Compounds and methods for treating toll-like receptor 2-related diseases and conditions   

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 11/697,651, filed Apr. 6, 2007, which is a divisional of U.S. patent application Ser. No. 10/973,164, filed Oct. 25, 2004 (U.S. Pat. No. 7,202,234), which claims the benefit of the filing date of U.S. provisional patent application No. 60/514,283, filed Oct. 24, 2003, the contents of which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

This invention relates to the prevention and treatment of diseases and conditions associated with Toll-like receptor 2 activation.

BACKGROUND OF THE INVENTION

The vertebrate immune system protects the body against undesirable foreign matter that enters the body, such as infecting pathogens (e.g., bacteria, viruses, fungi, and parasites) and their by-products. One manner by which this takes place involves the adaptive immune system, through which the body recognizes foreign antigens and generates specific immune responses against them. The induction of adaptive immunity takes time (e.g., 2-3 days post infection), and thus could leave the body vulnerable to the adverse effects of early infection, if it were not for the action of another division of the immune system, the innate immune system.

The innate immune system provides the body with a first line defense against invading pathogens. In an innate immune response, an invading pathogen is recognized by a germline-encoded receptor, the activation of which initiates a signaling cascade that leads to the induction of cytokine expression. Innate immune system receptors have broad specificity, recognizing molecular structures that are highly conserved among different pathogens. These receptors are known as Toll-like receptors (TLRs), due to their homology with receptors that were first identified and named in Drosophila, and are present in cells such as macrophages, dendritic cells, and epithelial cells.

There are at least ten different TLRs in mammals, and ligands and corresponding signaling cascades have been identified for some of these receptors. For example, TLR2 is activated by the lipoprotein of bacteria (e.g., E. coli.), TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharide (i.e., LPS or endotoxin) of Gram-negative bacteria (e.g., Salmonella and E. coli O157:H7), TLR5 is activated by flagellin of motile bacteria (e.g., Listeria), and TLR9 is activated by unmethylated CpG sequences of pathogen DNA. The stimulation of each of these receptors leads to activation of the transcription factor NF-κB, and other signaling molecules that are involved in regulating the expression of cytokine genes, including those encoding tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and certain chemokines.

SUMMARY

The present invention provides compounds and methods for use in preventing or treating diseases or conditions characterized by Toll-like receptor 2 (TLR2) activation in patients. Accordingly, in a first aspect, the invention features a compound of formula I:

or a pharmaceutically acceptable salt or prodrug thereof, where

a is an integer of 1 to 3;

b is an integer of 0 to 4, wherein when b is 0, the carbon bonded to X and W is not bonded to 2 or more heteroatoms;

R1 is H or C1-6 alkyl;

X is selected from the group consisting of —NRX1V, N(RX1)C(O)V, —N(RX1)C(S)V, —N(RX1)C(O)N(RX2)V, —N(RX1)C(S)N(RX2)V, —N(RX1)C(O)OV, —N(RX1)S(O)2V, —C(O)N(RX1)V, —C(O)OV, —OC(O)V, —OC(O)OV, and —OC(O)N(RX1)V, where each of RX1 and RX2 is, independently, H or C1-6 alkyl, and V is a C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl group, optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl, and optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain;

W is selected from the group consisting of H, —C(O)N(RW1)RW2, —C(O)ORW2, —(CH2)cORW3, —(CH2)cSRW3, —(CH2)cO(CH2)dCH(ORW3)RW4, —(CH2)cS(CH2)dCH(ORW3)RW4, —C(O)N(RW1)(CH2)cCH(ORW3)RW4, and —C(O)N(RW1)(CH2)cCH(ORW3)(CH2)eORW5, where each of c and d is an integer of 1 to 4, e is an integer of 2 to 4, RW1 is H or C1-6 alkyl, RW2 is C1-20 alkyl, C1-20 alkenyl, or C1-10 alkynyl, each of RW3 and RW5 is, independently, H, C1-20 alkyl, C1-21 acyl, C1-20 alkenyl, or C1-20 alkynyl, and RW4 is H, C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl, where each of RW2, RW3, RW4, and RW5 is optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl, optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain, and optionally contains 1 to 4 non-vicinal oxygen atoms in the carbon chain; and

