dd, J = 12.0 Hz,20.0Hz,2H),4.97(s,2H),4.33(t,J＝8.0Hz,1H),4.14 (t,J＝4.0Hz,2H),2.79(t,J＝8.0Hz,2H),2.50(s,3H), 2.49-2.13(m,1H),1.69-1.66(m,4H),0.95(d,J＝8.0Hz,3H), 0.91 (d, J=8.0 Hz, 3H); ESI-MS m/z 513 [M+H] ⁺ ; HPLC purity: 98.20% (220 nm), 94.25% (254 nm).

Example 243. 3-Chloro-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-243)

This compound was prepared in analogy to the method of Example 163 from methyl 3-chloro-4-hydroxybenzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.56 (d, J = 7.6Hz, 1H), 7.47 (d, J = 1.6Hz, 1H), 7.35-7.33 (m, 1H), 7.33-7.31 (m, 1H), 7.23 (d, J = 7.6Hz, 1H),7.16(d,J＝8.4Hz,1H),5.14-5.06(m,2H),4.97(s,2H), 4.33(t,J＝7.2Hz,1H),4.15(t,J＝6.0Hz,2H),2.81(t, J＝5.6Hz,2H),2.56-2.52(m,4H),2.44(s,3H),2.14(q,J =6.8, 13.6 Hz, 1H), 1.72-1.64 (m, 4H), 0.93 (dd, J=1.2 Hz, 7.2 Hz, 6H); ESI-MS m/z 529 [M+H] ⁺ ; HPLC purity: 98.38% (220 nm), 94.90% (254 nm).

Example 244. 4-Chloro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valine (6-244)

This compound was prepared in analogy to the method of Example 163 from methyl 4-chloro-3-hydroxybenzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 8.61 (d, J = 7.6Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 7.19 (s,1H),7.00-6.98(m,1H),5.18(s,2H),4.98(s,2H),4.35 (t,J＝7.2Hz,1H),4.12(t,J＝4.2Hz,2H),2.79(t,J＝5.6 Hz,2H),2.54-2.53(m,4H),2.45(s,3H),2.20-2.14(m,1H), 1.68-1.65 (m, 4H), 0.96 (dd, J=3.6, 3.2 Hz, 6H); ESI-MS m/z 529 [M+H] ⁺ ; HPLC purity: 96.52% (220 nm), 95.91% (254 nm).

Example 245. 4-Fluoro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valine (6-245)

This compound was prepared in analogy to the method of Example 163 from methyl 4-fluoro-3-hydroxybenzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.58 (d, J = 7.6Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.24-7.17 (m, 3H), 6.97-6.96 (m, 1H), 5.14 (d, J = 2.0Hz, 2H),4.97(s,2H),4.35-4.31(m,1H),4.09(t,J＝6.0Hz,2H), 2.76(t,J＝6.0Hz,2H),2.49-2.46(m,4H),2.43(s,3H), 2.19-2.10(m,1H),1.66-1.64(m,4H),0.95(dd,J＝3.2,6.4 Hz, 6H); ESI-MS m/z 513 [M+H] ⁺ ; HPLC purity: 98.72% (220 nm), 100% (254 nm).

Example 246. 3-Fluoro-4-(3-(pyrrolidin-1-yl)propoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valine (6-246)

This compound was prepared in analogy to the method of Example 163 from methyl 4-fluoro-3-hydroxybenzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 8.56 (d, J = 8.0Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.27-7.21 (m, 2H), 7.16-7.15 (m, 2H), 5.00 (q, J = 12.0 Hz,2H),4.97(s,2H),4.33(t,J＝8.0Hz,1H),4.09(t,J＝8.0Hz,2H),2.43(s,3H),2.16-2.11(m,1H),1.90(t,J＝4.0 Hz, 2H), 1.68 (s, 4H), 0.93 (dd, J = 8.0, 4.0Hz, 6H); ESI-MS m/z 527 [M+H] ⁺ ; HPLC purity: 96.19% (220 nm), 91.57% (254 nm).

