TREA

Inhibitors of coronavirus protease and methods of use thereof

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Information

  • Patent Application
  • 20050267071
  • Publication Number
    20050267071
  • Date Filed
    November 01, 2004
    20 years ago
  • Date Published
    December 01, 2005
    19 years ago
Information
Abstract
This invention provides organic boron-containing compounds, compositions thereof, and methods of using such compounds and compositions for inhibiting coronavirus protease(s) and for treating infections.
Description
FIELD OF THE INVENTION

The present invention relates to boron-containing compounds that are inhibitors of coronavirus protease and methods of use thereof.


BACKGROUND OF THE INVENTION

Severe Acute Respiratory Syndrome (SARS)


The first cases of Severe Acute Respiratory Syndrome (SARS) appeared at the end of 2002 in Southern China. By May 2003, SARS had spread to other continents through international travel. It is estimated by the World Health Organization that a total of 15,000 people were infected during the outbreak with an average mortality rate of 15%. The actual mortality rate appears to depend on the age of the patient. The fatality ratio is estimated to be less than 1% in persons aged 24 years or younger, 6% in persons aged 25 to 44 years, 15% in persons aged 45 to 64 years, and greater than 50% in persons aged 65 years and older.


SARS patients typically have high fever, malaise, rigor, headache and nonproductive cough or dyspnea and may progress to generalized interstitial infiltrated in the lung, requiring incubation and mechanical ventilation.


The causative agent of SARs is a coronavirus never before seen in humans. The genome of the SARS-associated coronavirus has been sequenced. The genome sequence of the SARS-associated coronavirus reveals that the virus does not belong to any of the known groups of coronaviruses, including two human coronaviruses, HCoV-OC43 and HCoV-229E (Drosten et al., Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome. N. Engl. J. Med. (2003); 348:1967-1976; Marra et al., Science (2003); 300:1399-1404; and Rota et al., Science (2003); 300:1394-1399). The SARS-associated coronavirus genome appears to be closer to the murine, bovine, porcine, and human coronaviruses in Group II and avian coronavirus IBV in Group I (Marra et al.,. Science 300:1399-404 (2003)).


At present, no effective therapy is available for the treatment of SARS.


Boron-Containing Compounds


Boric acid and various boronic acids have been used as inhibitors of β-lactamases (Koehler et al., Biochemistry 10, 2477-2483 (1971); Kiener et al., Biochem. J., 169, 197-204 (1978) (boric acid, phenylboronic acid and m-aminophenylboronate); Beesley et al., Biochem. J., 209, 229-233 (1983) (twelve substituted phenylborinic acids, including 2-formylphenylboronate, 4-formylphenylboronate, and 4-methylphenylboronate; and Amicosante et al., J. Chemotherapy, 1, 394-398 (1989) (boric acid, phenylboronic acid, m-aminophenylboronate and tetraphenylboronic acid)). m-(Dansylamidophenyl)-boronic acid has also been reported to be a submicromolar inhibitor of the Enterobacter cloacae P99 β-lactamase (Dryjanski et al., Biochemistry, 34, 3561-3568 (1995)). In addition, Strynadka and colleagues used the crystallographic structure of a mutant TEM-1 enzyme-penicillin G complex to design a novel alkylboronic acid inhibitor [(1R)-1-acetamido-2-(3-carboxyphenyl)ethane boronic acid] with high affinity for this enzyme. (Strynadka et al., Nat. Struc. Biol., 3, 688-695 (1996)). Various other boronic-acids are known and used as β-lactamase inhibitors. (e.g., Tondi et al., Chemistry & Biology, 8, 593-610 (2001); Martin et al., Bioorganic & Medicinal Chemistry Letters, 4(10), 1229-1234 (1994); Weston et al., J. Med. Chem., 41, 4577-4586 (1998); U.S. Pat. Nos. 6,075,014 and 6,184,363; and U.S. Provisional Patent Application Ser. No. 60/477,636, filed Jun. 10, 2003, and co-pending U.S. patent application Ser. No. 10/866,179, filed Jun. 10, 2004, both entitled “Beta-Lactamase Inhibitors and Methods of Use Thereof”.


No boron-containing compounds have been reported as inhibitors of coronavirus protease inhibitors.


Citation or identification of any references in the “Background of the Invention” or anywhere in the specification of this application is not an admission that such references available as prior art to the present invention.


SUMMARY OF THE INVENTION

The present invention relates to boron-containing compounds.


In one particular embodiment, such compounds are boric acid and boronic acids.


In another particular embodiment, such compounds are organic boron-containing compounds.


In a first preferred embodiment, the compounds are described by formula (1):
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In a second preferred embodiment, the compounds are described by formula (2):
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In a third preferred embodiment, the compounds are described by formula (3):
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In a fourth preferred embodiment, the compounds are described by formula (4):
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In a fifth preferred embodiment, the compounds are described by formula (5):
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In a sixth preferred embodiment, the compounds are described by formula (6):
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In a seventh preferred embodiment, the compounds are described by formula (7):
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In an eighth preferred embodiment, the compounds are described by formula (8):
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In a ninth preferred embodiment, the compounds are described by formula (9):
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In a tenth preferred embodiment, the compounds are described by formula (10):
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In an eleventh preferred embodiment, the compounds are described by formula (11):
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In a twelfth preferred embodiment, the compounds are described by formula (12):
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In a thirteenth preferred embodiment, the compounds are described by formula (13):
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In a fourteenth preferred embodiment, the compounds are described by formula (14):
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In a fifteenth preferred embodiment, the compounds are described by formula (15):
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R1 through R8, l, m, n, P, Q. U, V, W, X, Y, and Z in formulae (1)-(15) can vary as set forth below, in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


The invention also provides a method of inhibiting coronavirus protease(s), particularly coronavirus protease(s) that has one or more serine or threonine residue(s) at or near its active site, more particularly protease of SARS-associated coronavirus. The method comprises contacting the protease(s) with an effective amount of one or more boron-containing compounds, particularly compounds of formulae (1)-(15).


The invention additionally provides a method of treating infections caused by coronavirus, particularly by coronavirus that has protease(s) with one or more serine or threonine residue(s) at or near the protease active site, more particularly by SARS-associated coronavirus. Such method comprises administering to a subject suffering from such infections an effective amount of one or more boron-containing compounds, particularly compounds of formulae (1)-(15).


The invention further provides a method of detecting coronavirus, particularly coronavirus that has protease(s) with one or more serine or threonine residue(s) at or near the protease active site, more particularly by SARS-associated coronavirus. Such method comprises contacting the testing sample obtained from a patient with boron-containing compounds of formulae (1)-(15) that have been (1) tethered to an appropriate surface such that protease that becomes in contact and bound to the tethered compound can be detected; (2) labeled by fluorescent, radioactive or other markers that allow identification of coronavirus protease bound to the compound; or (3) that by any other mean can be used to detect the presence of coronavirus protease.


The invention also provides a pharmaceutical composition comprising one or more boron-containing compounds, particularly compounds of formulae (1)-(15), and a pharmaceutically acceptable carrier.




BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1. shows a sequence alignment of identified SARS-associated coronavirus protease and the MHV protease. Identities are shown in dark grey and similarities in light grey.



FIG. 2. shows an alignment of sequences around the serine cluster for sequences identified by BLAST search with SARS-associated coronavirus protease 3CLpro.




DETAILED DESCRIPTION

Analysis of the SARS-associated coronavirus genome identified the coding region for an essential protease (3CLpro) homologous to that of other coronaviruses. The 3CLpro coding is shown in FIG. 1 and in SEQ ID NO: 1. The highest homology was found with the mouse hepatitis coronavirus picorna 3C-like endopeptidase [MER02029] (MHV Protease) [SEQ ID NO: 2]. The alignment of the two sequences is shown in FIG. 1.


The sequences of the two enzymes are 50% identical (dark grey in FIG. 1) and 72% similar (dark grey and light grey in FIG. 1). These proteases are characterized by a catalytic cysteine (Cys 145) and histidine (His 41) and therefore are classified as cysteine proteases since the nucleophilic catalytic residue is a cysteine. These cysteine proteases are essential to the viral reproductive cycle since they are involved in the processing of all downstream domains of the replicase polyproteins of these viruses (Ziebuhr et al., (2000). Virus-encoded proteinases and proteolytic processing in the Nidovirales. J. Gen. Virol. 81, 853-879). For this reason, inhibition of this enzyme has been shown to inhibit viral replication in mouse hepatitis virus (MHV) infected cells (Kim et al., (1995). Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology 208, 1-8). The cleavage sites for the 3C-like viral proteases that have been studied are highly conserved, the P1 site being exclusively occupied by Gln and the P1′ site by small aliphatic residues (Ser, Ala, Asn, Gly, Cys).


The crystallographic structure of the SARS-associated coronavirus CL3pro protease is available in the public protein database (accession code 1q2w). Analysis of the active site of the protease reveals a cluster of serines (Ser 139, Ser 144 and Ser 147).


The serine cluster in the SARS-associated coronavirus protease 3CLpro is highly conserved in similar proteins from other coronavirus indicating that either the same compound or similar compounds can be used to target this region of the binding site and inhibit these proteases. In addition, the entire region is highly conserved opening the possibility for wide spectrum antivirals targeting this region of the protease. FIG. 2 shows the sequence alignments between residues 121 and 160 for the proteases of twenty different coronaviruses. Conserved serine residues being targeted are boxed. The sequences shown are from the following Genbank accession numbers for protein sequences: SARS-HCV (severe acute respiratory syndrome-human coronavirus): NP—828863 [SEQ ID NO: 3]; MHV ML-10 (murine hepatitis virus strain ML-10): AAF69341 [SEQ ID NO: 4]; MHV A59 (murine hepatitis virus strain A59): NP—740610 [SEQ ID NO: 5]; MHV JHM (murine hepatitis virus strain JHM): P19751 [SEQ ID NO: 6]; MHV-2 (murine hepatitis virus strain 2): AAF19383 [SEQ ID NO: 7]; MHV Penn 97-1 (murine hepatitis virus strain Penn 97-1): AAF69331 [SEQ ID NO: 8]; MHV ML-11 (murine hepatitis virus strain ML-11): AAF68919 [SEQ ID NO: 9]; BCV Quebec (bovine coronavirus strain Quebec): AAL40396 [SEQ ID NO: 10]; BCV LUN (bovine coronavirus strain LUN): AAL57315 [SEQ ID NO: 11]; BCV Mebus (bovine coronavirus strain Mebus): AAA64744 [SEQ ID NO: 12]; BCV ENT (bovine coronavirus strain ENT): NP—742132 [SEQ ID NO: 13]; PEDV-CV777 (porcine epidemic diarrhea virus strain CV777): NP—839959 [SEQ ID NO: 14]; TGEV Purdue-115 (transmissible gastroenteritis virus strain Purdue-115): CAA83979 [SEQ ID NO: 15]; TGEV PUR46-MAD (transmissible gastroenteritis virus strain PUR46-MAD): NP—840003 [SEQ ID NO: 16]; FIPV 79-1146 (feline infectious peritonitis virus strain 79-1146): AAK09095 [SEQ ID NO: 17]; HCV 229E (human coronavirus strain 229E): NP—835346 [SEQ ID NO: 18]; IBV Beaudette (avian infectious bronchitis virus strain Beaudette): NP—740623 [SEQ ID NO: 19]; IBV LX4 (avian infectious bronchitis virus strain LX4): AAQ21584 [SEQ ID NO: 20]; IBV Beaudette CK (avian infectious bronchitis virus strain Beaudette CK): CAC39112 [SEQ ID NO: 21]; IBV BJ (avian infectious bronchitis virus strain BJ): AAP92674 [SEQ ID NO: 22].


Without being bound by any particular theory, serine or threonine, particularly serine cluster, threonine cluster, and serine/threonine cluster, are chosen as a prime target site because the OH groups in serine and threonine residues are highly reactive with boron-containing compounds, particularly boric acid and boronic acids. Moreover, without being bound by any particular theory, since the coronavirus proteases such as SARS-associated coronavirus protease 3CLpro contains a cluster of two or more serines and/or threonines (SARS-associated coronavirus protease contains a cluster of three serines), it is believed that multifunctional boron-containing compounds (i.e., a compound containing two or more boron atoms), particularly multifunctional boronic acids (i.e., a compound containing two or more —B(OH)2 groups) would be even more potent, selective, and hence more effective than the monofunctional boron-containing compounds (i.e., a compound containing only one boron atom).


The boron-containing compounds of the present invention can be organic compounds that contain boron. Non-limiting examples of such boron-containing compounds include arylboronic acid, arylborates, arylboranes, alkylboronic acids, alkyl borates, alkylboranes and boron heterocyclics, and boron-containing compounds disclosed in Koehler et al., Biochemistry 10, 2477-2483 (1971); Kiener et al., Biochem. J., 169, 197-204 (1978); Beesley et al., Biochem. J., 209, 229-233 (1983); Amicosante et al., J. Chemotherapy, 1, 394-398 (1989); Dryjanski et al., Biochemistry, 34, 3561-3568 (1995); Strynadka et al., Nat. Struc. Biol., 3, 688-695 (1996); Tondi et al., Chemistry & Biology, 8, 593-610 (2001); Martin et al., Bioorganic & Medicinal Chemistry Letters, 4(10), 1229-1234 (1994); Weston et al., J. Med. Chem., 41, 4577-4586 (1998); U.S. Pat. Nos. 6,075,014 and 6,184,363; and co-pending U.S. Provisional Patent Application Ser. No. 60/477,636, entitled “Beta-Lactamase Inhibitors and Methods of Use Thereof,” filed: Jun. 10, 2003.


In one particular embodiment, the compound of the present invention is a compound described by formula (A)
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    • wherein T1 comprises a ring structure or any other organic functional group; and
    • B is boron.


Non-limiting examples of T1 include cycloalkyl, cyclic alkene or heterocyclic alkene with one or more substituents R.


In another particular embodiment, the compound of the present invention is a compound described by formula (B)
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    • wherein T1 and T3 each comprises a ring structure or any other organic functional group; and T2 is a linker; and
    • B is boron.


Non-limiting examples of T1 and T3 include cycloalkyl, cyclic alkene or heterocyclic alkene with one or more substituents R.


Non-limiting examples of the linker T2 include di-branched linker such as —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR—, any di-branched cycloalkane, cyclic alkene or heterocyclic alkene with one or more substituents R, —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N— etc; each R independently represents any group, non-limiting examples include hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy) trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3 and —SO2CH3 etc.


Non-limiting examples of cyclic alkene include, benzene, naphthalene, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, indene, fluorene, anthracene and phenanthrene.


Non-limiting examples of heterocyclic alkene include, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, benzofuran, thionaphtene, indole, dibenzofuran, dibenzothiophene, carbazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, coumarin, quinoline, isoquinoline, acridine, phenothiazine and phenazine.


In another particular embodiment, the compound of the present invention is a multifunctional boron-containing compound (i.e., a compound containing two or more boron atoms).


In another particular embodiment, the compound of the present invention is a multifunctional boronic acid (i.e., a compound containing two or more —B(OH)2 groups).


This application includes Tables 1-15 which set forth without limitation representative compounds 1-403. In all cases, when a compound no. is listed in more than row of tables 1-15, it is to be understood that all of the substituents listed for a given compound no. are found together on a single compound. In Table 1, for example, compound no. 1 comprises the groups R1=H, R2=H, R3=—NO2, R4=H, R7=H, R8=H, —X—=—CO—O—, —Y—=—O—CO—, m=0, n=0, and
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All other compounds listed in Tables 1-15 are to be similarly construed.


