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(12) Patent Application Publication (10) Pub. No.: US 2013/0065861 A1 Wu Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0065861 A1 Wu Et Al US 2013 OO65861A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0065861 A1 Wu et al. (43) Pub. Date: Mar. 14, 2013 (54) COMPOUNDS (CYSTEIN BASED Publication Classification LIPOPEPTIDES) AND COMPOSITIONS AS (51) Int. Cl. TLR2AGONSTS USED FORTREATING A63L/23 (2006.01) INFECTIONS, INFLAMMATIONS, A6IP II/06 (2006.01) RESPRATORY DISEASESETC. A6IP II/00 (2006.01) A6IPL/04 (2006.01) A6IPI/00 (2006.01) A6IP35/00 (2006.01) (75) Inventors: Tom Yao-Hsiang Wu, San Diego, CA A6IP 9/02 (2006.01) (US); Yefen Zou, San Diego, CA (US); C07F 9/40 (2006.01) Timothy Z. Hoffman, San Diego, CA A6IP3 L/18 (2006.01) (US); Jianfeng Pan, San Diego, CA A63/662 (2006.01) C07D 213/56 (2006.01) (US) A613 L/4402 (2006.01) C07C 237/06 (2006.01) C07D 265/30 (2006.01) (73) Assignee: IRM LLC, Hamiltona (BM) A 6LX3/5.375 (2006.01) C07D 233/6 (2006.01) (21) Appl. No.: 13/636,328 A613 L/4164 (2006.01) C07C 237/04 (2006.01) PCT Fled: Mar. 23, 2011 (52) U.S. Cl. (22) USPC ........... 514/119:554/101: 514/548; 546/335; 514/357: 514/547: 544/159; 514/237.8: 548/338.5; (86) PCT NO.: PCT/US11A29661 514/399 S371 (c)(1), (57) ABSTRACT (2), (4) Date: Sep. 20, 2012 The invention provides a novel class of compounds viz. gen erally lipopeptides like Pam3CSK4, immunogenic composi tions and pharmaceutical compositions comprising Such Related U.S. Application Data compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like (60) Provisional application No. 61/316,551, filed on Mar. Receptors 2. In one aspect, the compounds are useful as 23, 2010. adjuvants for enhancing the effectiveness a vaccine. US 2013/0065861 A1 Mar. 14, 2013 COMPOUNDS (CYSTEIN BASED nose receptors of macrophages, glucan receptors present on LIPOPEPTIDES) AND COMPOSITIONS AS all phagocytes and Scavenger receptors that recognize TLR2AGONSTS USED FORTREATING charged ligands. INFECTIONS, INFLAMMATIONS, RESPRATORY DISEASESETC. SUMMARY OF THE INVENTION 0008 Provided herein are compounds and pharmaceutical CROSS-REFERENCE TO RELATED compositions thereof, which are agonists of toll-like receptor APPLICATIONS 2 (TLR2). In certain embodiments, such TLR2 agonists are immune potentiators that bind to aluminum-containing adju 0001. This application claims the benefit of priority under vants, such as, by way of example only, aluminum hydroxide, 35 U.S.C. S 119(e) to U.S. Provisional Patent Application No. aluminum oxyhydroxide and aluminum hydroxyphosphate. 61/316,551, filed Mar. 23, 2010, the disclosure which is Thus, also provided herein are immunogenic compositions incorporated herein by reference in its entirety and for all that contain an antigen and a TLR2 agonist provided herein purposes. that bind to aluminum-containing adjuvants. When Such immunogenic compositions are administered to a Subject in STATEMENT OF GOVERNMENT SUPPORT need thereof. Such TLR2 agonists enhance the immune 0002 This invention was made in part with Government response to the immunogenic composition. support under DTRA Grant No. HDTRA1-07-9-0001 0009. In one aspect provided herein such compounds, and awarded by the Department of Defense. The Government has the pharmaceutically acceptable salts, pharmaceutically certain rights in the invention. acceptable Solvates (e.g. hydrates), the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers FIELD OF THE INVENTION and mixture of isomers thereof, have a structure according to Formula (I): 0003. The invention relates to modulators of Toll-Like Receptors (TLRs), and methods of using such compounds. Formula (I) R BACKGROUND OF THE INVENTION NH L-R 0004 Early detection of specific classes of pathogens is accomplished by the innate immune system with the help of O N-N L-R pattern recognition receptors (PRRs). The detected patho gens include viruses, bacteria, protozoa and fungi, and each constitutively expresses a set of class-specific, mutation-re t sistant molecules called pathogen-associated molecular pat R4 terns (PAMPs). These molecular markers may be composed wherein: of proteins, carbohydrates, lipids, nucleic acids or combina tions thereof, and may be located internally or externally. I0010) R' is H, —C(O)—C7-Cisalkyl or —C(O)—C- Examples of PAMPs include bacterial carbohydrates (li Calkyl, popolysaccharide or LPS, mannose), nucleic acids (bacterial 0011 R is C7-Calkyl: or viral DNA or RNA), peptidoglycans and lipotechoic acids 0012 R is C-Calkyl: (from Grampositive bacteria), N-formylmethionine, lipopro 0013 L is CHOC(O) , —CH-O-, -CHNRC teins and fungal glucans. (O)– or -CHOC(O)NR7 ; 0005 Pattern recognition receptors have evolved to take 0014) L, is OC(O)-, -O-, - NR7C(O) or