Example 247. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-(2-morpholinoethoxy) benzyl ester (6-247)

This compound was prepared in analogy to the method of Example 163 from methyl 4-(2-N-morpholinoethoxy)benzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.03 (s, 1H), 8.53 (d, J = 8.0Hz, 1H), 7.34-7.31 (m, 3H), 7.23 (d, J = 8.0Hz, 1H), 6.94 (d, J = 8.4Hz, 2H), 5.14-5.04 (m,2H),4.97(s,2H),4.32(t,J＝7.2Hz,1H),4.08(t,J＝6.0Hz,2H),3.57(t,J＝4.0Hz,4H),2.68(t,J＝5.6Hz,2H), 2.45(d,J＝4.4Hz,4H),2.43(s,3H),2.15-2.07(m,1H), 0.92-0.91 (m, 6H); ESI-MS m/z 511 [M+H] ⁺ ; HPLC purity: 95.94% (220 nm), 97.37% (254 nm).

Example 248. (S)-3-Hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carboxamido)-3-methylbutanoic acid (4,4-difluorocyclohexyl) methyl ester (6-248)

This compound was prepared from (S)-(4,4-difluorocyclohexyl)methyl 2-amino-3-hydroxy-3-methylbutanoate and acid-04 in analogy to the last step of Example 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.41 (d, J=8 Hz, 1H), 7.27 (d, J=8 Hz, 1H), 4.98 (s, 2H), 4.41 (s, 1H), 3.99 (d, J=5.6 Hz, 2H), 2.48 (s, 3H), 2.1-1.95 (m, 3H), 1.90-1.70 (m, 6H), 1.32-1.23 (m, 8H); LC-MS: m/z 440.35 [M+H] ⁺ . HPLC purity: 99.59% (220 nm); chiral HPLC purity: 99.54% (210 nm).

Example 249. 4-(3-(pyrrolidin-1-yl)propoxy)benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine ester (6-249)

This compound was prepared in analogy to the method of Example 163 from methyl 4-(3-(pyrrolidin-1-yl)propoxy)benzoate, N-Boc-(S)-valine and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 8.52 (d, J = 7.6Hz, 1H), 7.34-7.30 (m, 3H),7.22(d,J＝8.0Hz,1H),6.91(d,J＝8.8Hz,2H),5.13-5.04(m,2H),4.97(s,2H),4.33-4.30(m,1H),4.02-3.99(m,2H), 2.53-2.52(m,2H),2.43-2.41(m,7H),2.15-2.10(m,1H), 1.90-1.85 (m, 2H), 1.69-1.65 (m, 4H), 0.92 (d, J=6.8 Hz, 6H); ESI-MS m/z 509 [M+H] ⁺ ; HPLC purity: 96.08% (220 nm), 96.68% (254 nm).

Example 250. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (3-hydroxytetrahydrofuran-3-yl)methyl ester (6-250)

This compound was prepared in analogy to the last step of Example 1 from L-valine (3-hydroxytetrahydrofuran-3-yl)methyl ester and acid-04. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 8.51 (d, J = 7.8Hz, 1H), 7.38 (d, J = 8.0Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 5.07 (s, 1H), 4.98 (s, 2H), 4.39 (m, 1H),4.12(m,2H),3.90-3.70(m,2H),3.63(dd,J＝8.8Hz,1H), 3.5(d,J＝8.0Hz,1H),2.50(m,3H),2.23-2.1(m,1H),1.97-1.87 (m,1H),1.84-1.75(m,1H),0.96(m,6H); LC-MS: m/z 392.25 [M+H] ⁺ HPLC purity: 98.1% (220 nm).

Example 251. (5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (6-251)

To a solution of 5-bromo-2-chloro-3-fluoropyridine (17.0 g, 65.3 mmol) in THF (200 ml) at 0°C under nitrogen was added i-PrMgCl.LiCl (1.3 M, 60 ml) dropwise over 30 minutes. The mixture was stirred at 15°C for 2 hours. Methyl chloroformate (15.4 g, 163 mmol) was then added dropwise over 30 minutes at 0°C. The mixture was stirred at 15°C for 11 hours. The reaction was slowly quenched with water (100 ml) and then extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with brine (2 x 100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO ₂ ; petroleum ether/ethyl acetate = 100/1 to 50/1) to give methyl 6-chloro-5-fluoronicotinate (5.00 g, 32%) as a white solid.

