(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(10) International Publication Number (43) International Publication Date PCT 21 February 2008 (21.02.2008) WO 2008/021388 Al

(51) International Patent Classification: 92126 (US). URBAN, Jan [US/US]; 8841 Helen James C07D 213/75 (2006.01) Avenue, San Diego, CA 92126 (US). WANG, Zhijun [CN/US]; 14140 Chicarita Creek Road, San Diego, CA (21) International Application Number: 92128 (US). ZHU, Jay [US/US]; 13797 Kerry Lane, San PCT/US2007/0 18049 Diego, CA 92130 (US).

(22) International Filing Date: 16 August 2007 (16.08.2007) (74) Agents: WARBURG, Richard, J. et al; Foley & Lardner LLP, P.O. Box 80278, San Diego, CA 92138-0278 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (30) Priority Data: CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, 60/838,795 17 August 2006 (17.08.2006) US ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, 60/891,470 23 February 2007 (23.02.2007) US IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, (71) Applicant (for all designated States except US): KEMIA, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, INC. [US/US]; 5871 Oberlin Drive, Suite 100, San Diego, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, CA 92121 (US). TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (72) Inventors; and (75) Inventors/Applicants (for US only): BOMAN, Erik (84) Designated States (unless otherwise indicated, for every [US/US]; 2348 Porch Swing St., Chula Vista, CA 91915 kind of regional protection available): ARIPO (BW, GH, (US). ERNST, Justin [US/US] ; 3535 Lebon Drive, #5 105, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, San Diego, CA 92122 (US). MONTALBAN, Antonio, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Garrido [ES/US]; 10339 Azuaga Street, #213, San Diego, European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, CA 92129 (US). LARSON, Christopher [US/US]; 8761 FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, Chantilly Avenue, San Diego, CA 92123 (US). LUM, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, Christopher [US/US]; 13384 Bavarian Drive, San Diego, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). CA 92129 (US). PEI, Yazhong [US/US]; 5185 Seachase Street, San Diego, CA 92130 (US). SEBO, Lubomir Published: [SK/US]; 10175 Arrow Rock Avenue, San Diego, CA — with international search report

(54) Title: HETEROARYL DERIVATIVESAS CYTOKINE INHIBITORS

(57) Abstract: The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions mediated by cytokines. In particular, compounds of the invention are useful as anti-inflammatory, anti-pain or anti-cancer agents. HETEROARYL DERIVATIVES AS CYTOKINE INHIBITORS RELATED APPLICATIONS

[0001] This application is related to U.S. Application No. 60/838,795, filed August 17, 2006, entitled "Heteroaryl Derivatives as Cytokine Inhibitors", U.S. Application No. 60/891,470, filed February 23, 2007, entitled "Heteroaryl Derivatives as Cytokine Inhibitors", International Application No. PCT/US2006/006682, filed February 23, 2006, entitled "Cytokine Inhibitors and Their Use in Therapy", International Application No. PCT/US06/043896, filed November 13, 2006, entitled "Therapy using Cytokine Inhibitors", and International Application No. PCT/US2007/070547, filed June 8, 2007, entitled "Therapy using Cytokine Inhibitors", the entire contents of each of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to low molecular weight compounds and compositions thereof, useful as, e.g., cytokine inhibitors, and their preparation. The present invention relates to methods of treating, preventing, modifying and managing a variety of conditions, including cytokine-mediated disorders or related disorders, which comprise the administration of a cytokine inhibitor, alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosing regimens using the disclosed compounds, optionally in conjunction with other therapies, for the treatment of a variety of conditions, including autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and the like.

BACKGROUND OF THE INVENTION [0003] 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 of pro-inflammatory cytokines and are referred to as anti-inflammatory cytokines. For example, IL-4, IL-10, and IL- 13 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). [0004] 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 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.

[0005] Tumor necrosis factor-or (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- is 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 TNF-a receptor fusion protein (etanercept) (Moreland et al., Ann. Intern. Med. 1999, 130, 478) or the monoclonal TNFa antibody (infliximab), 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, 42,23 1; Reimold, Am J Med Sci. 2003, 325(2), 75). Thus, the reduction of pro-inflammatory cytokines such as TNF-α;(also referred to as TNFa) and interleukin-1 β (IL-Ib) has become an accepted therapeutic approach for potential drug intervention in these conditions.

SUMMARY OF THE INVENTION.

[0006] The present invention provides low molecular weight compounds and pharmaceutical compositions thereof. In particular, compounds of the invention are useful for a variety of applications including, e.g., 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, cardiovascular, and autoimmune disorders, cancer, pain, and others.

[0007] Thus, there are provided in accordance with one aspect of the invention a compound 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 or the NH 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 heteroaryl ring and attached to the NH or the carbonyl 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 6-membered aryl or heteroaryl moiety; 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 1 hydrogen bond interaction with an ATP-binding pocket of the target protein,

wherein the compound is a cytokine inhibitor.

[0008] 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%.

[0009] The targeting moiety can hydrogen bond to residues at the binding site of the target protein. Typically the targeting moiety is an amide group.

[001 0] 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

C2-4 alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl groups; substituted or unsubsituted C3.9 cycloalkyl groups, for example substituted or unsubstituted cyclohexyl or norbornyl groups; or substituted or unsubstituted heterocyclyl groups, such as substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl groups.

[001 1] 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. Such moieties include, for example, pyridyl, pyridyl-N-oxide or pyridazinyl, substituted by small hydrophobic moieties, exemplified by halogens, methyl, trifluoromethyl, and the like.

[0012] Typically, the linker moiety, L, comprises a phenyl, pyridyl, pyrimidyl, or pyridazinyl group, for example, L is a phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group.

[001 3] In some embodiments, the anchoring moiety is a hydrogen bond acceptor. In other embodiments, the anchoring bond moiety comprises both a hydrogen bond donor and acceptor. For example, the anchoring moiety may comprise an amide, amine, carbonyl, alkoxy, urethane, sulfoxide, sulfonamide, or OC(O) group, and may further comprise a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, phenyl, benzyl, phenethyl, 2-pyridyl, (CH 2)-2-pyridyl, (CH 2)2-2-pyridyl,

(CH 2)3-2-pyridyl, 3-pyridyl, (CH 2)-3 -pyridyl, (CH 2)2-3-pyridyl, (CH 2)3-3-pyridyl, 4-pyridyl,

(CH2)-4-pyridyl, (CH 2)2-4-pyridyl, (CH 2)3-4-pyridyl, tetrahydrofuranyl,

(CH2)-tetrahydrofuranyl, (CH^-tetrahydrofuranyl, (CH 2)3-tetrahydrofuranyl, tetrahydropyranyl, (CH 2)-tetrahydropyranyl, (CH 2)2-tetrahydropyranyl,

(CH 2)3-tetrahydropyranyl, pyrrolidinyl, (CH J-pyrrolidinyl, π (CH 2)3-py Olidinyl, piperidinyl, (CH 2)-piperidinyl, (CH 2)2-piperidinyl, (CH 2)3-piperidinyl, morpholinyl, (CHy-morpholinyl, (CH 2)2-morpholinyl, or (CH 2)3-morpholinyl group.

[0014] In another aspect, the invention provides for compounds of Formula I: stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein X is CH N, or NO; Y is CH, N, or NO, provided that X and Y are not both CH or NO;

A is F, Cl, Br, I, NR2, or a C1.3 alkyl or -0(C 1-3 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; G is an aryl or heteroaryl group, wherein G is substituted by one or more R 1, R2 or R3; Ar is a 6-membered aryl or heteroaryl group; L1 is -C(O)NH-; 2 L is a covalent bond, (CR' 2)S, (CR' 2)nO(CR' 2)t, (CR' 2)nNR(CR' 2)t,

(CR' 2)nC(NOR), (CR' 2)nSO2NR(CR' 2)t, (CR' 2)nC(O)(CR' 2)t, O(CR' 2)tC(O)(CR' 2)n,

O(CR' 2)sNR(CR'2)n, O(CR' 2)nC(O)NR(CR' 2)t, O(CR' 2)sNRC(O)(CR' 2)n, (CR' 2)nC(O)NR(CR' 2)t, (CR' 2)nC(O)NRNR(CR' 2)t, or (CR' 2)nNRC(O)O(CR' 2), group; Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl group; each R1 is independently F, Cl, Br, I, -NR , -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heterocyclylalkyl group; 2 each R is independently F, Cl, Br, I, -CN, -NO2, a substituted or unsubstituted

alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR' 2, -C(NR)NR2, 5 -C(NR)NROR, -NR' 2, -(CR 2)tNRR', -NRC(O)R", -NR C(O)OR", -NR SO2R",

-NR'C(O)NR 2, -NR'C(S)NR' 2, -S(O)mR", or -SO2NR' 2; each R3 is independently a substituted or unsubstituted alkyl, alkenyl, or

alkynyl group, or an -0(C 1- alkyl) group, wherein the 4 alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted C alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl or heterocyclylalkyl group; each m is independently 0, 1 or 2; n is 0, 1, or 2;

s is I 52 or 3; and each t is independently 0, 1, or 2; provided the compound is not 5-(biphenyl-4-yl)-6-chloro-N-(6- methoxypyridin-3-yl)nicotinamide.

[001 5] In some embodiments of compounds of Formula I, Ax is phenyl, pyridyl, pyrimidyl, or pyridazinyl. In others, Ar is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

[0016] All of the following compounds are contemplated by Formula I: I-AC I- AD I-AE I-AF I-AG

I-AH I-AI I-AJ

I-AN

I-AO I-AP I-AQ

I-AU I-AV i-AW

I-AX [0017] In some embodiments, the compound of Formula I is

[0018] In others, the compound is

[0019] In still others, the compound is

[0020] In yet other embodiments, the compound is

[0021] In some embodiments of compounds of Formula I, A is F, -CH 3, or -CF3. In others, G is a phenyl, pyrimidyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, or furanyl group. For example, G is

[0022] In some other embodiments of compounds of Formula I, L2 is a covalent bond,

O, NR, C(O)(CH2)n, C(NOR), SO2NR, O(CH2)tC(O), C(O)NR, C(O)NRNR OrNRC(O)O 2 group. In others, L is a covalent bond, O, OC(O), C(NOH), SO2NH3 OCH2C(O), C(O),

C(O)CH2 C(O)CH2CH2, C(O)NHNH, or C(O)NH. [0023] In some embodiments of compounds of Formula I, Q is a substituted or unsubstituted alkyl, cycloalkyl, (C0-4 alkyl)phenyl, (C0-4 alkyl)pyridyl, φ (Co-4 alkyl)pyrimidinyl, (C0-4 alkyl)mo holinyl, (Co- alkyl)thiomorpholinyl, (Co-4 alkyl)quinuclidinyl, (Q alkyl)(10-oxa-4-aza-tricycIo[5.2.1.0 2'6]decanyl),

(Co-4 alkyI)(8-oxa-3-aza-bicyclo[3.2.1]octanyl), (C0-4 alkyl)tetrahydropyranyl, π (Co-4 alkyl)tetrahydrofuranyl, (C0-4 alkyl)pyrrolidinyl, (Co-4 alkyl)piperidi yl, or (Co-4 alkyl)piperazinyl group. For example, Q is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl,

(CH 2)-cyclopropyl, (CHbVcyclopropyl, (CH2)3-cyclopropyl, cyclobutyl, (CH 2)-cyclobutyl,

(CH 2)2-cyclobutyl, (CH 2)3-cyclobutyl, cyclopentyl, (CH 2)-cyclopentyl, (CH 2)2-cyclopentyl,

(CH2)3-cyclopentyl, cyclohexyl, (CH2)-cyclohexyl, (CH2)2-cyclohexyl, (CH 2)3-cyclohexyl, bicyclo[2.2. l]heptanyl, (CH 2)-bicyclo[2.2. 1]heptanyl, (CH 2)2-bicyclo[2.2. 1]heptanyl,

(CH 2)3-bicyclo[2.2.1]heptanyl, cycloheptyl, phenyl, benzyl, phenethyl, 2-pyridyl,

(CH 2)-2-pyridyl, (CH 2)2-2-pyridyl, (CH 2)3-2-pyridyl, 3-pyridyl, (CH 2)-3-pyridyl,

(CH 2)2-3-pyridyl, (CH 2)3*3-pyridyl, 4-pyridyl, (CH 2)-4-pyridyl, (CH 2)2-4-pyridyl,

(CH 2)3-4-pyridyl, tetrahydrofuranyl, (CH2)-tetrahydrofuranyl, (CH 2)2-tetrahydrofuranyl,

(CH 2)3-tetrahydrofuranyl, tetrahydropyranyl, (CH 2)-tetrahydropyranyl,

(CH 2)2-tetrahydropyranyl, (CH 2)3-tetrahydropyranyl, pyrrolidinyl, (CH 2)-pyrrolidinyl, 2>6 (CH 2)2-pyrrolidinyl, (CH 2)3-pyrrolidinyl, 10-oxa-4-aza-tricyclo[5.2. 1.0 ]decanyl,

8-oxa-3-aza-bicyclo[3.2.1]octanyl, piperidinyl, (CH2)-piperidinyl, (CH 2)2-piperidinyl,

(CH 2)3-piperidinyl, piperazinyl, (CH2)- piperazinyl, (CH 2)2- piperazinyl, (CH 2)3- piperazinyl, morpholinyl, (CH 2)-morpholinyl, (CH 2)2-morpholinyl, or (CH2)3-morpholinyl group.

1 [0024] In some embodiments of compounds of Formula I, R is F, -CN, -NR 2, or a substituted or unsubstituted C i-4 alkyl, C3-9 cycloalkyl, heterocyclyl or heterocyclylalkyl 1 group. For example, R is F, -CN, -N(Ci alkyl) wherein each C i- alkyl group is independently substituted or unsubstituted; or R 1 is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, thiomorpholinyl, (CH 2)-pyrrolidinyl, (CH 2)-piperidinyl, ρ (CH 2)-oxazepanyl, (CH2)-morpholinyl > or (CH 2)-pi erazinyl group. [0025] In some embodiments, R2 is a substituted or unsubstituted (Ci-6 alkyl) or heterocyclylalkyl group, F, Cl, -CN, -NO2, -OR', -C(O)OR', -C(O)NR' 2, -(CH2)tNRR",

-C(NR)NR 2, -C(NR)NROR, -NRC(O)R", -NRC(O)OR", -NR'SO 2R", -NR'C(O)NR 2, or 2 -SO2NR' 2. For example, R is F, -CN, -CF3, -NO2, -0(C -6 alkyl), -C(O)O(Ci -6 alkyl),

-C(O)NH 2, -C(O)NH(Cu 6 alkyl), -C(O)NH(C 3.6 cycloalkyl), -C(O)NH(cycloalkylalkyl),

-C(O)NH(aralkyl), -(CH2)NH(Ci -6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl),

-C(NH)NH 2, -C(NH)NH(C 6 alkyl), -C(NH)NHOH, -C(NH)NHO(C 1-6 alkyl),

-NHC(O)(Ci -6 alkyl), -NHC(O)(C 3-6 cycloalkyl), -NHC(O)(cycloalkylalkyl), -NHC(O)(aryl),

-NHC(O)(aralkyl), -NHSO 2(Ci -6 alkyl), -NHSO 2(C3-6 cycloalkyl), -NHSO 2(cycloalkylalkyl),

-NHSO 2(aryl), -NHSO 2(aralkyl), -SO2NH(Ci 6 alkyl), -SO2NH(C 3-6 cycloalkyl),

-SO2NH(cycloalkylalkyl), -SO2NH(aryl), or -SO2NH(aralkyl), wherein each d .6 alkyl,

C3.6 cycloalkyl, cycloalkylalkyl aryl, and aralkyl group is substituted or unsubstituted.

3 [0026] In some embodiments, R is a substituted or unsubstituted Ci- alkyl or

-O(Ci-4 alkyl) group, or is a.partially or fully halogenated -O(Ci_2 alkyl) group.

[0027] In some embodiments of compounds of Formula I, G is phenyl and R 1 is F, Cl,

-CN, -N(Ci -3 alkyl) 2 wherein each C 3 alkyl group is independently substituted or unsubstituted; or R 1 is a substituted or unsubstituted morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl,

(CH2)-oxazepanyl, (CH2)-morpholinyl, (CH2)-piperazinyl, methyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, neopentyl, or cyclohexyl group. In some such embodiments, R 1 is F, Cl, a substituted or unsubstituted morpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, (CH2)-pyrrolidinyl, (CH2)- piperidinyl, (CH2)-morpholinyl, (CH2)-piperazinyl, methyl, tert-butyl, or cyclohexyl group. 2 In others, R is F, -CN, -CF 3, -NO2, -0(Ci 6 alkyl), -C(O)O(Ci -6 alkyl), -C(O)NH2,

-C(O)NH(Ci -6 alkyl), -C(O)NH(C 3 6 cycloalkyl), -C(0)NH(cycloalkylalkyl),

-C(O)NH(aralkyl), -NHC(O)(Ci -6 alkyl), -NHC(O)(C 3-6 cycloalkyl),

-NHC(O)(cycloalkylalkyl),-NHC(O)(aryl), -NHC(O)(aralkyl), -(CH2)NH(Ci -6 alkyl),

-(CH2)NH(aralkyl), -(CH 2)NH(heterocyclylalkyl), -NHSO 2(C 6 alkyl),

-NHSO2(C3-6 cycloalkyl), -NHSO 2(cycloalkylalkyl), -NHSO 2(aryl), -NHSO 2(aralkyl),

-SO2NH(Ci -6 alkyl), -SO2NH(C 3.6 cycloalkyl), -SO2NH(cycloalkylalkyl), -SO2NH(aryl), or θ -S 2NH(aralkyl), wherein each Ci- alkyl, C3-6 cycloalkyl, cycloalkylalkyl aryl, and aralkyl group is substituted or unsubstituted. In still others, F, -CN, -CF3, -C(O)NH2,

-C(O)NH(C 1-6 alkyl), -C(O)NH(C 3 6 cycloalkyl), -C(O)NH(cycloalkylalkyl),

-(CH2)NH(C 1-6 alkyl), -(CH2)NH(heterocyclylalkyl), -NHSO2(C 1-6 alkyl), or θ -S 2NH(Ci.6 alkyl), wherein each Ci_ alkyl group is substituted or unsubstituted. In yet 3 others, R is a substituted or unsubstituted C - alkyl or -0(Ci - alkyl) group, or is a partially or folly halogenated -O(Ci-2 alkyl) group.

[0028] In some embodiments of compounds of Formula I, L2 is O, OC(O), C(O),

C(O)NH, C(O)NHNH, C(O)NMe, OCH2C(O), SO2NH, CH(OH), or C(NOH), and Q is

[0029] In some embodiments, G is a phenyl group.

[0030] In some embodiments of compounds of Formula I, the compound at a concentration of 10 µM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. [0031] Where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents of Formula I as described herein. Thus, e.g., combination 1025 describes those embodiments in which Ar is 2-ρyridyl and G is phenyl.

[0032] Table 1: Exemplary combinations of G and Ar for Formula I. [0033] Table 2 sets forth various combinations of substituents L and Q of Formula I. Thus, e.g., combination 431 1 describes those embodiments in which L is C(O) and Q is morpholinyl. Further, those skilled in the art will understand that a combination of substituents is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 1, describing Ar and G, may be combined with any combination from Table 2, describing L2 and Q. For example, combination 1025 from Table 1 and combination 431 1 from Table 2 describe those embodiments of Formula I in which Ar is 2-pyridyl, G is phenyl, L2 is C(O) and Q is morpholinyl. Each G and Q in the tables is understood to be optionally substituted as described herein. Moreover, each value of

A (-F, Cl, Br, I, NR , or C]-3 alkyl or —O(C 1-3)alkyl group) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 431 1 describes those embodiments in which A is -F, L2 is C(O) and Q is morpholinyl, as well as those where A is -CH3, L2 is C(O) and Q is morpholinyl, etc.

[0034] Table 2. Exemplary combinations of L2 and Q for Formula I.

Table 2 (Continued)

Table 2 (Continued)

[0035] In another aspect of the invention, there are provided compounds of Formula II:

Formula II

stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein X is CH N, or NO;

Y is CH5 N or NO, provided that X and Y are not both CH or NO;

A is F5 Cl Br, I, NR2, or a C -3 alkyl or -O(Ci_3 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; B and D are each independently CR or N ; G is an aryl or heteroaryl group, wherein G is substituted by one or more R 1, R2 or R3; L1 is -C(O)NH-; 2 L is a covalent bond, CR' 2O, (CR' 2)mC(O)(CR'2)«, (CR' 2)mC(O)NR(CR' 2)t,

(CR' 2)mC(O)NRNR(CR' 2)t, (CR' 2)mC(NOR) (CR' 2)t, or (CR' 2)mNRC(O)O(CR' 2)t group; Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl group; each R 1 is independently F, Cl, Br, I, -NR , -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heterocyclylalkyl group; 2 each R is independently F, Cl, Br, I, -CN, -NO2, a substituted or unsubstituted

alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR' 2, -NR' 2,

-(CR' 2)tNRR', -NRC(O)R", -NR'C(O)OR", -NR SO2R", -NR'C(O)NR' 2, -NR'C(S)NR' 2,

-S(O)mR", or -SO2NR' 2; each R3 isandependently a substituted or unsubstituted alkyl, alkenyl, or

alkynyl group, or an -0(Ci - alkyl) group, wherein the Ci- alkyl group is optionally partially or fully halogenated;

each R is independently hydrogen or a substituted or unsubstituted Ci.6 alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl or heterocyclylalkyl group; each m is independently O, 1 or 2; and

t is O, I , or 2.

[0036] In some embodiments of compounds of Formula II, the compound is [0037] In others, the compound is

[0038] All of the following compounds are contemplated by Formula II:

W-A U-B ii-c

H-E H-F I G It-H

H-R ii-s H-T ll-U

It-V I-W U-X H-Y H-AM H-AN ii-AO H-AP

[0039] In some embodiments of compounds of Formula II, B is N . In others, D is N .

In still others, A is F, -CH 3, or -CF 3.

[0040] In some embodiments, G is a phenyl, pyrimidyl or pyridyl group. In others, G is

2 [0041] In some embodiments, L is a covalent bond, C(O), CH2O C(O)NHNH, C(NOH), or C(O)NH.