U is selected from the group consisting of

where

f is an integer of 1 to 4, g is an integer of 0 to 1,

each of RU1, RU2, and RU3 is, independently, H, optionally substituted C1-6 alkyl, optionally substituted C7-16 aralkyl, or optionally substituted C2-15 heterocyclylalkyl, or RU1 is H or optionally substituted C1-6 alkyl and RU2 and RU3 together with the carbon atom they are bonded to form an optionally substituted C3-6 aliphatic ring, or RU2 is H and RU3 and RU1 together with the carbon atom bonded to RU3 and the nitrogen atom bonded to RU1 form an optionally substituted 4-6-membered heterocyclic ring,

RU4 is selected from the group consisting of —CH2RU5, —C(O)RU6, —C(O)NH(RU7), and —C(O)O(RU8), where each of RU5, RU6, RU7, and RU8 is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C7-16 aralkyl, optionally substituted C2-15 heterocyclylalkyl, optionally substituted C6-10 aryl, and optionally substituted C1-9 heterocyclyl, or RU4 is a peptide chain of 1 to 10 natural or non-natural amino acids, or mixture thereof, linked via the C-terminal end and substituted at the N-terminal end of the peptide with a group selected from H, —CH2RU5, —C(O)RU6, —C(O)NH(RU7), and —C(O)O(RU8), where each of RU5, RU6, RU7, and RU8 is as defined above, and

RU5 is a peptide chain of 1 to 10 natural or non-natural amino acids, or mixture thereof, linked via the N-terminal end and the C-terminal end is CO2RU9, or CONRU10RU11, where each of RU9, RU10, and RU11 is selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C7-16 aralkyl, optionally substituted C2-15 heterocyclylalkyl, optionally substituted C6-10 aryl, and optionally substituted C1-9 heterocyclyl.

In a second aspect, the invention features a compound of formula II:

or a pharmaceutically acceptable salt or prodrug thereof, where each of a, b, U, X, and W is as defined above for the compound of formula I; each of R1, R2, and R3 is, independently, H or C1-6 alkyl; R4 is H, optionally substituted C1-6 alkyl, optionally substituted C7-16 aralkyl, or optionally substituted C2-15 heterocyclylalkyl; and R5 is CO2H, SO3H, OP(O)(OH)2, OSO3H, or 5-tetrazolyl.

In an embodiment of either the first or second aspect of the invention, X or W contains at least one linear alkyl moiety of 7 or more carbons. Preferably, each of X and W contains at least one linear alkyl moiety of 7 or more carbons.

Examples of compounds of the invention where W contains at least one linear alkyl moiety of 7 or more carbons include those compound in which W is selected from the group consisting of: —C(O)NH(CH2)2CH(OH)RW4, where RW4 is C7-19 alkyl; —C(O)NH(CH2)2CH2ORW3, where RW3 is —C(O)(CH2)aaCH3 and where aa is an integer of 6 to 18; and —C(O)NH(CH2)2CH(ORW3)RW4, where RW3 is —C(O)(CH2)aaCH3 and RW4 is CH2OC(O)(CH2)bbCH3, where each of aa and bb is, independently, an integer of 6 to 18.

In another embodiment of either the first or second aspect of the invention, U is C(O)C(RU2)(RU3)NHRU4 or —C(O)(CH2)fNHRU4, where f is an integer of 1 to 4, RU2 is an optionally substituted C1-6 alkyl, RU3 is H, and RU4 is an optionally substituted C6-10 aryl or an optionally substituted C2-9 heterocyclyl. Examples include those compounds in which RU4 is

where RU12 is optionally substituted C6-10 aryl, optionally substituted C6-10 aryloxy, optionally substituted C7-16 aralkyl, optionally substituted C7-16 aralkoxy, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyloxy, optionally substituted C3-15 heterocyclylalkyl, or optionally substituted C3-15 heterocyclylalkyloxy. Most preferably, RU4 is selected from the group consisting of:

Other compounds of the invention include those selected from the group consisting of

In a third aspect, the invention features a compound having the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein

i is an integer of 1 to 4

R6 is H or C1-6 alkyl;