To a solution of methyl 6-chloro-5-fluoronicotinate (5.00 g, 26.4 mmol) in acetonitrile (100 ml) was added TMSCl (5.73 g, 52.8 mmol). The mixture was stirred at 50°C for 55 minutes. The mixture was then cooled to 15°C and poured into a solution of NaI (39.54 g, 263.8 mmol) in acetonitrile ( ₁₀₀ ml) in a single portion. The mixture was stirred at 15°C for 5 minutes. The mixture was filtered and quenched with saturated _{Na₂S₂O₃} solution (100 _ml ) and then extracted with EtOAc (3 x 100 ml). The combined organic phases were rinsed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by recrystallization from MTBE (30 ml) to give 5-fluoro-6-iodonicotinate (3.00 g, 40%) as a yellow solid.

A mixture of 5-fluoro-6-iodonicotinate (1.50 g, 5.34 mmol), methyl 2,2-difluoro-2-fluorosulfonyl-acetate (5.13 g, 26.7 mmol), HMPA (2.87 g, 16.0 mmol), and CuI (3.05 g, 16.0 mmol) in DMF (15 ml) was stirred at 80°C under nitrogen for 12 hours. The reaction was slowly quenched with water (30 ml) and then extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography ( _SiO2 ; petroleum ether/ethyl acetate = 50/1 to 20/1) to yield methyl 5-fluoro-6-trifluoromethylnicotinate (470 mg, 35%) as an off-white solid.

To a solution of methyl 5-fluoro-6-trifluoromethylnicotinate (440 mg, 1.97 mmol) in THF (2 mL) was added LAH (75 mg, 1.97 mmol) at -20°C. The mixture was stirred at -20°C for 5 minutes. The reaction was quenched with saturated potassium sodium tartrate solution (1 mL), filtered, and concentrated in vacuo to yield (5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methanol (280 mg, 73%) as a colorless oil.

(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine was prepared from (5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methanol, N-Boc-(S)-valine and acid-04 in analogy to the method of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ )9.03 (s, 1H), 8.67-8.65 (m, 2H), 8.15 (d, J = 8.0Hz, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.24(d,J＝8.0Hz,1H),5.38(q,J＝8.0Hz,2H),4.97(s, 2H),4.39(t,J＝8.0Hz,1H),2.42(s,3H),2.22-2.17(m,1H), 0.97(d,J＝8.0Hz,6H); ESI-MS m/z 469[M+H] ⁺ ; HPLC purity: 99.10% (220nm), 97.74% (254nm).

Example 252. In vitro Alamar Blue 72-hour drug sensitivity analysis of Trypanosoma congolense

Compounds were tested in vitro for chemotherapeutic efficacy against the IL3000 (drug-sensitive) strain of Trypanosoma congolense using a modified Alamar Blue assay. For each assay, a 10 mg/ml DMSO stock solution of the test compound was prepared. Compounds were tested in at least three separate independent assays, and _IC50 values were determined using an 11-point dilution curve. Bloodstream trypanosomes were maintained in HMI medium containing 20% bovine serum and incubated with the test compound for 69 hours at 34°C in a humidified atmosphere containing 5% _CO2 . Resazurin dye (10 μl, 12.5 mg in phosphate-buffered saline (100 ml), Sigma-Aldrich, Buchs, Switzerland) was then added for 3 hours. The plate was then read using a fluorescence plate reader (Spectramax, Gemini XS, Bucher Biotec, Basel, Switzerland) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. Data points were averaged to generate a sigmoidal dose-response curve, and _IC50 values were determined using Softmax Pro 5.2 software.