1. First Preferred Embodiment

In a first preferred embodiment, the compounds are described by formula (1):
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    • wherein R1 through R8, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 1-a

In a more preferred first embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0, 1, or 2;
    • X and Y each independently represents —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)jOR18— (wherein R18 is hydrogen or C1-1 alkyl, and j is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-1 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 1-b

In another more preferred embodiment of the first embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0 or 1;
    • X and Y are each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, 2, 3 or 4 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 1-c

In another more preferred first embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0, 1, or 2;
    • X and Y each independently represents —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)jOR18— (wherein R18 is hydrogen or C1-6 alkyl, and j is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 are H, X is not a —NH—CH2— or —CH2—NH—;
    • (2) when R1=R2=H, X is not —CO—NH—;
    • (3) when Q is 3-boronophenyl, Y is not —CO—NH or —SO2—NH—;
    • (4) when X=—CO—O—, Y=—O—CO—, m=0, n=0 and U is a 1,4-benzene, a 1,4-benzocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13;
    • (5) when R1 through R8 are H, X=—CO—O—, m=n=1, U=1,4-benzene, Y=—O—CO—, Q is not 4-boronophenyl;
    • (6) when R1 through R8 are H, X=—CO—O—, m=n=1, U=1,3-benzene, Y=—O—CO—, Q is not 4-boronophenyl;
    • (7) when R1 through R8 are H, X=—CO—O—, m=n=1, U=1,2-benzene, Y=—O—CO—, Q is not 4-boronophenyl;
    • (8) when R1 through R4 are H, X=—NH—SO2—, m=n=0, U=4-methoxy-1,3-benzene, Y=—N═N—, Q is not 4-(dimethylamino)-1-naphthalenyl; and
    • (9) when R1 is amino, R2 through R4 are H, X=Y=—N═N—, m=n=0, U is 1,4-naphthalene, Q is not 3-boronophenyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 1-d

In another more preferred embodiment of the first embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0 or 1;
    • X and Y are each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, 2, 3 or 4 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 are H, X is not a —NH—CH2— or —CH2—NH—;
    • (2) when R1=R2=H, X is not —CO—NH—;
    • (3) when Q is 3-boronophenyl, Y is not —CO—NH or —SO2—NH—;
    • (4) when X=—CO—O—, Y=—O—CO—, m=0, n=0 and U is a 1,4-benzene, a 1,4-benzocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13;
    • (5) when R1 through R8 are H, X=—CO—O—, m=n=1, U=1,4-benzene, Y=—O—CO—, Q is not 4-boronophenyl;
    • (6) when R1 through R8 are H, X=—CO—O—, m=n=1, U=1,3-benzene, Y=—O—CO—, Q is not 4-boronophenyl;
    • (7) when R1 through R8 are H, X=—CO—O—, m=n=1, U=1,2-benzene, Y=—O—CO—, Q is not 4-boronophenyl;
    • (8) when R1 through R4 are H, X=—NH—SO2—, m=n=0, U=4-methoxy-1,3-benzene, Y=—N═N—, Q is not 4-(dimethylamino)-1-naphthalenyl; and
    • (9) when R1 is amino, R2 through R4 are H, X=Y=—N═N—, m=n=0, U is 1,4-naphthalene, Q is not 3-boronophenyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (1) are set forth in Table 1 below.

TABLE 1Representative Compounds in Formula (1):CompoundNo.R1R2R3R4R5R6R7R8—X——Y—mn 1.HH—NO2HHH—CO—O——O—CO—00 2.HHHH—CO—O——CO—O—00 3.—NO2HHH—CO—O——O—CO—00 4.HHHH—CO—O——O—CO—00 5.HHHH—CO—O——O—CO—00 6.—NO2HHH—CO—O——O—CO—00 7.HHHH—OCH2——CH2O—00 8.HHHH—OCH2——CH2O—00 9.HFHH—NHCH2——CH2NH—0010.HHHHHH—CO—O——CO—O—0111.HHHHHHHH—CO—O——CO—O—1112.HHHHHHHH—O—CO——CO—O—1113.HHHHHHHH—O—CO——CO—O—1114.HHHHHHHH—CO—O——O—CO—1115.HHHHHHHH—CO—O——SO2—NH—1116.HHHHHHHH—CO—O——SO2—NH—1117.HHHH—CO—NH——CO—NH—0018.HHHH—CO—NH——CO—O—0019.HHHH—CO—NH——CO—NH—0020.HHHH—CO—NH——CO—NH—0021.HHHH—CO—NH——CO—NH—0022.HHHH—CO—NH——CO—O—0023.HHHH—CO—NH——CO—O—0024.HHHH—CO—NH——CO—O—0025.HHHH—CO—NH——CO—O—0026.HHHH—CO—NH——CO—O—0027.HHHH—CO—NH——CO—O—0028.HHHH—CO—NH——CO—O—0029.HHHH—CO—NH——CO—O—0030.HHHH—CO—NH——CO—O—0031.HHHH—CO—NH——CO—NH—0032.HHHH—CO—NH——CO—NH—0033.HHHH—CO—NH——CO—NH—0034.HHHH—CO—NH——CO—NH—0035.HHHH—CO—NH——CO—NH—0036.HHHH—CO—NH——CO—NH—00CompoundNo.—U— 1.embedded image 2.embedded image 3.embedded image 4.embedded image 5.embedded image 6.embedded image 7.embedded image 8.embedded image 9.embedded image10.embedded image11.embedded image12.embedded image13.embedded image14.embedded image15.embedded image16.embedded image17.—CH2—18.—CH2—19.embedded image20.embedded image21.embedded image22.embedded image23.embedded image24.embedded image25.embedded image26.embedded image27.embedded image28.embedded image29.embedded image30.embedded image31.embedded image32.embedded image33.embedded image34.embedded image35.embedded image36.embedded image


A most preferred compounds in Formula (1) is
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Additional compounds in Formula (1) are:
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2. Second Preferred Embodiment

In a second preferred embodiment, the compounds are described by formula (2):
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    • wherein R1 through R8, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 2-a

In a more preferred second embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0, 1, or 2;
    • X and Y each independently represents —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)jOR18— (wherein R18 is hydrogen or C1-6 alkyl, and j is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R19 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 2-b

In another more preferred second embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, or 2, or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 2-c

In a more preferred second embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0, 1, or 2;
    • X and Y each independently represents —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-1 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)jOR18— (wherein R18 is hydrogen or C1-6 alkyl, and j is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 represent hydrogen, X is not —NH—CO—, —NH—SO2—, —NH—CH2— or —CH2—NH—;
    • (2) when Q is 3-boronophenyl, Y is not —CO—NH or —SO2—NH—;
    • (3) when X=—CO—O—, Y=—O—CO—, m=0, n=0 and U is a 1,3-benzene, 1,4-benzene, a 1,3-benzocyclic alkene, a 1,4-benzocyclic alkene, a 1,3-benzoheterocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13;
    • (4) when R4 is borono, R1 through R3 and R5 through R8 are H, X=—CO—NH—, Y=—CO—O—, m=n=1, U=—CH2—CH2—CH2—, Q is not 2,5-dioxo-1-pyrrolidinyl; and
    • (5) when R3 is borono, R1, R2 and R5 through R8 are H, X=—CO—NH—, Y=—CO—O—, m=n=1, U=—CH2—CH2—CH2—, Q is not 2,5-dioxo-1-pyrrolidinyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 2-d

In another more preferred second embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, 2, or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C6-4 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 represent hydrogen, X is not —NH—CO—, —NH—SO2—, —NH—CH2— or —CH2—NH—;
    • (2) when Q is 3-boronophenyl, Y is not —CO—NH or —SO2—NH—;
    • (3) when X=—CO—O—, Y=—O—CO—, m=0, n=0 and U is a 1,3-benzene, 1,4-benzene, a 1,3-benzocyclic alkene, a 1,4-benzocyclic alkene, a 1,3-benzoheterocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13;
    • (4) when R4 is borono, R1 through R3 and R5 through R8 are H, X=—CO—NH—, Y=—CO—O—, m=n=1, U=—CH2—CH2—CH2—, Q is not 2,5-dioxo-1-pyrrolidinyl; and
    • (5) when R3 is borono, R1, R2 and R5 through R8 are H, X=—CO—NH—, Y=—CO—O—, m=n=1, U=—CH2—CH2—CH2—, Q is not 2,5-dioxo-1-pyrrolidinyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, the heterocyclic alkene means a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (2) are set forth in Table 2 below.

TABLE 2Representative Compounds in Formula (2):CompoundNo.R1R2R3R4R5R6R7R8—X——Y—mn37.HH—NO2H—CO—O——O—CO—0038.HH—NO2H—CO—O——O—CO—0039.HH—NO2HHHHH—CO—O——O—CO—1140.HH—NO2H—CO—O——O—CO—0041.HHHH—O—CO——CO—O—0042.HH—NO2H—O—CO——CO—O—0043.HH—NO2H—O—CO——CO—O—0044.HH—HH—O—CO——CO—O—0045.HH—NO2H—CO—O——CO—NH—0046.HH—NO2H—CO—O——CO—NH—0047.HHHH—CO—O——CO—NH—0048.HHHH—CO—O——CO—NH—0049.HH—NO2H—CO—NH——CO—NH—0050.HH—NO2H—CO—NH——CO—O—0051.HH—NO2H—CO—NH——CO—NH—0052.HH—NO2H—CO—NH——CO—NH—0053.HH—NO2H—CO—NH——CO—NH—0054.HH—NO2H—CO—NH——CO—O—0055.HH—NO2H—CO—NH——CO—O—0056.HH—NO2H—CO—NH——CO—O—0057.HH—NO2H—CO—NH——CO—O—0058.HH—NO2H—CO—NH——CO—O—0059.HH—NO2H—CO—NH——CO—O—0060.HH—NO2H—CO—NH——CO—O—0061.HH—NO2H—CO—NH——CO—O—0062.HH—NO2H—CO—NH——CO—O—0063.HHHH—O—CO——CO—O—0064.HHHH—O—CO——CO—O—0065.HHHH—O—CO——CO—O—0066.HHHH—O—CO——CO—O—0067.HHHHHHHH—O—CO——CO—O—1168.HHHHHHHH—O—CO——CO—O—1169.HH—NO2HHHHH—CO—O——O—CO—1170.HH—NO2HHHHH—CO—O——SO2—NH—1171.HH—NO2HHHHH—CO—O——SO2—NH—1172.HH—N(CH3)2H—CO—O——O—CO—0073.HH—NO2H—CO—NH——CO—NH—0074.HH—NO2H—CO—NH——CO—NH—0075.HH—NO2H—CO—NH——CO—NH—0076.HH—NO2H—CO—NH——CO—NH—0077.HH—NO2H—CO—NH——CO—NH—0078.HH—NO2H—CO—NH——CO—NH—00CompoundNo.—U——Q37.embedded imageembedded image38.embedded imageembedded image39.embedded imageembedded image40.embedded imageembedded image41.embedded imageembedded image42.embedded imageembedded image43.embedded imageembedded image44.embedded imageembedded image45.embedded imageembedded image46.embedded imageembedded image47.embedded imageembedded image48.embedded imageembedded image49.—CH2—embedded image50.—CH2—embedded image51.embedded imageembedded image52.embedded imageembedded image53.embedded imageembedded image54.embedded imageembedded image55.embedded imageembedded image56.embedded imageembedded image57.embedded imageembedded image58.embedded imageembedded image59.embedded imageembedded image60.embedded imageembedded image61.embedded imageembedded image62.embedded imageembedded image63.embedded imageembedded image64.embedded imageembedded image65.embedded imageembedded image66.embedded imageembedded image67.embedded imageembedded image68.embedded imageembedded image69.embedded imageembedded image70.embedded imageembedded image71.embedded imageembedded image72.embedded imageembedded image73.embedded imageembedded image74.embedded imageembedded image75.embedded imageembedded image76.embedded imageembedded image77.embedded imageembedded image78.embedded imageembedded image


Most preferred compounds in Formula (2) are:
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Additional compounds in Formula (2) are:
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3. Third Preferred Embodiment

In a third preferred embodiment, the compounds are described by formula (3):
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    • wherein R1 through R8, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 3-a

In a more preferred third embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0, 1, or 2;
    • X and Y each independently represents —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)jOR18— (wherein R18 is hydrogen or C1-6 alkyl, and j is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-1 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 3-b

In another more preferred third embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, SO2CH3, —SO2NH2;
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH— or —NH—SO2—;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, 2 or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO— or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 3-c

In another more preferred third embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19H or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n are each independently 0, 1, or 2;
    • X and Y each independently represents —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5, or 6, and j=0, 1, or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)jOR18— (wherein R18 is hydrogen or C1-6 alkyl, and j is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 are H, X is not —CH2—NH—; and
    • (2) when Q is 3-boronophenyl, Y is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 3-d

In another more preferred third embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • R5 through R8 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH— or —NH—SO2—;
    • U represents —(CH2)i or —(CH═CH)j(wherein i=0, 1, 2 or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 are H, X is not —CH2—NH—, and
    • (2) when Q is 3-boronophenyl, Y is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO— or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (3) are set forth in Table 3 below.

TABLE 3Representative Compounds in Formula (3):CompoundNo.R1R2R3R4R5R6R7R8—X——Y—mn 79.HHHH—CO—O——CO—O—00 80.HHHH—CO—O——O—CO—00 81.HHHH—CO—O——O—CO—00 82.HHHH—OCH2——CH2O—00 83.HHHH—OCH2——CH2O—00 84.HFHH—NHCH2——CH2NH—00 85.HHHHHH—CO—O——CO—O—01 86.HHHHHHHH—CO—O——CO—O—11 87.HHHHHHHH—O—CO——CO—O—11 88.HHHHHHHH—O—CO——CO—O—11 89.HHHHHHHH—CO—O——O—CO—11 90.HHHHHHHH—CO—O——SO2—NH—11 91.HHHHHHHH—CO—O——SO2—NH—11 92.HHHH—CO—O——O—CO—00 93.HHHH—CO—NH——CO—NH—00 94.HHHH—CO—NH——CO—O—00 95.HHHH—CO—NH——CO—NH—00 96.HHHH—CO—NH——CO—NH—00 97.HHHH—CO—NH——CO—NH—00 98.HHHH—CO—NH——CO—O—00 99.HHHH—CO—NH——CO—O—00100.HHHH—CO—NH——CO—O—00101.HHHH—CO—NH——CO—NH—00102.HHHH—CO—NH——CO—NH—00103.HHHH—CO—NH——CO—NH—00104.HHHH—CO—NH——CO—NH—00105.HHHH—CO—NH——CO—NH—00106.HHHH—CO—NH——CO—NH—00CompoundNo.—U——Q 79.embedded imageembedded image 80.embedded imageembedded image 81.embedded imageembedded image 82.embedded imageembedded image 83.embedded imageembedded image 84.embedded imageembedded image 85.embedded imageembedded image 86.embedded imageembedded image 87.embedded imageembedded image 88.embedded imageembedded image 89.embedded imageembedded image 90.embedded imageembedded image 91.embedded imageembedded image 92.embedded imageembedded image 93.—CH2—embedded image 94.—CH2—embedded image 95.embedded imageembedded image 96.embedded imageembedded image 97.embedded imageembedded image 98.embedded imageembedded image 99.embedded imageembedded image100.embedded imageembedded image101.embedded imageembedded image102.embedded imageembedded image103.embedded imageembedded image104.embedded imageembedded image105.embedded imageembedded image106.embedded imageembedded image


The most preferred compounds in Formula (3) are:
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54. Fourth Preferred Embodiment

In a fourth preferred embodiment, the compounds are described by formula (4):
embedded image

    • wherein R1 through R6, m, n, Q, and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 4-a

In a more preferred fourth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl;
    • m and n is each independently 0, 1 or 2;
    • X is —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CH═CH—CO—O—, —CH═CH—CO—NH—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 4-b

In another more preferred fourth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0 or 1;
    • X is —CO—O—, —CH═CH—CO—O—, —O—CO—, —CO—NH—, —CH═CH—CO—NH—, —NH—CO—, —CH═N—, —CH═CH—, —NH—CH2—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-1 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 4-c