Z is selected from the group consisting of —NRZ1V, —N(RZ1)C(O)V, —N(RZ1)C(S)V, —N(RZ1)C(O)N(RZ2)V, —N(RZ1)C(S)N(RZ2)V, —N(R2)C(O)OV, and —N(RZ1)S(O)2V, where each of RZ1 and RZ2 is, independently, H or C1-6 alkyl, and V is a C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl group, optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl and optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain;

R7 is C1-20 alkyl, C1-20 alkenyl, or C1-20 alkynyl, optionally substituted with halo, hydroxyl, C1-21 acyloxy, oxo, C1-20 alkoxyl, or C1-20 thioalkoxyl and optionally contains 1 to 2 phenyl or biphenyl moieties in and/or at the end of the carbon chain; each of R8 and R9 is, independently H, optionally substituted C1-6 alkyl, optionally substituted C7-16 aralkyl, or optionally substituted C2-15 heterocyclylalkyl, or R8 and R9 together with the carbon atom they are bonded to form an optionally substituted C3-6 aliphatic ring; and

T is ORT1, NRT2RT3, or a peptide chain of 1 to 10 natural or non-natural amino acids, or mixture thereof, linked via the N-terminal end and the C-terminal end is CO2RT1, or CONRT2RT3, wherein each of RT1, RT2, and RT3 is selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C7-16 aralkyl, optionally substituted C2-15 heterocyclylalkyl, optionally substituted C6-10 aryl, and optionally substituted C1-9 heterocyclyl.

The invention also features a pharmaceutical composition that includes any of the compounds of the invention and a pharmaceutically acceptable excipient. The pharmaceutical compositions of the inventions can be used to treat or prevent a disease or condition characterized by Toll-like receptor 2 activation in a mammal, such as, for example, a human patient. Accordingly, the invention features a method for treating or preventing a disease in a mammal having, or predisposed to having, a condition characterized by Toll-like receptor 2 activation that includes administering a compound of formula I or formula II to the mammal in an amount sufficient to treat or prevent the disease or condition. The therapeutic methods of the invention can also involve administration of one or more compounds that is selective for TLR2 over, for example, TLR4, as well as methods involving administration of TLR2/TLR4 dual antagonists.

Examples of diseases or conditions characterized by TLR2 activation and that can be treated according to the invention include inflammatory bowel disease, sepsis, periodontal disease, mucositis, acne, cardiovascular disease, chronic obstructive pulmonary disease, arthritis, cystic fibrosis, bacterial-induced infections, viral-induced infections, mycoplasma-associated diseases, post-herpetic neuralgia, ischemia/reperfusion injury, asthma, stroke, brain injury, necrotizing enterocolitis, bed sores, leprosy, atopic dermatitis, psoriasis, trauma, allergy, neurodegenerative disease, amphotericin B-induced fever and nephritis, coronary artery bypass grafting, and atherosclerosis.

The invention also includes methods for identifying agents that decrease or inhibit activation of Toll-like receptor 2. These methods involve (i) contacting a cell expressing the receptor with a candidate agent in the presence of an activator of the receptor (in vitro or in vivo) and (ii) determining the effect of the agent on activation of the receptor. Detection of a decrease in activation of the receptor by the activator in the presence of the agent indicates the identification of agent that can be used to decrease or inhibit activation of the receptor. In these methods, the effect of the agent on the activation of the receptor can be determined by analysis of the expression of a reporter gene that is under the control of a promoter that is induced in a signaling pathway triggered by activation of the receptor.

The terms “acyl” or “alkanoyl,” as used interchangeably herein, represent an alkyl group, as defined herein, or hydrogen attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups are of 2 to 21 carbons.

The term “acyloxy” represents an alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group and an oxygen atom. Exemplary acyloxy groups are of 2 to 21 carbons.