[0042] In other embodiments, Q is a substituted or unsubstituted alkyl, cycloalkyl, 10- oxa-4-aza-tricyclo[5.2. 1.02>6]decanyl, 8-oxa-3-aza-bicyclo[3 .2. 1]octanyl, (Co alkyl)cycloalkyl, (Co-4 alkyl)phenyl, (C - alkyl)pyridyl, (C0 alkyl)pyrimidinyl,

(Co-4 alkyl)quinuclidinyl, (Co-4 alkyl)morpholinyl, (Co- alkyl)thiomorpholinyl,

(Co 4 alkyl)tetrahydropyranyl, (Co-4 alkyl)tetrahydrofuranyl, (Co 4 alkyl)pyrrolidinyl,

(Co-4 alkyl)piperidinyl, or (C0-4 alkyl)piperazinyl group. For example, Q is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, (CH 2)-cyclopropyl, (CH2)2-cyclopropyl, (CH2)3-cyclopropyl, cyclobutyl, (CH2)-cyclobutyl, (CH2)2-cyclobutyl, (CH2)3-cyclobutyl, cyclopentyl,

(CH2)-cyclopentyl, (CH2)2-cyclopentyl, (CH2)3-cyclopentyl, cyclohexyl, (CH2)-cyclohexyl 5

(CH2)2-cyclohexyl, (CH2)3-cyclohexyl, bicyclo[2.2.1]heptanyl, (CH2)bicyclo[2.2.1]heptanyl,

(CH2)2bicyclo[2.2.1]heptanyl, (CH2)3bicyclo[2.2.1]heptanyl, cycloheptyl, phenyl, benzyl, phenethyl, 2-pyridyl, (CH 2)-2-pyridyl, (CH2)2-2-pyridyl, (CH2)3-2-pyridyl, 3-pyridyl, (CH2)-

3-pyridyl, (CH2)2-3-pyridyl, (CH2)3-3-pyridyl, 4-pyridyI, (CH2)-4-pyridyl, (CH2)2-4-pyridyl,

(CH2)3-4-pyridyl, quinuclidinyl, (CH2)-quinuclidinyl, (CH2)2-quinuclidinyl, 2 6 (CH2)3-quinuclidinyl, 10-oxa-4-aza-tricyclo[5.2.1 .0 ' ]decanyl, 8-oxa-3-aza- bicyclo[3.2.1]octanyl, tetrahydrofiiranyl, (CH2)-tetrahydrofuranyl, (CH2)2-tetrahydrofuranyl,

(CH2)3-tetrahydro:furanyl, tetrahydropyranyl, (CH2)-tetrahydropyranyl,

(CH2)2-tetrahydropyranyl, (CH 2)3-tetrahydropyranyl, pyrrolidinyl, (CH2)-pyrrolidinyl, ρ (CH2)2-py Olidinyl, (CH 2)3- yrrolidinyl, piperazinyl, (CH2)-piperazinyl, (CH2)2-piperazinyl,

(CH2)3-piperazinyl, piperidinyl, (CH2)-piperidinyl, (CH2)2-piperidinyl, (CH2)3-piperidinyl, φ mo holinyl, (CH2)-morph όlinyl, (CH2)2-morpholinyl, or (CH2)3-morpholinyl group.

1 [0043] In some embodiments of compounds of Formula II, R is F, -CN, -NR2, or a substituted or unsubstituted C -4 alkyl, C3..9 cycloalkyl, heterocyclyl, or heterocyclylalkyl 1 group. For example, R is F5 -CN, -N(Ci - alkyl)2 wherein each C1.3 alkyl group is independently substituted or unsubstituted; or R1 is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, thiomorpholinyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)- oxazepanyl, (CH2)-morpholinyl, or (CH2)-piperazinyl group.

[0044] In other embodiments, R2 is a substituted or unsubstituted (Ci- alkyl) or heterocyclylalkyl group, F, Cl5 -CN, -NO2, -OR', -C(O)OR', -C(O)NR" 2, -(CH2)tNRR", - 2 NRC(O)R', -NRC(O)OR", -NR'SO 2R", -NR'C(O)NR' 2, or -SO2NR' 2. For example, R is F

-CN, -CF3, -NO2, -O(C,.6 alkyl), -C(O)O(C 1-6 alkyl), -C(O)NH 2, -C(O)NH(C 6 alkyl),

-C(O)NH(C3-6 cycloalkyl), -C(0)NH(cycloalkylalkyl), -C(O)NH(aralkyl), -(CH2)NH(C 6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -NHC(O)(C L 6 alkyl),

-NHC(O)(C3-6 cycloalkyl), -NHC(O)(cycloalkylalkyl), -NHC(O)(aryl), -NHC(O)(aralkyl),

-NHSO2(C 1-6 alkyl), -NHSO 2(C3 6 cycloalkyl), -NHSO2(cycloalkylalkyl), -NHSO2(aryl), -NHSO2(aralkyl), -SO 2NH(CL 6 alkyl), -SO2NH(C3-6 cycloalkyl), -S0 2NH(cycloalkylalkyl),

-SO2NH(aryl), or -SO2NH(aralkyl), wherein each Ci- alkyl, C3-6 cycloalkyl, cycloalkylalkyl, aryl, and aralkyl group is substituted or unsubstituted.

[0045] In yet other embodiments, R3 is a substituted or unsubstituted Ci alkyl or -

O(C -4 alkyl) group, or is a partially or fully halogenated -O(Ci-2 alkyl) group.

1 [0046] In some embodiments of Formula II, G is phenyl and R is F, Cl, -CN, -N(Ci - 1 alkyl)2 wherein each C 3 alkyl group is independently substituted or unsubstituted; or R a substituted or unsubstituted morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)-oxazepanyl, (CH2)-morpholinyl,

(CH2)-piperazinyl, methyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, or cyclohexyl group. In some such embodiments, R 1 is F, Cl, a substituted or unsubstituted morpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl,

(CH2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)-morpholinyl, (CH2)-piperazinyl, methyl, tert- 2 butyl, or cyclohexyl group. In others, R is F, -CN, -CF3, -NO2, -0(Ci -6 alkyl), -C(O)O(Ci -6

alkyl), -C(O)NH2, -C(O)NH(Ci -6 alkyl), -C(O)NH(C3-6 cycloalkyl),

-C(O)NH(cycloalkylalkyl), -C(O)NH(aralkyl), -NHC(O)(C 1-6 alkyl),

-NHC(O)(C 3-6 cycloalkyl), -NHC(O)(cycloalkylalkyl), -NHC(O)(aryl), -NHC(O)(aralkyl),

-(CH2)NH(Ci -6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl),

-NHSO2(C1-6 alkyl), -NHSO2(C3-6 cycloalkyl), -NHSO2(cycloalkylalkyl), -NHSO2(aryl),

-NHSO2(aralkyl), -SO2NH(Ci -6 alkyl), -SO2NH(C3-6 cycloalkyl), -S0 2NH(cycloalkylalkyl), θ -SO2NH(aryl) or -S 2NH(aralkyl), wherein each Ci-6 alkyl, C3-6 cycloalkyl, cycloalkylalkyl, 2 aryl, and aralkyl group is substituted or unsubstituted. For example, R is F, -CN, -CF3,

-C(O)NH2, -C(O)NH(Ci -6 alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH(cycloalkylalkyl),

-(CH2)NH(Ci -6 alkyl), -(CH2)NH(heterocyclylalkyl), -NHSO2(Ci -6 alkyl), or -SO2NH(C -6 3 alkyl), wherein each Ci-6 alkyl group is substituted or unsubstituted. In others, R is a

substituted or unsubstituted C ]- alkyl or -0(C alkyl) group, or is a partially or fully halogenated -Q(Ci -2 alkyl) group. 2 [0047] In some embodiments of compounds of Formula II, L is a bond, CH2O, C(O),

C(O)O, C(O)NH, C(O)NHNH, C(NOR), or C(CH )2C(O)NH, and Q is

[0048] In some such embodiments, B and D are N. In some other such embodiments, G is a.phenyl group.

[0049] In some embodiments of compounds of Formula II, the compound at a concentration of 10 µM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.

[0050] As before, Table 3 sets forth various combinations of G and the B, D-containing ring of Formula II as described herein, while Table 4 describes various combinations of L2 and Q. [005 1] Table 3: Exemplary combinations of G and the B, D-containing ring for Formula II.

[0053] In another aspect of the invention, there are provided methods of preparing a compound of Formula I, the method comprising contacting a compound of Formula IHA Formula IHA with (i) G-COOH in the presence of a coupling agent and a base; or with (ii) G-CO-Z in the presence of abase, wherein said contacting occurs under conditions suitable to provide a 2 compound of Formula I, wherein A, X, Y, R3 L , Q and G are as defined in Formula I, and Z is an activating moiety, which may be displaced by, e.g., an amine.

[0054] In another aspect of the invention, there are provided methods of preparing a compound of Formula I, the method comprising (i) contacting a compound of Formula IHB

Formula HIB with G-NH in the presence of a coupling agent and a base; or (ii) contacting a compound of Formula IIIC

Formula IHC with G-NH in the presence of a base, wherein said contacting occurs under conditions 2 suitable to provide a compound of Formula I, wherein A5X, Y, R, L , Q and G are as defined in Formula I, and Z is an activating moiety, which may be displaced by, e.g., an amine.

[0055] In another aspect of the invention, there are provided methods of preparing a compound of Formula II, the method comprising contacting a compound of Formula IVA Formula IVA with (i) G-COOH in the presence of a coupling agent and a base; or with (ii) G-CO-Z in the presence of a base; wherein said contacting occurs under conditions suitable to provide a compound of Formula II; wherein A, B, D, X, Y, R, L2, Q and G are as defined in Formula II, and Z is an activating moiety, which may be displaced by, e.g., an amine.

[0056] In another aspect of the invention, there are provided methods of preparing a compound of Formula II, the method comprising (i) contacting a compound of Formula IVB

Formula IVB

with G-NH2 in the presence of a coupling agent and a base; or (ii) contacting a compound of Formula IVC

Formula IVC

with G-NH2 in the presence of a base, wherein said contacting occurs under conditions suitable to provide a compound of Formula II; wherein A, B, D, X, Y, R, L2, Q and G are as defined in Formula II, and Z is an activating moiety, which may be displaced by, e.g., an amine. [0057] Typical coupling agents include DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU, HCTU, TATU, TBTU, TDBTU, DEPBT, TSTU, and the like. The activating moiety is typically F, Cl, Br, I, N3, N-hydroxysuccinirnido, 1-hydroxybenzotriazole, 1-hydroxy-7- azabenzotriazole, pentafluorophenoxy, pentachlorophenoxy, para-nitrophenoxy, or -OC(O)-OR y, wherein Ry is a substituted or unsubstituted C alkyl group. Suitable bases include sodium bicarbonate or a suitable organoamine, such as pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine.

[0058] In another aspect of the invention, there are provided methods of preparing a compound of Formula V

Formula V, the method comprising contacting a compound of Formula VI

Formula VI with nitromalonaldehyde sodium salt under conditions suitable to provide a compound of Formula V; wherein Ar' is a 5 or 6-membered aromatic or heteroaromatic group, optionally 3 3 substituted by L -Q; W is a C alkyl or C3-6 cycloalkyl group; L is a covalent bond, CH2O,

C(O), C(O)O, (CR2)mC(O)NR, C(O)NRNR, C(NOR), OrNRC(O)O group; Q is hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl

group; and each R is independently hydrogen or a substituted or unsubstituted Ci-6 alkyl group. For example: Ar' is a phenyl, triazolyl, pyrrolyl, or imidazolyl group. The reaction is

typically carried out in the presence of ammonium acetate, in for example EtOH/H2O solvent mixtures, and typically at temperatures between about 5O0C and about 8O0C. [0059] In another aspect of the invention, there are provided compounds of Formula VII

Formula VII

wherein Hal is Cl, Br, or I; T is O or (CBb)n; R m is H or a substituted or unsubstituted alkyl, aralkyl or heterocyclalkyl group; and n is 0, 1 or 2.

[0060] In yet another aspect, there are provided compounds of Formula VIII

Formula VIII

wherein T is O or (CH2)n; U is F, Cl, Br, CN, -SO2NR' 2, -C(O)NR' 2 or

-NR'SO 2R"; V is -0(C 1-6 alkyl); Rm is H or a substituted or unsubstituted alkyl, aralkyl or heterocyclalkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and n is O, I.or 2.

[0061] Also provided are compounds of Formula IX

Formula IX

wherein T is an (C2-6)alkyl or cycloalkyl group, optionally partially or fully halogenated; U is -CN, -SO2NR' 2, or-NR'SO 2R"; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; and each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and P N is H or an amine protecting group.

[0062] The invention further provides compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.

[0063] In yet another aspect, the invention provides methods of treating disorders mediated by cytokines, including but not limited to inflammatory disorders, autoimmune disorders, cardiovascular disorders, cancer and pain. The methods include administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein. In some such embodiments, the cytokine-mediated disorder is a p38 MAPK-mediated disorder. In other embodiments, the cytokine is selected from TNFa, IL-I, IL-6, IL-8, GM-CSF, and IFN-gamma, or a combination of any two or more thereof. In others, the cytokine is TNFa or IL-I . In some embodiments, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein.

[0064] Cytokine-mediated disorders include rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, such as intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis or fibromyalgic syndrome; and acute or chronic pain, including but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculo-skeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, post-surgery pain, herniated intervertebral disc-induced sciatica, cancer-related pain, vascular pain, visceral pain, childbirth-related pain, or HIV- related pain. [0065] Other cytokine-mediated disorders are stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, coronary heart disease, coronary artery disease, acute coronary syndrome, Takayasu arteritis, cardiac failure such as heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass; hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leucopenia or thrombocytopenia; or atherosclerosis. Yet other cytokine mediated disorders are allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, or surgery or trauma-induced proliferative vitreoretinopathy. Cytokine-mediated disorders further include allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obliterative bronchiolitis, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation. Also included are psoriasis, pemphigus, eczema, atopic dermatitis, contact dermatitis, or acne. Yet other cytokine-mediated disorders are Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral and bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF and MELAS syndromes, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy. In another aspect of the invention, the cytokine-mediated disorders include bone resorption diseases such as osteopetrosis, osteoporosis, or osteoarthritis. Also included are diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia or bulimia nervosa. Additonally, the cytokine-mediated disease can be sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, osteosarcoma or follicular lymphoma, Castleman's disease, or drug resistance. In some embodiments, the cytokine-mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's Disease, ulcerative colitis, inflammatory bowel disease, diabetes, psoriatic arthritis, psoriasis, pemphigus, chronic obstructive pulmonary disease, pain, atherosclerosis, ischemia reperfusion, restenosis, acute coronary syndrome, heart failure, multiple myeloma, follicular lymphoma or osteosarcoma.

[0066] In some embodiments of the invention, the cytokine mediated disorder is a neutrophil-mediated disorder, such as, for example, bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis.

[0067] In some embodiments of the invention, the disorder is or results from abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute . confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphospholipid syndrome, arteriosclerotic dementia, arteritis temporal, arthropod- borne encephalitis, asphyxia, atopic hypersensitivity, atrial fibrillation, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy, cardiac surgery, cardiomegaly, carditis, carotid angioplasty, carotid endarterectomy, carotid stents, carotid ulcer, celiac disease, cirrhosis, colitis, colitis granulomatous, coronary artery bypass graft, coronary artery bypass surgery, cortical cataracts, corticosteroid-resistant asthma, degenerative joint disease, dermatitis, diarrhea, erectile neuropathy, erectile vasculopathy (particularly diabetic erectile neuropathy and vasculopathy), dry eye, dyslipidemia (including hyperlipidemia (increased lipids), hypercholesterolemia (increased cholesterol), hyperglyceridemia (increased glycerides), hypertriglyceridemia (increased triglycerides), hyperlipoproteinemia (increased lipoproteins), hyperchylomicronemia (increased chylomicrons), combined hyperlipidemia (increased LDL and triglycerides), familial hypercholesterolemia (hypercholesterolemia due to a defect on chromosome 19 (19pl3. 1-13.3)), hypolipoproteinemia (decreased lipoproteins), hypocholesterolemia (decreased cholesterol), abetalipoproteinemia (decreased beta lipoproteins), and Tangier disease (decreased high density lipoprotein)), dyspnea, edema, end-stage renal disease, epstein-barr virus infections, fever, follicular thyroid carcinoma, gastroenteritis, heart attack, heart bypass surgery, heart surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, insulin resistance, kidney failure, kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacterial meningitis, myeloproliferative disorders, myopathies, myositis, neonatal-onset multisystem inflammatory disease, nephritis, neuromuscular disorders, neuropathy, obliterative bronchiolitis, oral cancer, percutaneous coronary intervention, periodontal bone loss, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, posterior capsular opafication, pruritus (including ocular, skin and general pruritus), pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, sympathetic opthalmia, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis.

[0068] In another aspect of the invention, there are provided methods of reducing levels of a cytokine in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to reduce a level of a cytokine relative to the level prior to administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. In some embodiments the subject suffers from, or is at risk for a cytokine-mediated disorder, as described herein. In some embodiments, the cytokine is selected from TNFa, IL-I, IL-6, IL- 8, GM-CSF, IFN-gamma, or a combination of any two or more thereof. In others, the cytokine is TNFa or IL-I . In some embodiments, the cytokine level is measured in the subject or samples from the subject, e.g., tissue or bodily fluids such as the subject's blood. In others, cytokine level is measured in the subject's synovium. In still others, the cytokine level is measured in the subject's skin. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredient(s) (hereafter referred to as ingredient(s) A), as described herein.

[0069] In yet another aspect of the invention, there are provided methods of reducing the level of a cytokine released from a cell in response to a pro-inflammatory stimulus. The methods comprise exposing a cell to an amount of a compound, such as a cytokine inhibitor, effective to reduce the level of cytokine released from the cell in response to a pro¬ inflammatory stimulus relative to the level of released cytokine prior to contacting the cell with the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. In some embodiments, the pro-inflammatory stimulus results from the presence of TNFa, IL-I, IL-6, IL-8, GM-CSF, EFN-gamma, LPS, or a combination of any two or more thereof. In other embodiments, the cytokine level is the level of TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof. In some embodiments of the invention, the method further includes exposing the cell to additional therapeutic ingredient(s) (hereafter referred to as ingredient(s) A), as described herein.

[0070] In yet another aspect of the invention, there are provided methods of inhibiting - p38 activity. The methods comprise contacting p38 with an amount of a compound, such as a cytokine inhibitor, effective to inhibit p38 activity, the phosphorylation of p38, or both, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the inhibition of p38 activity or phosphorylation of p38 is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. The p38 may be isolated such as in a cell-free in vitro system, a cellular preparation or it may be in a cell. In some other embodiments, the p38 is in a subject. In some embodiments, the subject suffers from, or is at risk for, a cytokine-mediated disorder as described herein. In some embodiments of the invention wherein the p38 is in a subject, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient(s) A) to the subject, as described herein. [0071] In another aspect of the invention, there are provided methods of reducing the activity of a pro-inflammatory mediator. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to reduce the activity of a pro-inflammatory mediator relative to the activity prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the reduction in pro-inflammatory mediator activity is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. In certain embodiments, the subject suffers from or is at risk for a cytokine-mediated disorder as described herein. In some embodiments, the reduction in activity results from a decrease in circulating levels of a pro¬ inflammatory mediator relative to the circulating levels prior to administration of the compound. In some such embodiments, the decrease in circulating pro-inflammatory mediator level is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. In some such embodiments, the pro-inflammatory mediator is a prostaglandin or a leukotriene, or a combination of two ør more thereof. In some other embodiments, the reduction in activity results from an inhibition of the production of a pro-inflammatory mediator. In some such embodiments, the inhibition of pro-inflammatory mediator production is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. In some such embodiments, the pro¬ inflammatory mediator is a prostaglandin, leukotriene, COX-2, NO-synthase, or a combination of any two or more thereof. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient(s) A), as described herein.

[0072] In another aspect of the invention, there are provided methods of reducing the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to reduce the circulating levels of C- Reactive Protein or Rheumatoid Factor, or both, in the subject's blood relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the circulating C-Reactive Protein levels before administration are higher than about 2.87 mg/1. In some embodiments, the reduction in circulating level is at least 10%, at least 30%, at least 50%, at least 70%, or at least 90%. In some embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In certain embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient(s) A), as described herein, for example, the method further includes administration of methotrexate.

[0073] In yet another aspect of the invention, there are provided methods of reducing at least one indicium of rheumatoid .arthritis. The methods comprise administering to a subject exhibiting one or more indicia of rheumatoid arthritis, an amount of a compound, such as a cytokine inhibitor, effective to reduce at least one of the indicia to a level below that which exists prior to the administration of the compound, wherein the indicia are selected from erythrocyte sedimentation rate (ESR), number of painful and tender joints, level of joint pain, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, and/or circulating C-reactive protein level, and wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient(s) A), as described herein.