The results are shown in Table 1. Compounds were designated as "A" if the _IC50 value was ≤ 0.5 nM, "B" if the _IC50 value was between 0.51 and 9.99 nM, and "C" if the _IC50 value was between 10 and 5000 nM.

Example 253. In vitro Alamar Blue 48-hour drug sensitivity analysis of T.vivax

Compounds were tested in vitro for chemotherapeutic efficacy against the active (drug-sensitive) strain of STIB719/ILRAD560 trypanosomes using an Alamar Blue assay with several modifications. A 10 mg/ml DMSO stock solution of the test compound was prepared for each assay. Compounds were tested in at least three separate independent assays, and _IC50 values were determined using an 11-point dilution curve. Bloodstream trypanosomes were propagated and harvested (via cardiac puncture) from highly parasitemic mice. Bloodstream trypanosomes were maintained in HMI medium containing 20% bovine serum and incubated with the test compound for 45 hours at 37°C in a humidified atmosphere containing 5% _CO2 . Resazurin dye (10 μl, 12.5 mg in 100 ml phosphate buffer, Sigma-Aldrich, Buchs, Switzerland) was then added for 3 hours. The plate was then read using a fluorescence plate reader (Spectramax, Gemini XS, Bucher Biotec, Basel, Switzerland) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. Data points were averaged to generate sigmoidal dose-response curves and _IC50 values were determined using Softmax Pro 5.2 software.

The results are shown in Table 1. Compounds were designated as "A" if the _IC50 value was ≤0.5 nM; "B" if the _IC50 value was between 0.51 and 49.9 nM; "C" if the _IC50 value was between 50 and 2000 nM; and "D" if the _IC50 value was >2,000 nM.

Example 254. In vitro _IC50 measurement of killing T. cruzi amastigotes using Td tomato modified T. cruzi

The Trypanosoma cruzi parasites used in this assay are genetically modified to express the TdTomato fluorescent protein. Vero cells (African green monkey kidney epithelial cells) were harvested from a continuous culture using trypsin and added to the inner 60 wells of a 96-well Greiner Bio One plate (plate catalog #655090) (200 μl/well and 2.5×10 ⁶ cells/ml). The cells were allowed to attach for 1 hour and then infected with Trypanosoma cruzi. The parasites used for infection were harvested from previously infected Vero cells, washed, sedimented, and resuspended (5×10 ⁶ cells/ml). Parasites (50 μl) were added to each well containing Vero cells. Compounds were prepared from a 5 mM stock solution in DMSO to a final concentration in the wells ranging from 5 μM to 5 nM. Wells lacking compound served as negative controls. The plate was placed in a 37°C incubator for 20 minutes and then read using a Synergy H4 plate reader at an excitation wavelength of 544 nm and an emission wavelength of 612 nm to record the starting fluorescence value for "Day 0." The 96-well plate was placed in a Tupperware container containing a moistened paper towel and incubated in a 37°C incubator for 72 hours. After 72 hours, the plate was read again (Day 3 reading) and the data analyzed using Excel and/or Graphpad software. The fluorescence data from Day 0 was subtracted from the fluorescence data from Day 3 reading to remove the input parasite fluorescence. Growth curves were generated and the 50% and 90% inhibitory concentrations were determined by nonlinear regression analysis.

The results are shown in Table 1. Compounds were scored as "A" if the _IC50 value was ≤20 nM, "B" if the _IC50 value was between 21 and 999 nM, and "C" if the _IC50 value was ≥1000 nM.

Table 1 shows the activity of selected compounds of the invention in the assays discussed in Examples 252 to 254, wherein each compound number corresponds to the compound number of Examples 1 to 251 herein above.

Table 1

equivalent

It should be understood that although the present disclosure has been described in detail in conjunction with the detailed description of the present disclosure, the foregoing description is intended to illustrate the present disclosure and not to limit the scope of the present disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

This application involves the following technical solutions.

1. Compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

^R1 is hydrogen or a _C1-6 aliphatic group;

R ^1a is hydrogen or C _1-6 aliphatic; or

R ¹ and R ^1a , together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocarbocyclic ring;

each R ² is independently hydrogen, -halogen, -OR, -NO ₂ , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) ₂ R, -C(O)N(R) ₂ , -SO ₂ N(R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)SO ₂ R, -OC(O)N(R) ₂ , or an optionally substituted group selected from C _1-6 aliphatic and 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl;

R ³ is hydrogen or an optionally substituted C _1-6 aliphatic group;

R ⁴ is hydrogen, a natural or non-natural amino acid side chain group, or an optionally substituted group selected from a C _1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a phenyl group; or

R ³ and R ⁴ together with the carbon atom to which R ⁴ is attached and the nitrogen atom to which R ³ is attached form an optionally substituted 3- to 6-membered heterocyclyl having 0 to 1 additional heteroatoms selected from O, N or S;

R ⁵ is hydrogen or optionally substituted C _1-6 aliphatic; or

^R4 and ^R5 , together with the carbon atom to which they are attached, form an optionally substituted ring selected from 3- to 6-membered spiroheterocyclyl having 1 to 2 heteroatoms selected from O, N or S and 3- to 6-membered saturated or partially unsaturated monocyclic spirocarbocyclyl;

L is a covalent bond or an optionally substituted divalent C _1-10 saturated or unsaturated linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are optionally and independently replaced by -Cy-, -O-, -SO-, -SO ₂ -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O)-, -N(R)C(O)-, -N(R)SO ₂ - or -SO ₂ N(R)-;

wherein each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from O, N, or S, a 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from O, N, or S, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclylene, an 8- to 10-membered bicyclic arylene, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from O, N, or S, and a 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from O, N, or S;

^R6 is hydrogen, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , -OC(O)N(R) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 2 heteroatoms selected from O, N or S, 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from O, N or S, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic group, 8- to 10-membered bicyclic aryl group, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms selected from O, N or S, 7- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms selected from O, N or S, and bridged bicyclic group;

Each R is independently hydrogen or an optionally substituted C _1-6 aliphatic group;

wherein when L is a covalent bond, then ^R6 is not -OR, -halogen, _-NO2 , -CN, -SR, -N(R) ₂ , -S(O)R, -S(O) _2R , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ ; and

When L is not a covalent bond, L includes the carbon atom bonded to the carboxyl oxygen represented by O*.

2. The compound of item 1, wherein L is selected from:

3. A compound according to any one of the preceding items, wherein R ⁶ is an optionally substituted group selected from:

.

4. The compound of item 1, wherein the compound is of formula II:

or a pharmaceutically acceptable salt thereof.

5. The compound of item 1, wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof.

6. The compound of item 5, wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt thereof.

7. The compound of item 1, wherein the compound is of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

each ^Ra is independently R, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ ;

R ^b is hydrogen or methyl; and

R ^b1 is hydrogen or methyl.

8. The compound of item 1, wherein the compound is of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

each ^Ra is independently R, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ ;

R ^b is hydrogen or methyl; and

R ^b1 is hydrogen or methyl.

9. The compound of item 1, wherein the compound is of formula V-a or V-b:

or a pharmaceutically acceptable salt thereof, wherein:

Each ^Ra is independently R, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ .

10. The compound of item 1, wherein the compound is of formula VI-a, VI-b, VI-c, VI-d, VI-e or VI-f:

or a pharmaceutically acceptable salt thereof, wherein:

each ^Ra is independently R, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ ; and

n is 0, 1, 2 or 3.

11. The compound of item 1, wherein the compound is of formula VII-a, VII-b or VII-c:

or a pharmaceutically acceptable salt thereof, wherein:

each ^Ra is independently R, -halogen, -OR, _-NO2 , -CN, -SR, -N(R) ₂ , -C(O)R, -C(O)OR, -S(O)R, -S(O) _2R , -C(O)N(R) ₂ , _-SO2N (R) ₂ , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R) _SO2R , or -OC(O)N(R) ₂ ; and

n is 0, 1, 2 or 3.