The term “alkenyl,” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to twenty carbon atoms; (2) alkylsulfinyl of one to twenty carbon atoms; (3) alkylsulfonyl of one to twenty carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, where the alkylene group is of one to twenty carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to twenty carbon atoms; (21) thiol; (22) —CO2RA, where RA is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-20 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group is of one to twenty carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group is of one to twenty carbon atoms; (23) —C(O)NRBRC, where each of RB and RC is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (24) —S(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (25) —S(O)2NRERF, where each of RE and RF is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; and (26) —NRGRH, where each of RG and RH is, independently, selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to twenty carbon atoms, (d) alkenyl of two to twenty carbon atoms, (e) alkynyl of two to twenty carbon atoms, (f) aryl, (g) arylalkyl, where the alkylene group is of one to twenty carbon atoms, (h) cycloalkyl of three to eight carbon atoms, and (i) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

The terms “alkoxy” or “alkyloxy,” as used interchangeably herein, represent an alkyl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted alkoxy groups are of 1 to 20 carbons.

The term “alkyl,” as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon of, unless otherwise specified, from 1 to 20 carbons and is exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two, three or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) alkoxy of one to twenty carbon atoms; (2) alkylsulfinyl of one to twenty carbon atoms; (3) alkylsulfonyl of one to twenty carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocyclyl; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxyl; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to twenty carbon atoms; (21) thiol; (22) —CO2RA, where RA is selected from the group consisting of (a) hydrogen, (b) substituted or unsubstituted C1-20 alkyl, (c) substituted or unsubstituted C6 or C10 aryl, (d) substituted or unsubstituted C7-16 arylalkyl, where the alkylene group is of one to twenty carbon atoms, (e) substituted or unsubstituted C1-9 heterocyclyl, and (f) substituted or unsubstituted C2-15 heterocyclylalkyl, where the alkylene group is of one to twenty carbon atoms; (23) C(O)NRBRC, where each of RB and RC is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (24) —S(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (25) —S(O)2NRERF, where each of RE and RF is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; and (26) —NRGRH, where each of RG and RH is, independently, selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to twenty carbon atoms, (d) alkenyl of two to twenty carbon atoms, (e) alkynyl of two to twenty carbon atoms, (f) aryl, (g) arylalkyl, where the alkylene group is of one to twenty carbon atoms, (h) cycloalkyl of three to eight carbon atoms, and (i) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

The term “alkylene,” as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.

The term “alkylthio,” as used herein, represents an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted alkylthio groups are of 1 to 20 carbons.

The term “alkynyl,” as used herein, represents monovalent straight or branched chain groups of 2 to 20 carbon atoms containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of (1) alkoxy of one to twenty carbon atoms; (2) alkylsulfinyl of one to twenty carbon atoms; (3) alkylsulfonyl of one to twenty carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, where the alkylene group is of one to twenty carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to twenty carbon atoms; (21) thiol; (22) —CO2RA, where RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (23) —C(O)NRDRC, where each of RB and RC is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (24) —S(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (25) —S(O)2NRERF, where each of RE and RF is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; and (26) —NRGRH, where each of RG and RH is, independently, selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to twenty carbon atoms, (d) alkenyl of two to twenty carbon atoms, (e) alkynyl of two to twenty carbon atoms, (f) aryl, (g) arylalkyl, where the alkylene group is of one to twenty carbon atoms, (h) cycloalkyl of three to eight carbon atoms, and (i) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group.

The term “alpha-amino acid residue,” as used herein, represents a —N(RA)C(RB)(RC)C(O)—linkage, where RA is selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, as defined herein; and each of RB and RC is, independently, selected from the group consisting of: (a) hydrogen, (b) optionally substituted alkyl, (c) optionally substituted cycloalkyl, (d) optionally substituted aryl, (e) optionally substituted arylalkyl, (f) optionally substituted heterocyclyl, and (g) optionally substituted heterocyclylalkyl, each of which is as defined herein. For natural amino acids, RB is H and RC corresponds to those side chains of natural amino acids found in nature, or their antipodal configurations. Exemplary natural amino acids include alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, aspartamine, ornithine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine, each of which, except glycine, as their D- or L-form. As used herein, for the most part, the names of naturally-occuring amino acids and aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in Nomenclature of α-Amino Acids (Recommendations, 1974), —Biochemistry 14 (2), 1975. The present invention also contemplates non-naturally occuring (i.e., non-natural) amino acid residues in their D- or L-form such as, for example, homophenylalanine, phenylglycine, cyclohexylglycine, cyclohexylalanine, cyclopentyl alanine, cyclobutylalanine, cyclopropylalanine, cyclohexylglycine, norvaline, norleucine, thiazoylalanine (2-, 4-, and 5-substituted), pyridylalanine (2-, 3-, and 4-isomers), naphthalalanine (1- and 2-isomers) and the like. Non-natural amino acids also include beta-amino acids, optionally substituted at the alpha or beta or both alpha and beta positions, independently, with RA and RB, as described above.