[0074] Also provided are methods of reducing the number or severity of the clinical signs of psoriasis. The methods comprise administering to a subject exhibiting one or more clinical signs of psoriasis an amount of a compound, such as a cytokine inhibitor, effective to reduce the number or severity of the clinical signs of psoriasis relative to those present in the subject prior to the administration of the compound, wherein the clinical signs of psoriasis are. the percentage of total body surface area (BSA) affected by psoriasis, psoriasis plaque thickness, level of lymphocytes within psoriatic lesions, epidermal thickness, T-cell infiltration, pathological epidermal hyperplasia, cell-mediated immunity reactions, tetanus antibody response, lymphocyte subpopulations, or any two or more thereof, and wherein the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, one or more of the clinical signs of psoriasis, especially BSA, is reduced by at least 10%, by at least 30%, by at least 50%, by at least 70% or by at least 90%. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient(s) A), as described herein. [0075] Combination therapy with other therapeutic ingredients A in the methods of the invention provides a beneficial therapeutic effect, particularly an additive or over-additive effect or an overall reduction of side effects of therapy. Such a beneficial therapeutic effect is desirable in the treatment of cytokine-mediated disorders and other methods as described herein. Thus, in one aspect, the invention provides methods that further include administering to a subject one or more, typically one, compound as described herein, for example a cytokine inhibitor, together with one or more, typically one, of the ingredients A described herein. In some embodiments, the methods are for treating cytokine-mediated disorders or conditions. In some embodiments, a combination of any two or more ingredients A are administered with a compound as described herein. An additive or over-additive (e.g., synergistic) effect of the pharmaceutical combinations according to the invention provides for dose reduction, side-effect reduction and/or interval extension when compared to the individual compounds of the invention alone, or ingredient(s) A alone. The effects mentioned above are observed both when the two substances are administered simultaneously in a single formulation and when they are administered successively in separate formulations. In the case of ingredient(s) A being an injectable, especially a biological agent, other benefits of adding a compound as described herein, e.g., a cytokine inhibitor, may be seen, such as, for example, cost reduction by way of interval and/or dose reduction. In some embodiments both the compound(s) as described herein and ingredient(s) A are administered orally. In others, both compound(s) and ingredient(s) A are administered intravenously, subcutaneously or by inhalation. In still others, compound(s) is administered orally and the ingredient(s) A is administered intravenously, subcutaneously, or by inhalation. Alternatively, compound(s) may be administered intravenously, subcutaneously, or by inhalation and the ingredient(s) A may be administered orally. In view of the present disclosure it is within the skill in the art to determine appropriate dosages, formulations and methods of administration for the combinations of the compounds of the invention and the ingredient(s) A for particular applications.

[0076] Biological agents shall be understood to mean any natural or artificial/synthetic biological molecule or fragment thereof as known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates, and the like. Therefore, ingredient(s) A includes biological agents, such as etanercept, infliximab, alefacept, adalimumab, efalizumab, anakinra, IL-IRA, alpha-interferon, interferon beta 1-B, CTLA-4, and other antibodies or receptor constructs directed against TNFa, IL-I and IL-6, LFA-I, or C5.

[0077] A variety of ingredients A are contemplated for use in the combinations of the invention. For example, non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of inflammation, pain and fever, may be used. Such NSAIDs include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like, or a combination of two or more thereof.

[0078] Angiogenesis inhibitors may serve as ingredient(s) A, such as VEGF inhibitors, taxol, pentoxyfylline and/or thalidomide.

[0079] Also within the scope of the invention for ingredient(s) A are steroids, such as glucocorticoids, and vitamin D3 an,d analogs thereof (cholecalciferols), alone (the latter being used mostly for psoriasis) or in combination. Steroids include budesonide, dexamethasone, fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, prednisone, clobetasone, deflazacort, fhiocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone. Among vitamin D3 derivatives are calcipotriol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, 1o 2,5- dihydroxyvitamin D3, and parathyroid hormone-related peptide.

[0080] Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with cytokine inhibitors as described herein. Exemplary agents include hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E., 1999, Cutis 64(5), 347); alefacept, leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-

CD25, peptide T, LFA3TIP, alicaforsen, DAB3s9, CTLA-4Ig, anti-CD80, for example IDEC- 114 or ABX-IL8, DAB-IL-2, IL-IO, anti-TAC, basiliximab and daclizumab. In addition, agents or therapies which act on other targets or immune mediated products are suitable as the ingredient(s) A. These include, for example, inhibitors of protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR), E-selectin inhibitors, and therapies widely used for psoriasis such as anthralin, coal tar, phototherapies including ultraviolet B (UVB) or psoralens ultraviolet A (PUVA), photodynamic therapy and laser therapy.

[0081] Retinoid therapy can also be used as ingredient(s) A. Thus, for example, bexarotene, acitretin, etretinate, tazarotene, hydroxyurea, 6-thioguanine and phototherapies are suitable additional ingredients. (Orfanos C E., 1999, Cutis 64(5), 347; see also Saurat J H., 1999, J.Am.Acad.Derm. 41(3 Pt 2), S2).

[0082] Ingredients A useful in the invention further include small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-I or ICAM-I.

[0083] Statins and HMG-CoA reductase inhibitors may also be employed as ingredients A including, e.g., atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL),

lovastatin (MEVACOR, ALTOCOR) 3mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR), or simvastatin (ZOCOR, LIPEX). Other ingredients A contemplated for use in methods of the invention include fibrates, such as bezafibrate (e.g., BEZALIP), ciprofibrate (e.g., MODALIM), clofibrate, clinofibrate, gemfibrozil (e.g., LOPID), or fenofibrate; cholesterol absorption inhibitors, such as, ezetimibe (e.g., ZETIA); nicotinic acid; bile acid sequestrants, such as cholestyramine (QUESTRAN) and colestipol (COLESTID); and/or plant sterol- containing products and ω3-fatty acids. Also contemplated are the combination of two or more of the above, for example the combination of ezetimibe/simvastatin (VYTORIN or INEGY). Combination therapy with the above ingredients A is contemplated for use in any method of the invention including treatment of cytokine-mediated disorders and conditions.

[0084] In another aspect, there are provided the above-mentioned combinations comprising ingredient(s) A and one or more compounds, as described herein, for example, cytokine inhibitors, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activity. Moreover, combinations comprising ingredient(s) A and a compound as described herein can be used for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine-mediated disorder or condition. The pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ingredient(s) A and the compound(s) as described herein further include pharmaceutically acceptable derivatives thereof, and may be optionally combined with a conventional excipient, carrier, or combination thereof.

[0085] In psoriasis, known combination treatments have been effective and are used as rotation therapy for maintenance of remission or if the subject is refractory to usual systemic products. Most of the combinations are with different modes of action either to improve efficacy or to reduce side effects by reduction of the dosage. See Van de Kerkhof, P. 1997 Clinics in Dermatology, 15, 831, which showed the effect of topical steroids or vitamin D with systemic agents. Two combinations which are widely accepted include ultraviolet B (UVB) or psoralens ultraviolet A (PUVA) each optionally administered with retinoids, methotrexate, or the combination of cyclosporine and retinoids.

[0086] A typical combination for treating psoriasis includes a compound described herein in combination with immunotherapy drugs which include cyclosporine, pimecrolimus, ' tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LFA3TIP, DAB389, CTLA-4Ig, E- selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher E. M., 1998 Hospital Medicine, 59 No 7, and variants thereof. Another typical combination for treating psoriasis is a compound as described herein with methotrexate (MTX). It is expected this combination will be effective because of the good tolerability of MTX in the short term and because of the acceptability if maintenance of remission is obtained with good quality of life. Another typical combination for treating psoriasis is a compound as described herein with cyclosporine, especially because of cyclosporine' s efficiency for induction of remission. Another embodiment of the invention comprises administration in the following sequence: induction with a compound described herein and cyclosporine, followed by continuation with the compound after decrease of dosing and discontinuation of cyclosporine. Another typical combination for treating psoriasis is a compound described herein in combination with retinoids. Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, and this would be alleviated by continuation of therapy with the compound. Yet another typical combination for treating psoriasis is a compound described herein, in combination with ingredient(s) A selected from steroids, such as glucocorticosteroids, vitamin D analogs, retinoids and dithranol. In some such combination treatments, the steroids and retinoids can be administered topically. A more typical combination for treating psoriasis is a compound as described herein with vitamin D derivatives, most typically calcipotriol or tacalcitol. Another typical combination for treating psoriasis is a compound described herein in combination with macrolides, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecrolimus. Another typical combination for treating psoriasis is a compound described herein in combination with cell adhesion molecule inhibitors, such as anti-LFA3, and/or anti-LFAl . This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti-LFA3-IgCl, or by anti-CD11 monoclonal antibodies, efalizumab, and the obvious variants thereof. Cell adhesion molecule inhibitors appear to provide an acceptable response rate with limited tolerability problems. Combination with a compound described herein should avoid the disadvantage of their injectable form, with CAM inhibitors being used intermittently. Another embodiment of the invention comprises administration in the following sequence: induction with compound as described herein and CAM inhibitor(s), followed by maintenance treatment with the compound alone and retreatment with CAM inhibitor(s) in case of significant relapse.

[0087] Another typical combination for treating psoriasis is a compound as described herein with another anti-TNFa ingredient. A typical embodiment is one wherein the other anti-TNFa ingredient is selected from infliximab or etanercept, typically infliximab. Within the scope of the invention is the use of topical or general antisense inhibitors of TNFa, such as alicaforsen in combination with a cytokine inhibitor compound. Another typical combination for treating psoriasis is a compound described herein with anti-CD4, aπti-CD80

(IDEC-1 14 or ABX-IL8), DAB-IL-2, DAB389-IL-25 CTLA4-Ig, IL-10, IL-2 receptor inhibitors such as daclizumab (anti-TAC), or basiliximab. (See Tutrone, "Biologic Therapy for Psoriasis, A Brief History, I, " Biologic Therapy for Psoriasis, 2001, 68, 331; Ben-Bassat, "Biological activity of tyrosine kinase inhibitors: Novel agents for psoriasis therapy,"

Current Opinion in Investigational Drugs, 2001, 2(1 1)5 1539; Salim, et. al., "Targeting interleukin-2 as a treatment for psoriasis," Current Opinion in Investigational Drugs, 2001, 2(1 1), 1546). [0088] The combinations described herein can also be used to reduce the number or severity of the clinical indicia of psoriasis.

[0089] Any of the herein mentioned combinations within the scope of the invention may be tested by animal models known in the art. Reference in this regard may be made to: Schon, Michael P. 1999 Animal models of Psoriasis—What can we learn from them, The Society for Investigative Dermatology—Reviews, 112. No. 4, 405.

[0090] In rheumatoid arthritis, combination of immunosuppressive or immunomodulatory agents is a long and well established therapeutic paradigm. Combination partners may be selected from various therapeutic entities. Their identification is either based on empirical data supported by evolving knowledge about the underlying mechanisms or based on a well defined mode of action. These agents are generally referred to as Disease Modifying Antirheumatic Drugs (DMARDs) or Slow Acting Antirheumatic Drugs (SAARDs). In addition to the combinations listed below, combination of the cytokine inhibitor, with one or mote agents classified as DMARD/SAARD or NSAID and/or steroids, are contemplated in this invention.

[0091] A typical combination for treating rheumatoid arthritis is a compound as described herein combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D- penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine or cyclophosphamide. Another typical combination for treating rheumatoid arthritis is a compound as described herein combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha-interferon. Yet another typical combination for treating rheumatoid arthritis is a compound as described herein in combination with Inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I.

[0092] Another typical combination for treating rheumatoid arthritis is a compound as described herein combined with anti-TNFa antibodies or TNFa-receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA-I, IL-6, ICAM-I, C5, or IL-I receptor. In another embodiment a compound as described herein is combined with infliximab alone or infliximab and methotrexate. Another typical combination for treating rheumatoid arthritis is a compound as described herein in combination with IL-I receptor antagonists, such as anakinra (KINERET). Yet another typical combination for treating rheumatoid arthritis is a compound as described herein combined with NSAIDs, including acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like. Another typical combination for treating rheumatoid arthritis is a compound as described herein combined with steroids, such as glucocorticosteroids, for example, betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort.

[0093] The combinations described herein can also be used to reduce at least one of the indicia of rheumatoid arthritis.

[0094] Any of the herein mentioned combinations within the scope of the invention may be tested by animal models known in the art. (See Wooley, P. H. 1998, Animal models of arthritis, in Klippel J. H., Dieppe, P. A., (eds.) Rheumatology, second edition, 5.8.1, Mosby, London, Philadelphia, St. Louis, Sydney, Tokio).

[0095] In Crohn's disease, the following groups of drugs may be combined with a compound as described herein: steroids such as budesonide, 5-ASA drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors. A typical combination for treating Crohn's disease is a compound as described herein with one or more of the following: steroids including all those listed herein, 5-ASA, methotrexate and azathioprine. Another typical combination for treating Crohn's disease is a compound described herein combined with IL-I receptor antagonists, such as anakinra (KINERET). Yet another typical combination for treating Crohn's disease is a compound described herein with anti-TNFa antibodies or TNFa-receptor antagonists, such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA-I, IL-6, ICAM-I, or C5. In another embodiment a compound described herein is combined with infliximab and methotrexate. More typically, the compound is a cytokine inhibitor and is combined with infliximab. Another typical combination for treating Crohn's disease is a compound described herein combined with IL- 10, alicaforsen (anti ICAM 1), or antegren (VCAM receptor antagonist).

[0096] In another aspect of the invention, there are provided methods of increasing HDL-levels of a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to increase the HDL-level of the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a p38 inhibitor. In certain embodiments, the subject suffers from or is at risk for a cytokine- mediated disorder as described herein. In some embodiments, the HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/ml, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. For example, the HDL level prior to administration is less than about

55 mg/dl. In some embodiments, the HDL is HDL , while in others it is HDL3. In other embodiments, the subject has an LDL level less than about 150 mg/ml.

[0097] In some embodiments of methods for increasing HDL-levels in a subject, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. In still other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome.

[0098] In some embodiments, the methods of increasing HDL-levels in a subject additionally comprise administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR), or simvastatin (ZOCOR, LlPEX); fibrates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, or clinofibrate; bile acid sequestrants, such as, cholestyramine (QUESTRAN); cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibe (ZETIA); niacin; plant sterol- containing products; ω3-fatty acids ; or combinations of two or more thereof, for example ezetimibe/simvastatin (VYTORIN or INEGY). In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. In other embodiments the HDL level of the subject may be increased by about 5% to about 20%.

[0099] In another aspect, there are provided methods of increasing Apo-Al -levels of a subject. The methods comprise administering to a subject an amount of a compound, such as a cytokine inhibitor, effective to increase the Apo-Al -level of the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the Apo-Al -level is increased by at least about 5% or by at least about 10%. In certain subjects in which the Apo-Al level is increased, the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml. In some embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. For example, the vascular event can be a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the cytokine inhibitor. In other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. In other embodiments the HDL level of the subject may be increased by about 5% to about 20%.

[00100] In another aspect, there are provided methods of decreasing or preventing from increasing the systolic or diastolic blood pressure of a subject in need thereof. The methods comprise administering to a subject an amount of a compound effective to decrease or to prevent from increasing the systolic or diastolic blood pressure of the subject relative to the blood pressure prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the blood pressure is the systolic blood pressure. In others, the blood pressure is the diastolic blood pressure. In some embodiments, the subject's systolic blood pressure prior to administration is above 140 mm Hg, and the diastolic blood pressure prior to administration of the compound is above 90 mm Hg. In others, the diastolic blood pressure prior to administration of the compound is higher than 85 mm Hg. In some embodiments, the decrease in systolic or diastolic blood pressure, or both, is at least about 5 mm Hg, at least about 3 mm Hg or at least about 2 mm Hg. In certain subjects in which the systolic or diastolic blood pressure is decreased or is prevented from increasing, the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml. In some embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. For example, the vascular event may be a cardiovascular event or a cerebrovascular event. In some embodiments, the present methods produce a reduction of the occurrence or severity of the vascular event in the subject, relative to a subject who is at risk of a vascular event who has not been administered a compound described herein. In other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the HDL level of the subject may be increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. In other embodiments the HDL level of the subject may be increased by about 5% to about 20%.

[00101] Compounds disclosed herein, such as cytokine inhibitors, may be used in combination therapy with one or more anti-hypertensive agents, for example, ACE inhibitors, calcium channel blockers, aldosterone antagonists, angiotensin II antagonists, diuretics, benzothiazepine derivatives, beta blocking agents, dihydropyridine derivatives, potassium- sparing agents, urologicals, sulfonamides, or thiazides. Examples include benazepril, enalapril, lisinopril, quinapril, captopril, ramipril, spironolactone, olmesartan, valsartan, telmisartan, valsartan, losartan, irbesartan, diltiazem, verapamil, trandolapril, atenolol, bisoprolol, metoprolol, toprol, tenoretic, amlodipine, nifedipine, felodipine, nisoldipine, triamterene, furosemide, lasix, prazosin, propanolol, hydrochlorothiazide, or combinations of two or more thereof.

[001 02] In another aspect, there are provided methods of decreasing or preventing an elevation in PAI-I levelsr The methods comprise administering to a subject at risk for increased PAI-I levels (for example in a subject suffering from, or at risk of obesity, metabolic syndrome or inflammatory conditions) an amount of a compound effective to decrease or prevent an elevation in the PAI-I -level of the subject relative to the level in the untreated subject, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof.

[00103] In yet another aspect of the invention, there are provided methods of decreasing the triglyceride-level of a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the triglyceride-level of the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the triglyceride-level prior to administration is above 500 mg/dl, above 200 mg/dl, or above 150 mg/dl. For example, the triglyceride-level prior to administration is above 200 mg/dl. In certain embodiments, the subject suffers from or is at risk for a cytokine-mediated disorder as described herein. In other embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. In some embodiments of the invention, the method additionally comprises administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR), or simvastatin (ZOCOR, LIPEX); fibrates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, or clinofibrate; bile acid sequestrants, such as, cholestyramine (QUESTRAN); cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibe (ZETIA); niacin; plant sterol- containing products; ω3-fatty acids ; or combinations of two or more thereof, for example ezetimibe/simvastatin (VYTORIN or INEGY). In other embodiments, the subject is suffering from, or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the subject is a primate, particularly a human. In some embodiments of the invention, the triglyceride level of the subject is reduced by at least about 10%. In others, the triglyceride level of the subject is reduced by at least about 20%.

[00104] In yet another aspect of the invention, there are provided methods of decreasing the fasting glucose-level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the glucose level prior to the administration is above about 130 mg/dl. In others, the glucose level is decreased by about 5%, about 10%, about 20% or about 30%. In certain embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In others, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound.

[00105] In another aspect of the invention, there are provided methods of decreasing the HbAIc value in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the HbAIc value in the subject relative to the level prior to the administration of the compound, wherein the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some such embodiments, the subject has a HbAIc value above about 8%, above about 7.5%, or above about 7%. In others, the HbAIc level is decreased to between about 4% and about 6.5%. In certain embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In other embodiments, the subject suffers from, or is at risk of suffering from, diabetes, insulin resistance or metabolic syndrome. In some embodiments, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof. In some embodiments of the.invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. [00106] In yet another aspect of the invention, there are provided methods for decreasing the insulin level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the insulin-level in the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some such embodiments, the subject has a fasting insulin level prior to administration of above about 100 pmol/1, above about 150 pmol/1, above about 200 pmol/1, above about 250 pmol/1, above about 300 pmol/1, above about 350 pmol/1, above about 400 pmol/1, or above about 500 pmol/1. In others, the subject has a postprandial insulin level of above about 400 pmol/1, above about 500 pmol/1, above about 600 pmol/1, above about 700 pmol/1, or above about 800 pmol/1. In some embodiments, the insulin level is reduced by about 10%, about 20%, about 30%, or about 40%. In certain embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In yet other embodiments, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance or metabolic syndrome. In some embodiments of the invention, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound.

[00107] In another aspect of the invention, there are provided methods for decreasing the HOMA Insulin Resistance Index in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the HOMA Insulin Resistance Index in the subject relative to the Index prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some such embodiments, the Insulin Resistance Index is reduced to below about 2.5, below about 2.0, or below about 1.8. In some embodiments, the Insulin Resistance Index is reduced by about 10%, about 20%, or about 30%. In certain embodiments, the subject is in need of a decreased HOMA Insulin Resistance Index because, e.g., the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In others, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance or metabolic syndrome. In some embodiments of the invention, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound.

[00108] In yet another aspect of the invention, there are provide methods of increasing the indirect bilirubin-level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to increase the indirect bilirubin-level in the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the indirect bilirubin level is increased to about 0.4 mg/dl, to about 0.5 mg/dl, to about 0.6 mg/dl, or to about 0.7 mg/dl. In others, the indirect bilirubin level is increased by about 10%, about 20%, or about 30%. In other embodiments, the bilirubin level is increased without causing jaundice. In certain embodiments, the subject is in need of increased indirect bilirubin-level because, e.g., the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In some embodiments of this aspect of the invention, the subject is at risk of a vascular event, for example, the vascular event is one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In other embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound.

[001 09] In some embodiments, compounds described herein possess inhibitory effects on the procoagulant and profibrinolytic responses during human endotoxemia. In another aspect, the invention therefore also provides a method of anticoagulant and fibrinolytic therapy for a disease or condition relating to blood coagulation or fibrinolysis, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound as described herein, for example, a cytokine inhibitor. This administration may be of benefit given either prophylactically to subjects at risk or therapeutically to subjects who have developed complications related to these pathways.

[001 10] Compounds disclosed herein, such as cytokine inhibitors, may be used in combination therapy with one or more other anticoagulant or fibrinolytic agents. These include recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxoparin, dalteparin, coumarin anticoagulants, aspirin, dipyrimidamole, aggrennox, ticlopidine, clopidogrel (Plavix), abciximab, RheoPro, integrilin, aggrestat, and the like. Particular dosages, formulations and methods of administration of the anticoagulant and fibrinolytic agents are known in the art.

[001 11] In another aspect of the invention, there is provided a method comprising administering to a subject a combination of a compound, as described herein, for example, a cytokine inhibitor, and one or more ingredients A, in an amount effective to control, treat or prevent obesity or obesity-related conditions or disorders in a subject in need thereof, wherein ingredient(s) A is selected from agents useful in the treatment of obesity or an obesity—related condition or disorder. In some such embodiments, the obesity-related disorder is selected from overeating, binge eating, bulimia, diabetes, elevated plasma insulin concentrations, insulin resistance, metabolic syndrome, dyslipidemias, hyperlipidemia, lipodystrophy, osteoarthritis, arthritis deformans, lumbodynia, emmeniopathy, obstructive sleep apnea, cholelithiasis, gallstones, nonalcoholic steatohepatitis, heart disease, abnormal heart rhythms and abnormal heart arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, coronary artery disease, angina pectoris, hypertension, sudden death, stroke, cerebral infarction, cerebral thrombosis, transient ischemic attack, polycystic ovary disease, craniopharyngioma, Pickwickian syndrome, fatty liver, Prader-Willi Syndrome, Frohlich's syndrome, GH-deficiency, normal variant short stature, Turner's syndrome, pediatric acute lymphoblastic leukemia, infertility, hypogonadism in males, hirsutism in females, gastrointestinal motility disorders, respiratory disorders, cardiovascular disorders, inflammation, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, endometrial cancer, breast cancer, prostate cancer, colon cancer or kidney cancer. In other embodiments of the invention, the subject desires to lose body weight relative to the subject's body weight prior to administration of the combination. In some embodiments, the method additionally comprises treatment of the subject with lipoplasty, gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty.