advantage of three PAMP qualities. First, constitutive expres OC(O)NR7 ; sion allows the host to detect the pathogen regardless of its life 0.015 R is -LR or -LR; cycle stage. Second, the PAMPs are class specific, which 0016 R is N(R7), OR7, -P(O)(OR7), C(O) allows the host to distinguish between pathogens and thereby OR7, NRC(O)IR, NRC(O)ILR, OLR, tailor its response. Third, mutation resistance allows the host C(O)NR'LR, C(O)NR'LR, S(O),OR7, to recognize the pathogen, regardless of its particular strain. —OS(O).OR, C-Calkyl, a Caryl, a Coaryl, a 0006 Pattern recognition receptors are involved in more Caryl, 5 to 14 ring membered heteroaryl containing 1 than just recognition of pathogens via their PAMPs. Once to 3 heteroatoms selected from O, S and N, bound, pattern recognition receptors tend to cluster, recruit C-C scycloalkyl or a 5 to 6 ring membered heterocy other extracellular and intracellular proteins to the complex, and initiate signaling cascades that ultimately impact tran cloalkyl containing 1 to 3 heteroatoms selected from O, Scription. Additionally, pattern recognition receptors are S and N, wherein the aryl, heteroaryl, cycloalkyl and involved in activation of complement, coagulation, phagocy heterocycloalkyl of Rare each unsubstituted or the aryl, tosis, inflammation, and apoptosis functions in response to heteroaryl, cycloalkyl and heterocycloalkyl of R are pathogen detection. each substituted with 1 to 3 substituents independently 0007 Pattern recognition receptors (PRRs) may be selected from —OR. --OLR, OLR, OR, and divided into endocytic PRRs or signaling PRRs. The signal C(O)CR7; ing PRRs include the large families of membrane-bound Toll 001.7 L is a C-Coalkylene, wherein the like receptors (TLRs) and cytoplasmic NOD-like receptors, C-Coalkylene of L is unsubstituted, or the while the endocytic PRRs promote the attachment, engulf C-Coalkylene of L is substituted with 1 to 4 R ment and destruction of microorganisms by phagocytes with groups, or the C-Coalkylene of L is Substituted with 2 out relaying an intracellular signal, are found on all phago C-Calkyl groups on the same carbon atom which cytes and mediate removal of apoptotic cells. In addition, together, along with the carbon atom they are attached endocytic PRRS recognize carbohydrates and include man to, form a C-C scycloakyl; US 2013/0065861 A1 Mar. 14, 2013 (0018) La is (CR'R').O)(CR'R''), or 0043. In certain embodiments of such compounds and -(CR'R'')(CR'R').O),(CRR), , wherein pharmaceutically acceptable salts thereof. R' is H. In other each R'' is a C-Calkyl groups which together, along embodiments of Such compounds and pharmaceutically with the carbon atom they are attached to, form a acceptable salts thereof, R is C(O) Calkyl. In other C-C scycloakyl; embodiments of Such compounds and pharmaceutically I0019 each R is independently selected from halo, acceptable salts thereof. R' is —C(O)—Co-Cisalkyl. C-Calkyl, C-Calkyl substituted with 1-2 hydroxyl 0044. In certain embodiments of such compounds and groups, OR7, N(R), —C(O)OH, -C(O)N(R), -P(O)(OR7), a Caryl, a Coaryland a Caryl; pharmaceutically acceptable salts thereof, L is —CH2OC I0020 each R" is independently selected from H and (O)—and L is —OC(O)— —O , NRC(O)—or —OC C-Calkyl, (O)NR7 ; (0021 R is selected from - SR", C(O)OH, -P(O) 0.045 or L is —CHO—and L is (OR7), and a 5 to 6 ring membered heterocycloalkyl NR7C(O) or OC(O)NR7 ; containing 1 to 3 heteroatoms selected from O and N: 0046) or L is —CHNRC(O)—and Lis—OC(O) , 0022 R is phenyl: -O-, - NRC(O) or —OC(O)NR' : I0023 each R' is independently selected from H and 0047 or L is —CHOC(O)NR7 and L is OC halo; (O) - O - NRC(O)– or - OC(O)NR' . 0024 each p is independently selected from 1, 2, 3, 4, 5 0048. In certain embodiments of such compounds and and 6, and pharmaceutically acceptable salts thereof, L is —CH2OC (0025 q is 1, 2, 3 or 4. (O)—and L is —OC(O)—. In other embodiments of such 0026. In certain embodiments of such compounds and compounds and pharmaceutically acceptable salts thereof, L. pharmaceutically acceptable salts thereof, is —CHO—and L is —O—. In other embodiments of such I0027) R' is H. —C(O) Co-Cisalkyl; compounds and pharmaceutically acceptable salts thereof, L. 10028 R is Co-Cisalkyl: is —CHO and L is NRC(O)—. In other embodiments 0029 R is Co-Calkyl: of Such compounds and pharmaceutically acceptable salts 003.0 L is CHO , —CHOC(O) , —CHNRC thereof, Lis-CHOC(O)NR7 and Lis–OC(O)NR' . 0031 L is - O -, - OC(O) or - NRC(O)–: In other embodiments of Such compounds and pharmaceuti 0032 R is -LRor-LR; cally acceptable salts thereof, L is —CHNRC(O)—and L. (0033 R is N(R), —OR7, -P(O)(OR7), —C(O) is NRC(O)-. OR7, NRC(O)IR, OLR, C(O)NR'LR, 0049.
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