(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 11 September 2009 (11.09.2009) WO 2009/111337 Al (51) International Patent Classification: 92122 (US). LL Yongkai [CN/US]; 935 Babauta Road, C07O 221/12 (2006.01) C07D 491/12 (2006.01) Unit 7, San Diego, CA 92129 (US). CORTEZ, Alex C07D 471/04 (2006.01) C07D 495/04 (2006.01) [US/US]; 4073 Kendall Street, Apt.C, San Diego, CA C07D 471/12 (2006.01) A61K 31/4375 (2006.01) 92109 (US). ZOU, Yefen [CN/US]; 3420 Lebon Drive, C07D 491/056 (2006.01) A61P 37/04 (2006.01) San Diego, CA 92122 (US). MISHRA, Pranab [US/US]; 11948-3 Cypress Canyon Road, San Diego, CA 9213 1 (21) International Application Number: (US). ZHANG, Xiaoyue [CN/US]; 7698 Palmilla Drive, PCT/US2009/035563 Apt. 1113, San Diego, CA 92122 (US). SKIBINSKI, (22) International Filing Date: David [GB/IT]; C/O Novartis Vaccines and Diagnostics 27 February 2009 (27.02.2009) SrI, Via Fiorentia 1, I-53 1OO Siena (IT). SINGH, Man- mohan [US/US]; c/o Novartis Vaccines And Diagnostics, (25) Filing Language: English Inc., 4560 Horton Street, Emeryville, CA 94608 (US). (26) Publication Language: English VALIANTE, Nicholas [US/US]; c/o Novartis Vaccines And Diagnostics, Inc., 4560 Horton Street, Emeryville, (30) Priority Data: CA 94608 (US). 61/033,1 39 3 March 2008 (03.03.2008) US 61/148,336 29 January 2009 (29.01 .2009) US (74) Agents: RAYMOND, Daniel, E. et al; Genomics Insti tute of the Novartis Research Foundation, 10675 John Jay (71) Applicants (for all designated States except US): IRM Hopkins Drive, San Diego, CA 92121 (US). LLC [US/US]; 13 1 Front Street, P.O. Box 2899, HM LX Hamilton (BM). NOVARTIS AG. [CWCH]; Lichtstrasse (81) Designated States (unless otherwise indicated, for every 35, CH-4056 Basel (CH). kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (72) Inventors; and CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, (75) Inventors/Applicants (for US only): WU, Tom Yao- EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, Hsiang [CA/US]; 9175 Judicial Drive, San Diego, CA HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, [Continued on next page] (54) Title: COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS (57) Abstract: The invention provides a novel class of compounds, Summary of MenB SBA data pharmaceutical compositions comprising such compounds and meth ods of using such compounds to treat or prevent diseases or disorders (§ experiments) associated with Toll-Like Receptors, including TLR7 and TLR8. In are useful as adjuvants for enhancing the (formula I) wherein: X 3 is N; X4 is N Or KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, MR, NE, SN, TD, TG). SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, . .. , . UG, US, UZ, VC, VN, ZA, ZM, ZW. Published: . , — with international search report (Art. 21(3)) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, — before the expiration of the time limit for amending the GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, claims and to be republished in the event of receipt of ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, amendments (Rule 48.2Qi)) TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, _ wUh sequence Usting part of description (Ruie 5 .2 (a)) ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61/033,139, filed March 3, 2008 and U.S. Provisional Patent Application No. 61/148,336, filed January 29, 2009. The disclosure of the priority applications are incorporated herein by reference in their entirety and for all purposes. STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made in part with Government support under DTRA Grant No. HDTRA 1-07-9-0001 awarded by the Department of Defense. The Government has certain rights in the invention. FIELD OF THE INVENTION [0003] The invention relates to modulators of Toll-Like Receptors (TLRs), and methods of using such compounds. BACKGROUND OF THE INVENTION [0004] Early detection of specific classes of pathogens is accomplished by the innate immune system with the help of pattern recognition receptors (PRRs). The detected pathogens include viruses, bacteria, protozoa and fungi, and each constitutively expresses a set of class-specific, mutation-resistant molecules called pathogen-associated molecular patterns (PAMPs). These molecular markers may be composed of proteins, carbohydrates, lipids, nucleic