In another preferred fourth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-1 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl;
    • m and n is each independently 0, 1 or 2;
    • X is —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CH═CH—CO—O—, —CH═CH—CO—NH—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when m=0 and Q is 3-boronophenyl, X is not —CO—NH or —SO2—NH—;
    • (2) when R1 through R4 are H, m=n=0, X is not —CO—O—;
    • (3) when R1=R2=H, X is not —CO—NH—;
    • (4) when X=—CO—O—, R5=H, R6=H, m=1 and n=0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13;
    • (5) when X=—CO—O—, m=0 and n=0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13;
    • (6) when R1 through R4 are H, X=—CO—O— and m=n=0, Q is not 2,5-dioxo-1-pyrrolidinyl;
    • (7) when R1 through R4 are H, X=—CO—O— and m=n=0, Q is not cyclohexyl;
    • (8) when R1 through R4 are H, X=—O—CO— and m=n=0, Q is not cyclopropyl;
    • (9) when R1 through R4 are H, X=—NH—SO2—, m=n=0, Q is not 4-(4,5-dihydro-3-phenyl-1H-pyrazol-1-yl)phenyl;
    • (10) when R1 through R4 are H, X=—NH—SO2—, m=n=0, Q is not 5-(dimethylamino)-1-naphthalenyl;
    • (11) when R1 through R4 are H, X=—NH—CH2— and m=n=0, Q is not phenyl;
    • (12) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not phenyl;
    • (13) when R1 through R4 are H, X=—NH—CO— and m=n=0, Q is not phenyl;
    • (14) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not 4-chloro-3-(4-methyl-1-piperazinyl)phenyl;
    • (15) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not 4-methoxy-3-(4-methyl-1-piperazinyl)phenyl;
    • (16) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not 3-methoxy-4-(4-methyl-1-piperazinyl)phenyl;
    • (17) when R1, R3 through R6 are H, R2 is methoxyl, X=—NH—CO—, m=2, n=0, Q is not phenyl;
    • (18) when R1 through R4 are H, X=—N═N—, m=n=0, Q is not 4-(dimethylamino)phenyl;
    • (19) when R1 is amino, R2 through R4 are H, X=—N═N—, m=n=0, Q is not 1-naphthalenyl;
    • (20) when R1 is amino, R2 through R4 are H, X=—N═N—, m=n=0, Q is not 4-carboxyphenyl; and
    • (21) when R1 through R4 are H, X=—N═N—, m=n=0, Q is not 2-hydroxy-1-naphthalenyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 4-d

In another more preferred fourth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0 or 1;
    • X is —CO—O—, —CH═CH—CO—O—, —O—CO—, —CO—NH—, —CH═CH—CO—NH—, —NH—CO—, —CH═N—, —CH═CH—, —NH—CH2—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R1, represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when m=0 and Q is 3-boronophenyl, X is not —CO—NH or —SO2—NH—;
    • (2) when R1 through R4 are H, m=n=0, X is not —CO—O—;
    • (3) when R1=R2=H, X is not —CO—NH—;
    • (4) when X=—CO—O—, R5=H, R6=H, m=1 and n=0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13;
    • (5) when X=—CO—O—, m=0 and n=0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13;
    • (6) when R1 through R4 are H, X=—CO—O— and m=n=0, Q is not 2,5-dioxo-1-pyrrolidinyl;
    • (7) when R1 through R4 are H, X=—CO—O— and m=n=0, Q is not cyclohexyl;
    • (8) when R1 through R4 are H, X=—O—CO— and m=n=0, Q is not cyclopropyl;
    • (9) when R1 through R4 are H, X=—NH—SO2—, m=n=0, Q is not 4-(4,5-dihydro-3-phenyl-1H-pyrazol-1-yl)phenyl;
    • (10) when R1 through R4 are H, X=—NH—SO2—, m=n=0, Q is not 5-(dimethylamino)-1-naphthalenyl;
    • (11) when R1 through R4 are H, X=—NH—CH2— and m=n=0, Q is not phenyl;
    • (12) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not phenyl;
    • (13) when R1 through R4 are H, X=—NH—CO— and m=n=0, Q is not phenyl;
    • (14) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not 4-chloro-3-(4-methyl-1-piperazinyl)phenyl;
    • (15) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not 4-methoxy-3-(4-methyl-1-piperazinyl)phenyl;
    • (16) when R1 through R4 are H, X=—NH—CO—, m=n=0, Q is not 3-methoxy-4-(4-methyl-1-piperazinyl)phenyl;
    • (17) when R1, R3 through R6 are H, R2 is methoxyl, X=—NH—CO—, m=2, n=0, Q is not phenyl;
    • (18) when R1 through R4 are H, X=—N═N—, m=n=0, Q is not 4-(dimethylamino)phenyl;
    • (19) when R1 is amino, R2 through R4 are H, X=—N═N—, m=n=0, Q is not 1-naphthalenyl;
    • (20) when R1 is amino, R through R4 are H, X=—N═N—, m=n=0, Q is not 4-carboxyphenyl; and
    • (21) when R1 through R4 are H, X=—N═N—, m=n=0, Q is not 2-hydroxy-1-naphthalenyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (4) are set forth in Table 4 below.

TABLE 4Representative Compounds in Formula (4):Com-poundNo.R1R2R3R4R5R6—X—mn107.HHHH—CO—O—00108.HHHH—CO—O—01109.HHHH—CO—O—02110.HHHH—CO—O—00111.HHHH—CO—O—01112.HHHH—CO—O—02113.HHHH—CO—NH—00114.HHHH—CO—NH—01115.HHHH—CO—NH—02116.HHHH—CO—NH—00117.HHHH—CO—NH—01118.HHHH—CO—NH—02119.HHHH—CO—NH—00120.HHHH—CO—NH—01121.HHHH—CO—NH—02122.HHHH—CO—NH—00123.HHHH—CO—NH—01124.HHHH—CO—NH—02125.HHHH—CO—NH—00126.HHHH—CO—NH—01127.HHHH—CO—NH—02128.HHHH—CO—NH—00129.HHHH—CO—NH—01130.HHHH—CO—NH—02131.HHHH—CO—NH—00132.HHHH—CO—NH—01133.HHHH—CO—NH—02134.HHHH—CO—NH—00135.HHHH—CO—NH—01136.HHHH—CO—NH—02137.HHHHembedded image00138.HHHHembedded image00139.HHHHembedded image00140.HHHHembedded image00141.HHHHembedded image00142.HHHHembedded image00143.HHHHembedded image00144.HHHHembedded image00145.HHHHembedded image00146.HHHHembedded image00147.HFHH—CO—O—00CompoundNo.—Q107.embedded image108.embedded image109.embedded image110.embedded image111.embedded image112.embedded image113.embedded image114.embedded image115.embedded image116.embedded image117.embedded image118.embedded image119.embedded image120.embedded image121.embedded image122.embedded image123.embedded image124.embedded image125.embedded image126.embedded image127.embedded image128.embedded image129.embedded image130.embedded image131.embedded image132.embedded image133.embedded image134.embedded image135.embedded image136.embedded image137.embedded image138.embedded image139.embedded image140.embedded image141.embedded image142.embedded image143.embedded image144.embedded image145.embedded image146.embedded image147.embedded image


A most preferred compound in Formula (4) is:
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Additional compounds in Formula (4) are:
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5. Fifth Preferred Embodiment

In a fifth preferred embodiment, the compounds are described by formula (5):
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    • wherein R1 through R6, m, n, Q, and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 5-a

In a more preferred fifth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl;
    • m and n is each independently 0, 1 or 2;
    • X is —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CH═CH—CO—O—, —CH═CH—CO—NH—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R1, represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 5-b

In another more preferred fifth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0 or 1;
    • X is —CO—O—, —CH═CH—CO—O—, —O—CO—, —CO—NH—, —CH═CH—CO—NH—, —NH—CO—, —CH═N—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH— or —NH—SO2—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 5-c

In another more preferred fifth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl;
    • m and n is each independently 0, 1 or 2;
    • X is —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CH═CH—CO—O—, —CH═CH—CO—NH—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when m=0 and Q is 3-boronophenyl, X is not —CO—NH or —SO2—NH—;
    • (2) when R2 and R3 are H, m=n=0, X is not —CH═CH—;
    • (3) when m=0, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —CO—O—;
    • (4) when m=0, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —NH—CO—;
    • (5) when m=0, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —O—CO—;
    • (6) when R5 and R6=H, m=1, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —CO—O—;
    • (7) when R1 through R4 are H, X=—CO—NH—, m=n=0, Q is not phenyl;
    • (8) when R1 and R2 are H, R3 is F, R4 is methyl, X=—CO—NH—, m=n=0, Q is not cyclopropyl;
    • (9) when R1 through R6 are H, X=—CO—NH—, m=3, n=0, Q is not phenyl;
    • (10) when R1 through R6 are H, X=—CH2—CH—, m=1, n=0, Q is not phenyl;
    • (11) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=1, Q is not phenyl;
    • (12) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=0, Q is not pentafluorophenyl;
    • (13) when R1 through R4 are H, X=—CH═CH—, m=0 and n=0, Q is not phenyl; and
    • (14) when R1 through R4 are H, X=—CH═CH—, m=0 and n=0, Q is not 2-boronophenyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 5-d

In another more preferred fifth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0 or 1;
    • X is —CO—O—, —CH═CH—CO—O—, —O—CO—, —CO—NH—, —CH═CH—CO—NH—, —NH—CO—, —CH═N—, —NH—CH2—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH— or —NH—SO2—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when m=0 and Q is 3-boronophenyl, X is not —CO—NH or —SO2—NH—;
    • (2) when R and R3 are H, m=n=0, X is not —CH═CH—,
    • (3) when m=0, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —CO—O—;
    • (4) when m=0, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —NH—CO—;
    • (5) when m=0, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —O—CO—;
    • (6) when R5 and R6=H, m=1, n=0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not —CO—O—;
    • (7) when R1 through R4 are H, X=—CO—NH—, m=n=0, Q is not phenyl;
    • (8) when R1 and R2 are H, R3 is F, R4 is methyl, X=—CO—NH—, m=n=0, Q is not cyclopropyl;
    • (9) when R1 through R6 are H, X=—CO—NH—, m=3, n=0, Q is not phenyl;
    • (10) when R1 through R6 are H, X=—CH2—CH—, m=1, n=0, Q is not phenyl;
    • (11) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=1, Q is not phenyl;
    • (12) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=0, Q is not pentafluorophenyl;
    • (13) when R1 through R4 are H, X=—CH═CH—, m=0 and n=0, Q is not phenyl; and
    • (14) when R1 through R4 are H, X=—CH═CH—, m=0 and n=0, Q is not 2-boronophenyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (5) are set forth in Table 5 below.

TABLE 5Representative Compounds in Formula (5):CompoundNo.R1R2R3R4R5R6-X-mn-Q148.HH—COOHH—NH—CO—00embedded image149.HH—NO2HHH—CO—O—10embedded image150.HH—NO2H—CO—O—00embedded image151.HH—NO2HHH—CO—O—10embedded image152.HHHH—CO—O—00embedded image153.HHHH—CO—O—01embedded image154.HHHH—CO—O—02embedded image155.HHHH—CO—O—00embedded image156.HHHH—CO—O—01embedded image157.HHHH—CO—O—02embedded image158.HHHH—CO—NH—00embedded image159.HHHH—CO—NH—01embedded image160.HHHH—CO—NH—02embedded image161.HHHH—CO—NH—00embedded image162.HHHH—CO—NH—01embedded image163.HHHH—CO—NH—02embedded image164.HHHH—CO—NH—00embedded image165.HHHH—CO—NH—01embedded image166.HHHH—CO—NH—02embedded image167.HHHH—CO—NH—00embedded image168.HHHH—CO—NH—01embedded image169.HHHH—CO—NH—02embedded image170.HHHH—CO—NH—00embedded image171.HHHH—CO—NH—01embedded image172.HHHH—CO—NH—02embedded image173.HHHH—CO—NH—00embedded image174.HHHH—CO—NH—01embedded image175.HHHH—CO—NH—02embedded image176.HHHH—CO—NH—00embedded image177.HHHH—CO—NH—01embedded image178.HHHH—CO—NH—02embedded image179.HHHH—CO—NH—00embedded image180.HHHH—CO—NH—01embedded image181.HHHH—CO—NH—02embedded image182.HHHHembedded image00embedded image183.HHHHembedded image00embedded image184.HHHHembedded image00embedded image185.HHHHembedded image00embedded image186.HHHHembedded image00embedded image187.HHHHembedded image00embedded image188.HHHHembedded image00embedded image189.HHHHembedded image00embedded image190.HHHHembedded image00embedded image191.HHHHembedded image00embedded image192.HH—NO2H—CO—O—00embedded image193.HH—NO2H—CO—O—01embedded image194.HH—NO2H—CO—O—02embedded image195.HH—NO2H—CO—O—00embedded image196.HH—NO2H—CO—O—01embedded image197.HH—NO2H—CO—O—02embedded image198.HH—NO2H—CO—NH—00embedded image199.HH—NO2H—CO—NH—01embedded image200.HH—NO2H—CO—NH—02embedded image201.HH—NO2H—CO—NH—00embedded image202.HH—NO2H—CO—NH—01embedded image203.HH—NO2H—CO—NH—02embedded image204.HH—NO2H—CO—NH—00embedded image205.HH—NO2H—CO—NH—01embedded image206.HH—NO2H—CO—NH—02embedded image207.HH—NO2H—CO—NH—00embedded image208.HH—NO2H—CO—NH—01embedded image209.HH—NO2H—CO—NH—02embedded image210.HH—NO2H—CO—NH—00embedded image211.HH—NO2H—CO—NH—01embedded image212.HH—NO2H—CO—NH—02embedded image213.HH—NO2H—CO—NH—00embedded image214.HH—NO2H—CO—NH—01embedded image215.HH—NO2H—CO—NH—02embedded image216.HH—NO2H—CO—NH—00embedded image217.HH—NO2H—CO—NH—01embedded image218.HH—NO2H—CO—NH—02embedded image219.HH—NO2H—CO—NH—00embedded image220.HH—NO2H—CO—NH—01embedded image221.HH—NO2H—CO—NH—02embedded image222.HH—NO2Hembedded image00embedded image223.HH—NO2Hembedded image00embedded image224.HH—NO2Hembedded image00embedded image225.HH—NO2Hembedded image00embedded image226.HH—NO2Hembedded image00embedded image227.HH—NO2Hembedded image00embedded image228.HH—NO2Hembedded image00embedded image229.HH—NO2Hembedded image00embedded image230.HH—NO2Hembedded image00embedded image231.HH—NO2Hembedded image00embedded image


The most preferred compounds in Formula (5) are:
embedded imageembedded imageembedded imageembedded imageembedded imageembedded imageembedded imageembedded image


Additional compounds in Formula (5) are:
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6. Sixth Preferred Embodiment

In a sixth preferred embodiment, the compounds are described by formula (6):
embedded image

    • wherein R1 through R6, m, n, Q and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 6-a

In a more preferred sixth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0, 1 or 2;
    • X is —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CH═CH—CO—O—, —CH═CH—CO—NH—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 6-b

In another more preferred sixth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0 or 1;
    • X is —CO—O—, —CH═CH—CO—O—, —O—CO—, —CO—NH—, —CH═CH—CO—NH—, —NH—CO—, —CH═N—, —CH═CH—, —NH—CH2—, —CH2—NH—, —CH2—O—, —SO2—O—, —O—SO2—, —SO2—NH—, or —NH—SO2—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 6-c