[001 12] Examples of ingredient(s) A useful in the treatment of obesity or an obesity- related condition or disorder include an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an oglucosidase inhibitor, a cholesterol lowering agent, a PPAR δ agonist, a CB receptor ligand, a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a MCH receptor antagonist, an amylin and/or calcitonin receptor agonist, an NPY antagonist, an orexin antagonist, a GLP-I agonist, an MC agonist, a ghrelin antagonist, a leptin agonist, a CCK agonist, a PYY agonist, a CNTF, a GH secretagogue, a GH secretagogue receptor modulator, a DP-IV inhibitor, a H3 antagonist or inverse agonist, a 5HT agonist, a serotonin transport or reuptake inhibitor, a dopamine agonist, a NE transport inhibitor, a DAG inhibitor, a glucose transporter inhibitor, a -HSD-l inhibitor, a CETP inhibitor, a squalene synthase inhibitor, a glucocorticoid antagonist, a PDE inhibitor, an anti¬ platelet agent, an ACE inhibitor, an All receptor antagonist, a UCP-I, -2, or -3 activator, a thyroid hormone β agonist, a COX-2 inhibitor, a monoamine reuptake inhibitor, a mGlu5 receptor antagonist, an acyl-estrogen, a FAS inhibitor, an ACC2 inhibitor, a corticotropin- releasing hormone agonist, a galanin antagonist, a BRS3 agonist, a PTP-IB inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a phosphate transporter inhibitor, a urocortin binding protein antagonist, a urocortin ligand, a human agouti-related protein, a neuromedin U receptor agonist, topiramate, oxyntomodulin, tagatose, CP741 952, zonisamide, IDl 101, BDC03, S2367, AOD9604, fluasterone, GT389255, QCBTl 6, MK0916, MK0493, MK0364, PD6735, c2735, adiponectin, or a combination of two or more thereof. In some such embodiments, ingredient(s) A is an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an -glucosidase inhibitor, or a glucose transporter inhibitor. In others, ingredient(s) A is a cholesterol lowering agent, or a PPARδ agonist. In still others, ingredient(s) A is a CB receptor ligand, a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a DP-IV inhibitor, a H3 antagonist or inverse agonist, a 5HT agonist, a serotonin transport or reuptake inhibitor, a dopamine agonist, a NE transport inhibitor, a CETP inhibitor, a squalene synthase inhibitor, a PDE inhibitor, or an acyl-estrogen. In other embodiments, ingredient(s) A is a MCH receptor antagonist, an NPY antagonist, an orexin antagonist, a GLP-I agonist, an MC agonist, a ghrelin antagonist, a leptin agonist, a CCK agonist, a PYY agonist, a CNTF, a GH secretagogue, or a GH secretagogue receptor modulator. In some embodiments, ingredient(s) A is rimonabant, sibutramine, fluoxetine, phentermine, bupropion, radafaxine, orlistat, cetilistat, oxyntomodulin, or oleoyl-estrone.

[00 113] Typical examples of ingredient A, and combinations of any two or more thereof, that may be combined with compounds described herein, for the treatment or prevention of obesity and/or obesity-related disorders, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:

[001 14] (a) insulin sensitizers including (i) peroxisome proliferator activated receptors (PPAR) 7 agonists, such as glitazones (e.g.isaglitazone; pioglitazone; rosiglitazone; rivoglitazone, netoglitazone), naveglitazar, farglitazar, metaglidasen, GW6779542, CSO38, MBX2044, AZD6610, PLX204, LBM642, AMG131, AVE0847, AVE5376, ONO5129, TAK654, CLX0921, and the like); (ii) biguanides such as metformin and phenformin;

[001 15] (b) insulin or insulin mimetics, such as insulin aspart, insulin glulisine, insulin glargine, insulin lispro, insulin detemir, NN5401, NN9101, NN344, AT1391, DTYOOl, betaRx, insulin zinc suspension (lente and ultralente); insulintropin (by "insulin" is meant a polypeptide or its equivalent useful in regulation of blood glucose levels. A general description of such insulins is provided in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press (1990). Such insulins can be fast acting, intermediate acting, or long acting. Various derivatives of insulin exist and are useful in this invention. Such compositions can be administered by any standard route, including oral, nasal, pulmonary, or transdermal administration.);

[001 16] (c) sulfonylureas, such as acetohexamide; chlorpropamide; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipeήtide; gliquidone; glisolamide; tolazamide; and tolbutamide;

[001 17] (d) αf-glucosidase inhibitors, such as alglucosidase alfa, voglibose, celgosivir, miglitol, acarbose, and the like;

[001 18] (e) cholesterol lowering agents such as (i) 3-hydroxy-3-methylglutaryl- Coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pitavastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin and other statins); (ii) bile acid absorbers/sequestrants, such as colesevelam, colestipol, cholestyramine, dialkylaminoalcyl derivatives of a cross-inked dextran, and the like; (ii) nicotinyl alcohol, nicotinic acid or a salt thereof; (iii) PPARa agonists such as fenofibric acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fenofibrate and benzafibrate), GW677954, CS038, ABT335, LY674, GFT14, PLX204, K i ll, naveglitazar, LBM642, GW590735, NS220, AVE5376, AVE8134, DRF10945, ONO5129, KRPlOl, GW641597, and DRF4832; (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and acyl CoA cholesterol acyltransferase (ACAT) inhibitors such as SMP797, K604, and SR-45023A, (v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics;

[001 19] (f) PPAR δ agonists, such as GW677954, CS068, RWJ800025, GW501516, and CKD501; and

[00120] (g) other therapeutic agents, including anti-obesity and anti-diabetic agents, such as

[00121] (1) cannabinoid (CB) receptor ligands, such as CB-I receptor antagonists or inverse agonists, for example rimonabant, surinabant,, AVEl 625, CP945598, and SLV-319, and those disclosed in U.S. Pat. Nos. 6,344,474, 6,028,084, 5,747,524, 5,596,106, 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, PCT Application Nos. WO 96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WOOO/10968, WO97/29079, WO99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, W002/076949, and WO 03/007887, WO 02/076949; and EPO Application No. EP-658546, EP-656354, EP-576357;

[00122] (2) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, DOVl 02677, zimeldine, and sibutramine;

[00123] (3) adrenoceptor agonists, including /33-adrenoreceptor agonists, such as solabregon, YMl 78, amibregon, tesofensince, fenfluramine, amphetamine, phenmetrazine, phentermine, and N5984;

[00124] (4) pancreatic lipase inhibitors, such as orlistat, cetilistat, and GT389255;

[00125] (5) apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo- B/MTP) inhibitors, such as ISIS301012, ISIS301012, JTT130, and SLx4090;

[00126] (6) melanin-concentrating hormone (MCH) receptor antagonists, including MCHlR and MCH2R antagonists, for example, 856464, and AMG076, and those described in U.S. Patent Application Publication Nos. 2005/0009815, 2005/0026915, 2004/0152742, 2004/0209865; PCT Patent Application Publication Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809; and Japanese Patent Application No. JP 13226269;

[00127] (7) neuropeptide Y (NPY) antagonists, such as NPYl antagonists, for example, BIBP3226, J l 15814, BIBO3304, LY357897, CP671906, GI264879A, and those disclosed in U.S. Pat. No. 6,001,836 and PCT Application Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; NPY5 antagonists, for example, S2367, FMS586, GW569180A, GW594884A, GW587081, GW5481 18., FR226928, FR240662, FR252384, 1229U91, GI264879A, CGP71683A, LY377897, PD160170, SR120562A, SR120819A and JCF104, and those disclosed in U.S. Pat. Nos. 6,124,331, 6,140,354, 6,191,160, 6,214,853, 6,258,837, 6,313,298, 6,337,332, 6,329,395, 6,326,375, 6,335,345, and 6,340,683, European Patent Nos. EP-01010691, and EP-01044970, and PCT Application Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248 152, and WO 02/49648; .

[00128] (8) peptide YY (PYY) agonists, such as PYY, PYY 3-36, peptide YY analogs, and PYY agonists, for example, AC162352, N-Acetyl [Leu(28,3 1)]NPY 24-36, and

PYY(3-36)NH 2, cyclo-(28/32)-Ac-[Lys28- Glu32]-(25-36)-pNPY, TASP-V, pancreatic peptide (PP), 122U91, and those disclosed in U.S. Pat. Publication No. 2002/0141985 and PCT Application Publication No. WO 2005/077094, WO 03/026591, WO 03/057235, and WO 03/027637;

[00129] (9) orexin antagonists, such as orexin-1 receptor antagonists, for example SB334867-A, and those disclosed in PCT Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838;

[00130] (10) glucagon-like peptide (GLP)-I agonists, including GLP-I, GLP-I analogs and derivatives, such as exenatide, exenatide-LAR, liraglutide, CJC 1134PC, LY548806, 716155, and AVEOOlO;

[001 31] ( 11) melanocortin (MC) agonists, including MC4 agonists and MC4R agonists, such as Melanotan II, PTl 5, BL3020, API 030, or those described in PCT Application Nos. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 02/12166, WO 02/1 1715, WO 02/12178, WO 03/007949, WO 02/068388, WO 02/068387, - WO 02/067869, WO 03/040117, WO 03/066587, WO 03/068738, WO 03/094918, and WO 03/031410;

[001 32] ( 12) ghrelin receptor antagonists, such as NOXB 11, CYT009GhrQb, TZP300, EP01492, and those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250;

[00133] ( 13) leptin agonists, including recombinant human leptin and recombinant methionyl human leptin, and leptin derivatives, such as OB3, and those disclosed in U.S. Pat. Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, 6,777,388 and 6,936,439, and PCT Application Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, WO 96/23520, WO 96/05309, WO 96/40912; WO 97/06816, WO 00/20872, WO 97/18833, WO 97/38014, WO 98/08512, WO 98/284427, U.S. patent publications 2004/0072219, 2003/049693, 2003/0166847, and 2003/0092126;

[00134] (14) cholecystokinin (CCK) agonists, such as ARR15849, GI181771, JMV180, A71378, A71623, SR146131, UCL2000, and A71378, and those described in U.S. Pat. No. 5,739,106;

[001 35] ( 15) ciliary neurotrophic factors (CNTF), including CNTF, CNTF modulators, and CNTF derivatives, such as Axokine and NT501, and those disclosed in U.S. Pat. Nos. 6,680,291 and 6,767,894 and in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813;

[00136] (16) growth hormone (GH) secretagogues, growth hormone secretagogue receptor modulators, such as SUN 11031, RC1291, tesamorelin, sermorelin, examorelin, NN703, hexarelin, MK677, SM-130686, CP-424,391, L-692,429 and L-163,255;

[00137] ( 17) dipeptidyl peptidase IV (DP-IV or DPP-IV) inhibitors, such as denagliptin, sitagliptin, SYR322, RO0730699, TS021, ALS20426, vidagliptin, GRC8200, MP513, PHX1149, PSN9301, TA6666, saxagliptin, SSR162369, R1438, KRP104, 825964, and the compounds disclosed in PCT Application Nos. WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181;

[00138] (18) histamine receptor-3 (H3) antagonists/inverse agonists, such as GSK189254A, A331440, ABT239, ABT834, BP294, thioperamide, 3-(lH-imidazol-4- yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394, and those described and disclosed in PCT Application Nos. WO 02/15905;

[00139] (19) 5-hydroxytryptamine (5HT) agonists, for example 5HT2C (serotonin receptor 2C) agonists, such as lorcaserin, vabicaserin, APD356, and those disclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; and 5HT6 agonists, such as PRX07034; [00140] (20) serotonin transport or serotonin reuptake inhibitors such as nefazodone, citalopram, dapoxetine, duloxetine, desvenlafaxine, fluvoxamine, escitalopram, sibutramine, venlafaxine, vilazodone, DOV21947, LUAA21004, BGC201259, NS2359, UK416244, DOV102677, SEP225289, OPC14523, SLV314, WLlOI l , WL1017, zimeldine, fluoxetine, paroxetine, fenfluramine, imipramine and sertraline, and those disclosed in U.S. Pat. No. 6,365,633, and PCT Application Nos. WO 01/27060 and WO 01/162341;

[00141] (21) dopamine agonists, for example dopamine D2 agonists, such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP 104, quinagolide, nolomirole, NHOOl, SLV308, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol;

[00142] (22) norepinephrine (NE) transport inhibitors, such as lisdexamfetamine, atomoxetine, duloxetine, SLE381, desvenlafaxine, amfebutamone, sibutramine, venlafaxine, DOC21947, radafaxine, bupropion, DOV216303, reboxetine, AD337, NS2359, DOV102677, SEP225289, Xen2174, indeloxazine, protriptyline, and S33005;

* [00143] (23) diacylglycerdl acyltransferase (DAG) inhibitors, such as BAY7441 13;

[00144] (24) glucose transporter inhibitors, for example, sodium glucose cotransporter (SGLT) inhibitors, such as, KGT1251, 189075, AVE2268, and SGLOOlO;

[00145] (25) 11/3-hydroxy steroid dehydrogenase- 1 (jS-HSD-1) inhibitors, such as INCBl 3739, and AMG221;

[00146] (26) cholesterol ester transfer protein (CETP) inhibitors, such as torcetrapib, CETiI, JTT705, BAY605521, and JTT302;

[00147] (27) squalene synthase inhibitors, for example, lapaquistat;

[00148] (28) glucocorticoid antagonists, for example, mifepristone, Org34517, and Org34850;

[00149] (29) phosphodiesterase (PDE) inhibitors, including phosphodiesterase-3B (PDE3B) inhibitors, for example, tetomilast, tadalafil, atopik, vardenafil, tipelikast, HT0712, QAD171A, SK3530, oglemilast, acanafil, cilostazol, roflumilast, parogrelil, udenafil, EHT0202, dasantafil, MEM1414, SLx2101, CC10004, 256066, cilomilast, vinpocetine, ibudilast, pimobendan, ND7001, LAS37779, K123, UK357903, ND1251, tofimilast, UKl 69003, senazodan, trapidil, arofylline, theophylline, doxofylline, olprinone, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast;

[00150] (30) antiplatelet agents, such as, limaprost, clopidogrel, felbinac, eptifibatide, NCX4016, ticagrelor, tirofiban, abcixmab, sarpogrelade, DA697B, argatroban, SCH530348, cilostazol, YSPSL, parogrelil, asasantin, DG041, prasugrel, ramatroban, cangrelor, epoprostenol, beraprost, aspirin, Kl 34, triflusal, YY280, xemilofiban, ozagrel, alprostadil alfadex, TP9201, procainamide, AT1015, Z335, BGC728, glyrofam, EF5077, SH529, and ME3229;

[001 51] (31) angiotensin converting enzyme (ACE) inhibitors, such as peridopril, enalapril, ramipril, fosinopril, quinapril, lisinopril, imidapril, benazepril, ilepatril, captopril, trandolapril, temcapil, cilazapril, MC4232, CHF1521, omapatrilat, spirapril, moexipril, zofenopril, delapril, alacepril, S5590, and fasidotril;

[00152] (32) angiotensin II (All) receptor antagonists, for example, losartan, candesartan, temisartan, coaprovel, imidapril, azilsartan. valsartan, irbesartan, olmesartan, CYT006AngQb, TAK491, eprosartan, VNP489, CGP63170, fimesartan, pratosartan, and saralasin;

[00153] (33) uncoupling protein (UCP)-I, 2, or 3 activators, such as phytanic acid, 4- [(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123;

[00154] (34) thyroid hormone β agonists, such as thyroid hormone, levothyroxine, KB21 15, 3,5-diiodothyropropionic acid, liothyronine, methimazole, and those disclosed in PCT Patent Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190;

[001 55] (35) cyclo-oxygenase (COX)-2 inhibitors such as etoricoxib, GW40638 1, meloxicam, lumiracoxib, diclofenac, valdecoxib, parecoxib, PMIOOl, 6444784, SVT2016, nimesulfide, CS706, cimicoxib, LR3001, LAS34475, P54, rofecoxib, celecoxib, and arcoxia; [00156] (36) monoamine reuptake inhibitors, such as those disclosed in PCT Application No. WO 01/27068, and WO 01/62341;

[00157] (37) metabotropic glutamate 5 (mGlu5) receptor antagonists, such as ADXl 0059, AFQ-056, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), (3-[(2-methyl-l,3- thiazol-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson et al. (2003) J. Eur. J. Pharmacol. 473:35-40; Cosford et ai. (2003) Bioorg. Med. Chem. Lett. 13(3):351-4; and Anderson et al. (2002) J. Pharmacol. Exp. Ther. 303:1044-1051 ;

[00158] (38) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001);

[00159] (39) fatty acid synthase (FAS) inhibitors, such as Cerulenin, and C75;

[00160] (40) acetyl-CoA carboxylase-2 (ACC2) inhibitors;

[00161] (41) corticptropin-releasing hormone agonists;

[00162] (42) galanin antagonists;

[00163] (43) bombesin receptor subtype 3 (BRS3) agonists;

[00164] (44) protein tyrosine phosphatase- 1B (PTP- 1B) inhibitors ;

[00 165] (45) fatty acid transporter inhibitors;

[00166] (46) dicarboxylate transporter inhibitors;

[00167] (47) phosphate transporter inhibitors;

[001 68] (48) urocortin binding protein antagonists and urocortin ligands, such as urocortin II;

[00169] (49) human agouti-related proteins (AGRP);

[00170] (50) neuromedin U receptor agonists; [00171] (51) topiramate, oxyntomodulin, tagatose, CP741952, zonisamide, IDl 101, BDC03, S2367, AOD9604, fluasterone, GT389255, QCBT16, MK0916, MK0493, MK0364, PD6735, c2735, and adiponectin.

[001 72] Examples of other anti-obesity agents that can be employed in combination with compounds described herein are disclosed in "Patent focus on new anti-obesity agents," Exp. Opin. Ther. Patents, 10: 819-831 (2000); "Novel anti-obesity drugs," Exp. Opin. Invest. Drugs, 9: 1317-1326 (2000); and "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity, Exp. Opin. Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y in obesity is discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346 (2000). Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs, 9: 1553-1571 (2000).

[00173] Obesity and weight loss treatments that can be used in conjunction with compounds described herein also include surgery. Typically the weight loss surgical procedure is liposuction ©r lipoplasty. Surgical obesity treatments include gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty.

[00174] In another aspect, there is provided a method comprising administering a compound, such as a cytokine inhibitor, and one or more ingredients A to a subject in need thereof, in an amount effective to increase or enhance the effectiveness of the ingredient A when used alone, wherein ingredient A is selected from agents useful in the treatment of obesity an obesity—related condition or disorder, and wherein the compound is as described herein, or is a mixture of any two or more thereof and/or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the effectiveness enhancement is obtained by allowing administration of lower dosages of one or more of the ingredients A used in combination, relative to the use of either agent alone.

[00175] In another aspect of the invention, there is provided a method comprising administering to a subject a compound as described herein, for example, a cytokine inhibitor, and ingredient(s) A, in an amount effective to reduce the risk of metabolic disorders in a subject in need thereof relative to the subject's risk prior to administration of the compound and ingredient(s) A, wherein ingredient(s) A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorder. In some embodiments, the reduction in risk of metabolic disorders is obtained by reducing the body weight of the subject, relative to the subject's body weight prior to administration of the combination of the cytokine inhibitor and ingredient(s) A.

[00176] In yet another aspect of the invention, there are provided methods of treating a cancer. The methods comprise administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound, such as a cytokine inhibitor, as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00177] In some embodiments of the invention, the method of treating cancer further comprises treating the subject with surgery, radiation, cryotherapy, or one or more anti¬ proliferative agents or a combination thereof. In some such embodiments, the antiproliferative agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immunomodulator, hormonal or antihormonal agent, photodynamic agent, angiogenesis inhibitor, or a tyrosine kinase inhibitor. In some of these embodiments, the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, or chlorambucil. Examples of platinum agents include spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin. In some embodiments, the antimetabolite is azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6- thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine. In others, the topoisomerase inhibitor is amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl- 10-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novusphaπna), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-11), or topotecan. In yet others, the antitumor antibiotic is dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafϊ de. Examples of antimitotic agents are colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner-Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), auristatin PE (Teikoku Hormone), azaepothilone B (BMS), ixabepilone (BMS), tavocept (BioNumerik), BMS 184476 (BMS), combrestatin A4 disodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatin-10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKline), docetaxel, vinorelbine, or vincristine. In some embodiments, the aromatase inhibitor is aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole. In others, the thymidylate synthase inhibitor is pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5,10-methylenetetrahydrofolate (BioKeys). In yet others, the DNA antagonist is trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics). In still others, the farnesyltransferase inhibitor is arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer). Examples of pump inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG). Examples of histone acetyltransferase inhibitors include tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG). In some embodiments, the metalloproteinase inhibitor is neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech). In others, the ribonucleoside reductase inhibitor is gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health). In yet others, the endothelin A receptor antagonist is atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca). In still others, the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD-1 550 (Ligand). In some embodiments, the immuno-modulator is interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CD154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), b-alethine (Dovetail), melanoma vaccine (CTL Imrnuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax). In others, the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzόxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofϊ ne, fiutamide, goserelin, nilutamide, or leuporelin. In yet others, the photodynamic agent is talaporfin (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharrhacyclics), or hypericin. In still others, the angiogenesis inhibitor is neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Sugen). Examples of tyrosine kinase inhibitors include imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX- H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panitumumab (Abgenix), IMC-ICl 1 (ImClone), sorafenib (Bayer) or trastuzumab (Genentech). In some embodiments, the antiproliferative agent is melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, or paclitaxel (Taxol®).

[001 78] In some embodiments of the invention, the cancer is osteosarcoma, Kaposi's sarcoma, colorectal cancer, brain cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell cancer, basal cell cancer, prostate cancer, renal cell carcinoma; leukemia, lymphoma, erythroblastoma, glioblastoma, glioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma. In some such embodiments, the cancer is acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiatied carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, or Wilm's tumor.