acids or combinations thereof, and may be located internally or externally. Examples of PAMPs include bacterial carbohydrates (hpopoly saccharide or LPS, mannose), nucleic acids (bacterial or viral DNA or RNA), peptidoglycans and lipotechoic acids (from Gram positive bacteria), N- formylmethionine, lipoproteins and fungal glucans. [0005] Pattern recognition receptors have evolved to take advantage of three PAMP qualities. First, constitutive expression allows the host to detect the pathogen regardless of its life cycle stage. Second, the PAMPs are class specific, which allows the host to distinguish between pathogens and thereby tailor its response Third, mutation resistance allows the host to recognize the pathogen regardless of its particular strain. [0006] Pattern recognition receptors are involved in more than just recognition of pathogens via their PAMPs. Once bound, pattern recognition receptors tend to cluster, recruit other extracellular and intracellular proteins to the complex, and initiate signaling cascades that ultimately impact transcription. Additionally, pattern recognition receptors are involved in activation of complement, coagulation, phagocytosis, inflammation, and apoptosis functions in response to pathogen detection. [0007] Pattern recognition receptors (PRRs) may be divided into endocytic PRRs or signaling PRRs. The signaling PRRs include the large families of membrane-bound Toll-like receptors (TLRs) and cytoplasmic NOD-like receptors, while the endocytic PRRs promote the attachment, engulfment and destruction of microorganisms by phagocytes without relaying an intracellular signal, are found on all phagocytes and mediate removal of apoptotic cells. In addition, endocytic PRRs recognize carbohydrates and include mannose receptors of macrophages, glucan receptors present on all phagocytes and scavenger receptors that recognize charged ligands. SUMMARY OF THE INVENTION [0008] Provided herein are compounds and pharmaceutical compositions thereof, which are useful modulators of toll-like receptors. [0009] In one aspect provided herein such compounds, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, having a structure according to Formula (I) as described herein. Certain embodiments of the invention include compounds of Formula (I-A), methods of using them, and pharmaceutical compositions comprising these compounds: Formula (I-A) wherein: X3 is N; X4 is N or CR3, and X5 is -CR4=CR5-; R1 and R2 are H ; R3 is H; R4 and R5 are each independently selected from H, halogen, -C(O)OR7, -C(O)R7, 11 12 1 1 12 9 9 7 7 7 8 10 -C(O)N(R R ), -N(R R ), -N(R )2, -NHN(R )2, -SR , -(CFb)nOR , -(CH2)nR , -LR , -LR , - 8 10 OLR , -OLR , -Ci-Cealkyl, Cr C6heteroalkyl, Cr C6haloalkyl, C2-C8alkene, C2-C8alkyne, Ci- Cgalkoxy, CrC haloalkoxy, aryl, heteroaryl, C3-Cscycloalkyl, and C3-C8heterocycloalkyl, wherein the Ci-Cealkyl, Cr C6heteroalkyl, Cr C5haloalkyl, C2-C8alkene, C2-C8alkyne, Cr C6alkoxy, C1- 4 5 C6haloalkoxy, aryl, heteroaryl, C3-Cscycloalkyl, and C3-C8heterocycloalkyl groups of R and R are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -NO2. 7 8 8 8 8 9 8 8 10 -R , -OR . -C(O)R ,-OC(O)R , -C(O)OR , -N(R )2, -P(O)(OR )2, -OP(O)(OR )2, -P(O)(OR )2, - 10 9 8 9 9 8 3 4 4 5 OP(O)(OR )2, -C(O)N(R )2, -S(O) 2R , -S(O) 2N(R )2, and -NR S(O)2R ; or R and R , or R and R . when present on adjacent ring atoms, can optionally be linked together to form a 5-6 membered ring, wherein the 5-6 membered ring is optionally substituted with R7; each L is independently selected from a bond, -(0(CH 2)m)r , Q-C alkyl, C2-C6alkenylene and C2-C6alkynylene, wherein the Ci-C6alkyl, C2-C6alkenylene and C2-C6alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, -R8, -OR8, - 9 8 8 10 10 N(R )2, -P(O)(OR )2, -OP(O)(OR )2, -P(O)(OR )2, and -OP(O)(OR )2; 7 R is selected from H, Ci-C alkyl, aryl, heteroaryl, C3-C8cycloalkyl, Ci-C heteroalkyl, C1- C haloalkyl, C2-Csalkene, C2-Csalkyne, Ci-C6alkoxy, Ci-C6haloalkoxy, and C3-Csheterocycloalkyl, wherein the Ci-C alkyl, aryl, heteroaryl, C3-C8cycloalkyl, Ci-C heteroalkyl. Ci-C6haloalkyl, C2- 7 Cgalkene, C2-Cgalkyne, Q-C alkoxy, CrC haloalkoxy, and C3-Csheterocycloalkyl groups of R are each optionally substituted with 1 to 3 R13 groups, and each R13 is independently selected from halogen, -CN, -LR9, -LOR9, -OLR9, -LR10, -LOR10 , -OLR10, -LR8,