12. The compound of item 1, wherein the compound is of formula VIII-a, VIII-b or VIII-c:

or a pharmaceutically acceptable salt thereof.

13. The compound of item 1, wherein the compound is of formula IX-a or IX-b:

or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or methyl.

14. The compound of item 13, wherein L is selected from:

15. The compound of claim 1, wherein the compound is selected from compound 6-001 to compound 6-251 or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is selected from:

(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 3,4-difluorobenzyl ester;

((S)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-carbonyl)-L-valine; and

(1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine (tetrahydro-2H-pyran-4-yl)methyl ester,

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborolane-6-carbonyl)-L-valine 4-fluorobenzyl ester or a pharmaceutically acceptable salt thereof.

18. A method of treating a disease or condition mediated by Trypanosoma congolense or active Trypanosoma vegetative in a subject, comprising administering to the subject a compound according to any one of items 1 to 17.

19. The method of claim 18, wherein the disease or disorder is trypanosomiasis.

20. A method of treating a disease or condition mediated by Trypanosoma cruzi in a subject, comprising administering to the subject a compound according to any one of items 1 to 17.

21. The method of claim 20, wherein the disease or disorder is Chagas disease.

Claims (13)

1. Compounds, selected from: (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborphanecyclopentane-6-carbonyl)-L-valine (6-(trifluoromethyl)pyridin-3-yl)methyl ester; (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborphanecyclopentane-6-carbonyl)-L-valine 4-fluorobenzyl ester; (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhexacyclopentane-6-carbonyl)-L-valine 4,4-difluorocyclohexyl ester; and (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborane-6-carbonyl)-L-valine tetrahydro-2H-pyran-4-yl ester Or its pharmaceutically acceptable salt. 2. The compound of claim 1, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborphanecyclopentane-6-carbonyl)-L-valine (6-(trifluoromethyl)pyridin-3-yl)methyl ester; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhecyclopentane-6-carbonyl)-L-valine 4-fluorobenzyl ester; or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhexacyclopentane-6-carbonyl)-L-valine 4,4-difluorocyclohexyl ester; or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhecyclopentane-6-carbonyl)-L-valine tetrahydro-2H-pyran-4-yl ester; or a pharmaceutically acceptable salt thereof. 6. Use of the compound in the preparation of a medicament for treating a parasitic disease in a subject, wherein the compound is selected from the following compounds: (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborphanecyclopentane-6-carbonyl)-L-valine (6-(trifluoromethyl)pyridin-3-yl)methyl ester; (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborphanecyclopentane-6-carbonyl)-L-valine 4-fluorobenzyl ester; (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhexacyclopentane-6-carbonyl)-L-valine 4,4-difluorocyclohexyl ester; and (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborane-6-carbonyl)-L-valine tetrahydro-2H-pyran-4-yl ester Or its pharmaceutically acceptable salt. 7. The use as claimed in claim 6, wherein the disease caused by the parasite involves a parasite selected from the group consisting of Trypanosoma cruzi, Trypanosoma congo, Trypanosoma vivax, and Trypanosoma ivorystrobin. 8. The use as claimed in claim 6, wherein the disease caused by the parasite is trypanosomiasis. 9. The use as claimed in claim 6, wherein the disease caused by the parasite is African trypanosomiasis. 10. The use of claim 6, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborphanecyclopentane-6-carbonyl)-L-valine (6-(trifluoromethyl)pyridin-3-yl) methyl ester; or a pharmaceutically acceptable salt thereof. 11. The use of claim 6, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhecyclopentane-6-carbonyl)-L-valine 4-fluorobenzyl ester; or a pharmaceutically acceptable salt thereof. 12. The use as claimed in claim 6, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhexacyclopentane-6-carbonyl)-L-valine 4,4-difluorocyclohexyl ester; or a pharmaceutically acceptable salt thereof. 13. The use as claimed in claim 6, wherein the compound is (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborhecyclopentane-6-carbonyl)-L-valine tetrahydro-2H-pyran-4-yl ester; or a pharmaceutically acceptable salt thereof.