In another more preferred sixth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0, 1 or 2;
    • X is —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CH═CH—CO—O—, —CH═CH—CO—NH—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-1 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 are H, X is not —CH2—NH—;
    • (2) when m=0 and Q is 3-boronophenyl, X is not —CO—NH or —SO2—NH—;
    • (3) when R1 through R4 are H, X=—NH—CO—, m=0 and n=1, Q is not phenyl;
    • (4) when R1 through R4 are H, X=—NH—CO—, m=0 and n=0, Q is not phenyl;
    • (5) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=1, Q is not phenyl;
    • (6) when R1 through R6 are H, X=—NH—CH2—, m=2 and n=1, Q is not phenyl;
    • (7) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=1, Q is not 10-(hydroxymethyl)-9-anthracenyl;
    • (8) when R1 through R4 are H, X=—NH—CH2—, m=n=0, Q is not phenyl;
    • (9) when R1 through R8 are H, X=—CH2—NH—, m=n=1, U is 1,3-benzene, Y=Z=—NH—CH2—, Q is not 2-boronophenyl; and
    • (10) when R1 through R6 are H, X=—CO—O—, m=1 and n=0, Q is not 4-methoxyphenyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 6-d

In another more preferred sixth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • R5 and R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl;
    • m and n is each independently 0 or 1;
    • X is —CO—O—, —CH═CH—CO—O—, —O—CO—, —CO—NH—, —CH═CH—CO—NH—, —NH—CO—, —CH═N—, —CH═CH—, —NH—CH2—, —CH2—NH—, —CH2—O—, —SO2—O—, —O—SO2—, —SO2—NH—, or —NH—SO2—;
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R1 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when R1 through R4 are H, X is not —CH2—NH—;
    • (2) when m=0 and Q is 3-boronophenyl, X is not —CO—NH or —SO2—NH—;
    • (3) when R1 through R4 are H, X=—NH—CO—, m=0 and n=1, Q is not phenyl;
    • (4) when R1 through R4 are H, X=—NH—CO—, m=0 and n=0, Q is not phenyl;
    • (5) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=1, Q is not phenyl;
    • (6) when R1 through R6 are H, X=—NH—CH2—, m=2 and n=1, Q is not phenyl;
    • (7) when R1 through R4 are H, X=—NH—CH2—, m=0 and n=1, Q is not 10-(hydroxymethyl)-9-anthracenyl;
    • (8) when R1 through R4 are H, X=—NH—CH2—, m=n=0, Q is not phenyl;
    • (9) when R1 through R8 are H, X=—CH2—NH—, m=n=1, U is 1,3-benzene, Y=Z=—NH—CH2—, Q is not 2-boronophenyl; and
    • (10) when R1 through R6 are H, X=—CO—O—, m=1 and n=0, Q is not 4-methoxyphenyl.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (6) are set forth in Table 6 below.

TABLE 6Representative Compounds in Formula (6):CompoundNo.R1R2R3R4R5R6-X-mn-Q232.HHHH—CO—O—00embedded image233.HHHH—CO—O—01embedded image234.HHHH—CO—O—02embedded image235.HHHH—CO—O—00embedded image236.HHHH—CO—O—01embedded image237.HHHH—CO—O—02embedded image238.HHHH—CO—NH—00embedded image239.HHHH—CO—NH—01embedded image240.HHHH—CO—NH—02embedded image241.HHHH—CO—NH—00embedded image242.HHHH—CO—NH—01embedded image243.HHHH—CO—NH—02embedded image244.HHHH—CO—NH—00embedded image245.HHHH—CO—NH—01embedded image246.HHHH—CO—NH—02embedded image247.HHHH—CO—NH—00embedded image248.HHHH—CO—NH—01embedded image249.HHHH—CO—NH—02embedded image250.HHHH—CO—NH—00embedded image251.HHHH—CO—NH—01embedded image252.HHHH—CO—NH—02embedded image253.HHHH—CO—NH—00embedded image254.HHHH—CO—NH—01embedded image255.HHHH—CO—NH—02embedded image256.HHHH—CO—NH—00embedded image257.HHHH—CO—NH—01embedded image258.HHHH—CO—NH—02embedded image259.HHHH—CO—NH—00embedded image260.HHHH—CO—NH—01embedded image261.HHHH—CO—NH—02embedded image262.HHHHembedded image00embedded image263.HHHHembedded image00embedded image264.HHHHembedded image00embedded image265.HHHHembedded image00embedded image266.HHHHembedded image00embedded image267.HHHHembedded image00embedded image268.HHHHembedded image00embedded image269.HHHHembedded image00embedded image270.HHHHembedded image00embedded image271.HHHHembedded image00embedded image


The most preferred compounds in Formula (6) are:
embedded image


7. Seventh Preferred Embodiment

In a seventh preferred embodiment, the compounds are described by formula (7):
embedded image

    • wherein R1 through R6, m, n, Q, U, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 7-a

In a more preferred seventh embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R3 through R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5 or 6, and j=0, 1 or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, —CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C4-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 7-b

In another more preferred seventh embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R3 through R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m or n is each independently 0 or 1;
    • X is —CO—O—, —CH2—O—CO—, —CO—NH—, —CH2—O—NH—, —CH2—CH2, —CH═CH—, —CH2—O—, —CH═N—, or —CH2—NH—;
    • Y is —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N=═N—;
    • W is oxygen or lone-pair electrons;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, 2 or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (7) are set forth in Table 7 below.

TABLE 7Representative Compounds in Formula 7:CompoundNo.R1R2R3R4R5R6W-X--Y-mn-U--Q272.HHHHHH—CH2O——OCH2—11embedded imageembedded image273.HH—CO—O——O—CO—00embedded imageembedded image274.HH—CO—O——CO—O—00embedded imageembedded image275.HH—CO—NH——CO—NH—00—CH2—embedded image276.HH—CO—NH——CO—NH—00—CH2—embedded image277.HH—CO—NH——CO—NH—00embedded imageembedded image278.HH—CO—NH——CO—NH—00embedded imageembedded image279.HHHHHHO—CH2O——OCH2—11embedded imageembedded image280.HHO—CO—O——O—CO—00embedded imageembedded image281.HHO—CO—O——CO—O—00embedded imageembedded image282.HHO—CO—NH——CO—NH—00—CH2—embedded image283.HHO—CO—NH——CO—NH—00—CH2—embedded image284.HHO—CO—NH——CO—NH—00embedded imageembedded image285.HHO—CO—NH——CO—NH—00embedded imageembedded image


The most preferred compounds in Formula (7) are:
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58. Eighth Preferred Embodiment

In an eighth preferred embodiment, the compounds are described by formula (8):
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    • wherein R1 through R6, m, n, Q, U, V, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 8-a

In a more preferred eighth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R3 through R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5 or 6, and j=0, 1 or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, —CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 8-b

In another more preferred eighth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R3 through R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m or n is each independently 0 or 1;
    • X is —CO—O—, —CH2—O—CO—, —CO—NH—, —CH2—O—NH—, —CH2—CH2, —CH═CH—, —CH2—O—, —CH═N—, or —CH2—NH—;
    • Y is —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • U represents —(CH2)i or —(CH═CH)i (wherein i=0, 1, 2 or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-1 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (8) are set forth in Table 8 below.

TABLE 8Representative Compounds in Formula 8:CompoundNo.R1R2R3R4R5R6W-X--Y-mn-U--Q286.HHHHHH—CH2O——OCH2—11embedded imageembedded image287.HH—CO—O——O—CO—00embedded imageembedded image288.HH—CO—O——CO—O—00embedded imageembedded image289.HH—CO—NH——CO—NH—00—CH2—embedded image290.HH—CO—NH——CO—NH—00—CH2—embedded image291.HH—CO—NH——CO—NH—00embedded imageembedded image292.HH—CO—NH——CO—NH—00embedded imageembedded image293.HHHHHHO—CH2O——OCH2—11embedded imageembedded image294.HHO—CO—O——O—CO—00embedded imageembedded image295.HHO—CO—O——CO—O—00embedded imageembedded image296.HHO—CO—NH——CO—NH—00—CH2—embedded image297.HHO—CO—NH——CO—NH—00—CH2—embedded image298.HHO—CO—NH——CO—NH—00embedded imageembedded image299.HHO—CO—NH——CO—NH—00embedded imageembedded image


The most preferred compounds in Formula (8) are:
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9. Ninth Preferred Embodiment

In a ninth preferred embodiment, the compounds are described by formula (9):
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    • wherein R1 through R4, l, m, n, P, Q, V, W. X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 9-a

In a more preferred ninth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m and n is each independently 0, 1 or 2;
    • X, Y and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-1 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 9-b

In another more preferred ninth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-1 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


C. Preferred Embodiment 9-c

In another more preferred ninth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m and n is each independently 0, 1 or 2;
    • X, Y and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 9-d

In another more preferred ninth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (9) are set forth in Table 9 below.

TABLE 9Representative Compounds in Formula (9):CompoundNo.R1R2R3R4-X--Y--Z-lmn300.HHHH—CO—O——O—CO——O—CO—000301.HHHH—CO—O——O—CO——O—CO—000302.HHHH—CO—O——O—CO——O—CO—222303.HHHH—CH2O——OCH2——OCH2—000304.HHHH—CO—O——NH—CO——CO—O—000305.HHHH—O—CO——NH—CO——CO—O—000306.HHHH—O—CO——NH—CO——CO—O—000307.HHHH—CO—O——CO—NH——CO—O—010308.HHHH—CO—O——CO—NH——CO—O—010Compound No.-P-Qembedded image300.embedded imageembedded imageembedded image301.embedded imageembedded imageembedded image302.embedded imageembedded imageembedded image303.embedded imageembedded imageembedded image304.embedded imageembedded imageembedded image305.embedded imageembedded imageembedded image306.embedded imageembedded imageembedded image307.embedded imageembedded imageembedded image308.embedded imageembedded imageembedded image


The most preferred compounds in Formula (9) are:
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10. Tenth Preferred Embodiment

In a tenth preferred embodiment, the compounds are described by formula (10):
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    • wherein R1 through R4, l, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 10-a

In a more preferred tenth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m and n is each independently 0, 1 or 2;
    • X, Y and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-1 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 10-b

In another more preferred tenth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —CH═N—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—. Y or Z is not —CO—NH or —SO2—NH—;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C6-4 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO— or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 10-c

In another more preferred tenth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m and n is each independently 0, 1 or 2;
    • X, Y and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • when R1 through R4 represent hydrogen, X is not —NH—CO— or —NH—SO2—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 10-d

In another more preferred tenth embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —CH═N—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—. Y or Z is not —CO—NH or —SO2—NH—;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • when R1 through R4 represent hydrogen, X is not —NH—CO— or —NH—SO2—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO— or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (10) are set forth in Table 10 below.

TABLE 10Representative Compounds in Formula (10):CompoundNo.R1R2R3R4-X--Y--Z-lmn309.HHHH—CO—O——O—CO——O—CO—000310.HHHH—CO—O——O—CO——O—CO—000311.HHHH—CO—O——O—CO——O—CO—222312.HHHH—CH2O——OCH2——OCH2—000313.HHHH—CO—O——NH—CO——CO—O—000314.HHHH—O—CO——NH—CO——CO—O—000315.HHHH—O—CO——NH—CO——CO—O—000316.HHHH—CO—O——O—CO——CO—O—010317.HHHH—CO—O——O—CO——CO—O—010318.HH—NO2H—CO—O——O—CO——O—CO—000319.HH—NO2H—CO—O——O—CO——O—CO—000320.HH—NO2H—CO—O——O—CO——O—CO—222321.HH—NO2H—CH2O——OCH2——OCH2—000322.HH—NO2H—CO—O——NH—CO——CO—O—000323.HH—NO2H—O—CO——NH—CO——CO—O—000324.HH—NO2H—O—CO——NH—CO——CO—O—000325.HH—NO2H—CO—O——O—CO——CO—O—010326.HH—NO2H—CO—O——O—CO——CO—O—010Compound No.-P-Qembedded image309.embedded imageembedded imageembedded image310.embedded imageembedded imageembedded image311.embedded imageembedded imageembedded image312.embedded imageembedded imageembedded image313.embedded imageembedded imageembedded image314.embedded imageembedded imageembedded image315.embedded imageembedded imageembedded image316.embedded imageembedded imageembedded image317.embedded imageembedded imageembedded image318.embedded imageembedded imageembedded image319.embedded imageembedded imageembedded image320.embedded imageembedded imageembedded image321.embedded imageembedded imageembedded image322.embedded imageembedded imageembedded image323.embedded imageembedded imageembedded image324.embedded imageembedded imageembedded image325.embedded imageembedded imageembedded image326.embedded imageembedded imageembedded image


Most preferred compounds in Formula (10) are:
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Additional compounds in Formula (10) are:
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11. Eleventh Preferred Embodiment

In an eleventh preferred embodiment, the compounds are described by formula (11):
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    • wherein R1 through R4, l, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 11-a

In a more preferred eleventh embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m and n is each independently 0, 1 or 2;
    • X, Y and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C6-4 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 11-b

In another more preferred eleventh embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —CH═N—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-1 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12[wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 11-c

In another more preferred eleventh embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m and n is each independently 0, 1 or 2;
    • X, Y and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • (1) when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—; and
    • (2) when R1 through R4 are H, X=—CH2—NH—, l=m=n=2, V is a nitrogen, Y=Z=—NH—CH2—, P and Q is not 2-boronophenyl at the same time.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 11-d

In another more preferred eleventh embodiment,

    • R1 through R4 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —CH═N—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • (1) when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—; and
    • (2) when R1 through R4 are H, X=—CH2—NH—, l=m=n=2, V is a nitrogen, Y=Z=—NH—CH2—, P and Q is not 2-boronophenyl at the same time.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (11) are set forth in Table 11 below.

TABLE 11Representative Compounds in Formula (11):CompoundNo.R1R2R3R4-X--Y--Z-lmn327.HHHH—CO—O——O—CO——O—CO—000328.HHHH—CO—O——O—CO——O—CO—000329.HHHH—CO—O——O—CO——O—CO—222330.HHHH—CH2O——OCH2——OCH2—000331.HHHH—CO—O——NH—CO——CO—O—000332.HHHH—O—CO——NH—CO——CO—O—000333.HHHH—O—CO——NH—CO——CO—O—000334.HHHH—CO—O——CO—NH——CO—O—010335.HHHH—CO—O——CO—NH——CO—O—010Compound No.-P-Qembedded image327.embedded imageembedded imageembedded image328.embedded imageembedded imageembedded image329.embedded imageembedded imageembedded image330.embedded imageembedded imageembedded image331.embedded imageembedded imageembedded image332.embedded imageembedded imageembedded image333.embedded imageembedded imageembedded image334.embedded imageembedded imageembedded image335.embedded imageembedded imageembedded image


The most preferred compounds in Formula (11) are:
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12. Twelfth Preferred Embodiment

In a twelfth preferred embodiment, the compounds are described by formula (12):
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    • wherein R1 through R2, l, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 12-a

In a more preferred twelfth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons.


V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);

    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 12-b

In another more preferred twelfth embodiment,

    • R1 and R1 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 12-c

In another more preferred twelfth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons.
    • V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-1 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 12-d

In another more preferred twelfth embodiment,

    • R1 and R1 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR2)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-1 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (12) are set forth in Table 12 below.

