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Wo 2007/075896 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 5 July 2007 (05.07.2007) WO 2007/075896 A2 (51) International Patent Classification: Arrow Rock Avenue, San Diego, CA 92126 (US). LUM, A61K 31/501 (2006.01) C07D 417/02 (2006.01) Christopher [US/US]; 13384 Bavarian Drive, San Diego, CA 92129 (US). ERNST, Justin [US/US]; 3535 Lebon (21) International Application Number: Drive #5105, San Diego, CA 92122 (US). PCT/US2006/048803 (74) Agents: CARSTEN, Douglas, H. et al; FOLEY & (22) International Filing Date: LARDNER LLP, P.O. Box 80278, San Diego, CA 20 December 2006 (20.12.2006) 92138-0278 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (26) Publication Language: English CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, (30) Priority Data: JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, 60/753,634 22 December 2005 (22.12.2005) US LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, 60/787,362 30 March 2006 (30.03.2006) US MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, 60/842,051 1 September 2006 (01.09.2006) US RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicant (for all designated States except US): KEMIA, INC. [US/US]; 9390 Towne Centre Drive, Suite 200, San (84) Designated States (unless otherwise indicated, for every Diego, CA 92121 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (75) Inventors/Applicants (for US only): BOMAN, Erik European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, [US/US]; 2348 Porch Swing St., Chula Vista, CA 91915 FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (US). MONTALBAN, Antonio, Garrido [ES/US]; 10339 RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, Azuaga Street, #213, San Diego, CA 92129 (US). PEI, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Yazhong [US/US]; 5185 Seachase Street, San Diego, CA 92130 (US). LARSON, Christopher [US/US]; 8761 Published: Chantilly Avenue, San Diego, CA 92123 (US). WANG, — without international search report and to be republished Zhijun [CN/US]; 14140 Chicarita Creek Road, San upon receipt of that report Diego, CA 92128 (US). URBAN, Jan [US/US]; 8841 Helen James Ave., San Diego, CA 92126 (US). DELEAT, For two-letter codes and other abbreviations, refer to the "G uid Nancy, GJ. [BE/US]; 7285 Rock Canyon Drive, San ance Notes on Codes and Abbreviations" appearing at the beg in Diego, CA 92126 (US). SEBO, Lubomir [SK/US]; 10175 ning of each regular issue of the PCT Gazette. (54) Title: HETEROCYCLIC CYTOKINE INHIBITORS (57) Abstract: The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory, anti-pain or anti-cancer agents. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions mediated by cytokines. HETEROCYCLIC CYTOKINE INHIBITORS FIELD OF THE INVENTION [0001] The present invention relates to low molecular weight compounds and compositions thereof, useful, e.g., as cytokine inhibitors, and their preparation. The invention further relates to methods of prevention and treatment of cytokine-mediated disorders. BACKGROUND OF THE INVENTION [0002] The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation and are called pro-inflammatory cytokines, whereas other cytokines suppress the activity ofpro-inflammatory cytokines and are referred to as anti-inflammatory cytokines. For example, IL-4, IL-10, and IL-1 3 are potent activators of B lymphocytes, but are also potent anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for pro-inflammatory cytokines such as IL-I, TNF, and chemokines (CA. Dinarello, Chest. 2000, 118: 503-508). [0003] Unregulated activities of these mediators can lead to the development of serious inflammatory conditions. For example, autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers. One hypothesis is that lymphocytes recognize at some point an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders. [0004] Tumor necrosis factor- (TNF- a) and interleukin-1 (IL-I) are pro inflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-I and TNF-oπ s believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure, and psoriasis among others (Dinarello, CA. et al., Rev. Infect. Diseases 1984, 6, 51; Salituro et al., Curr. Med. Chem. 1999, 6, 807; Henry et al., Drugs Fut. 1999, 24,1345). Recent data from clinical trials support the use of protein antagonists of cytokines, for example soluble TNFa receptor fusion protein (etanercept) (Moreland et al., Ann. Intern. Med. 1999, 130, 478) or the monoclonal TNFa antibody (Enbrel), for the treatment of rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis and psoriatic arthritis (Rankin et al., Br. J. Rheumatol. 1995, 34, 334; Galadari et al. Int J Dermatol. 2003, 42,231; Reimold, Am J Med Sci. 2003, 325(2), 75). Thus, the reduction of pro-inflamrnatory cytokines such as TNF- (also referred to as TNFa) and interleukin-1/3 (IL-Ib) has become an accepted therapeutic approach for potential drug intervention in these conditions. SUMMARY OF THE INVENTION [0005] The present invention provides low molecular weight compounds and pharmaceutical compositions thereof. In .particular, compounds of the invention are useful as cytokine release inhibitory agents. There are further provided methods for the preparation of such compounds and for the use of these compounds alone, in mixtures thereof, or in mixtures with other therapeutic agents in the preparation of medicaments for use in treating various disease states. For example, methods are provided for the use of compounds of the invention in the prevention and treatment of various disorders mediated by cytokines such as inflammatory disorders, cancer, pain, and others. [0006] Thus, there are provided in accordance with one aspect of the invention compounds comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with a target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with a target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety (L), wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein, wherein the compound is a cytokine inhibitor. [0007] In this aspect of the invention, cytokine inhibitors have the structure PEM-TM-OM-L-AM. At a concentration of 10 µM, such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%. [0008] The targeting moiety can hydrogen bond to residues at the binding site of the target protein. Typically the targeting moiety is an amide group. [0009] The pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein. Such moieties include 6 membered aryl and heteroaryl groups, for example, phenyl, pyridyl, or the like, substituted by bulky moieties. Bulky moieties fill a large volume of space in comparison to, for example, a methyl group, and include groups such as substituted or unsubstituted C alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec- butyl groups; substituted or unsubsituted 3.9 cycloalkyl groups, for example substituted or unsubstituted cyclohexyl or norbornyl groups; or substituted or unsubstituted heterocyclyl groups, such as substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidyl, 8-oxa-3-aza- bicyclo[3.2.1]octan-3-yl, oxazepanyl, thiazolyl, or thiomorpholinyl groups. [001 0] The orienting moiety, by binding to a hydrophobic pocket on the target protein, provides the proper orientation of the targeting moiety and pocket-expanding moiety for binding of the cytokine inhibitor to its target protein.
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