The term “amino,” as used herein, represents an —NH2 group.

The term “aryl,” as used herein, represents a mono- or bicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indenyl and the like and may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) alkanoyl of one to twenty carbon atoms; (2) alkyl of one to twenty carbon atoms; (3) alkoxy of one to twenty carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (5) alkylsulfinyl of one to twenty carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (7) alkylsulfonyl of one to twenty carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group is of one to twenty carbon atoms; (11) amino; (12) aminoalkyl of one to twenty carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to twenty carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group is of one to twenty carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to twenty carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to twenty carbon atoms; (29) nitro; (30) nitroalkyl of one to twenty carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group is of one to twenty carbon atoms; (33) oxo; (34) thioalkoxy of one to twenty carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (36) —(CH2)qCO2RA, where q is an integer of zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (37) —(CH2)qCONRBRC, where RB and RC are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (38) —(CH2)qS(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (39) —(CH2)qS(O)2NRERF, where each of RE and RF is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (40) —(CH2)qNRGRH, where each of RG and RH is, independently, selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) alkyl of one to twenty carbon atoms, (d) alkenyl of two to twenty carbon atoms, (e) alkynyl of two to twenty carbon atoms, (f) aryl, (g) arylalkyl, where the alkylene group is of one to twenty carbon atoms, (h) cycloalkyl of three to eight carbon atoms, and (i) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.

The terms “arylalkyl” or “aralkyl,” as used interchangeably herein, represent an aryl group attached to the parent molecular group through an alkyl group. Exemplary unsubstituted arylalkyl groups are of 7 to 16 carbons.

The term “aryloxy,” as used herein, represents an aryl group that is attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted aryloxy groups are of 6 or 10 carbons.

The terms “aryloyl” or “aroyl,” as used interchangeably herein, represent an aryl group that is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloxycarbonyl groups are of 7 or 11 carbons.

The term “carbonyl” as used herein, represents a C═O group.

The term “carboxy” or “carboxyl,” as used interchangeably herein, represents a —CO2H group.

The terms “carboxy protecting group” or “carboxyl protecting group,” as used herein, represent those groups intended to protect a —CO2H group against undersirable reactions during synthetic procedures. Commonly used carboxy-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis, 3rd Edition” (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.

The phrase “compound selective for antagonism of Toll-like receptor 2 over Toll-like receptor 4” is used to describe those compounds that have an IC50 value when tested by the TLR2 in vitro assay described herein that is less than the IC50 value obtained when the compound is tested by the TLR4 in vitro assay described herein.

The term “cycloalkyl,” as used herein, represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl and the like. The cycloalkyl groups of this invention can be optionally substituted with (1) alkanoyl of one to twenty carbon atoms; (2) alkyl of one to twenty carbon atoms; (3) alkoxy of one to twenty carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (5) alkylsulfinyl of one to twenty carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (7) alkylsulfonyl of one to twenty carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group is of one to twenty carbon atoms; (11) amino; (12) aminoalkyl of one to twenty carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to twenty carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group is of one to twenty carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to twenty carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to twenty carbon atoms; (29) nitro; (30) nitroalkyl of one to twenty carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group is of one to twenty carbon atoms; (33) oxo; (34) thioalkoxy of one to twenty carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (36) —(CH2)qCO2RA, where q is an integer of zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (37) —(CH2)qCONRBRC, where each of RB and RC is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (38) —(CH2)qS(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (39) —(CH2)1S(O)2NRERF, where each of RE and RF is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (40) —(CH2)1NRGRH, where each of RG and RH is, independently, selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to twenty carbon atoms; (d) alkenyl of two to twenty carbon atoms; (e) alkynyl of two to twenty carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.