[00179] In some embodiments, the cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma or follicular lymphoma. In some embodiments, the cancer is follicular lymphoma, acute myelogenous leukemia, multilple myeloma or non-hodgkin's lymphoma.

[00180] In other embodiments, the cancer is brain cancer, glioblastoma, meningioma, astocytoma, medulloblastoma, neuroblastoma or retinoblastoma. In some such embodiments, the cancer is glioma or glioblastoma.

[00181] In yet other embodiments, the cancer is osteosarcoma, Kaposi's sarcoma, chondosarcoma, Ewing's sarcoma or myoblastoma. In some such embodiments, the cancer is osteosarcoma bone cancer.

[00182] In some embodiments, the cancer is breast, lung, kidney or prostate cancer metastasis. In some such embodiments, the neoplasm is bone metastasis.

[001 83] In yet another aspect of the invention, there are provided methods of treating, modifying or managing pain. The methods comprise administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a compound, such as a cytokine inhibitor, as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the composition further comprises an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, a-adrenergic receptor agonist, a-adrenergic receptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, a2d ligand, NMDA receptor antagonist, or a combination of any two or more thereof. In some such embodiments, the antidepressant is nortriptyline, amitriptyline, imipramine, doxepin, clomipramine, fluoxetine, sertraline, nefazodone, venlafaxine, trazodone, or bupropion. In others, the anti-hypertensive is nifedipine, terazosin, prazosin, losartan, verapamil, telmisartan, fosinopril, bosentan, or olmesartan. In yet others, the anxiolytic is fluoxetine, paroxetine, sertraline, or venlafaxine. Examples of calcium channel blockers include nifedipine, verapamil and clonidine. In other embodiments, the a-adrenergic receptor agonist is clonidine or midodrine. In yet others, the a-adrenergic receptor antagonist is terazosin, prazosin, or doxasozin. In some embodiments, the anesthetic is procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, or ropivacaine. Examples of opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and fentanyl transdermal patch. In some embodiments, the NSAID is a COX-2 inhibitor, salicylic acid acetate, ibuprofen, ketoprofen, naproxen sodium, ketorolac, diclofenac, indometacin, or acetaminophen. In some such embodiments, the COX-2 inhibitor is rofecoxib, celecoxib, or valdecoxib. In yet others, the corticosteroid is prednisone, dexamethasone or hydrocortisone. In others, the anticonvulsant is carbamazepine, oxcarbazepine, gabapentin, pregabalin, phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, tiagabine, famotodine, phenobarbital, diphenylhydantoin, mephenytoin, ethotoin, mephobarbital, primidone, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, clobazam, sulthiame, dilantin, diphenylan, or L-5-hydroxytryptophan. In some embodiments, the NMDA receptor antagonist is dextromethorphan, dextrorphan, ketamine, memantine, amantadine, agmatine, aptiganel, gavestinel, selfotel, 7-chlorokynurate, remacemide, riluzole, pyrroloquinoline quinone or cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid. In others, the a2d ligand is gabapentin, pregabalin, [(lR,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6- yl]acetic acid, S-O-Aminomethyl-cyclohexylmethyl^H-tl^^-oxadiazol-S-one and C-[I- (lH-Tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-Aminomethyl-3,4-dimethyl- cyclopentyl)-acetic acid, (la,3a,5a)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-Amino-5-methyl-octanoic acid. In yet other embodiments, the composition further comprises acetylsalicylic acid, diclofenac, ibuprofen, indometacin, flufenamic acid, mefenamic acid, morphine, pethidine, methadone, fentanyl, buprenorphine, tramadol, gabapentin, pregabalin, carbamazepine, lamotrigin, topiramate, phenyloin, levitiracetam, procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, ropivacaine, amitryptiline, paroxetine, citalopram, bupropione, duxoletine, ketamine, memantine, 2,3-benzodiazepines, or a combination of any two or more thereof. [00184] In some embodiments of the invention, the pain is acute pain, chronic pain, pain resulting from soft tissue and peripheral damage from acute trauma; neuropathic pain; post-stroke pain; postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; pain associated with osteoarthritis and rheumatoid arthritis; musculoskeletal pain; spinal pain, central nervous system pain; lower back pain, sciatica, dental pain, myofascial pain syndromes, episiotomy pain, gout pain, and pain resulting from burns; deep and visceral pain; muscle pain, eye pain, inflammatory pain, orofacial pain; abdominal pain, gynecological pain; somatogenic pain; pain associated with nerve and root damage; pain associated with limb amputation, tic douloureux, neuroma, or vasculitis; diabetic neuropathy, chemotherapy-induced-neuropathy, acute herpetic and postherpetic neuralgia; atypical facial pain, neuropathic lower back pain, and arachnoiditis, trigeminal neuralgia, segmental or intercostal neuralgia, HIV related neuralgias, AIDS related neuralgias and other neuralgias; allodynia, hyperalgesia, burn pain, idiopathic pain, pain caused by chemotherapy; occipital neuralgia, psychogenic pain, brachial plexus avulsion, pain associated with restless leg syndrome; pain associated with gallstones; pain caused by chronic alcoholism or hypothyroidism or uremia or vitamin deficiencies; neuropathic and non-neuropathic pain associated with carcinoma, cancer pain, phantom limb pain, functional abdominal pain; headache; temporomandibular pain and maxillary sinus pain; pain resulting from ankylosing spondylitis; pain caused by increased bladder contractions; complex regional pain syndrome, sympathetic maintained pain syndrome, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, chronic fatigue syndrome, radiculopathy, luetic neuropathy; or painful neuropathic condition induced from a drug post operative pain, scar pain, or chronic non-neuropathic pain.

[00185] In some such embodiments, the musculo-skeletal pain is pain associated with strains, sprains or broken bones. In others, the central nervous system pain is pain due to spinal cord or brain stem damage. In yet others, the deep and visceral pain is heart pain. In others, the orofacial pain is odontalgia. In some embodiments, the gynecological pain is dysmenorrhoea, labour pain and pain associated with endometriosis. In others, the pain associated with nerve and root damage, is pain associated with peripheral nerve disorders. In some such embodiments, the peripheral nerve disorder is nerve entrapment or brachial plexus avulsions. In some other embodiments, the headache is migraine with aura, migraine without aura, vascular headaches, acute or chronic tension headache, sinus headache or cluster headache. In yet other embodiments, the chronic non-neuropathic pain is pain associated with HIV, anthralgia, vasculitis or fibromyalgia. In some embodiments, the complex regional pain syndrome is type I or type II.

[001 86] In some other embodiments, the pain is nociceptive pain or neuropathic pain. In some such embodiments, the nociceptive pain is associated with chemical or thermal bum, cut of the skin, contusion of the skin, osteoarthritis, rheumatoid arthritis, systemic lupus erthrematosis (SLE), tendonitis, or myofascial pain. In others, the neuropathic pain is diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, post-stroke pain, complex regional pain syndrome, sympathetic maintained pain syndrome, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, spinal cord injury pain, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, pain related to cancer or metastases, phantom limb pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, luetic neuropathy, or painful neuropathic condition induced by a drug. In embodiments where the pain is related to cancer or metastases, the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukemia; lymphoma; or angiogenesis including neoplasia. In other embodiments, the metastases are breast, lung, kidney or prostate cancer metastases.

[001 87] In yet another aspect of the invention, there are provided methods of treating pemphigus. The methods comprise administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound, such as a cytokine inhibitor as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments of methods of treating pemphigus, the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, cicatricial pemphigoid, bullous impetigo, or staphylococcal scalded-skin syndrome. [001 88] In another aspect, there are provided methods comprising administering to a subject in need thereof a combination of (i) an effective amount of a compound of the invention and (ii) an effective amount of one or more therapeutic ingredients A useful in the treatment of pemphigus as described herein, wherein the effective amount of ingredients A is less than the effective amount of ingredient(s) A when used alone.

[00189] Also provided are methods to reduce the number and/or severity of clinical indicia of pemphigus. The methods comprise administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a compound of the invention, such as a cytokine inhibitor, effective to reduce the number and/or severity of clinical indicia of pemphigus relative to those present in the subject prior to the administration of the cytokine inhibitor, wherein the clinical indicia of pemphigus include the percentage of total body surface area (BSA) affected by pemphigus, pemphigus lesion thickness, the number of new pemphigus lesions, the number of active pemphigus lesions (including blisters and erosions), the healing time of active lesions (for example, time to 80% healing), serum anti-desmoglein- 1 (DSGl) antibody levels, serum anti-DSG3 antibody levels, serum TNFa-levels, serum IL-6 levels, skin TNFa-mRNA levels, skin IL-6 mRNA levels, or any two or more thereof. In some embodiments of the invention, the methods additionally comprise administering to the subject an effective amount of one or more ingredient(s) A, useful in the treatment of pemphigus, as described herein. In some such embodiments, the effective amount of ingredient(s) A is less than the effective amount of ingredient A when used alone.

[00190] In some embodiments of the methods of the invention, the methods further comprise administering to the subject an ingredient A, wherein the ingredient A is an anti¬ inflammatory agent, an immunosuppressant, an anti-infective, an antibiotic, a gold salt, an alkylating agent, an immunoglobulin, or a combination of two or more thereof.

[00191] In some embodiments in which ingredient A is an anti-inflammatory agent, the anti-inflammatory may be a corticosteroid, a COX-2 inhibitor, a non-steroidal anti¬ inflammatory drug (NSAID), a TNFa antagonist, or an IL-I . antagonist. For example, the corticosteroid can be prednisone, prednisolone, or methylprednisolone. Corticosteroids such as these may also be administered with either chlorambusil or mycophenylate mofetil. In some embodiments, the TNFa antagonist is infliximab, etanercept, or adalimumab. In others, the IL-I antagonist is anakinra. [00192] In other embodiments, the immunosuppressant is mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituximab, anti-interferon gamma, or cyclophosphamide. In some other embodiments, the anti-infective is dapsone, or hydroxychloroquine. In some embodiments, the gold salt is myochrysine, or solganal. In some embodiments, the alkylating agent is lukeran. In some embodiments, the antibiotic is tetracycline, minocycline, or doxycycline. In some such embodiments, the method further comprises administration of nicotinamide, or niacinamide. In other embodiments of the methods of the invention, the methods of the invention further comprise administering plasmapheresis therapy or photophoresis therapy to the subject.

[001 93] In some embodiments of the methods of the invention, the dosage of ingredient(s) A is reduced by from about 10% to about 90% in comparison to the dosage used to achieve the same therapeutic effect with ingredient(s) A alone. In some embodiments, the dosage is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, or about 60%. In some embodiments, ingredient(s) A is a corticosteroid, for example, prednisone or prednisolone. In some other embodiments, ingredient(s) A comprises a corticosteroid and either chlorambusil or mycophenylate mofetil. In some embodiments, the dosage of prednisone is reduced to less than about 70 mg/day, less than about 50 mg/day, less than about 30 mg/day, less than about 20 mg/day, less than about 15 mg/ day, or less than about 10 mg/day.or

[001 94] In yet other embodiments, the cytokine inhibitor is administered orally or topically. In some embodiments, ingredient(s) A is a corticosteroid or antibiotic and is administered orally, topically, in a mouthwash or in a mouth spray. For therapeutic use, the pharmaceutical combinations of ingredient A and compound(s) described herein may be administered in any conventional dosage form in any conventional manner, including any of the routes described herein. Accordingly, routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, by infusion, sublingual, transdermal, oral, topical and by inhalation. Typical modes of administration are oral, topical or intravenous.

[00195] The pharmaceutical combinations of ingredient A and the compound as described herein may be administered separately, or in a combination formulation with other ingredients or adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, or provide like advantages. Such combination therapies typically utilize lower dosages of the conventional therapeutics, and avoid the possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Pharmaceutical combinations of ingredient A and the compound may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. The ingredient A and/or the compound may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereoisomer or mixtures of stereoisomers, including racemates.

[00196] The proportions in which the two components, ingredient A and the compound as described herein, may be used in the combinations according to the invention are variable. Ingredient(s) A and the compound are optionally present in the form of their solvates or hydrates. Depending on the choice of ingredient(s) A and the compound as described herein, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. Determination of ratios by weight is dependent on the particular ingredient A and the compound, and are within the skill in the art.

[00197] In accordance with yet another aspect of the invention there are provided the following compounds of List I, including representative examples of compounds of Formulae I and II:

List 3-tert-butyl-5-cyano-N-(6-methyl-5-(3-(neopentylcarbamoyl)phenyl)-pyridin-3- yl)benzamide; N-(5-(4-(benzyloxy)phenyl)-6-methylpyridin-3-yl)-3-tert-butyl-5-cyanobenzamide; 3-tert-butyl-5-cyano-N-(5-(4-(3,3-dimethyl-2-oxobutoxy)phenyl)-6-methylpyridin-3- yl)benzamide; 4-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylpyridin-3-yl)phenyl acetate; 3-tert-butyl-5-cyano-N-(5-(4-methoxy-2-methylphenyl)-6-methylpyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3- yl)benzamide; 3-fluoro-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5- morpholinobenzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl)pyridin- 3-yl)benzamide; 3-fluoro-N-(5-(4-methoxyphenyl)-6-methylpyridin-3-yl)-5-moφ holinobenzamide; N-(5-(4-acetylphenyl)-6-methylpyridin-3-yl)-5-tert-butyl-3-cyano-2-methoxybenzamide; 3-(aminomethyl)-5-tert-butyl-N-(5-(4-(l-hydroxyethyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-(N-hydroxycarbamimidoyl)-N-(5-(4-(l-(hydroxyimino)ethyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; 5'-(3-tert-butyl-5-cyanobenzamido)-2l-methyl-N-((tetrahydrofuran-2-yl)methyl)-2 3'- bipyridine-5-carboxamide; t l 5'-(3-tert-butyl-5-cyanobenzarnido)-2 -rnethyl-N-((tetrahydrofuran-2-yl)methyl)-353 - bipyτidine-6-carboxamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(piperidin-l-ylcarbamoyl)phenyl)pyridin-3- yl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(N-neopentylsulfamoyl)phenyl)pyridin-3- yl)benzamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-((tetrahydrofuran-2- yl)methyl)-l H-1 ,2,3-triazole-4-carboxamide; N-(5-(4-tert-butyl-lH-l,2,3-triazol-l-yl)-6-methylpyridin-3-yl)-3-fluoro-5- morpholinobenzamide; 3-fluoro-N-(6-methyl-5-(4-(pyridin-2-yl)-lH-l,2,3-triazol-l-yl)pyridin-3-yl)-5- moφ holinobenzamide; 3-fluoro-N-(5-(4-(methoxymethyl)-lH-l,2,3-triazol-l-yl)-6-methylpyridin-3-yl)-5- moφ holinobenzamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole- 4-carboxamide;

3-tert-butyI-5-cyano-N-(6-methyl-5-(4-(3-methylbutanoyl)-lH-l 52,3-triazol-l-yl)pyridin-3- yl)benzamide; (Z)-3-tert-butyl-5-cyano-N-(5-(4-(l-(^ydroxyimino)-3-methylbutyl)-lH-l,2,3-triazol-l-yl)-6- methylpyridin-3 -yl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(2 -methyl- 1-(neopentylamino)- 1-oxopropan-2-yl)- 1H- 1,2,3-triazol- 1-yl)pyridin-3 -yl)benzamide; N-(3-tert-butyl-5-cyanophenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3-triazol-l- yl)nicotinamide; N-(6-methyl-5-(4-(neopentyl carbamoyl)- 1H-1,2,3-triazol- 1-yl)pyridin-3 -yl)-2- morpholinoisonicotinamide; N-(6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3-triazol-l-yl)pyridin-3-yl)-2-(piperidin-l- yl)isonicotinamide; S-fluoro-N-C -methyl-S-CS-faeopentylcarbamoytyphenytypyridin-S-yty-S- morpholinobenzamide; 3-tert-butyl-5-cyano-N-(5-(3-(dimethylcarbamoyl)phenyl)-6-methyIpyridin-3-yl)benzamide; l-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH-l,2,3- triazole-4-carboxamide; 1-(5-(3-fluoro-5-morpholinobenzamido)-2 -methylpyridin-3 -yl)-N-neopentyl- 1H-1,2,3- triazole-4- carboxamide; 5-tert-butyl-2-methoxy-N-(5-(6-methoxynaphthalen-2-yl)-6-methylpyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(5-(3-(3,3-dimethylbutanamido)phenyl)-6-methylpyridin-3- yl)benzamide; N-(2,6l-dimethyl-3,4'-bipyridin-5-yl)-3-fluoro-5-morpholinobenzamide; 3-tert-butyl-5-cya πo-N-(2,6'-dimethyl-3,4'-bipyridin-5-yl)benzamide; 3-fluoro-N-(5-(4-methoxy-3-methylphenyl)-6-methylpyridin-3-yl)-5-morpholinobenzamide; N-(5-(4-acetylphenyl)-6-methylpyridin-3-yl)-5-tert-b tyl-2-methoxybenzamide; N-(5-(4-acetylphenyl)-6-methylpyridin-3-yl)-5-tert-butyl-2-methoxy-3- (methylsulfonamido)benzamide; N-(5-(4-acetyl ρhenyl)-6-methylpyridin-3-yl)-3-fluoro-5-morpholinobenzamide; N-(5-(4-(benzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5-tert-bxityl-2-methoxybenzamide; 5-tert-butyl-N-(5-(4-(3,4-dimethoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-2-methoxy-N-(5-(4-(3-methoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3- yl)benzamide; N-(5-(4-(benzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-fluoro-5-morpholinobenzamide; N-(5-(4-(3,5-dimethoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-fluoro-5- morpholinobenzamide; 3-fluoro-N-(5-(4-(3-methoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5- moφ holinobenzamide; 3-fluoro-N-(5-(4-(4-methoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5- moφ holinobenzamide; N-(5-(4-(benzo[d][l,3]dioxol-5-ylmethylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-fluoro- 5-morpholinobenzamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-(pyridin-3-ylmethyl)-lH- 1,2,3-triazole-4-carboxamide; l-CS-CS-fluoro-S-morphoUnobenzamido^l-methylpyridin-S-yO-N-isobutyl-lH-l^.S-triazole- 4-carboxamide; N-(cyclopropylmethyl)-l-(5-(3-fluoro-5-mo φ holinobenzamido)-2-methylpyridin-3-yl)-lH- l,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-5-rnorpholinobenzamido)-2-methylpyridin-3-yl)-N-(3,3,3-trifluoropropyl)-lH- 1,2,3-triazole-4-carboxamide; 3-fluoro-N-(6-methyl-5-(4-((tetrahydro-2H-pyran-4-yl)methylcarbamoyl)phenyl)pyridin-3- yl)-5-morpholinobenzamide; 3-fluoro-N-(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-5- moφ holinobenzamide; 5-tert-butyl-N-(5-(4-(3,5-dimethoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; N-(5-(4-(benzo[d][l,3]dioxol-5-ylmethylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5-tert- butyl-2-methoxybenzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4- yridin-3-ylmethylcarbamoyl)phenyl)pyridin-3- yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(tetrahydro-2H-pyran-4- ylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-((tetrahydro-2H-pyran-4- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-((tetrahydrofuran-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; N-(5-(4-(3,4-dimethoxybenzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-flu6ro-5- morpholinobenzamide; 3-fluoro-N-(6-methyl-5-(4-(pyridin-3-ylmethylcarbamoyl)phenyl)pyridin-3-yl)-5- morpholinobenzamide; methyl 4-((4-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylpyridin-3- yl)benzamido)methyl)benzoate; 3-fluoro-N-(6-methyl-5-(4-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl)pyridin-3-yl)-5- morpholinobenzamide; , methyl 4-((4-(5-(3-fluoro-5-moφ holinobenzaπiido)-2-methylpyridin-3- yl)benzamido)methyl)benzoate; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-((tetrahydrofuran-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-((tetrahydro-2H-pyran-4- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; N-(5-(4-(benzylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-tert-butyl-5-cyanobenzamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N,N-dimethyl-lH-l,2,3- triazole-4-carboxamide; l-(2-methyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)pyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide; l-(2-methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)-benzamido)pyridin-3-yl)-N-neopentyl- IH-1 ,2,3-triazole-4-carboxamide;