TABLE 12Representative Compounds in Formula (12):CompoundNo.R1R2W-X--Y--Z-lmn336.HH—CO—O——O—CO——O—CO—000337.HH—CO—O——O—CO——O—CO—000338.HH—CO—O——O—CO——O—CO—222339.HH—CH2O——OCH2——OCH2—000340.HH—CO—O——NH—CO——CO—O—000341.HH—O—CO——NH—CO——CO—O—000342.HH—O—CO——NH—CO——CO—O—000343.HH—CO—O——CO—NH——CO—O—010344.HH—CO—O——CO—NH——CO—O—010345.HHO—CO—O——CO—NH——O—CO—000346.HHO—CO—O——O—CO——O—CO—000347.HHO—CO—O——O—CO——O—CO—222348.HHO—CH2O——OCH2——OCH2—000349.HHO—CO—O——NH—CO——CO—O—000350.HHO—O—CO——NH—CO——CO—O—000351.HHO—O—CO——NH—CO——CO—O—000352.HHO—CO—O——CO—NH——CO—O—010353.HHO—CO—O——CO—NH——CO—O—010Compound No.-P-Qembedded image336.embedded imageembedded imageembedded image337.embedded imageembedded imageembedded image338.embedded imageembedded imageembedded image339.embedded imageembedded imageembedded image340.embedded imageembedded imageembedded image341.embedded imageembedded imageembedded image342.embedded imageembedded imageembedded image343.embedded imageembedded imageembedded image344.embedded imageembedded imageembedded image345.embedded imageembedded imageembedded image346.embedded imageembedded imageembedded image347.embedded imageembedded imageembedded image348.embedded imageembedded imageembedded image349.embedded imageembedded imageembedded image350.embedded imageembedded imageembedded image351.embedded imageembedded imageembedded image352.embedded imageembedded imageembedded image353.embedded imageembedded imageembedded image


The most preferred compounds in Formula (12) are:
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13. Thirteenth Preferred Embodiment

In a thirteenth preferred embodiment, the compounds are described by formula (13):
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    • wherein R1 through R2, l, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 13-a

In a more preferred thirteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons.


V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);

    • P and Q each independently represents —CHCHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 13-b

In another more preferred thirteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 13-c

In another more preferred thirteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons.


V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);

    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R1 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 13-d

In another more preferred thirteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (13) are set forth in Table 13 below.

TABLE 13Representative Compounds in Formula (13):CompoundNo.R1R2W-X--Y--Z-lmn354.HH—CO—O——O—CO——O—CO—000355.HH—CO—O——O—CO——O—CO—000356.HH—CO—O——O—CO——O—CO—222357.HH—CH2O——OCH2——OCH2—000358.HH—CO—O——NH—CO——CO—O—000359.HH—O—CO——NH—CO——CO—O—000360.HH—O—CO——NH—CO——CO—O—000361.HH—CO—O——CO—NH——CO—O—010362.HH—CO—O——CO—NH——CO—O—010363.HHO—CO—O——CO—NH——O—CO—000364.HHO—CO—O——O—CO——O—CO—000365.HHO—CO—O——O—CO——O—CO—222366.HHO—CH2O——OCH2——OCH2—000367.HHO—CO—O——NH—CO——CO—O—000368.HHO—O—CO——NH—CO——CO—O—000369.HHO—O—CO——NH—CO——CO—O—000370.HHO—CO—O——CO—NH——CO—O—010371.HHO—CO—O——CO—NH——CO—O—010Compound No.-P-Qembedded image354.embedded imageembedded imageembedded image355.embedded imageembedded imageembedded image356.embedded imageembedded imageembedded image357.embedded imageembedded imageembedded image358.embedded imageembedded imageembedded image359.embedded imageembedded imageembedded image360.embedded imageembedded imageembedded image361.embedded imageembedded imageembedded image362.embedded imageembedded imageembedded image363.embedded imageembedded imageembedded image364.embedded imageembedded imageembedded image365.embedded imageembedded imageembedded image366.embedded imageembedded imageembedded image367.embedded imageembedded imageembedded image368.embedded imageembedded imageembedded image369.embedded imageembedded imageembedded image370.embedded imageembedded imageembedded image371.embedded imageembedded imageembedded image


The most preferred compounds in Formula (13) are:
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14. Fourteenth Preferred Embodiment

In a fourteenth preferred embodiment, the compounds are described by formula (14):
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    • wherein R1 through R2, l, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 14-a

In a more preferred fourteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons.


V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);

    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 14-b

In another more preferred fourteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


c. Preferred Embodiment 14-c

In another more preferred fourteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons.


V represents nitrogen, —CH═C═, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR11)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);

    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R1 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


d. Preferred Embodiment 14-d

In another more preferred fourteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • l, m, and n is each independently 0, 1, or 2;
    • X, Y, and Z is each independently —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH═CH—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • V represents a nitrogen, —CH2—CH═, —CH2—CH2—CH═, —CHCH3—CH═, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • P and Q each independently represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • with the proviso that,
    • when P or Q is 3-boronophenyl, Y or Z is not —CO—NH or —SO2—NH—.


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (14) are set forth in Table 14 below.

TABLE 14Representative Compounds in Formula (14):CompoundNo.R1R2W-X--Y--Z-lmn372.HH—CO—O——O—CO——O—CO—000373.HH—CO—O——O—CO——O—CO—000374.HH—CO—O——O—CO——O—CO—222375.HH—CH2O——OCH2——OCH2—000376.HH—CO—O——NH—CO——CO—O—000377.HH—O—CO——NH—CO——CO—O—000378.HH—O—CO——NH—CO——CO—O—000379.HH—CO—O——CO—NH——CO—O—010380.HH—CO—O——CO—NH——CO—O—010381.HHO—CO—O——CO—NH——O—CO—000382.HHO—CO—O——O—CO——O—CO—000383.HHO—CO—O——O—CO——O—CO—222384.HHO—CH2O——OCH2——OCH2—000385.HHO—CO—O——NH—CO——CO—O—000386.HHO—O—CO——NH—CO——CO—O—000387.HHO—O—CO——NH—CO——CO—O—000388.HHO—CO—O——CO—NH——CO—O—010389.HHO—CO—O——CO—NH——CO—O—010Compound No.-P-Qembedded image372.embedded imageembedded imageembedded image373.embedded imageembedded imageembedded image374.embedded imageembedded imageembedded image375.embedded imageembedded imageembedded image376.embedded imageembedded imageembedded image377.embedded imageembedded imageembedded image378.embedded imageembedded imageembedded image379.embedded imageembedded imageembedded image380.embedded imageembedded imageembedded image381.embedded imageembedded imageembedded image382.embedded imageembedded imageembedded image383.embedded imageembedded imageembedded image384.embedded imageembedded imageembedded image385.embedded imageembedded imageembedded image386.embedded imageembedded imageembedded image387.embedded imageembedded imageembedded image388.embedded imageembedded imageembedded image389.embedded imageembedded imageembedded image


The most preferred compounds in Formula (14) are:
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15. Fifteenth Preferred Embodiment

In a fifteenth preferred embodiment, the compounds are described by formula (15):
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    • wherein R1 through R6, m, n, Q, U, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.


a. Preferred Embodiment 15-a

In a more preferred fifteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • R3 through R6 each independently represents hydrogen, C1-1 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m and n is each independently 0 or 1;
    • X and Y is each independently —O—, —NH—, —S—, —SO2—, —CO—, —CH2—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • U represents —(CH2)i—, —(CH═CH)j—, —(CH2CH2O)j— or —(CH2CH2N)j— (wherein i=0, 1, 2, 3, 4, 5 or 6, and j=0, 1 or 2), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, —CH2COOH, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R1 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C6-4 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NHR17 (wherein R17 is hydrogen or C1-6 alkyl), —O(CH2)kOR18— (wherein R18 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), —CONR19OH or —CHR20N(COR19)OH (wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).


b. Preferred Embodiment 15-b

In another more preferred fifteenth embodiment,

    • R1 and R2 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, R14R15N— (wherein R14 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —C(CH3)═NOH, —C(OH)═NOH, —CONHOH, —SO3H, —SO2CH3, or —SO2NH2;
    • R3 through R6 each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Ris, they together form C3-7 cycloalkyl;
    • m or n is each independently 0 or 1;
    • X is —CO—O—, —CH2—O—CO—, —CO—NH—, —CH2—O—NH—, —CH2—CH2, —CH═CH—, —CH2—O—, —CH═N—, or —CH2—NH—;
    • Y is —CO—O—, —O—CO—, —CO—NH—, —NH—CO—, —CH2—CH2—, —CH═CH—, —O—CH2—, —CH2—O—, —NH—CH2—, —CH═N—, —CH2—NH—, —SO2—O—, —O—SO2—, —SO2—NH—, —NH—SO2— or —N═N—;
    • W is oxygen or lone-pair electrons;
    • U represents —(CH2)i or —(CH═CH)j (wherein i=0, 1, 2 or 3 and j=0 or 1), —CHR9— [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10, and each R10 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl);
    • Q represents —CH2CHR11COR12 or —CHR11COR12 [wherein R11 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), —NR19OH (wherein R19 represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N— (wherein R14 and R15 are each independently hydrogen, hydroxyl or C1-6 alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N— (wherein R14 and R15 are each independently hydrogen or C1-6 alkyl), R14R15R16N+G− (wherein R14, R15 and R16 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, C1-6 alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl, —CH═NOH, —CH2NHOH, —C(CH3)═NOH, —C(OH)═NOH, —SO3H, —SO2CH3, —SO2NH2, —CONR19OH or —CHR20N(COR21)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl).


In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form —CO—. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes —O—, —NH—, —S—, —SO2—, —CO—, or —CH2—).


In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).


Non-limiting representative compounds of formula (15) are set forth in Table 15 below.

TABLE 15Representative Compounds in Formula (15):CompoundNo.R1R2R3R4R5R6W-X--Y-mn-U--Q390.HHHHHH—CH2O——OCH2—11embedded imageembedded image391.HH—CO—O——O—CO—00embedded imageembedded image392.HH—CO—O——CO—O—00embedded imageembedded image393.HH—CO—NH——CO—NH—00—CH2—embedded image394.HH—CO—NH——CO—NH—00—CH2—embedded image395.HH—CO—NH——CO—NH—00embedded imageembedded image396.HH—CO—NH——CO—NH—00embedded imageembedded image397.HHHHHHO—CH2O——OCH2—11embedded imageembedded image398.HHO—CO—O——O—CO—00embedded imageembedded image399.HHO—CO—O——CO—O—00embedded imageembedded image400.HHO—CO—NH——CO—NH—00—CH2—embedded image401.HHO—CO—NH——CO—NH—00—CH2—embedded image402.HHO—CO—NH——CO—NH—00embedded imageembedded image403.HHO—CO—NH——CO—NH—00embedded imageembedded image


The most preferred compounds in Formula (15) are:
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Proteases


The compounds of the present invention can be used to inhibit any coronavirus proteases.


In yet another embodiment, such protease has one or more serine or threonine residues at or near the catalytic site.


In a preferred embodiment, such protease has two or more serine or threonine residues at or near the catalytic site.


In a more preferred embodiment, such protease is a cysteine protease, that is, the catalytic residue of the protease is a cysteine.


In a most preferred embodiment, such protease is a 3CLpro.


Coronaviruses


The boronic acid-based compounds of the present invention can be used to treat infections caused by various viruses and can be used to inhibit protease(s) of various viruses. These various viruses are described in, for example, Fields Virology (4th Edition, Lippincott Williams & Wilkins (2001)).


In one embodiment, the virus belongs to the Coronaviridae family. The Coronaviridae family includes two genera, coronavirus and torovirus, which share many features of genome organization and replication strategy but have different virion morphology and genome lengths. The viral envelopes are studded with long, petal shaped spikes, giving coronaviruses the appearance of a crown (Latin, corona), and the nucleocapsids are long, flexible helices. Other characteristics that define Coronaviridae include the 3′-coterminal, nested-set structure of the mRNAs, unique RNA transcription strategy, genome organization, nucleotide sequence homology, and the properties of their structural proteins.


In one particular embodiment, the virus is a coronavirus. Coronaviruses, a genus in the family Coronaviradae, are large, enveloped, positive-stranded RNA viruses that cause highly prevalent diseases in humans and domestic animals. They have the largest genomes of all RNA viruses and replicate by a unique mechanism, which results in a high frequency of recombination. Virions mature by budding at intracellular membranes, and infection with some coronaviruses induces cell fusion. Coronaviruses were first recognized as a distinct virus group by their characteristic virion morphology in negatively stained preparations. Most coronaviruses can be divided into three serologically distinct groups, although SARS-associated virus does not fit into any of these three known groups. Within each serogroup, the viruses are classified according to their natural hosts, nucleotide sequences, and serologic relationships. Most coronaviruses naturally infect only one animal species or, at most, a limited number of closely related species. Virus replication in vivo can be either disseminated, causing systemic infections, or restricted to a few cell types, often the epithelial cells of the respiratory or enteric tracts and macrophages, causing localized infections. Group I coronaviruses include, for example, HCoV-229E (human respiratory coronavirus), TGEV (porcine transmissible gatroenteritis virus), PRCoV (porcine respiratory coronavirus), CCoV (canine coronavirus), FECoV (Feline enteric coronavirus), FIPV (feline infectious peritonitis virus), and RbCoV (rabbit coronavirus). Group II coronaviruses include, for example, HCoV-OC43 (human respiratory coronavirus), MHV (murine hepatitis virus), SDAV (sialodacryoadenitis virus), HEV (porcine hemagglutinating encephalomyelitis virus), and BCoV (bovine coronavirus). Group III coronaviruses include, for example, IBV (avain infectious bronchitis virus) and TCoV (turkey coronavirus). The SARS-associated coronavirus genome appears to be closer to the murine, bovine, porcine, and human coronaviruses in Group II and avian coronavirus IBV in Group I.


Non-limiting examples of the coronavirus include SARS-associated virus, rat coronavirus (ATCC Nos. VR-1410 (Sialodacryoadenitis virus, deposited as rat coronavirus), and VR-882), murine hepatitis virus (ATCC Nos. VR-1426, VR-246, VR-261, VR-764, VR-765 (murine hepatitis virus deposited as mouse hepatitis virus), and VR-766), human enteric coronavirus (ATCC No. VR-1475), feline coronavirus (ATCC Nos. VR-2004, VR-2009. VR-2125, VR-2126, VR-2127, VR-2128, VR-2201, VR-2202, VR-867, VR-989, and VR-990), canine coronavirus (ATCC Nos. VR-2068 and VR-809), infectious bronchitis virus (ATCC Nos. VR-21, VR-22, VR-817, and VR-841), human coronavirus 229E (ATCC No. VR-740), transmissible gastroenteritis virus (porcine respiratory coronavirus) (ATCC Nos. VR-743 and VR-763), human coronavirus OC43 (ATCC No. VR-759), bovine coronavirus (calf diarrheal coronavirus) (ATCC No. VR-874), rat coronavirus (ATCC No. VR-882); turkey coronavirus (ATCC No. VR-911), rabbit coronavirus (ATCC No. VR-920), and transmissible gastroenteritis virus (ATCC No. VR-2384).


Salts and Derivatives


Various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility altering derivatives of the active compound also are encompassed by the present invention. The present invention further includes all individual enantiomers, diastereomers, racemates, and other isomer of the compound. The invention also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein.


Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or inorganic ligands, such as quaternary ammonium salts.


Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate salts of the compound of the present invention.


Prodrugs and active metabolites of compounds disclosed herein are also within the scope of the invention.


A prodrug is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. In vivo, a prodrug is acted on by naturally occurring enzyme(s) resulting in liberation of the pharmacologically active agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.


An active metabolite is a compound which results from metabolism of another compound after administration of the latter to a subject. Metabolites can be identified by techniques well-known in the art.


Formulation and Administration


Suitable dosage forms include but are not limited to oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterille administration, and other dosage forms for systemic delivery of active ingredients. In a preferred embodiment, the dosage form is suitable for injection.


To prepare such pharmaceutical dosage forms, one or more of the aforementioned compounds of formulae (A), (B) and (1)-(15), are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.


For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.


In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.


In some applications, it may be advantageous to utilize the active agent in a “vectorized” form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.


Treatment methods of the present invention using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.


A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.


A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.


Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.


Parenteral administration may comprise any suitable form of systemic delivery or delivery directly to the CNS. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.


Nasal and other mucosal spray formulations (e.g. inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.


Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.


Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.


In addition to the aforementioned ingredients, formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.


The formulation of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.


The subject is preferably an animal, including, but not limited, to an animal such a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, etc., and is more preferably a mammal, and most preferably a human.


EXAMPLES

The following examples illustrate the invention, but are not limiting.