The term “halogen” or “halo,” as used interchangeably herein, represents F, Cl, Br, and I.

The term “heteroaryl,” as used herein, represents that subset of heterocycles, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system. Exemplary unsubstituted heteroaryl groups are of 1 to 9 carbons.

The terms “heterocycle” or “heterocyclyl,” as used interchangeably herein, represent a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds. The term “heterocycle” also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroinidolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, and the like. Heterocyclic groups also include compounds of the formula

where

F is selected from the group consisting of —CH2—, —CH2O—, and —O—, and G′ is selected from the group consisting of —C(O)— and (C(R′)(R″))v—, where each of R′ and R″ is, independently, selected from the group consisting of hydrogen or alkyl of one to four carbon atoms, and v is one to three and includes groups such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Any of the heterocycle groups mentioned herein may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) alkanoyl of one to twenty carbon atoms; (2) alkyl of one to twenty carbon atoms; (3) alkoxy of one to twenty carbon atoms; (4) alkoxyalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (5) alkylsulfinyl of one to twenty carbon atoms; (6) alkylsulfinylalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (7) alkylsulfonyl of one to twenty carbon atoms; (8) alkylsulfonylalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (9) aryl; (10) arylalkyl, where the alkyl group is of one to twenty carbon atoms; (11) amino; (12) aminoalkyl of one to twenty carbon atoms; (13) aryl; (14) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to twenty carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, where the alkylene group is of one to twenty carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to twenty carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to twenty carbon atoms; (29) nitro; (30) nitroalkyl of one to twenty carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, where the alkylene group is of one to twenty carbon atoms; (33) oxo; (34) thioalkoxy of one to twenty carbon atoms; (35) thioalkoxyalkyl, where the alkyl and alkylene groups are independently of one to twenty carbon atoms; (36) —(CH2)qCO2RA, where q is an integer of zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (37) —(CH2)qCONRBRC, where each of RB and RC is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (38) —(CH2)qS(O)2RD, where RD is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (39) —(CH2)qS(O)2NRERF, where each of RE and RF is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (40) (CH2)qNRGRH, where each of RG and RH is, independently, selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to twenty carbon atoms; (d) alkenyl of two to twenty carbon atoms; (e) alkynyl of two to twenty carbon atoms; (f) aryl; (g) arylalkyl, where the alkylene group is of one to twenty carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, where the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy.

The term “heterocyclyloxy,” as used herein, represents a hetercyclyl group which is attached to the parent molecular group through an oxygen atom.

The term “hydroxy” or “hydroxyl,” as used interchangeably herein, represents an —OH group.

The term “N-protected amino,” as used herein, refers to an amino group, as defined herein, to which is attached an N-protecting or nitrogen-protecting group, as defined herein.

The terms “N-protecting group,” “nitrogen protecting group,” or “amino protecting group,” as used herein, represent those groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis, 3rd Edition” (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. N-protecting groups comprise acyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected L- or D-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

The term “non-vicinal oxygen atoms” refers to oxygen atoms that are not bonded to the same carbon atom.

The term “pharmaceutically acceptable salt,” as use herein, refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 66:1-19, 1977. The salts can be prepared in situ during the final isolation and purification of a compound of the invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The term “pharmaceutically acceptable ester,” as used herein, represents esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioie acids, in which each alkyl or alkenyl group preferably has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyates, acrylates, and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs,” as used herein, means prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The term “phenyl” means an aromatic ring containing 6 carbons. Phenyl rings can be optionally substituted. When a phenyl ring is in a carbon chain it is part of the carbon chain linkage (i.e., the phenyl ring is bonded to the chain at two positions in either an ortho, meta, or para fashion). When a phenyl ring is at the end of a carbon chain, it is bonded to the end of the carbon chain.

The term “prodrug,” as used herein, represents compounds that are transformed in vivo into a parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., “Bioreversible Carriers in Drug Design,” American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al., Synthetic Communications 26(23):4351-4367, 1996, each of which is incorporated herein by reference.

The term “sulfonyl,” as used herein, represents —S(O)2—.