1-(5-(3-fluoro-5-(piperidin-l -yl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-l H-1 ,2,3- triazole-4-carboxamide; 1-(5-(3- uOrO-S-(PyTToIi Un- 1-yl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-l H-1 ,2,3- triazole-4-carboxamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-(2-methylbutyl)-lH-l,2.3- triazole-4-carboxamide; N-(cyclohexylmethyl)-l -(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)- 1H- 1,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-((tetrahydro-2H-pyran-4- yl)methyl)-l H-1 ,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-(2-hydroxy-2- phenylethyl)- 1H-1,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-5-mo φ holinobenzamido)-2-methylpyridin-3-yl)-N-(l-hydroxy-3- methylbutan-2-yl)-lH-l,2,3-triazole-4-carboxamide; N-(( 1-ethylpyrrolidin-2-yl)methyl)-l -(5-(3-fluoro-5-morpholinoben2amido)-2-methylpyridin- 3-yl)- IH-1 ,2,3-triazole-4;carboxamide; 5-tert-butyl-3-cyano-N-(5-(4-((l-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; 5-tert-butyl -3-cyano-2-methoxy-N-(6-methyl-5-(4-( 1-methylpiperidin-4- ylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-((l-methylpiperidin-4- yl)methylcarbamoyl)-phenyl)pyridin-3-yl)benzamide; 3-fluoro-N-(6-methyl-5-(4-(l-methylpiperidin-4-ylca τbamoyl)phenyl)pyridin-3-yl)-5- moφ holinob enzamide; 3-fluoro-N-(6-methyl-5-(4-((l-methylpiperidin-4-yl)methylcarbamoyl)phenyl)pyridin-3-yl)- 5-morpholinobenzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(pyridin-3- ylmethylcarbamoyl)phenyl) ρyridin-3-yl)benzamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4- yl)- 1H-1,2,3-triazole-4-caτboxamide; N-cyclohexyl-l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-lH-l,2,3- triazole-4-carboxamide; N-cyclopentyl-l-(5-(3-fluoro-5-morpholinoben2amido)-2-methylpyridin-3-yl)-lH-l,2,3- triazole-4-carboxamide; l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-(3-hydroxy-2,2- dimethylpropyl)-lH- 1,2,3-triazole-4-carboxamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3 -yl)-N-((tetrahydrofuran-2- yl)methyl)-lH-l ,2,3-triazole-4-carboxamide; tert-butyl 1-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)- 1H-1,2,3- triazole-4-carboxylate; 1-(5-(3-cyano-5-moφ holinobenzamido)-2-methylpyridin-3 -yl)-N-((tetrahydrofuran-2- yl)methyl)-lH-l,2,3-triazole-4-carboxamide; 1-(5-(3-cyano-5-(piperidin- 1-yl)benzamido)-2-methylpyridin-3-yl)-N-((tetrahydroftiran-2- yl)methyl)-lH-l,2,3-triazole-4-carboxamide; 1-(5-(3-cyano-5-(pyrrolidin- 1-yl)benzamido)-2-methylpyridin-3-yl)-N-((tetrahydrofuran-2- yl)methyl)-l H-1 ,2,3-tria3θle-4-carboxamide; N-(5-(4-((l-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-fluoro-5- morpholinobenzamide; l-(5-(5-tert-butyl-3-cyano-2-metho 'xybenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide; l-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)-N-(pyridin-3- ylmethyl)-lH-l,2,3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-((l-ethylpyrrolidin-2- yl)methyl)-l H-1 ,2,3-triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(4-methylpiperazine-l-carbonyl)-lH-l,2,3-triazol-l- yl)pyridin-3-yl)benzamide; l-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)-N-((tetrahydrofuran- 2-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(morpholine-4-carbonyl)- 1H- 1,2,3-triazol- 1- yl)pyridin-3-yl)benzamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(l -methylpiperidin-4-yl)-l H- 1,2,3-triazole-4-carboxamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2-(pyrrolidin- 1-yl)ethyl)- IH-1 ,2,3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2-(dimethylamino)ethyl)- 1H-1,2,3-triazole-4-carboxamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3 -yl)-N-(2-methoxyethyl)- 1H-1,2,3- triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(quinuclidin-3-yl)-lH-l,2,3- triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(piperidin-4-yl)-lH-l,2,3- triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(piperidin-3-yl)-lH-l s2,3- triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methyIpyridin-3-yl)-N-(2-hydroxypropyl)-lH-l,2,3- triazole-4-carboxamide; , l-(5-(3-fluoro-5-(l,4-oxazepan-4-yl)benzamido)-2-methylpyridin-3-yl)-N-((tetrahydrofuran- 2-yl)methyl)- IH-1 ,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-5-(pyrrolidin-l-yl)benzamido)-2-metbylpyridin-3-yl)-N-((tetrahydrofuran-2- yl)methyl)-l H-1 ,2,3-triazole-4-carboxamide; 1-(S-Q-cyano-S-Cpyrrolidin- 1-yl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-l H-1,2,3- triazole-4-carboxamide; l - - S-cyano-S- piperidin-l-y^benzamido^-methylpyridin-S-yO-N-neopentyl- IH-1, 2,3- triazole-4-carboxamide; l - S- -cyano- -morpholinobenzamido -methylpyri din- -y -N-neopentyl-l H-l - triazole-4-carboxamide;

1-(5-(3-fluoro-5-thiomorpholinobenzamido)-2-methylpyridin-3-yl)-N-neopentyl- 1H-1 ,2,3- triazole-4-carboxamide; l-{5-[3-Fluoro-5-(l-oxo-l λ4-; thiomorpholin-4-yl)-benzoylamino]-2-methyl~pyridin-3 -yl}-1H-[ 1,2,3]triazole-4-carboxylic acid (2,2-dimethyl-propyl)-amide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-((l-methylpiperidin-4- yl)methyl)- 1H-1,2,3-triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(5-(4-(4-(2-hydroxyethyl)piperazine- 1-carbonyl)- 1H-1,2,3-triazol-1- yl)-6-methylpyridin-3-yl)benzamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2,2,6 96-tetramethylpiperidin- 4-yl)- IH-1 ,2,3-triazole-4-carboxamide; 1-(2-methyl-5-(3-(pyrrolidin-1-yl)-5-(trifluoromethyl)benzamido)-pyridin-3-yl)-N-(pyridin- 2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide; l-{5-[3-(l,l-Dioxo-l λ6-thiomoφ holin-4-yl)-5-fluoro-benzoylamino]-2-methyl-pyτidin-3- yl}-lH-[l,2,3]triazole-4-carboxylic acid (2,2-diinethyl-propyl)-amide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(pyridin-2-ylmethyl)-lH- 1,2,3-triazole-4-carboxamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- yl)benzamide; 3-bromo-5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- yl)benzamide; (R)-5-tert-butyl-3-cyano-N-(5-(4-((l-ethylpyrrolidin-2-yl)inethylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; l-(5-(3-cyano-5-(piperidin-l-yl)benzamido)-2-methylpyridin-3-yl)-N-(pyridin-2-ylmethyl)- 1H-1,2,3-triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(pyridin-2-ylmethylcarbamoyl)phenyl)pyridin-3- yl)benzamide; N-(6-methyl-5-(4-(pyridin-2-ylmethylcarbamoyl)phenyl)pyridin-3-yl)-3-(pyrrolidin-l-yl)-5- (trifluoromethyl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(( 1-methylpiperidin-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; N-(6-methyl-5-(4-((l-methylpiperidin-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-3- (pyτrolidin-l-yl)-5-(trifl oromethyl)benzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-((l-methylpiperidin-2- yl)methylcarbamoyl)-phenyl)pyridin-3-yl)benzamide; (R)-3-tert-butyl-5-cyano-N-(5-(4-((l-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-6- methylpyridin-3-yl)benzamide; (R)-N-(5-(4-((l-ethylpyrrolidin-2-yl)methylcarbainoyl)phenyl)-6-methylpyridin-3-yl)-3- morpholino-5-(trifluoroinethyl)benzamide; (R)-N-(5-(4-((l-ethylpy τrolidin-2-yl)methylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3- (pyrrolidin- 1-yl)-5-(trifluoromethyl)benzamide; (R)-N-(5-(4-((l-ethylpy πrolidin-2-yl)methylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3- (piperidin- 1-yl)-5-(trifluoromethyl)benzamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-((l-methylpiperidin-2- yl)methyl)- 1H-1,2,3-triazole-4-carboxamide; 1-(5-(5-tert-butyl-3 -cyano-2-methoxybenzamido)-2-me ylpyridin-3-yl)-N-(( 1- methylpiperidin-2-yl)methyl)- IH-1 ,2,3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-cyclohexyl-lH-l,2,3-triazole- 4-carboxamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(piperidin- 1-yl)-l H-1 ,2,3- triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-((6-methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-((6-methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)benzamide; N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-3- (pyrrolidin-l-yl)-5-(trifl υoromethyl)benzamide; methyl 3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbamoyl)-phenyl)pyridin-3- ylcarbarnoyl)benzoate; 3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbamoyl)-phenyl)pyridin-3-ylcarbamoyl)benzoic acid; N-(6-methyl-5-(4-(neopentylcarbamoyl) ρhenyl)ρyridin-3-yl)-2-(piperidin-l- yl)isonicotinamide; 5-tert-butyl-N 1-(2-(dimethylamino)ethyl)-N3-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)- pyridin-3-yl)isophthalamide; 3-fluoro-N-(5-(4-(l-(hydroxyimino)ethyl)phenyl)-6-methylpyridin-3-yl)-5- morpholinobenzamide; methyl 4-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)benzoate; ethyl 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3 -yl)-IH-1 ,2,3-triazole-4- carboxylate; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2-(diethylamino)ethyl)- 1H- 1,2,3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2-(diisopropylamino)ethyl)- IH-1 ,2 3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2-methyl-2-(piperidin-l- yl)propyl)-lH-l,2,3-triazoIe-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-((l-(piperidin-l- yl)cyclohexyl)methyl)- 1H-1,2,3-triazole-4-carboxamide; N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-2-mo φ holinoisonicotinamide; 3-cyano-N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-5- morpholinobenzamide; 3-cyano-N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-5- (pyrrolidin-1 -yl)benzamide; 3-cyano-N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-5- (piperidin-1-yl)benzamide; methyl 4-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)benzoate; 3-tert-butyl-5-cyano-N-(5-(4-(cyclohexylcarbamoyl)phenyl)-6-methylpyridin-3- yl)benzamide; 3-tert-butyl-5-cyano-N-(5-(4-(2-(diethylamino)ethylcarbamoyl)-phenyl)-6-methylpyridin-3- yl)benzamide; 3-tert-butyl-5-cyano-N-(5-(4-(2-(diisopropylamino)ethylcarbamoyl)phenyl)-6-methylpyridin- 3-yl)benzamide; 3-tert-butyl-5-cyano-N-(6-tnethyl-5-(4-(2-methyl-2-(piperidin-l- yl)propylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(( 1-(piperidin- 1- yl)cyclohexyl)methylcarbamoyl)phenyl)pyridin-3 -yl)benzamide; 3-tert-butyl-5-(((2-methoxyethyl)(methyl)amino)methyl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin-3-yl)benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-5-(pyrrolidin-l- ylmethyl)benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3 -yl)-5-(piperidin- 1- ylmethyl)benzamide; 3-fluoro-N-(5-(4-(l-hydroxyethyl)phenyl)-6-methylpyridin-3-yl)-5-morpholinobenzainide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-morpholino-l H-1 ,2,3- triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)- 1H-1 ,2,3-triazole-4-carboxamide; 5-tert-butyl-3-cyano-N-(5-(4-(cyclohexylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(piperidin-l-ylcarbamoyl)phenyl)pyridin- 3-yl)benzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(tetrahydro-2H-pyran-4- ylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(mo φ holinocarbamoyl)phenyl)-pyridin-3- yl)benzamide; 3-tert-.butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-5-((4- methylpiperazin- 1-yl)methyl)benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5- (((tetrahydrofiαran-2-yl)methylamino)methyl)benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5-((prop-2- ynylamino)methyl)benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5- (morpholinomethyl)benzamide; 3-tert-buty l-N-(6-methyl-5 -(4-(neopentylcarbamoyl)phenyl)-pyridin-3 -yl)-5-((3- oxopiperazin- 1-yl)methyl)benzamide; 3-tert-butyl-N-(5-(4-(2-tert-butylhydrazinecarbonyl)-l H-1,2,3-triazol-l -yl)-6-methylpyridin- 3-yl)-5-cyanobenzamide; 3-tert-butyl-5-cyano-N-(5-(4-(2-cyclohexylhydrazinecarbonyl)- 1H-1,2,3-triazol- 1-yl)-6- methylpyridin-3-yl)benzamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(2,6-dimethylpiperidin- 1-yl)- IH-1 ,2,3-triazole-4-carboxamide; N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-2-(pyrrolidin-l- yl)isonicotinamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5-((2- (methylthio)ethyl amino)methyl)-benzamide; 3-tert-butyl-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)ph nyl)-pyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(morpholinocarbamoyl)phenyl)-pyridin-3- yl)benzamide; 3-tert-butyl-N-(5-(4-(2-tert-butylhy 'drazinecarbonyl)phenyl)-6-methylpyridin-3-yI)-5- cyanobenzamide; 3-tert-butyl-5-cyano-N-(5-(4-(2-cyclohexylhydrazinecarbonyl)-phenyl)-6-methylpyridin-3- yl)benzamide; 5-tert-butyl-N-(5-(4-(2-tert-butylhydrazinecarbonyl)phenyl)-6-methylpyridin-3-yl)-3-cyano- 2-methoxybenzamide; l-(5-(3-fluoro-2-methoxy-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-2-methoxy-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N- ((tetrahydrofuran-2-yl)methyl)-lH-l,2,3-triazole-4-carboxamide; l-(5-(3-fluoro-2-methoxy-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-(pyridin-3- ylmethyl)-lH- 1,2,3-triazole-4-carboxamide; 3-fluoro-2-methoxy-N-(6-methyl-5-(4-(pyridin-3-ylmethylcarbamoyl)phenyl)pyridin-3-yl)-5- morpholinobenzamide; 3-fluoro-2-methoxy-N-(6-methyl-5-(4-((tetrahydrofuran-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)-5-mo φ holinoben2amide; 3-fluoro-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5- morpholinobenzamide; 3-tert-butyl-5-cyano-N-(5-(4-(2,6-dimethylpiperidin-l-ylcarbamoyl)phenyl)-6- methylpyridin-3-yl)benzamide; 5-tert-butyl-3-cyano-N-(5-(4-(2,6-dimethylpiperidin-l-ylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; l-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)-N-(2,6- dimethylpiperidin-1 -yl)- IH-1 ,2,3-triazole-4-carboxamide; l-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)-N-(piperidin-l-yl)- IH-1 ,2,3-triazole-4-carboxamide; 5-tert-butyl-N-(5-(4-(2-tert-butylhydrazinecarbonyl)- IH-1 ,2,3-triazol-1-yl)-6-methylpyridin- 3-yl)-3-cyano-2-methoxybenzamide; l-(5-(3-tert-butyl-5-(morpholinomethyl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide; 5-tert-butyl-3-cyano-N-(5-(4-(2-cyclohexylhydrazinecarbonyl)-lH-l,2,3-triazol-l-yl)-6- methylpyridin-3-yl)-2-methoxybenzamide; l-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylpyridin-3-yl)-N- neopentyl-1H-1,2,3-triazole-4-carboxamide; 3-cyano-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5- morpholinobenzamide; N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3- triazol- 1-yl)nicotinamide; N-(3-cyano-5-morpholinophenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3-triazol-l- yl)nicotinamide; N-(3-fluoro-5-morpholinophenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3-triazol-l- yl)nicotinamide; N-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3- triazol- 1-yl)nicotinamide; 1-(5-(3-((I S,5R)-8-oxa-3-aza-bicyclo[3.2. l]octan-3-yl)-5-fluorobenzamido)-2- methylpyridin-3-yl)-N-neopentyl- 1H-1,2,3-triazole-4-carboxamide; 3-cyano-N-(6-rnethyl-5-(4-((tetrahydrofuran-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)-5- morpholinobenzamide; 3-cyano-N-(6-methyl-5-(4-(pyridin-3-ylmethylcarbamoyl)phenyl)-pyridin-3-yl)-5- morpholinobenzamide; N-(3-tert-butylphenyl)-6-methyl-5-(4-(neopentylcarbamoyl)- 1H-1,2,3-triazol-1- yl)nϊ cotinamide; N-(5-tert-butyl-2-methoxyphenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-l H-1 ,2,3-triazol-l - yl)nicotinamide; tert-butyl 2-(3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbamoyl)- 1H-1,2,3-triazol- 1- yl)pyridin-3-ylcaτbamoyI)benzylamino)acetate; tert-butyl 2-(3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3- ylcarbamoyl)benzylaminp)acetate; 2-(3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3- ylcarbamoyl)benzylamino)acetic acid; N-(5-(4-(8-oxa-3-aza-bicyclo[3.2.1 ]octane-3-carbonyl)phenyl)-6-methylpyridin-3-yl)-3-tert- butyl-5-cyanobenzamide; N-(5-(4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-lH-l ,2,3-triazol-l -yl)-6- methylpyridin-3-yl)-5-tert-butyl-3-cyano-2-methoxybenzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4- carbonyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmo φ holine-4- carbonyl)-lH-l ,2,3-triazol-l -yl)pyridin-3-yI)benzamide; N-(5-(4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-lH-l,2,3-triazol-l-yl)-6- methylpyridin-3-yl)-3-tert-butyl-5-cyanobenzamide; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4-carbonyl)-lH-l,2,3- triazol-1-yl)pyridin-3-yl)benzami de; N-(5-tert-butyl-3-carbamoyl-2-methoxyphenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH- 1,2,3-triazol-l -yl)nicotinamide; N-(5-tert-butyl-3-(cyclopropylcarbamoyl)-2-methoxyphenyl)-6-methyl-5-(4- (neopentylcarbamoyl)-l H-1,2,3-triazol- 1-yl)nicotinamide; N-(5-tert-butyl-2-methoxy-3-(methylsul fonamido)phenyl)-6-methyl-5-(4- (neopentylcarbamoyl)-l H-1 ,2,3rtriazol- 1-yl)nicotinamide; N-(5-(4-(8-oxa-3-aza-bicyclo[3 .2. 1]octane-3-carbonyl)phenyl)-6-methylpyridin-3-yl)-5-tert- butyl-3-cyano-2-methoxybenzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4- carbonyl)phenyl)pyridin-3-yl)benzamide; 5-tert-Butyl-3-cyano-2-methoxy-N- {6-methyl-5-[4-(l0-oxa-4-aza-tricyclo[5.2. 1.02,6]decane- 4-carbonyl)-phenyl]-pyridin-3-yl}-benzamide; 5-tert-Butyl-3-cyano-2-methoxy-N- {6-methyl-5-[4-(l 0-oxa-4-aza-tricyclo[5.2. 1.02,6]decane- 4-carbonyl)-[l,2,3]triazol-l-yl]-pyridin-3-yl}-benzamide; 3-tert-Bυtyl-5-cyano-N-{6-methyl-5-[4-(10-oxa-4-aza-tricyclo[5.2.1.02; decane -carbonyl - l tri azol-l -yl -pyri din- -y -benzamide; 3-tert-Butyl-5-cyano-N- {6-methyl-5-[4-(l 0-oxa-4-aza-tricyclo[5 .2. 1.02,6]decane-4- carbonyl)-phenyl]-pyridin-3-yl}-benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5-((2- (methylsulfinyl)ethylamino)methyl)benzamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-5-((2- (methylsulfonyl)ethylamino)methyl)benzamide; N-(3-tert-butyl-5-cyanophenyl)-6-methyl-5-(4-(piperidin- 1-ylcarbamoyl)- IH-1 ,2,3-triazol-1- yl)nicotinamide; N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-6-methyl-5-(4-(piperidin- 1- ylcarbamoyl)-l H-1 ,2,3-triazol-l -yl)nicotinamide; N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-6-methyl-5-(4-(piperidin-l-ylcarbamoyl)-lH- 1,2,3-triazol-1-yl)nicotinamide; l-(5-(5-tert-butyl-3-cyano-2-(2-(4-methylpiperazin-l-yl)ethoxy)benzamido)-2- methylpyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4-carboxamide; 5-tert-butyl-3-cyano-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-2-(2-(4- methylpiperazin-l-yl)ethoxy)benzamide; 3-cyano-N-(6-methyl-5-(4-(N-neopentylsulfamoyl)phenyl)pyridin-3-yl)-5- moφ holinobenzamide; 3-cyano-N-(6-methyl-5-(4-(N-neopentylsulfamoyl)phenyl)pyridin-3-yl)-5-(pyrrolidin-l- yl)benzamide; 5-tert-butyI-3-cyano-2-methoxy-N-(6-methyl-5-(4-(N-neopentylsυlfamoyl)phenyl)pyτidin-3- yl)benzamide; N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)isoxazole-3-carboxamide; 3-tert-butyl-l-methyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)-lH- pyrazole-5-carboxamide; 5-tert-butyl-2-methyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)-phenyl)pyridin-3-yl)furan-3- carboxamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-lH-pyrazole-5- carboxamide; 5-tert-butyl-N-(6-methyl- -(4-(neopentylcarbamoyl)phenyl)-pyridin-3-yl)isoxazole-3- carboxamide; 1-(5-(3-tert-butyl-5-cyanobenzamido)-2-ethylpyridin-3-yl)-N-neopentyl-l H-1 ,2,3-triazole-4- carboxamide; 5-tert-butyl-N1-methyl-N3-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- yl)isophthalamide; 5-tert-butyl-N1-cyclopropyl-N3-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- yl)isophthalamide; 5-tert-butyl-N I-(cyclopropylmethyl)-N3-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin- 3-yl)isophthalamide; 5-tert-butyl-N 1-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)isophthalamide; ethyl 1-(5-(3-fluoro-5-moφ holinobenzamido)-2-methylpyridin-3-yl)-l H-1 ,2,3-triazole-4- carboxylate; methyl S-tert-butyl-S-Co-methyl-S^-CneopentylcarbamoyO-lH-l^^-triazol-l-y^pyridin-S- ylcarbamoyl)benzoate; 1-(5-(3-fluoro-5-(trifluoromethyl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl- 1H-1,2,3- triazole-4-carboxamide; 3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbampyl)-lH-l,2,3-triazol-l-yl)pyridin-3- ylcarbamoyl)benzoic acid;