Example 1
Synthesis of Select Compounds

1.1 General Procedure A: Synthesis of Boronobenzoic Acid Esters
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In step (i) of general procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of carboxyl boronic acid derivative A-1 (0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride A-2 as a yellow solid, which was used without further purification.


In step (ii), a solution of the acid chloride A-2 (0.2 mmol, obtained from step (i) above) in 5 mL of anhydrous CH2Cl2 was added dropwise to an ice-cold solution of A-3, anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anhydrous CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was then dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10). The product yielded from step (ii) is A4.


3-(4-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-061)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with p-nitrophenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 42 mg (84% yield) of the desired compound as a white powder, mp: 205-207° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 7.61-7.66 [m, 2H, Ar—H], 8.30-8.35 [m, 2H, Ar—H], 8.78-8.89 [m, 3H, Ar—H].


3-(2-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-062)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with o-nitrophenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 36 mg (72% yield) of the desired compound as a pale yellow powder, mp: 128-130° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 7.52-7.71 [m, 2H, Ar—H], 7.81-7.94 [m, 1H, Ar—H], δ8.13-8.24 [m, 1H, Ar—H], 8.70-8.93 [m, 3H, Ar—H].


3-(3-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-063)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with m-nitrophenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (82% yield) of the desired compound as a light yellow crystal, mp: 185-187C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.72-7.81 [m, 2H, Ar—H], δ8.15-8.29 [m, 2H, Ar—H], 8.76-8.89 [m, 3H, Ar—H).


3-(4-Methoxyphenoxycarbonyl)-5-nitrophenylboronic acid (FL-064)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with p-methoxyphenol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white needle, mp: 67° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 3.74 [s, 3H, OCH3], 6.93-6.99 [m, 2H, Ar—H], 7.19-7.24 [m, 2H, Ar—H], 8.72-8.87 [m, 3H, Ar—H].


3-(4-Ethoxycarbonylphenoxycarbonyl)-5-nitrophenylboronic acid (FL-065)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ethyl 4-hydroxybenzoate (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 51 mg (94% yield) of the desired compound as a white powder, mp: 230-232° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ1.31 [t, 2H, CH2CH3], 4.30 [q, 3H, CH2CH3], 7.50 [d, 2H, Ar—H], 8.05 [d, 2H, Ar—H], 8.78-8.90 μm, 3H, Ar—H].


3-(2-Oxo-benzo[1,3]oxathiol-6-oxycarbonyl)-5-nitrophenylboronic acid (FL-067)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 6-hydroxy-1,3-benzoxathiol-2-one (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 50 mg (92% yield) of the desired compound as a white powder, mp: 145-147° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.28-7.36 [m, 1H, Ar—H], 7.56-7.64 [m, 1H, Ar—H], 7.78-7.86 [m, 1H, Ar—H], 8.72-8.86 [m, 3H, Ar—H].


3-(2-Cyanophenoxycarbonyl)-5-nitrophenylboronic acid (FL-068)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-hydroxybenzonitrile (18 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (92% yield) of the desired compound as a white powder, mp: 248-250° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ7.48-7.57 [m, 1H, Ar—H], 7.62-7.69 [m, 1H, Ar—H], 7.78-7.89 [m, 1H, Ar—H], 7.96-8.01 [m, 1H, Ar—H], 8.83-8.94 [m, 3H, Ar—H].


3-(2-Chloro-6-nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-069)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-6-nitrophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (71% yield) of the desired compound as a yellow needle, mp: 179° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.54-7.72 [m, 1H, Ar—H], 8.01-8.24 [m, 2H, Ar—H], 8.65-8.94 [m, 3H, Ar—H].


3-(2-Ethoxycarbonyl-phenoxycarbonyl)-5-nitrophenylboronic acid (FL-071)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ethyl salicylate (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (64% yield) of the desired compound as a yellow semisolid. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ1.24 [t, 2H, CH2CH3], 4.31 [q, 3H, CH2CH3], 7.41-7.57 [m, 2H, Ar—H], 7.81-8.05 [m, 2H, Ar—H], 8.67-8.93 [m, 3H, Ar—H].


3-(2-Chlorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-072)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with o-chlorophenol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (90% yield) of the desired compound as a white powder, mp: 138-140C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 7.38-7.78 [m, 4H, Ar—H], 8.71-9.04 [m, 3H, Ar—H].


3-(2-Methylphenoxycarbonyl)-5-nitro-phenylboronic acid (FL-073)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with o-cresol (16 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (89% yield) of the desired compound as a yellow powder, mp: 175° C. (dec). 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 2.17 [t, 3H, CH3], 7.21-7.40 [m, 3H, Ar—H], 8.15-8.22 [m, 1H, Ar—H], 8.65-8.91 [m, 3H, Ar—H].


3-(2-Methoxylphenoxycarbonyl)-5-nitrophenylboronic acid (FL-074)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with guaiacol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (92% yield) of the desired compound as a yellow semisolid. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ3.69[s, 3H, OCH3], 7.46-8.03 [m, 4H, Ar—H], 8.64-8.97 [m, 3H, Ar—H].


3-(3-Methylphenoxycarbonyl)-5-nitrophenylboronic acid (FL-075)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with m-cresol (16 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (82% yield) of the desired compound To make compound (1m), was treated according to general procedure A, step (ii), to give 41 mg (91% yield) of the desired compound as a yellow semisolid. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ2.35 [t, 3H, CH3], 7.79-8.30 [m, 4H, Ar—H], 8.71-8.91 [m, 3H, Ar—H].


3-(2,6-Dichlorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-080)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-dichlorophenol (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (80% yield) of the desired compound as a pale yellow powder, mp: 167-169° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.39-7.44 [m, 1H, Ar—H], 7.52-7.67 [m, 2H, Ar—H], 8.83 [s, 1H, Ar—H], 8.94-8.96 [m, 2H, Ar—H].


3-(2-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-081)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-fluorophenol (17 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (85% yield) of the desired compound as a white needle, mp: 144-146C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 7.29-7.53 [m, 4H, Ar—H], 8.80 [s, 1H, Ar—H], 8.89-8.93 [m, 2H, Ar—H].


3-(2,6-Difluorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-082)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-difluorophenol (20 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white powder, mp: 124-126° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ7.23-7.38 [m, 2H, Ar—H], 7.38-7.48 [m, 1H, Ar—H], 8.81 [s, 1H, Ar—H], 8.86-8.96 [m, 2H, Ar—H].


3-(4-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-085)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-fluorophenol (17 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (89% yield) of the desired compound as a white powder, mp: 233-235° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ 7.21-7.42 [m, 4H, Ar—H], 8.76 [s, 1H, Ar—H], 8.83-8.95 [m, 2H, Ar—H].


3-(2,6-Dichlorobenzyloxycarbonyl-5-nitrophenylboronic acid (FL-086)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-dichlorobenzyl alcohol (27 mg, 0.15 mmol) according to general procedure A, step (ii), to give 49 mg (89% yield) of the desired compound as a pale yellow semisolid. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ5.62 [s, 2H, Ar—CH2], 7.26-7.62 [m, 3H, Ar—H], 8.57-8.95 [m, 3H, Ar—H].


3-(4-pyridyloxycarbonyl)-5-nitro-phenylboronic acid (FL-087)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-pyridinol (14 mg, 0.15 mmol) according to general procedure A, step (ii), to give 34 mg (79% yield) of the desired compound as a pale yellow powder, mp: 165° C. (dec). 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ7.43-7.50 [m, 1H, Ar—H], 8.67-8.72 [m, 1H, Ar—H], 8.77-8.86 [m, 3H, Ar—H], 8.86-8.97 [m, 1H, Ar—H].


3-(2-Chloro-3-pyridyloxycarbonyl)-5-nitrophenylboronic acid (FL-089)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-3-pyridinol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 37 mg (77% yield) of the desired compound as a white powder, mp: 146-148° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ7.57-7.63 [m, 1H, Ar—H], 8.05-8.09 [m, 1H, Ar—H], 8.39-8.43 [m, 1H, Ar—H], 8.81 [s, 1H, Ar—H], 8.89-8.94 [m, 2H, Ar—H].


3-(2-Bromo-1-indanoxycarbonyl)-5-nitrophenylboronic acid (FL-090)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-bromo-1-indanol (32 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (71% yield) of the desired compound as a white powder, mp: 177-179C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ3.30 [d, 2H, —CH2—], 4.26[q, 1H, Br—CH—], 5.44 [d, 2H, O—CH—], 7.20-7.32 [m, 4H, Ar—H], 8.78 [s, 1H, Ar—H], 8.86-8.95 [m, 2H, Ar—H].


3-Phenoxycarbonyl-5-nitrophenylboronic acid (FL-092)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with phenol (14 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (91% yield) of the desired compound as a white needle, mp: 139-141° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ 7.28-7.34 [m, 3H, Ar—H], 7.44-7.51 [m, 2H, Ar—H], 8.78 [s, 1H, Ar—H], 8.86-8.92 [m, 2H, Ar—H].


3-(3-Nitrobenzyloxycarbonyl)-5-nitrophenylboronic acid (Compound FL-094)



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In step (i) of procedure A, oxalyl chloride (35 μl, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-nitrobenzyl alcohol (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (82% yield) of the desired compound as a pale yellow powder, mp: 142-144° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ5.46 [s, 2H, Ar—CH2], 7.65-7.70 [m, 1H, Ar—H], 7.93-7.97 [m, 1H, Ar—H], 8.09-8.12 [m, 1H, Ar—H], 8.17-8.21 [m, 1H, Ar—H], 8.62-8.94 [m, 3H, Ar—H].


3-(3-Chlorobenzyloxycarbonyl)-5-nitrophenylboronic acid (FL-095)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-chlorobenzyl alcohol (22 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (88% yield) of the desired compound as a white powder, mp: 91° C. (dec). 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ5.41 [s, 2H, Ar—CH2], 7.41-7.61 [m, 4H, Ar—H], 8.62-8.95 [m, 3H, Ar—H].


3-(2-Bromophenoxycarbonyl)-5-nitro-phenylboronic acid (FL-096)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-bromophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 49 mg (90% yield) of the desired compound as a pale yellow powder, mp: 128-130° C. 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ7.26-7.35 [m, 1H, Ar—H], 7.47-7.56 [m, 2H, Ar—H], 7.76-7.81 [m, 1H, Ar—H], 8.83-8.94 [m, 3H, Ar—H].


3-(1-Benzoyl-1-Phenylmethoxycarbonyl)-5-nitrophenylboronic acid (FL-097)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with benzoin (32 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (71% yield) of the desired compound as a white powder, mp: 237° C. (dec). 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ 7.37-7.55 [m, 3H, Ar—H], 7.58-7.69 [m, 3H, Ar—H], 7.75-7.83 [m, 1H, Ar—H], 7.88-7.94 [m, 1H, Ar—H], 8.07-8.13 [m, 1H, Ar—H), 8.77 [s, 1H, Ar—H], 8.80-8.96 [m, 2H, Ar—H].


3-(3-Boronophenoxycarbonyl)-5-nitrophenylboronic acid (Compound FL-100)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 32 mg (64% yield) of the desired compound as a pale yellow powder, mp: 228-230° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.30-7.36 [m, 1H, Ar—H], 7.41-7.47 [m, 1H, Ar—H], 7.60-7.63 [m, 1H, Ar—H], 7.68-7.73 [m, 1H, Ar—H], 8.76-8.79 [m, 1H, Ar—H], 8.84-8.90 [m, 2H, Ar—H].


3-(3-Boronobenzyloxycarbonyl)-5-nitrophenylboronic acid (FL-101)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 5.39 [s, 2H, Ar—CH2], 7.27-7.84 [m, 4H, Ar—H], 8.79-8.90 [m, 3H, Ar—H].


4-(2-Chloro-6-nitrophenoxycarbonyl)-3-fluorophenylboronic acid (FL-104)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-6-nitrophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (79% yield) of the desired compound as a pale yellow powder, mp: 174-175° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.61-7.36 [m, 1H, Ar—H], 7.71-7.74 [m, 1H, Ar—H], 7.77-7.79 [m, 1H, Ar—H], 8.07-8.11 [m, 2H, Ar—H], 8.18-8.21 [m, 2H, Ar—H].


3-(2,4-Dichloro-6-nitro-phenoxycarbonyl)-5-nitro-phenylboronic acid (FL-107)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,4-dichloro-6-nitrophenol (80%) (39 mg, 0.15 mmol) according to general procedure A, step (ii), to give 52 mg (87% yield) of the desired compound as a pale yellow powder, mp: 184-186° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): 8.34-8.38 [m, 1H, Ar—H], 8.82-8.84 [m, 1H, Ar—H], 8.90-8.91 [m, 1H, Ar—H], 8.94-8.96 [m, 1H, Ar—H].


3-(2,4-Dichloro-6-nitro-phenoxycarbonyl)-5-nitro-phenylboronic acid (FL-132)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 5-chloro-2-(2,4-dichlorophenoxy)phenol (43 mg, 0.15 mmol) according to general procedure A, step (ii), to give 51 mg (71% yield) of the desired compound as a pale yellow powder, mp: 193° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ6.61-6.94 [m, 3H, Ar—H], 7.15-8.07 [m, 3H, Ar—H], 8.71-8.76 [m, 1H, Ar—H], 8.84-8.89 [m, 1H, Ar—H], 8.89-8.96 [m, 1H, Ar—H].


3-(4-Coumarinoxycarbonyl)-5-nitrophenylboronic acid (FL-133)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-hydroxycoumarin (24 mg, 0.15 mmol) according to general procedure A, step (ii), to give 36 mg (67% yield) of the desired compound as a white powder, mp: 230-232° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.12-7.22 [m, 1H, Ar—H], 7.23-7.36 [m, 2H, Ar—H], 7.55-7.64 [m, 1H, Ar—H], 7.72-7.86 [m, 1H, Ar—H], 8.60 [s, 1H, Ar—H], 8.72 [s, 1H, Ar—H], 8.77 [s, 1H, Ar—H].


3-(2,4,6-Trichlorophenoxycarbonyl)-5-nitro-phenylboronic acid (FL-139)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,4,6-trichlorophenol (30 mg, 0.15 mmol) according to general procedure A, step (ii), to give 45 mg (77% yield) of the desired compound as a white powder, mp: 217° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.24 [s, 2H, Ar—H], 8.77-8.80 [m, 1H, Ar—H], 8.90-8.96 [m, 2H, Ar—H].


3-(1-Naphthalenemethoxycarbonyl)-5-nitrophenylboronic acid (FL-148)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1-naphthalenemethanol (24 mg, 0.15 mmol) according to general procedure A, step (ii), to give 38 mg (73% yield) of the desired compound as a pale yellow powder, mp: 230° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 5.84 [s, 2H, Ar—CH2—], 7.47-7.61 [m, 3H, Ar—H], 7.65-7.72 [m, 1H, Ar—H], 7.92-7.99 [m, 1H, Ar—H], 8.02-8.16 [m, 1H, Ar—H], 8.58 [s, 1H, Ar—H], 8.68 [s, 1H, Ar—H], 8.77 [s, 1H, Ar—H].


3-(1,1-Diphenylmethoxycarbonyl)-5-nitrophenylboronic acid (FL-149)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with (40 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (70% yield) of the desired compound as a pale yellow powder, mp: 217° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 5.66 [s, 2H, Ar—CH—], 7.13-7.18 μm, 1H, Ar—CH—], 7.23-7.31 [m, 3H, Ar—H], 7.31-7.46 [m, 5H, Ar—H], 7.48-7.54 [m, 1H, Ar—H], 8.73 [s, 1H, Ar—H], 8.83-8.87 [m, 2H, Ar—H].


3-(2-Naphthoxycarbonyl)-5-nitrophenylboronic acid (FL-151)



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In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-naphthol (22 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (82% yield) of the desired compound as a pale yellow powder, mp: 256° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.42-7.54 [m, 3H, Ar—H], 7.78-8.02 [m, 4H, Ar—H], 8.74-8.79 [m, 1H, Ar—H], 8.80-8.86 [m, 1H, Ar—H], 8.86-8.91 [m, 1H, Ar—H].