By “thiol” is meant an —SH group.

Asymmetric or chiral centers may exist in the compounds of the present invention. The present invention includes the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds or the present invention may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparation of mixtures of enantiometic compounds followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a racemic mixture of enantiomers, designated (+/−), to a chiral auxiliary, separation of the resulting diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Enantiomers are designated herein by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom, or are drawn by conventional means with a bolded line defining a substituent above the plane of the page in three-dimensional space and a hashed or dashed line defining a substituent beneath the plane of the printed page in three-dimensional space. If no stereochemical designation is made, it is to be assumed that the structure definition includes both stereochemical possibilities.

The invention provides several advantages. For example, as is noted above, the invention provides an approach for treating inflammatory bowel disease, which can be a very painful and debilitating condition that is difficult to treat, and affects more than one million people in the United States alone. The methods of the invention can also be used to prevent or to treat other conditions associated with TLR2 activation, as is discussed elsewhere herein. Finally, the screening methods of the invention provide straightforward approaches for identifying and characterizing agents that can be used in the prevention and treatment of TLR2-associated diseases and conditions.

Other features and advantages of the invention will be apparent from the following detailed description and the claims.

DETAILED DESCRIPTION

The invention is based in part on our discovery that animals that do not express Toll-like receptor 2 (TLR2) are protected from dextran sulfate sodium (DSS) induction of colitis, a model for inflammatory bowel disease (IBD). Based on this discovery, we concluded that agents that block activation of TLR2 can be used to treat or to prevent colitis and related diseases or conditions, as well as other diseases or conditions characterized by activation of TLR2. Accordingly, the invention provides compounds and methods for preventing or treating diseases or conditions associated with activation of TLR2, as well as methods for identifying agents that decrease or inhibit activation of this receptor. The compounds and methods of the invention are described in further detail, as follows.

A compound of formula I,

where X is —NHC(O)—; each of a and b is 1; W is —C(O)N(RW1)(CH2)cCH(ORW3)RW4—, where c is 2, each of RW1 and RW4 is H, and each of U, V, and RW5 is as defined above can be prepared by a sequence of reactions shown in Scheme 1. Accordingly, a compound of formula III is epoxidized to produce a compound of formula IV, and the epoxy group reacted with a cyano group, which nucleophilically opens up the epoxide to produce a compound of formula V. Methods of preparing chiral epoxides from achiral starting materials are known to those skilled in the art and such methods would produce a compound of formula V of known configuration. Protection of the hydroxyl group as the t-butyldiphenylsilyl ether, followed by reduction of the cyano group with Raney nickel, produces a compound of formula VII. Compounds of formula VIII can be prepared by coupling a compound of formula VII with the L- or D-form of N-Fmoc-serine. The hydroxyl group derived from the serine can be subsequently reacted with phosphorylating agent IX, and the intermediate phoshine oxidized with hydrogen peroxide to produce a compound of formula X. The Fmoc protecting group can be selectively removed with piperidine and the resulting amine acylated with an acyl chloride or coupled to a compound containing a carboxyl group in a reaction mediated by a carbodiimide or other suitable coupling reagent. Subsequent removal of the silyl protecting group with fluoride ion produces a compound of formula XI. Removal of the Boc protecting group under acidic conditions (e.g., TFA or HCl/dioxane) and acylation, reductive amination, or sulfonation of the resulting amine results in a compound of formula XII. Treatment with a Pd(0) catalyst removes the phosphonate allyl protecting group to produce a compound of formula XIII.

Examples of compounds of Formula XIII are shown in Table 1, where R1 is H, C2 has an (S)-configuration, and C3′ is an (R,S)-configurational mixture, unless otherwise specified.

TABLE 1 Compounds of formula XIII, where R1 is H Compound No. U V RW4 ER810702 —(CH2)18CH3 —(CH2)6CH3 (R)-config. ER811133 —(CH2)10CH3 —(CH2)12CH3 ER811134 —(CH2)4CH3 —(CH2)12CH3 ER811392 —(CH2)2C6H5 —(CH2)9CH3 ER811393 —(CH2)18CH3 —(CH2)12CH3 ER811394

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