5-(3-tert-butyl-5-cyanobenzarnido)-2-methyl-3-(4-(neopentylcarbamoyl)phenyl)pyridine 1- oxide; 5-(3-tert-butyl-5-cyanobenzamido)-2-methyl-3-(4-(neopentylcarbamoyl)-l H-1,2,3-triazol- 1- yl)pyridine 1-oxide; 5-tert-butyl-N 1-(cyclopropylmethyl)-N 3-(6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3- triazol-1-yl)pyridin-3 -yl)isophthalamide; l-(5-(2,5-dimethoxybenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH-l 52,3-triazole-4- carboxamide; 5-tert-butyl-N1-methyl-N 3-(6-methyl-5-(4-(neopentylcarbamoyl)- 1H-1,2,3-triazol- 1- yl)pyridin-3-yl)isophthalamide; 3-cyano-5-(4-methyl-lH-imidazol-l-yl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)ph nyl)pyridin-3-yl)benzamide; 1-(2-methyl-5-(3-(4-methyl- 1H-imidazol- 1-yl)-5-(trifluoromethyl)benzamido)pyridin-3-yl)- N-neopentyl- 1H-1,2 3-triazole-4-carboxamide; l-(5-(3-cyano-5-(4-methyl-lH-imi azol-l-yl)benzamido)-2-methylpyridin-3-yl)-N- neopentyl-1H-1,2,3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-(3-hydroxy-2,2- dimethylpropyl)-lH-l,2,3-triazole-4-carboxamide; (R)-I -(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-((tetrahydrof υran-2- yl)methyl)-IH- 1,2,3-triazole-4-carboxamide; (S)-l-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-((tetrahydrofuran-2- yl)methyl)-l H-1 ,2,3-triazole-4-carboxamide; 1-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3 -yl)-N-((1- hydroxycyclopropy methy -l H-l -tri azole -carboxamide; l-CS-CS.S-dipivalamidobenzamido^-inethylpyridin-S-yO-N-neopentyl- IH-1,2,3-triazole-4- carboxamide; N-(3-tert-butyl-5-cyanophenyl)-6-methyl-5-(4-(neopentylcarbamoyl)phenyl)nicotinamide; N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-6-methyl-5-(4- (neopentylcarbamoyl)phenyl)nicotinamide; 5-tert-butyl-3-cyano-N-(5-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; 5-tert-butyl-3-cyano-N-(5-(4-((l-hydroxycyclopropyl)methylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-πiethoxybenzamide; l-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylpyridin-3-yl)-N-(3-hydroxy-2,2- dimethylpropyl)- IH-1 ,2,3-triazole-4-carboxamide; l-(5-(3-tert-butyl-5-(N-propylsulfamoyl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxarnide; l - S- -bis neopentyloxy enzamido -methylpyri din- -y -N-neopentyl-lH-l - triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(5-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)phenyl)-6- methylpyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(5-(4-((l-hydroxycyclopropyl)methylcarbamoyl)phenyl)-6- methylpyridin-3-yl)benzamide; 5-tert-butyl-N1,N 1-dimethyl-N 3-(6-ftiethyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- yl)isophthalamide; N-(5-(4-(2-amino-2-methylpropylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-3-tert-butyl-5- cyanobenzamide; l-(2-methyl-5-(3-pivalamidobenzamido)pyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4- carboxamide; 5-tert-butyl-N1-(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylcarbamoyl)phenyl)pyridin-3-yl)- N3-(pyridin-3-ylmethyl)isophthalamide; l-(5-(5-tert-butyl-2-methoxy-3-nitrobenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5 -(4-(neopentylcarbamoyl)phenyl)pyridin-3 -yl)-3- nitrobenzamide; (R)-l-(5-(5-tert-butyl-2-methoxy-3-(pyrrolidine-2-carboxamido)benzamido)-2- methylpyridin-3-yl)-N-neopentyl-lH-l 52,3-triazole-4-carboxamide; (R)-N-(5-tert-butyl-2-methoxy-3-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- ylcarbamoyl)phenyl)pyrrolidine-2-carboxamide; 5-tert-butyl-N 1-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-N 3-(pyridin-3- ylmethyl)isophthalamide; N-(5-tert-butyl-2-methoxy-3-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- ylcarbamoyl)phenyl)-5-oxopyrrolidine-2-carboxamide; 5-tert-butyl-3-(lH-imidazol-l-yl)-2-methoxy-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; l-(5-(5-tert-butyl-3-(lH-imidazol-l-yl)-2-methoxybenzamido)-2-methyIpyridin-3-yl)-N- neopentyl-lH-l,2,3-triazole-4-carboxamide; methyl 3-tert-butyl-5-(6-methyl-5-(4-((tetrahydrofliran-2- yl)methylcarbamoyl)phenyl)pyridin-3-ylcarbamoyl)benzoate; 3-tert-b tyl-5-cyano-N-(6-methyl-5-(4-(2-(piperidin-l-yl)acetyl)phenyl)pyridin-3- yl)benzamide; l-(5-(3-tert-butyl-5-methoxybenzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH-l,2,3- triazole-4-carboxamide; 3-tert-butyl-5-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3- yl)benzamide; 3-tert-butyl-5-(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylcarbamoyl)phenyl)pyridin-3- ylcarbamoyl)benzoic acid; 5-tert-butyl-N 1,N 1-dimethyl-N3-(6-methyl-5-(4-((tetrahydrofuraπ-2- yl)methylcarbamoyl)ρhenyl)pyridin-3-yl)isophthalamide; 5-tert-butyl-N1-methoxy-N 1-methyl-N3-(6-methyl-5-(4-((tetrahydroftiran-2- yl)methylcarbamoyl)phenyl)pyridin-3-yl)isophthalamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-5-(2- moφ holinoethoxy)benzamide; 5-tert-butyl-2-methoxy-3-(4-methyl-lH-imidazol-l-yl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; l-(5-(5-tert-butyl-2-methoxy-3-(4-methyl-lH-imidazol-l-yl)benzamido)-2-rnethylpyridin-3- yl)-N-neopentyl-l H-1 ,2,3-triazole-4-carboxamide; 5-tert-butyl-NI-((l-hydroxycyclopropyl)methyl)-N 3-(6-methyl-5-(4-((tetrahydrofuran-2- yl)methylcarbamoyl)phenyI)pyridin-3-yl)isophthalainide; 5-tert-butyl-3-cyano-N-(5-(4-(cyclopentylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-cyano-N-(5-(4-(4,4-difluorocyclohexylcarbamoyl)phenyl)-6-methylpyridin-3- yl)-2-methoxybenzamide; 5-tert-bυtyl-3-cyano-N-(5-(4-(isopropylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-cyano-N-(5-(4-(isobutylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-cyano-N-(5-(4-(cyclopropylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(2-(piperidin-l-yl)acetyl)phenyl)pyridin- 3-yl)benzamide; 5-tert-butyl-N1-(6-methyl-5-(4-(neopentylcarbamoyl)-1H-1,2,3-triazol-l -yl)pyridin-3-yl)-N3- (2-(pyrrolidin-1-yl)ethyl)isophthalamide; 5-tert-butyl-Nι-(6-methyl-5-(4-(neόpentylcarbamoyl)-lH-l,2,3-triazol-l-yl)pyridin-3-yl)-N 3- ((1-methylpiperidin-2-yl)methyl)isophthalamide; 5-tert-butyl-3-cyano-N-(5-(4-((lr,4r)-4-hydroxycyclohexylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; N-(5-(4-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-ylcarbamoyl)phe πyl)-6-methylpyridin-3-yl)-5- tert-butyl-3-cyano-2 -methoxybenzamide; 5-tert-butyl-3-cyaπo-N-(5-(4-(3-hydroxypropylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-3-cyano-N-(5-(4-(2-hydroxyethylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2- methoxybenzamide; 5-tert-butyl-N1-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-N3-(2-(pyrrolidin- 1-yl)ethyl)isophthalamide; 5-tert-butyl-N1-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-N3-((l- methylpiperidin-2-yl)methyl)isophthalamide; l-(5-(3-tert-butyl-5-(N,N-dimethylsulfamoyl)benzamido)-2-inethylpyridin-3-yl)-N- neopentyl- IH-1 ,2,3-triazole-4-carboxamide; 3-tert-butyl-5-(N,N-dimethylsulfamoyl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide;

3-tert-butyl-5-(5-methyl-l,2 >4-oxadiazol-3-yl)-N-(6-methyl-5-(4- (neopeπtylcarbamoyl)phenyl)pyridin-3-yl)benzamide; l-(5-(3-tert-butyl-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzamido)-2-methylpyridin-3-yl)-N- neopentyl- IH- 1,2,3-triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(5-(4-(2-(dimethylamino)-2-methylpropylcarbamoyl)phenyl)-6- methylpyridin-3-yl)benzamide; 5-tert-butyl-N1-(3-hydroxy-2,2-dimethylpropyl)-N 3-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)isophthalamide; 5-tert-butyl-3-cyano-N-(5-(4-(2,2-dimethylcyclohexylcarbamoyl)phenyl)-6-methylpyridin-3- yl)-2-methoxybenzamide; N-(5-(4-((lR,2S,4R)-bicyclo[2.2.1]heptan-2-ylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5- tert-butyl-3-cyano-2-methoxybenzamide; l-(5-(3-tert-butyl-5-(N-methylsulfamoyl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-5-(N- methylsulfamoyl)benzamide; 5-tert-butyl-3-(isoxazol-4-yl)-2-methoxy-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-3-(2,3-dihydroisoxazol-4-yl)-2-methoxy-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 3-tert-butyl-5-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 3-tert-butyl-5-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 3-tert-butyl-N-(5-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)phenyl)-6-methylpyridin-3- yl)-5-(N-methylsulfamoyl)benzamide; 3-tert-butyl-N-(5-(4-(4,4-difluorocyclohexylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5-(N- methylsulfamoyl)benzamide; 3-tert-butyl-5-(5-tert-butyl-l,2,4-oxadiazol-3-yl)-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-3-(lH- pyrazol-1 -yl)benzamide; 5-tert-butyl-3-cyano-N-(5-(4-(2 2-dimethyl-3-(pyrrolidin-l-yl)propylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxyb enzamide; 5-tert-butyl-3-cyano-N-(5-(4-(2,2-dimethyl-3-(4-methyl ρiperazin-l- yl)propylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide; 5-tert-butyl-3-cyano-N-(5-(4-(2,2-dimethyl-3-mo φ holinopropylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; N-(5-(4-(3-amino-2,2-dimethylpropylcarbamoyl)phenyl)-6-methylpyridin-3-yl)-5-tert-butyl- 3-cyano-2-meth.oxybenzan.ide; 5-tert-butyl-3-cyano-N-(5-(4-(3-(dimethylamino)-2,2-dimethylpropylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenzamide; 5-tert-butyl-3-(4-(hydroxymethyl)-lH-l,2,3-triazol-l-yl)-2-methoxy-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-3-(4- (pyτrolidin-1 -ylmethyl)-lH-l ,2,3-triazol-l -yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbainoyl)phenyl)pyridin-3-yl)-3-(4- (piperidin-1-ylmethyl)-1H-1,2,3-triazol- 1-yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-3-(4- ((4-methylpiperazin-l -yl)methyl)- IH-1 ,2,3-triazol-1-yl)benzamide; 5-tert-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-3-(4- (moφ holinomethyl)-1H-1,2,3-triazol- 1-yl)benzamide; 5-tert-butyl-3-(4-((diethylamino)methyl)-lH-l,2,3-triazol-l-yl)-2-methoxy-N-(6-methyl-5- (4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide;

5-tert-butyl-3-(4-((dimethylamino)methyl)-lH--l J2,3-triazol-l-yl)-2-methoxy-N-(6-methyl-5- (4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; 5-tert-butyl-3-(4-((isopropyiamino)methyl)-lH-l,2,3-triazol-l-yl)-2-methoxy-N-(6-methyl-5- (4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benz amide; 5-tert-butyI-3-(4-((cyclopropylamino)methyl)-l H-1,2,3-triazol- 1-yl)-2-methoxy-N-(6- methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide; and 5-tert-butyl-3-cyano-N-(5-(4-(2-(dimethylamino)-2-methylpropylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-2-methoxybenz amide.

DETAILED DESCRIPTION OF THE INVENTION

[001 98] The following terms are used throughout as defined below.

[00199] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Hence, isotopically labeled compounds are within the scope of the invention.

[00200] In general,' "substituted" refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbόn(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent . groups include halogens (i.e., F, Cl, Br3 and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sufides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitriles (i.e. CN); and the like.

[00201] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below. [00202] .Alkyl groups include straight chain and branched alkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups further include cycloalkyl groups as defined below. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above.

[00203] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 10 or 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like. In some embodiments, polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with non- hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.

[00204] Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene bridge, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1 or 2 carbon atoms. Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1 .l]hexane, or tricyclic, such as, for example, adamantyl. Representative bridged cycloalkyl groups include bicyclo[2.1 .l]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bomyl, or norbornyl groups. Substituted bridged cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with substituents such as those listed above.

[00205] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. In some embodiments, cycloalkylalkyl groups have from 4 to 20 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.

[00206] Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7 or 8 carbon atoms. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH 3), -CH=C(CH3)2, -C(CH 3)=CH2, -C(CH3)=CH(CH3),

-C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others. Representative substituted alkenyl groups may be mono- substituted or substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above.

[00207] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above. [00208] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples include, but are not limited to -C≡CH,

-C=C(CH3), -CsC(CH 2CH3), -CH2C CH, -CH2C=C(CH3), and -CH2C^C(CH 2CH3), among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.

[00209] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentaienyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[002 10] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4- ethyl-indanyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above. [0021 1] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 ring members. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, teteahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.

[00212] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.

[00213] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4- propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.

[00214] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl, or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above. [002 15] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[00216] The terms "aryloxy" and "arylalkoxy" refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

[00217] Alkyl, alkenyl, and alkynyl groups may be divalent as well as monovalent. The valency of an alkyl, alkenyl, or alkynyl group will be readily apparent from the context to those of skill in the art. For example, the aikyl group in an aralkyl group is divalent. In some embodiments, divalency is expressly indicated by appending the suffix "ene" or "ylene" to terms defined herein. Thus, for example, "alkylene" refers to divalent alkyl groups and alkenylene refers to divalent alkene groups.

[00218] The term "carboxylate" as used herein refers to a -COOH group.

[00219] The term "carboxylic ester" as used herein refers to -COOR 30 groups. R30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[00220] The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(O)NR3 1R32, and -NR 3 1C(O)R32 groups, respectively. R3 1 and R32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). [00221] Urethane groups include N- and O-urethane groups, i.e., -NR33C(O)OR34 and -OC(O)NR33R34 groups, respectively. R33 and R34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.

[00222] The term "amine" (or "amino")as used herein refers to -NHR35 and -NR36R37 groups, wherein R35, R36 and R37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is NH , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[00223] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,

38 39 38 39 38 39 -SO2NR R and -NR SO2R groups, respectively. R and R are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO NH2).

[00224] The term "thiol" refers to -SH groups, while sulfides include -SR 40 groups,

4 1 42 sulfoxides include -S(O)R groups, sulfones include -SO2R groups, and sulfonyls include 43 40 4 1 42 43 -SO 2OR . R , R , R , and R are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00225] The term "urea" refers to -NR 4^C(O)-NR 45R46 groups. R44, R45, and R46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[00226] The term "amidine" refers to -C(NR 47)NR48R49 and -NR47C(NR48)R49, wherein R47, R48, and R49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00227] The term "guanidine" refers to -NR50C(NR5 NR52R53, wherein R50, R5 1, R52 and R53 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00228] The term "enamine" refers to -C(R 54)=C(R 55)NR56R57 and -NR54C(R55)=C(R56)R57, wherein R54, R55, R56 and R57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00229] The term "imide" refers to -C(O)NR 58C(O)R59, wherein R5S and R59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0023 0] The term "imine" refers to -CR 60(NR6 1) and -N(CR 60R6 1) groups, wherein R60 and R6 1 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R60 and R6 1 are not both simultaneously hydrogen.

[0023 1] The term "protected" with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups. Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures, such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoroacetate.

[00232] N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, 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, c -dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl, and the like. Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9,-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[00233] Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.

[00234] Representative carboxy protecting groups are Ci to C alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl, and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylm ethyl, and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups, and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl, and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)- 1-ethyl, 1-(pivaloyloxyl)-l -ethyl, 1-methyl-1-(propionyloxy)-l -ethyl, pivaloyloxymethyl, propionyloxymethyl, and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl, and the like; arylalkylcarbonyloxyalkyl, such as. benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl, and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-l -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy- 1-ethyl, 1-cyclohexyloxycarbonyloxy- 1- ethyl, and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl, and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl, and the like; alkanoylaminoalkyl, such as acetylaminomethyl, and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl, and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, and the like; (5-(alkyl)-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-l,3-dioxolen-4-yl)methyl, and the like; and (5-phenyl-2-oxo-l,3-dioxolen-4- yl)alkyl, such as (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl, and the like.

[00235] Those of skill in the art will appreciate that compounds of the invention may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.

[00236] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other: [00237] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds as described herein are within the scope of the present invention.

[00238] Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.

[00239] As used herein, a solvate is an aggregation of a molecule and one or more molecules of solvent. Some compounds have a tendency to associate with a fixed molar ratio of solvent molecules in the solid state. The solvent molecules may interact with the non- solvent molecule by dipole-dipole interactions, ion-dipole interactions, coordinate bonds, and the like. When the solvent is water, the solvate is referred to as a hydrate. Many organic solvents can also form solvates, including, e.g., ethers such as diethyl ether and tetrahydrofuran, alcohols such as methanol and ethanol, ketones such as acetone, DMF, DMSO and others. Solvates may be identified by various methods known in the art. For example, solvates in which the solvent molecules contain hydrogen may be observable by 1H NMR. Additional methods useful in identifying solvates include thermogravimetric analysis, differential scanning calorimetry, X-ray analysis and elemental analysis. Solvates are readily formed simply by dissolving a compound in a solvent and removing the unassociated solvent by suitable techniques, e.g., evaporation, freeze drying or crystallization techniques. It is therefore well within the skill in the art to produce such solvates. Indeed, it is often the case that careful drying of a compound is necessary to remove the residual solvent that is part of a solvate. Compounds described herein may form solvates and all such solvates are within the scope of the invention. [00240] Certain compounds within the scope of the invention are derivatives referred to as "prodrugs". The expression "prodrug" denotes a derivative of a known direct acting drug, e.g., esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in En∑ymology JJ2:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 5:165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992. The preceding references and all references listed herein are hereby incorporated in their entirety by reference.

[00241] Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the invention has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine and ornithine).

[00242] Compounds of the invention may be readily synthesized by techniques well known to those of skill in the art. For example, compounds of Formula I, wherein L' is a precursor to L2 (see below), Hal is a halogen, such as Br, Cl, or I, and G, L1, X, Y, A, L2, R, n, and Q are as defined herein, may be prepared as shown in Scheme 1. Scheme 1

[00243] A suitably derivatized halogenated pyridine (X=N, Y=CH, or X=CH, Y=N) or pyridazine (X, Y=N), is coupled, via a palladium mediated cross-coupling, with a suitable aryl or heteroaryl boronic acid, in the presence of a base such as K2CC«3, C S2CO3, or Na2CO , to yield intermediate c, wherein L' is a precursor for L2-Q or wherein L' is L2-Q (intermediate e). For example, when L' contains a carbonyl moiety or oxygen linker, L' can 2 2 be L -Q, wherein L is -C(O)- or O(CH2)nC(O) respectively, and Q is as defined herein. Alternatively, when L' contains a protected carboxylate group (e.g. ester), this group is deprotected under basic or acidic conditions (for example, NaOH or TFA respectively), followed by coupling with HNR-Q to form compound e, wherein L2 is C(O)NR. Likewise, when L' contains a protected amine, it can be deprotected and coupled with Q-COOH by the methods described herein, leading to compound e, wherein L2 is C(O)NR.

[00244] Coupling between amine and carboxylate-containing moieties may be effected, for example, by the use of typical amide-bond-forming reagents such as DCC, EDC, CDI,

BOP, PyBOP, HATU, HBTU, HCTU, TATU, TBTU, TDBTU, DEPBT 5 TSTU, and the like, or by introduction of an activating moiety on the carboxylate. The activating moiety is a sufficiently reactive leaving group to allow for amide bond formation under mild conditions. Typical activating moieties include F, Cl, Br, I, N3, N-hydroxysuccinimide, 1-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, pentafluorophenol, y y pentachlorophenol, para-nitrophenol, or OC(O)-OR , wherein R is a C1.6 alkyl group. Suitable bases include sodium bicarbonate or a suitable organoamine, such as pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine. Thus, any suitable amide- bond forming procedure may be used, such as those described in Bodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis, Springer-Verlag (1984); or Jones, J. Amino Acid and Peptide Synthesis Ed. Steven G. Davies, Oxford Science (1992).

[00245] The synthesis may be continued by reducing the nitro group of compound e to the amine as in compound f. Any suitable method may be used for the reduction including, for example, hydrogenation in a solvent such as MeOH, EtOH, or the like, using Raney nickel or Pd/C as a catalyst, or reaction with SnCl in a solvent such as DMF at room temperature. Target compounds of Formula I may be obtained by coupling compound f with a G-COOH moiety by one of the coupling methods described herein. Alternatively, the nitro group in compound c is reduced first, followed by coupling with G-COOH, and finally conversion of L' to L2-Q, using the methods described herein. In yet another approach, the nitro group in compound a is reduced, followed by coupling of the amine group with G-COOH, cross-coupling with a suitable arylboronic acid to obtain compound h, and finally conversion of L' to L2-Q, again using the methods described herein. Using similar methods, compounds containing the alternate orientation of L1 can also be obtained by starting from a derivatized pyridine containing a protected carboxylate instead of a nitro moiety. [00246] Compounds of Formula II, wherein B and D are N, can be prepared as shown in Scheme 2.

Scheme 2

[00247] A suitably derivatized amino-pyridine (X=N, Y=CH, or X=CH, Y=N) or amino- pyridazine (X, Y=N), is converted to its azide derivative i, for example, via treatment with sodium nitrite under aqueous acidic conditions (for example in the presence of HCl, H SO ), followed by treatment with sodium azide. Alternatively, the azide moiety is introducted by reacting a suitably derivatized bromo-pyridine or bromo-pyridazine with an organolithium reagent, followed by tosylazide. Heating (40-1 00 0C) the azide with a derivatized alkyne (R-C ≡€-L') in a protic solvent, such as, for example water, acetonitrile, or mixtures thereof, optionally in the presence of copper (Cu(0) metal, Cu(I) or Cu(!l) salts), leads to formation of the triazole-containing intermediate j, wherein L' is a precursor for L2-Q or wherein L' is L2. For example, when L' is an alkyl, cycloalkyl, aryl, heterocycyl, aralkyl or heterocyclylalkyl group, L' can be L2-Q, wherein L2 is a covalent bond, and Q is as defined herein. Alternatively, when L' contains a protected carboxylate group (e.g. ester), this group is deprotected under basic or acidic conditions (for example, NaOH or TFA respectively), followed by coupling with HNR-Q to form compound m, wherein L2 is C(O)NR. In a next step, the nitro group of compound m is reduced to the amine as in compound n, by the methods described herein. Target compounds of Formula II, wherein B and D are N, are obtained by coupling compound n with a G-COOH moiety by one of the coupling methods described herein. Alternatively, the nitro group in compound j can be reduced first, followed by coupling with G-COOH, and finally conversion of L' to L2-Q, using the methods described herein.

[00248] Intermediates of structure q can serve as precursors to compounds of Formula II, wherein B is N and D is CR. Intermediates of structure q can be prepared as shown in Scheme 3 (See also US publication US2005/0256 Ϊ 13).