3-(3-Boronobenzyloxycarbonyl)-5-nitrophenylboronic acid (Compound FL-171)



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In step (i) of procedure A, oxalyl chloride (35 μl, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 5.39 [s, 2H, Ar—CH2], 7.27-7.84 [m, 4H, Ar—H], 8.79-8.90 [m, 3H, Ar—H].


1.2 General Procedure B: Synthesis of Boronobenzoic Acid Phenylene Esters
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In step (i), oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of compound B-1 (0.2 mmol), 1 drop of DMF and 5 mL of dried CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride B-2 as a solid, which was used without further purification in step (ii).


In step (ii), a suspension of the acid chloride B-2 (0.2 mmol, obtained from step (i) above) in 5 mL of dried THF was added dropwise to an ice-cold solution of B-3 (0.075 mmol), anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10). The product yielded from step (ii) is B-4.


3-Borono-5-nitrobenzoic acid 1,4-phenylene ester (FL-078)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with hydroquinone (9 mg, 0.075 mmol) according to general procedure B, step (ii), to give 32 mg (86% yield) of the desired compound as a white powder, mp: 271-273° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 7.43 [s, 4H, Ar—H], 8.79 [s, 2H, Ar—H], 8.84 [s, 2H, Ar—H], 8.86 [s, 2H, Ar—H].


3-Borono-5-nitrobenzoic acid 2-chloro-1,4-phenylene ester (FL-079)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with chlorohydroquinone (11 mg, 0.075 mmol) according to general procedure B, step (ii), to give 31 mg (78% yield) of the desired compound as a white powder, mp: 264-266° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.46-7.79 [m, 3H, Ar—H], 8.79 [d, 1H, Ar—H], 8.88-8.92 [m, 2H, Ar—H].


4-Borono-2-fluorobenzoic acid 2-chloro-1,4-phenylene ester (FL-103)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with and chlorohydroquinone (11 mg, 0.075 mmol) according to general procedure B, step (ii), to give 26 mg (74% yield) of the desired compound as a pale yellow powder, mp: 228-230° C. 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ6.52-6.55 [m, 1H, Ar—H], 6.68-6.76 [m, 2H, Ar—H], 6.94-7.06 [m, 1H, Ar—H], 7.21-7.34 [m, 1H, Ar—H], 7.57-7.78 [m, 3H, Ar—H], 7.99-8.11 [m, 1H, Ar—H].


3-Borono-5-nitrobenzoic acid 1,3-phenylene ester (FL-106)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with resorcinol (9 mg, 0.075 mmol) according to general procedure B, step (ii), to give 26 mg (70% yield) of the desired compound as a pale yellow powder, mp: 134° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 6.14-6.18 [m, 2H, Ar—H], 7.33-7.45 [m, 2H, Ar—H], 8.75-8.82 [m, 2H, Ar—H], 8.85-8.90 [m, 4H, Ar—H].


3-Borono-5-nitrobenzoic acid 1,2-benzenedimethanol ester (FL-136)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1,2-benzenedimethanol (10 mg, 0.075 mmol) according to general procedure B, step (ii), to give 21 mg (53% yield) of the desired compound as a pale yellow powder, mp: 142° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ 5.64 [s, 4H, CH2], 6.14-6.18 [m, 2H, Ar—H], 7.33-7.45 [m, 4H, Ar—H], 8.77-8.84 [m, 2H, Ar—H], 8.87-8.93 [m, 4H, Ar—H].


3-Borono-5-nitrobenzoic acid 2,3,5,6-tetrachloro-1,4-phenylene ester (FL-141)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted tetrachlorohydroquinone (19 mg, 0.075 mmol) according to general procedure B, step (ii), to give 33 mg (69% yield) of the desired compound as a white powder, mp: 252° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): 8.71-8.75 [m, 2H, Ar—H], 8.93-8.99 [m, 4H, Ar—H].


3-Borono-5-nitrobenzoic acid, 1,4-dihydroxynaphthalene ester (FL-167)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1,4-naphthalenediol (12 mg, 0.075 mmol) according to general procedure B, step (ii), to give 24 mg (59% yield) of the desired compound as a pale yellow powder, mp: 270° C. (dec). 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 6.89 [s, 2H, Ar—H], 7.68-7.74 [m, 2H, Ar—H], 8.08-8.13 [m, 2H, Ar—H], 8.70 [s, 2H, Ar—H], 8.85 [s, 2H, Ar—H], 8.93 [s, 2H, Ar—H].


3-Borono-5-nitrobenzoic acid, 2-tert-butyl-1,4-phenylene ester (FL-169)



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In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with tert-butylhydroquinone (12 mg, 0.075 mmol) according to general procedure B, step (ii), to give 22 mg (43% yield) of the desired compound as a brown powder, mp: 268° C. (dec). 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 1.37 [s, 9H, —CH3], 7.10-7.13 [m, 1H, Ar—H], 7.27-7.31 [m, 1H, Ar—H], 7.51-7.54 [m, 1H, Ar—H], 8.65 [s, 2H, Ar—H], 8.77 [s, 2H, Ar—H], 8.88 [s, 2H, Ar—H].


1.3 General Procedure C: Synthesis of Acyloxyphenylboronic Acids
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To an ice-cold solution of C-1 (0.15 mmol), dried triethyl amine (28 μL, 0.2 mmol) and 10 mL of dried THF was added dropwise a solution of C-2 (0.1 mmol) in 5 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10). The product yielded is C-3.


1,4-Benzenedicarboxylic acid, di 3-boronophenyl ester (Compound FL-156)



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3-Hydroxyphenylboronic acid (21 mg, 0.15 mmol) and terephthaloyl chloride (21 mg, 0.1 mmol) were reacted according to general procedure C, to give 16 mg (51% yield) of the desired compound as a white powder, mp: 214° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.28-7.34 [m, 2H, Ar—H], 7.38-7.46 [m, 2H, Ar—H], 7.59-7.63 [m, 2H, Ar—H], 7.68-7.73 [m, 2H, Ar—H], 8.30 [s, 4H, Ar—H].


1.4 General Procedure D: Synthesis of Amide of Boronoanilines
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To an ice-cold solution of D-1 (0.5 mmol) and NaHCO3 (105 mg, 1.25 mmol) in 10 mL of water and 10 mL of ether was add dropwise D-2 (0.5 mmol) over a period of 30 min. The reaction mixture was kept at 0° C. for 1 h and then stirred at room temperature overnight. It was then extracted twice with 10 mL of ethyl ether. The aqueous solution was acidified with 1N aqueous HCl and extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine solution, dried (Na2SO4) and concentrated. The residue was recrystallized from ethyl acetate/hexane. The product yielded is D-3.


3-(2-Fluorobenzamido)-5-carboxylphenylboronic acid (Compound FL-083)



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2-Fluorobenzoyl chloride (60 μL, 0.5 mmol) and 3-amino-5-carboxylphenylboronic acid (91 mg, 0.5 mmol) were reacted according to general procedure D, to give 94 mg (62% yield) of the desired compound as a white powder, mp: 224-225° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 7.21-7.38 [m, 2H, Ar—H], 7.48-7.72 [m, 2H, Ar—H], 8.12-8.33 [m, 3H, Ar—H].


3-(2-Fluorobenzamido)-5-nitrophenylboronic acid (FL-084)



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2-Fluorobenzoyl chloride (60 μL, 0.5 mmol) and 3-amino-5-nitrophenylboronic acid hydrochloride (109 mg, 0.5 mmol) were reacted according to general procedure D, to give 82 mg (54% yield) of the desired compound as a white powder, mp: 212-214° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.22-7.42 [m, 2H, Ar—H], 7.53-7.63 [m, 1H, Ar—H], 7.64-7.72 [m, 1H, Ar—H], 8.34 [s, 1H, Ar—H], 8.37 [s, 1H, Ar—H], 8.79 [s, 1H, Ar—H].


3-(2,6-Dichlorobenzamido)-5-nitrophenylboronic acid (FL-108)



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2,6-Dichlorobenzoyl chloride (72 μL, 0.5 mmol) and 3-amino-5-carboxylphenylboronic acid hydrochloride (109 mg, 0.5 mmol) were reacted according to general procedure D, to give 113 mg (64% yield) of the desired compound as a white powder, mp: 267° C. (dec). 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.46-7.53 [m, 1H, Ar—H], 7.54-7.60 [m, 2H, Ar—H], 8.27 [s, 1H, Ar—H], 8.40 [s, 1H, Ar—H], 8.74 [s, 1H, Ar—H].


3-(2,6-Dichlorobenzamido)-4-chlorophenylboronic acid (FL-109)



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2,6-Dichlorobenzoyl chloride (72 μL, 0.5 mmol) and 3-amino-4-chlorophenylboronic acid hydrochloride (104 mg, 0.5 mmol) were reacted according to general procedure D, to give 98 mg (57% yield) of the desired compound as a pale yellow powder, mp: 246° C. (dec). 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.41-7.57 [m, 4H, Ar—H], 7.62-7.68 [m, 1H, Ar—H], 7.95-8.01 [m, 1H, Ar—H].


3-(2,6-Dichlorobenzamido)-4-methylphenylboronic acid (FL-110)



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2,6-Dichlorobenzoyl chloride (72 μL, 0.5 mmol) and 3-amino-4-methylphenylboronic acid hydrochloride (94 mg, 0.5 mmol) were reacted according to general procedure D, to give 79 mg (49% yield) of the desired compound as a white powder, mp: 234-236° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ 2.26 [s,3H,—CH3], 7.15-7.25 [m, 1H, Ar—H], 7.40-7.47 [m, 1H, Ar—H], 7.47-7.60 [m, 3H, Ar—H], 7.71-7.77 [m, 1H, Ar—H].


3-Benzamido-5-nitrophenylboronic acid (FL-113)



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Benzoyl chloride (58 μL, 0.5 mmol) and 3-amino-5-nitrophenylboronic acid hydrochloride (109 mg, 0.5 mmol) were reacted according to general procedure D, to give 94 mg (66% yield) of the desired compound as a pale yellow powder, mp: 227-229° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.49-7.54 [m, 2H, Ar—H], 7.56-7.61 [m, 1H, Ar—H], 7.94-7.99 [m, 2H, Ar—H], 8.36 [s, 1H, Ar—H], 8.46 [s, 1H, Ar—H], 8.84 [s, 1H, Ar—H].


1.5 General Procedure E: Synthesis of Boronobenzoic Acid Phenylene Amides
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In step (i), oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of compound E-1 (0.2 mmol), 1 drop of DMF and 5 mL of dried CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride E-2 as a solid, which was used without further purification in step (ii).


In step (ii), a suspension of the acid chloride E-2 (0.2 mmol, obtained from step (i) above) in 5 mL of dried THF was added dropwise to an ice-cold solution of E-3 (0.075 mmol), anhydrous triethylamine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ether and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was recrystallized from ethyl acetate/hexane. The product yielded from step (ii) is E-4.


3-Borono-5-nitrobenzoyl-1,4-phenylenediamine (FL-166)



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In step (i) of procedure E, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with p-phenylenediamine (8 mg, 0.075 mmol) according to general procedure E, step (ii), to give 29 mg (78% yield) of the desired compound as pale yellow powder, mp: 254-256° C. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.73 [s, 4H, Ar—H], 8.67-8.70 [m, 2H, Ar—H], 8.72-8.78 [m, 4H, Ar—H].


1.6 Additional Synthetic Examples
3-amino-5-carboxylphenylboronic acid (FL-088)



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To make desired compound, a solution of 3-carboxyl-5-nitrophenylboronic acid (422 mg, 2 mmol) in absolute ethanol (5 ml) was hydrogenated in the presence of Raney Nickel (150 mg) for 6 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness, then the residue was recrystallized from water to give 257 mg (71% yield) of the desired compound as a pale yellow powder, mp: 210-212° C. (Ref. mp: 212-214° C.). 1H-NMR(400 MHz, 5% D2O in d6-DMSO): δ7.06 [s, 1H, Ar—H], 7.16 [s, 1H, Ar—H], 7.55 [s, 1H, Ar—H] (Torssell, K.; Meyer, H.; Zacharias, B. Arkiv Kemi 1957, 10, 497-505).


3-(2,6-dichlorophenylcarbonyloxy)phenyl boronic acid (FL-099)



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To make desired compound, a solution of 2,6-dichlorobenzoyl chloride (29 μL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethylamine (42 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.08-7.19 [m, 1H, Ar—H], 7.22-7.30 [m, 1H, Ar—H], 7.22-7.30 [m, 1H, Ar—H], 7.42-7.50 [m, 1H, Ar—H], 7.54-7.60 [m, 1H, Ar—H], 7.60-7.68 [m, 2H, Ar—H], 7.73-7.78 [m, 3H, Ar—H].


3-benzenesulfonamido-5-nitrophenylboronic acid (FL-114)



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To make desired compound, a solution of benzenesulfonyl chloride (19 μL, 0.15 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-amino-5-nitrophenylboronic acid, HCl (33 mg, 0.15 mmol), dried triethylamine (63 μL, 0.45 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ether and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 37 mg (77% yield) of desired compound as a white powder, mp: 238° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.49-7.61 [m, 3H, Ar—H], 7.72-7.78 [m, 2H, Ar—H], 7.82-7.85 [m, 1H, Ar—H], 7.93-7.96 [m, 1H, Ar—H], 8.25-8.29 [m, 1H, Ar—H].


Tris-(3-borono-5-nitrobenzoic acid), 1,3,5-trihydroxybenzene ester (FL-164)



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In step (i), oxalyl chloride (79 μL, 0.9 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).


In step (ii), a suspension of the above acid chloride (0.45 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of phloroglucinol (13 mg, 0.1 mmol), anhydrous triethylamine (63 μL, 0.45 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 17 mg (24% yield) of the desired compound as a pale yellow powder, mp: 274° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.46 [s, 1H, Ar—H], 8.72-8.76 [m, 1H, Ar—H], 8.78-8.86 [m, 2H, Ar—H].


Tris(3-borono-5-nitrobenzoic acid), triethanolamine ester (FL-165)



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In step (i), oxalyl chloride (79 μL, 0.9 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).


In step (ii), a suspension of the above acid chloride (0.45 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of triethanolamine (15 mg, 0.1 mmol), anhydrous triethylamine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with water, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 14 mg (19% yield) of the desired compound as a pale yellow powder, mp: 235° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ2.05 [t, 3H, —CH2—], 4.05 [t, 2H, —CH2—], 8.59-8.63 [m, 3H, Ar—H], 8.71-8.76 [m, 3H, Ar—H], 8.77-8.81 [m, 3H, Ar—H].


3-borono-5-nitrobenzoyl-L-phenylalanine ethyl ester (FL-170)



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In step (i), oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 10 mL of dried CH2Cl2 The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).


In step (ii), a solution of the above acid chloride (0.2 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of L-phenylalanine ethyl ester hydrochloride (34 mg, 0.15 mmol), anhydrous triethylamine (63 μL, 0.45 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 31 mg (54% yield) of the desired compound as a pale yellow powder, mp: 264° C. (dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ1.35 [t, 2H, —CH2CH3], 3.13 [dd, 1H, —CH2—], 4.02 [q, 2H, —CH2CH3], 4.71 [m, 1H, —CH—], 7.05-7.37 [m, 5H, Ar—H], 8.57-8.63 [m, 1H, Ar—H], 8.67-8.72 [m, 2H, Ar—H], 8.73-8.80 [m, 1H, Ar—H].


3-(3-boronobenzyloxycarbonyl)-5-aminophenylboronic acid (FL-171)



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To make the desired compound, a solution of 3-(3-boronobenzyloxycarbonyl)-5-nitrophenylboronic acid (172 mg, 0.5 mmol) in absolute ethanol (10 ml) was hydrogenated in the presence of Raney Nickel (80 mg) for 4 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness, then the residue was recrystallized from ethanol/H2O to give 60 mg (38% yield) of the desired compound as a pale yellow semisolid. 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ5.25 [s, 2H, Ar—CH2], 6.56-6.97 [m, 2H, Ar—H], 7.15-8.09 [m, 5H, Ar—H].


(3-carboxy-5-hydroxyphenyl)boronic acid (FL-172)



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To make the desired compound, 3-amino-5-carboxylphenylboronic acid hydrochloride (22 mg, 0.1 mmol) was suspended in 2 mL of 50% H2SO4 and treated at −5° C. with a solution of NaNO2 (8 mg, 0.1 mmol) in 1 mL of water. After the mixture had been stirred for 1 h at this temperature, water (10 mL) was added and the mixture was warmed to 60° C. until the evolution of gas ceased. The dark brown solution was extracted twice with ether, and the extracts were washed with water and brine and dried with Na2SO4. The solvent was evaporated to dryness, then the residue was recrystallized from methanol to give 5 mg (27% yield) of the desired compound as a pale yellow powder, mp: 229° C. (dec). 1H-NMR(300 MHz, 5% D2O in d6-DMSO): δ7.19-7.41 [m, 2H, Ar—H], 7.77-7.87 [m, 1H, Ar—H].


3-Benzyloxycarbonyl-5-nitrophenylboronic acid (Compound FL-1201)



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FL-1201 is available from Combi-Blocks, Inc. (San Diego, Calif., Cat. No. BB-2188).


3-(Benzylcarbamoyl)phenylboronic acid (Compound FL-1010)



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FL-1010 is available from Combi-Blocks, Inc. (San Diego, Calif., Cat. No. BB-3055).


Example 2
Cloning of Recombinant SARS-Associated 3CLpro Protease

cDNA corresponding to the SARS 3CL protease gene (Tor2 strain, GenBank #AY274119) inserted in a pBR194c vector was kindly provided by British Columbia Cancer Agency Branch (Vancouver, British Columbia, Canada). Competent cells (XL-1 Blue, Stratagene) were transformed for plasmid propagation under ampicillin selection. DNA plasmid was isolated (Plasmid Midi Kit, Qiagen) and the gene was amplified by PCR with appropriate primers using Pfu Turbo DNA Polymerase (Stratagene). To prevent artifacts afterward, the original plasmid was degraded by DpnI (Stratagene) digestion reaction (1 hour at 37° C.) followed by inactivation of DpnI (20 minutes at 80° C.). Cloning reaction was performed by blunt-end directional cloning (Champion pET Directional TOPO Expression and Cloning Kit, Invitrogen) by topo-isomerase reaction in a pET100 vector, where the protein expression is chemically induced and under the control of the T7 promoter. The protease gene was cloned in frame with an N-terminal peptide containing a poly-histidine tag for further purification by affinity chromatography. An enterokinase recognition site was present to remove the amino terminal tag after purification. One Shot TOP10 competent cells (Invitrogen) were transformed with the product from the cloning reaction. DNA plasmid was purified and the gene insertion and its directionality, as well as the integrity of pET100 vector were confirmed by DNA sequencing. BL21 Star DE3 (Invitrogen) competent cells were transformed for protein expression under ampicillin selection and IPTG induction.


Example 3
Expression and Purification of Recombinant SARS-Associated 3CLpro Protease

Plasmid-encoded SARS 3CL protease was expressed as a soluble fraction in BL21 Star DE3 Escherichia coli competent cells (Invitrogen). Cells were grown in LB supplemented with ampicillin (50 μg/ml) at 37° C., induced with IPTG when the optical density was ˜0.8 and harvested after 3-4 hours. Cells were re-suspended in lysis buffer (potassium phosphate 50 mM, pH 7.8, sodium chloride 400 mM, potassium chloride 100 mM, glycerol 10%, triton-X 0.5%, imidazole 10 mM) and broken with three passes through a French pressure cell (>16,000 psi). Cell debris was collected by centrifugation (20,000g at 4° C. for 20 min.). The supernatant was diluted 1:3 with binding buffer (sodium phosphate 50 mM, pH 7.5, sodium chloride 0.3 M, imidazole 10 mM), filtered using a 0.22 μm pore size filter (Millipore) and applied directly to a nickel-affinity column (H is Select, Sigma) which had been pre-equilibrated with five column volumes of the binding buffer. The protease was eluted with a linear gradient of elution buffer (sodium phosphate 50 mM, pH 7.5, sodium chloride 0.3 M, imidazole 250 mM) at fractions corresponding to 0-30% elution buffer. Protease fractions were pooled and concentrated. During concentration the elution buffer was exchanged gradually for storage buffer (sodium phosphate 10 mM, pH 7.4, sodium chloride 10 mM, DTT 1 mM, EDTA 0.5 mM). The poly-histidine tag of the fusion protein was cut through incubation with 0.1 units of enterokinase (Invitrogen) for 48 hours at 4° C. Efficiency of the cleavage reaction was inspected by SDS PAGE. This reaction mixture was passed again through the nickel-affinity column and the flow-through containing the protease was collected. The sample was diluted 4-fold with storage buffer and then concentrated (>10 mg/ml). The purified protein was then stored at −20° C. Purity of the sample was higher than 95%, assessed by SDS PAGE.


Example 4
Enzymatic Characterization of Recombinant SARS-Associated 3CLpro Protease

The activity of the SARS protease was determined by continuous kinetic assays using the fluorogenic substrate Dabcyl-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Arg-Edans (Bachem). The hydrolysis of the substrate is accompanied by a proportional increase of the fluorescence intensity of the Edans group due to a decreased FRET efficiency following the release of the Dabcyl-linked peptide quencher fragment. The fluorescent intensity was monitored in a Cary Eclipse fluorescence spectrophotometer (Varian) using wavelengths of 360 nm and 500 nm for the excitation and emission, respectively. The experiments were performed with the same buffer used to store the enzyme (sodium phosphate 10 mM, pH 7.4, sodium chloride 10 mM, DTT 1 mM, EDTA 0.5 mM).


To determine the kinetic parameters, Km and kcat, initial rate measurements were performed by incubating the enzyme with the substrate at room temperature. In a microcuvette with a final volume of 120 μL, the reaction was initiated by adding the protease (final concentration 1 μM) to a solution of substrate at final concentration of 0-120 μM.


Example 5
Inhibition Kinetics of Recombinant SARS-Associated 3CLpro Protease

Inhibition assays were performed under the same conditions at increasing concentration of inhibitor. Protease (final concentration 1 μM) was incubated for 20 minutes at room temperature with the inhibitor (final concentration 0-150 μM) and the reaction was initiated adding substrate to a final concentration of 5 μM. Inhibition constants, Ki, were obtained as adjustable parameters through non-linear square fitting of the initial enzymatic rates as a function of the inhibitor concentration according to the following equation:
vIv0=1-[I]T+[E]T+Ki-([I]T+[E]T+Ki)2-4⁡[I]T⁡[E]T2⁡[E]T

where v1 and v0 are the initial rate at a given inhibitor concentration and at zero inhibitor concentration, respectively, [I]T is the total inhibitor concentration and [E]T is the total enzyme concentration. The reversibility of the inhibition was confirmed by dilution experiments.


Table 16 shows the results obtained for nine different members of the family of SARS-associated coronavirus protease 3CLpro inhibitors described in this disclosure.

TABLE 16Inhibition of SARS Associated CoronavirusProtease 3CLpro by Boronic AcidsCompound NameKiapp (μM)FL-061-FL-062-FL-063-FL-064-FL-065-FL-067-FL-068-FL-069-FL-071-FL-072-FL-073-FL-074-FL-075-FL-0786.7 ± 0.9FL-07923.7 ± 3.0 FL-08062 ± 6 FL-081179 ± 70 FL-082158 ± 109FL-083104 ± 38 FL-084> 1000 μMFL-08595 ± 30FL-086> 1000 μMFL-08766 ± 2 FL-08863 ± 14FL-089241 ± 85 FL-090> 1000 μMFL-09215.5 ± 6.5 FL-09439 ± 5 FL-09591.8 ± 8.8 FL-096137 ± 61 FL-097153 ± 58 FL-099> 1000 μMFL-100190 ± 100FL-10121.7 ± 3.27FL-10339.1 ± 2.1 FL-10418.0 ± 1.0 FL-1068.5 ± 0.5FL-1076.9 ± 0.3FL-10815.0 ± 7.0 FL-10961.5 ± 19.7FL-11036.95 ± 9.7 FL-113-FL-11449.8 ± 4.4 FL-132-FL-133> 1000 μMFL-1368.0 ± 1.7FL-13973.3 ± 38.0FL-14139.3 ± 11.7FL-14821.5 ± 8.7 FL-149313 ± 170FL-15116.6 ± 6.0 FL-15633.04 ± 9.4 FL-16479.6 ± 14.1FL-16550.6 ± 21.5FL-1660.022 ± 0.01 FL-16710.2 ± 2.2 FL-16932.7 ± 2.5 FL-17010.6 ± 7.5 FL-1713.53 ± 3.0 FL-1723.5 ± 3.9 FL-101084 ± 45 FL-120135.8 ± 11.5


Example 6
Binding Energetics of Inhibitors

The binding of the various boronic acids of the present invention to the SARS-associated coronavirus protease 3CLpro was measured by isothermal titration calorimetry and the results are set forth in Table 17 below. Isothermal titration calorimetry does not only measure the binding affinity of inhibitors but also dissects the enthalpic and entropic components to binding, thus allowing identification of the forces involved in the association reaction. In general a binding reaction characterized by a favorable enthalpy change indicates that the inhibitor establishes strong interactions with the target, whereas an inhibitor characterized by unfavorable binding enthalpy is driven by non-specific hydrophobic interactions, i.e. a tendency to escape water rather than a strong attraction to the target (Velazquez-Campoy et al, 2001; Luque and Freire, 2002; Ohtaka et al, 2002).

TABLE 17Binding Enthalpy of Selected Compounds to 3CLproΔHCompoundcal/molFL-078−4900FL-079−1700FL-106−5300FL-136−9200


The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.


Numerous references, including patents, patent applications, protocols and various publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety and to the same extent as if each reference was individually incorporated by reference.

Claims
  • 1. A compound described by formula (1):
  • 2. A compound described by formula (2):
  • 3. A compound described by formula (3):
  • 4. A compound described by formula (4):
  • 5. A compound described by formula (5):
  • 6. A compound described by formula (6):
  • 7. A compound described by formula (7):
  • 8. A compound described by formula (8):
  • 9. A compound described by formula (9):
  • 10. A compound described by formula (10):
  • 11. A compound described by formula (11):
  • 12. A compound described by formula (12):
  • 13. A compound described by formula (13):
  • 14. A compound described by formula (14):
  • 15. A compound described by formula (15):
  • 16. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
  • 17. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.
  • 18. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.
  • 19. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.
  • 20. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.
  • 21. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier.
  • 22. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.
  • 23. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.
  • 24. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable carrier.
  • 25. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.
  • 26. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier.
  • 27. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.
  • 28. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.
  • 29. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable carrier.
  • 30. A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable carrier.
  • 31. A method for treating infection caused by coronavirus comprising administering to a subject suffering from such an infection an effective amount of a boron-containing compound.
  • 32. The method of claim 31 where in the boron-containing compound is described by formula (A)
  • 33. The method of claim 31 wherein the boron-containing compound is described by formula (B)
  • 34. The method of claim 31, wherein the boron-containing compound is a multi-functional boronic acid.
  • 35. The method of claim 31, wherein the boron-containing compound is a bi-functional boronic acid.
  • 36. The method of claim 31, wherein the boron-containing compound is described by formula (1)
  • 37. The method of claim 31, wherein the boron-containing compound is desecribed by formula (2)
  • 38. The method of claim 31, wherein the boron-containing compound is described by formula (3)
  • 39. The method of claim 31, wherein the boron-containing compound is desecribed by formula (4)
  • 40. The method of claim 31, wherein the boron-containing compound is desecribed by formula (5)
  • 41. The method of claim 31, wherein the boron-containing compound is desecribed by formula (6)
  • 42. The method of claim 31, wherein the boron-containing compound is described by formula (7)
  • 43. The method of claim 31, wherein the boron-containing compound is desecribed by formula (8)
  • 44. The method of claim 31, wherein the boron-containing compound is desecribed by formula (9)
  • 45. The method of claim 31, wherein the boron-containing compound is desecribed by formula (10)
  • 46. The method of claim 31, wherein the boron-containing compound is desecribed by formula (11)
  • 47. The method of claim 31, wherein the boron-containing compound is desecribed by formula (12)
  • 48. The method of claim 31, wherein the boron-containing compound is desecribed by formula (13)
  • 49. The method of claim 31, wherein the boron-containing compound is desecribed by formula (14)
  • 50. The method of claim 31, wherein the boron-containing compound is desecribed by formula (15)
  • 51. The method of claim 31, wherein the coronavirus is a coronavirus having protease(s) that has one or more serine or threonine residue(s) at or near its active site.
  • 52. The method of claim 31, wherein the coronavirus is SARS-associated coronavirus.
  • 53. A method for inhibiting coronavirus protease comprising contacting the coronavirus protease with an effective amount of a boron-containing compound.
  • 54. The method of claim 53 where in the boron-containing compound is described by formula (A)
  • 55. The method of claim 53 wherein the boron-containing compound is described by formula (B)
  • 56. The method of claim 53, wherein the boron-containing compound is a multi-functional boronic acid.
  • 57. The method of claim 53, wherein the boron-containing compound is a bi-functional boronic acid.
  • 58. The method of claim 53, wherein the boron-containing compound is described by formula (1)
  • 59. The method of claim 53, wherein the boron-containing compound is described by formula (2)
  • 60. The method of claim 53, wherein the boron-containing compound is described by formula (3)
  • 61. The method of claim 53, wherein the boron-containing compound is described by formula (4)
  • 62. The method of claim 53, wherein the boron-containing compound is described by formula (5)
  • 63. The method of claim 53, wherein the boron-containing compound is described by formula (6)
  • 64. The method of claim 53, wherein the boron-containing compound is described by formula (7)
  • 65. The method of claim 53, wherein the boron-containing compound is described by formula (8)
  • 66. The method of claim 53, wherein the boron-containing compound is described by formula (9)
  • 67. The method of claim 53, wherein the boron-containing compound is described by formula (10)
  • 68. The method of claim 53, wherein the boron-containing compound is described by formula (11)
  • 69. The method of claim 53, wherein the boron-containing compound is described by formula (12)
  • 70. The method of claim 53, wherein the boron-containing compound is described by formula (13)
  • 71. The method of claim 53, wherein the boron-containing compound is described by formula (14)
  • 72. The method of claim 53, wherein the boron-containing compound is described by formula (15)
  • 73. The method of claim 53, wherein the coronavirus is a coronavirus having protease(s) that has one or more serine or threonine residue(s) at or near its active site.
  • 74. The method of claim 53, wherein the coronavirus is SARS-associated coronavirus.
  • 75. A method for detecting coronavirus in a test sample comprising contacting the sample with an effective amount of a boron-containing compound.
  • 76. The method of claim 75 where in the boron-containing compound is described by formula (A)
  • 77. The method of claim 75 wherein the boron-containing compound is described by formula (B)
  • 78. The method of claim 75, wherein the boron-containing compound is a multi-functional boronic acid.
  • 79. The method of claim 75, wherein the boron-containing compound is a bi-functional boronic acid.
CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) of provisional application 60/516,008, filed Oct. 31, 2003, which is hereby incorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENT INTEREST

A portion of this invention was made with support under Grant No. GM-57144, awarded by the National Institutes of Health. The United States Government may have certain rights in this invention.

Provisional Applications (1)
Number Date Country
60516008 Oct 2003 US