Scheme 3

[00249] A suitably derivatized amino-pyridine (X=N, Y=CH, or X=CH5Y=N) or amino- pyridazine (X, Y=N), is converted to the hydrazine p, for example via reduction of the diazonium salt with Na2SO . Reaction with (Z)-ethyl 2-formyl-3-hydroxyacrylate (J.Org.Chem., 1982, 47, 2216) leads to formation of the pyrazole intermediate q, wherein R is H, and L' is C(O)OEt. Alternatively p is reacted with for example, methyl 2-acetyl-3- oxobutanoate, to form intermediate q, wherein R is methyl. As before L' can be converted into L2-Q, wherein L2 is C(O)NR, by deprotection and coupling with HNR-Q. Finally, compounds of Formula II, wherein B is N and D is CR are obtained by reducing the nitro group and coupling of the resulting amine with G-C(O)OH, using the methods described herein.

[00250] Scheme 3 also shows the synthesis of intermediates of structure r which are precursors to compounds of Formula II, wherein B is CR and D is N. Treatment of a suitably derivatized amino-pyridine (X=N, Y=CH, or X=CH, Y=N) or amino-pyridazine (X, Y=N) with ethyl 2-nitroacetate (US2005/02561 13) in the presence of tetramethyl orthoformate, and Fe in a subsequent step, provides intermediates r, which, as before, can be converted into the target compounds of Formula II using the methods described herein. The sequence of derivatization can also be reversed, so that G-L2 is attached to the core ring first, followed by the synthesis steps shown in Scheme 3.

[00251] Scheme 4 shows additional synthesis routes towards intermediates for compounds of Formula II.

Scheme 4.

[00252] Compounds v can be obtained by nucleophilic aromatic substitution of fluorinated pyridine or pyridazine derivatives s by the appropriately derivatized 5-membered heterocycles. Alternatively, compounds of structure t (wherein Hal is Br, Cl, or I) or u (wherein W is a boronic acid or boronic ester derivative) can be submitted to palladium or copper mediated cross-coupling reactions with the appropriately derivatized heterocycles to obtain intermediates v, which can be father elaborated as before. Compounds of structure u may be obtained from compounds of structure t wherein Hal is Br. The sequence of synthesis steps, as before, can be altered, so that coupling of G-L2 is performed before attachment of the 5-membered heterocyclyl moiety.

[00253] Suitably derivatized pyridine and pyridazine starting materials used in the schemes above can be obtained as known in the art. For example, pyridine precursors for the alternate orientations of L1 can be prepared by reported methods (see for example, International Application PCT/US06/042679, J. Med. Chem., 1974, 17, 172; J. Org. Chem., 1984, 49, 193; J. Am. Chem. Soc, 1953, 75, 737; J. Med. Chem., 1977, 20, 129; J. Am. Chem. Soc, 1961, 26, 3420; J. Am. Chem. Soc, 1947, 69, 2574; J. Med. Chem., 1978, 21, 194; J. Med. Chem., 1993, 36, 2676; J. Med. Chem., 1990, 33, 1859; Synthesis, 1986, 400), or by routine modification or extension of those methods. [00254] Alternatively, compounds of Formula I and II are obtained via formation of the central core moiety, as shown in Schemes 5 and 6, respectively.

Scheme 5

[00255] Reaction of 2-nitromalonaldehyde (prepared as in Org. Synth. Coll., 4, 844, 1963) and a suitable ketone, in the presence of ammonium acetate in acohol water mixtures at elevated temperature, afforded the pyridine precursors, which were derivatized as before to yield compounds of Formula I.

Scheme 6.

[00256] Intermediates y of compounds of Formula II were similarly obtained by reaction of 2-nitromalonaldehyde and a suitably derivatized (lH-l,2,3-triazol-l-yl)propan-2-one x. The latter intermediate x was prepared starting from the corresponding epoxide derivative, via ring opening with sodium azide to generate the azidoethanol derivative. The latter intermediate was cyclized to the (lH-l,2,3-triazol-l-yl)propan-2-ol intermediate by reaction with a suitable alkyne in the presence of copper wire. Finally intermediate x was obtained by oxidation of the (lH-l,2,3-triazol-l-yl)propan-2-ol intermediate by well known methods (e.g. Dess-Martin oxidation). Alternatively, intermediate x was prepared starting from either the corresponding chloroethanone or tosylethanone derivative (prepared from the hydroxyethanone derivative) by reaction with sodium azide to generate the azidoethanone intermediate, which was cyclized with a suitable alkyne in the presence of copper wire.

[00257] A "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 µM inhibits induced cytokine release from a cell by about 50% or greater than 50%. For example, induction of TNFa release can be achieved by, but not limited to, treatment of a cell or cell line with lipopolysaccharide (LPS) or IL-Ib and is inhibited by compounds described herein.

[00258] The association of disorders with imbalances in specific cytokine levels is well known in the art, as documented by the references in List II.

LIST II. References describing cytokine-mediated processes and disorders.

[00259] "Treating" within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder. As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder. As will be apparent to those of skill in the art, it is to be expected that the therapeutically effective amount of a compound disclosed herein may vary depending on the indication being treated, e.g., the therapeutically effective amount of a compound described herein would likely be different for treating subjects suffering from, or at risk for, cytokine- mediated disorders relative to the therapeutically effective amount of the compound for treating subjects suffering from, or at risk of, a different disorder, e.g., vascular event(s), diabetes, insulin resistance, or metabolic syndrome. Similarly, it is also to be expected that, for example, the therapeutically effective amount of a compound for decreasing CRP-levels in a subject would likely be different from the therapeutically effective amount for raising HDL-levels in a subject. [00260] A subject is any animal that can benefit from the administration of a compound as described herein. In some embodiments, the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse. Typically, the subject is a human.

[00261] C-reactive protein (CRP) is a plasma protein, and an acute phase protein produced by the liver. CRP is a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occurring in the body. CRP is used mainly as a marker of inflammation. Measuring and charting C-reactive protein values can prove useful in determining disease progress or the effectiveness of treatments. Blood, usually collected in a serum-separating tube, is analysed in a medical laboratory or at the point of testing. Various analytical methods are available for CRP determination, such as ELISA, immunoturbidimetiy, rapid immunodiffusion and visual agglutination. Research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes, hypertension and cardiovascular disease. It is thought that CRP levels 3mg/l represent high risk.

[00262] Lipoproteins are complexes which contain both a lipid and protein. Most of the lipids in plasma are present as lipoproteins and are transported as such. Lipoproteins are characterized by their flotation constants (e.g., densities). Various classes of lipoproteins exist and include high density lipoproteins (HDL) and low density lipoproteins (LDL). The HDL fraction comprises two major fractions, namely HDL2 (large, buoyant HDL, density 1.063 - .

1.125 g/ml) and HDL3 (small, dense HDL, density 1.125-1.21 g/ml). LDLs are particularly rich in cholesterol esters. Traditionally, high levels of LDL and/or low levels of HDL are associated with coronary artery disease. Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dl) have protective value against cardiovascular diseases. Low concentrations of HDL (below 40 mg/dl for men, below 50 mg/dl for women) are a positive risk factor for atherosclerotic diseases. A near optimal level of LDL is considered to be between 100 to 129 mg/dl, with levels below 100 mg/dl considered optimal, while very high LDL levels (above 190 mg/dl) correspond to the highest increased risk of heart disease.

[00263] Assessment of these levels is associated with assessing the risk of cardiovascular and/or cerebrovascular disease. Lipoprotein levels and triglyceride levels are measured and assessed using routine methods known in the art. Commercially available kits and assays may be used to evaluate the level of HDL-C, LDL-C and the level of triglycerides in a subject. Typically, cholesterol analysis is performed by two methods, namely an NMR based method and an ultracentrifugation method. The first method is based on NMR analysis of the lipid environment to determine the size classes and utilizes deconvolution to determine the number of particles in each class. The second method, based on density gradient ultracentrifugation, measures the amount of cholesterol across a range of densities and utilizes deconvolution to determine the amount of cholesterol in each fraction (HDL, including HDL2 and HDL3, LDL, IDL, VLDL).

[00264] Apolipoprotein A-I (ApoA-I) is the major protein component of HDL in plasma. The protein promotes cholesterol efflux from tissues to the liver for excretion and helps to clear cholesterol from arteries.

[00265] Glucose, or "blood sugar", is normally present in humans at concentrations of about 80-120 mg/dl and is the principal source of carbohydrate energy for man and many other organisms. Excess glucose is stored in the body (especially in the liver and muscles) as glycogen, a starch-like substance which is, essentially, polymerized glucose. Glycogen is metabolized into glucose as needed to meet bodily requirements.

[00266] Glucose normally stimulates both the secretion and biosynthesis of insulin. In addition to this glucose-stimulated insulin secretion, however, there exists a basal insulin secretion, namely the biological process by which insulin is released into the circulation in the absence of stimulation by levels of glucose, or other agents that promote insulin secretion, that are elevated above their "fasting" or non-fed levels. The values for fasting and post prandial (after a meal) insulin are about 14 to 145 pmol/1, and 100 to 300 pmol/1 respectively in healthy people, with perhaps 3-to 4-fold higher levels in insulin-resistant people.

[00267] Glycosylated (or glycated) hemoglobin (hemoglobin AIc, HbIc, HbAIc or HgAIc) is a form of hemoglobin used primarily to identify the plasma glucose concentration over time. The normal range (that found in healthy subjects) is 4% to 5.9%. People with diabetes mellitus often have higher levels of HbAIc. While diabetic subject treatment goals vary, many include a target range of HbAIc values. A diabetic with good glucose control has a HbAIc level that is close to or within the reference range. The International Diabetes Federation and American College of Endocrinology recommends HbAIc values below 6.5%, while the range recommended by the American Diabetes Association extends to 7%. A very high HbAIc represents poor glucose control.

[00268] Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin resistance in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma. Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to elevate blood glucose. High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes. Metabolic syndrome, also known as Syndrome X, metabolic syndrome X insulin resistance syndrome, is a combination of medical disorders, having at least three of the following symptoms and features: fasting hyperglycemia (including diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance or insulin resistance), high blood pressure, central obesity (also known as visceral adiposity), decreased HDL cholesterol, and elevated triglycerides.

[00269] Insulin resistance can be detected by the following indications: as an increased level of blood insulin, increased blood level of glucose in response to oral glucose tolerance test (OGTT), decreased level of phόsphorylated protein kinase B (AKT) in response to insulin administration, and the like. Insulin resistance may be caused by decreased sensitivity of the insulin receptor-related signaling system in cells and/or by loss of beta cells in the pancreas through apoptosis. There is also evidence that insulin resistance can be characterized as having an underlying inflammatory component.

[00270] Bilirubin is formed when red blood cells die and their hemoglobin is broken down within the macrophages to heme and globins. The heme is further degraded to Fe2+, carbon monoxide and bilirubin via the intermediate compound biliverdin. Since bilirubin is poorly soluble in water, it is carried to the liver and bound to albumin. Bilirubin is made water-soluble in the liver by conjugation with glucuronic acid. Conjugated bilirubin, or bilirubinglucuronide, moves into the bile canaliculi of the liver and then to the gall bladder. Bilirubin is found in blood either in the conjugated form (also called direct bilirubin), or in the unconjugated form (also called indirect bilirubin). The reference range for total bilirubin is 0.3 - 1.0 mg/dl. For direct bilirubin, it is 0.1 - 0.3 mg/dl, while for indirect bilirubin it is 0.2 - 0.7 mg/dl. In diseases where too much hemoglobin is broken down or the removal of bilirubin does not function properly, the accumulating bilirubin in the body causes jaundice.

Usually the concentration of total bilirubin in the blood must exceed 2—3 mg/dl for the coloration to be easily visible.

[00271] Subjects who are at risk for a cardiovascular and/or cerebrovascular event are also subjects who manifest at least one symptom indicative of a vascular disorder/event. Symptoms that are indicative of a coronary-related vascular event, for example, include chest pain, abnormal electrocardiograms, elevated levels of ischemic markers, necrosis markers, or thrombin/fϊbrin generation markers. Such markers include, but are not limited to, Creatine Kinase with Muscle and/or Brain subunits (CKMB), D-Dimer, Fl .2, thrombin anti-thrombin (TAT), soluble fibrin monomer (SFM), fibrin peptide A (FPA), myoglobin, thrombin precursor protein (TPP), platelet monocyte aggregate (PMA) and troponin (cTn). Subjects who are at risk also include subjects having a history of a thrombotic event (e.g., disorder), including coronary heart disease (CHD), stroke, or transient ischemic attacks (TIA). A history of CHD can include, for example, a history of MI, coronary revascularization procedure, angina with ischemic changes, or a positive coronary angiogram (e.g., showing greater than about 50% stenosis of at least one major coronary artery).

[00272] The term "cancer" refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites. Both benign and malignant tumors are classified according to the type of tissue in which they are found. For example, fibromas are neoplasms of fibrous connective tissue, and melanomas are abnormal growths of pigment (melanin) cells. Malignant tumors originating from epithelial tissue, e.g., in skin, bronchi, and stomach, are termed carcinomas. Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas. Malignant growths of connective tissue, e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among the white blood cells.

[00273] In the context of neoplasia, cancer, tumor growth or tumor cell growth, inhibition may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.

[00274] The term "nociceptive pain" includes, but is not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.

[00275] The term "neuropathic pain" includes, but is not limited to, CRPS (Complex Regional Pain Syndrome) type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer and metastases related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy,' post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine, velcade and thalidomide. The neuropathic pain can result from a mononeuropathy, polyneuropathy, complex regional pain syndromes or deafferentation.

[00276] The term "neuropathy" includes, but is not limited to, a functional disturbance or pathological change in the nervous system, especially in the peripheral nervous system, and is characterized clinically by sensory or motor neuron abnormalities. The term mononeuropathy indicates that a single nerve is affected, while the term polyneuropathy indicates that several nerves are affected. Deafferentation indicates a loss of the sensory input from a portion of the body, and can be caused by interruption of either peripheral sensory fibers or nerves from the central nervous system. The etiology of a neuropathy can be known or unknown. Known etiologies include complications of a disease or toxic state such as diabetes, which is the most common metabolic disorder causing neuropathy, or irradiation, ischemia or vasculitis. It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology. [00277] A therapeutically effective amount of a compound as described herein used in the present invention may vary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0.001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day. Typically, the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and

ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

[00278] Treatment may also include administering the compounds or pharmaceutical formulations of the present invention in combination with other therapies. Combinations of the invention may be administered simultaneously, separately or sequentially. For example, the compounds and pharmaceutical formulations of the present invention maybe administered before, during, or after surgical procedure and/or radiation therapy. Alternatively, the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, anticancer agents and other agents described herein. In the context of inflammation, many types of immunomodulatory, immunosuppressive or cytostatic drugs, as described herein, can be used in combination with the cytokine inhibitors.

[00279] The specific amount of the additional active agent will depend on the specific agent used, the type of condition being treated or managed, the severity and stage of the condition, and the amount(s) of compounds and any optional additional active agents concurrently administered to the subject.

[00280] In some embodiments of the invention, one or more compounds of the invention and an additional active agent are administered to a subject, more typically a human, in a sequence and within a time interval such that the compound can act together with the other agent to provide an enhanced benefit relative to the benefits obtained if they were administered otherwise. For example, the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound and the additional active agents exert their effects at times which overlap. Each additional active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound is administered before, concurrently or after administration of the additional active agents.

[00281] In various examples, the compound and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In other examples, the compound and the additional active agents are administered concurrently. In yet other examples, the compound and the additional active agents are administered concurrently by coformulation.

[00282] In other examples, the compound and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.

[00283] In certain examples, the inventive compound and optionally the additional active agents are cyclically administered to a subject. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can provide a variety of benefits, e.g., reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one or more of the therapies, and/or improve the efficacy of the treatment.

[00284] In other examples, the inventive compound and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of an inventive compound and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle, about 30 minutes every cycle or about 15 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[00285] Courses of treatment can be administered concurrently to a subject, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the inventive compound can work together with the additional active agents. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.

[00286] The additional active agents can act additively or, more typically, synergistically with the inventive compound. In one example, the inventive compound is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another example, the inventive compound is administered concurrently with one or more second active agents in separate pharmaceutical compositions. In still another example, the inventive compound is administered prior to or subsequent to administration of a second active agent. The invention contemplates administration of an inventive compound and a second active agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when the inventive compound is administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.

[00287] The instant invention also provides for pharmaceutical compositions and medicaments which may be prepared by mixing one or more compounds of the invention, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with excess cytokine production. The compounds and compositions of the invention may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with excess cytokine production as disclosed herein, e.g., diseases and pathological conditions involving inflammation, pain, cancer, etc. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.

[00288] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

[00289] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[00290] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[00291] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non¬ volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[00292] For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[00293] For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives. [00294] Compounds of the invention may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9- lauryl ether, glycocholate and deoxycholate. Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.

[00295] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. A nonaqueous suspension (e.g., in a fluorocarbon propellant) can also be used to deliver compounds of the invention.

[00296] Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound.

[00297] For nasal administration, the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. For administration in the form of nasal drops, the compounds may be formulated in oily solutions or as a gel. For administration of nasal aerosol, any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.

[00298] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00299] Transdermal- patches have the added advantage of providing controlled delivery of a compound of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the inventive compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[00300] Ophthalmic formulations, eye ointments, powders, solutions and the. like, are also contemplated as being within the scope of this invention. The compounds of this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated.

[00301] Intrathecal administration, via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).

[00302] Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents.

[00303] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[00304] The formulations of the invention may be designed to be short-acting, fast- releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

[00305] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.

[00306] The present disclosure also provides medical devices incorporating the cytokine inhibitors as described herein. A representative device includes a vascular stent coated or impregnated with the cytokine inhibitors as described herein. The device can be configured to be inserted into a blood vessel where it can release the cytokine inhibitors as described herein to help reduce or prevent vascular inflammation, for example vascular inflammation.

[00307] Other embodiments disclose medical devices that include cytokine inhibitors as described herein, or a combination of the cytokine inhibitors with additional ingredients A, as described herein. The cytokine inhibitors as described herein can be coated on the surface of the medical device or the device can be saturated with the cytokine inhibitors such that the cytokine inhibitors are released from the device, for example over a period of time. Exemplary medical devices including the cytokine inhibitors as disclosed herein include, but are not limited to, vascular medical devices such as vascular stents.

[00308] Stents and methods for making and using stents coated or impregnated with therapeutic agents are well-known in the art: see, e.g., U.S. Application No. US20050181977 and U.S. Application No. US20050 129729.

[00309] Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.

[003 10] A therapeutically effective amount of a compound of the present invention may vary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0.001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day. Typically, the compound or compounds of the instant invention are selected to provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

[003 11] In the context of cancer, the cytokine inhibitors can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients or a combination thereof. Additional treatments comprise treatment by surgery, radiation, or cryotherapy, while treatment with additional active ingredients comprises the use of antiproliferative agents. Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects to each drug. The specific amount of the additional active agent will depend on the specific agent used, the type of cancer being treated or managed, the severity and stage of the cancer, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the subject. Typically, the additional active ingredients that can be used in combination with the cytokine inhibitors of the present invention are used at dosages well known in the art.

[003 12] In general, surgery and radiation therapy are employed as potentially curative therapies for humans under 70 years of age who present with clinically localized disease and are expected to live at least 10 years.

[003 13] The phrase "antiproliferative agents" includes agents that prevent the development, maturation, or spread of cells, by acting directly on the cell, e.g., by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification. There are large numbers of antiproliferative agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be included in the present invention for treatment of cancer by combination drug chemotherapy.

[003 14] Typical antiproliferative agents can be categorized as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, endothelin A receptor antagonists, retinoic acid receptor agonists, immunomodulators, hormonal or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyrosine kinase inhibitors, and the like. Some antiproliferative agents operate through multiple or unknown mechanisms and can thus be classified into more than one category.

[003 15] A family of antiproliferative agents which may be used in combination with the present invention includes alkylating-type agents. The alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases in DNA, arresting cell division. Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas. A disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa, and fetal tissue. Suitable alkylating-type agents that may be used in the present invention include, but are not limited to, busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, and chlorambucil.

[003 16] A family of antiproliferative agents which may be used in combination with the present invention includes platinum agents. Suitable platinum agents that may be used in the present invention include, but are not limited to spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin.

[003 17] An additional family of antiproliferative agents which may be used in combination with the present invention includes antimetabolite-type agents. Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids. Suitable antimetabolite agents that may be used in the present invention include, but are not limited to azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fiudarabine, gemcitabine, raltitrexed, or capecitabine. [003 18] Another family of antiproliferati ve agents which may be used in combination with the present invention includes topoisomerase inhibitors. Suitable topoisomerase agents that may be used in the present invention include, but are not limited to amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-10-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNiimerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-1 1), or topotecan.

[003 19] Another family of antiproliferative agents which may be used in combination with the present invention includes antibiotic-type antiproliferative agents. Suitable antibiotic-type antiproliferative agents that may be used in the present invention include, but are not limited to dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafide.

[00320] Another family of antiproliferative agents which maybe used in combination with the present invention includes antimitotic agents. Suitable antimitotic antiproliferative agents that may be used in the present invention include, but are not limited to colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner-Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881 A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), auristatin PE (Teikoku Hormone), azaepothilone B (BMS), ixabepilone (BMS), tavocept (BioNumerik), BMS 184476 (BMS), combrestatin A4 disodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatin-10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKline), docetaxel, vinorelbine, or vincristine.

[0032 1] Another family of antiproliferative agents which may be used in combination with the present invention includes aromatase inhibitors. Suitable aromatase inhibitors that may be used in the present invention include, but are not limited to aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole.

[00322] An additional family of antiproliferative agents which may be used in combination with the present invention includes the thymidylate synthase inhibitors. Suitable thymidylate synthase inhibitors that may be used in the present invention include, but are not limited to, pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5,10-methylenetetrahydrofolate (BioKeys).

[00323] Yet another family of antiproliferative agents which may be used in combination with the present invention includes DNA antagonists. Suitable DNA antagonists that may be used in the present invention include, but are not limited to trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics).

[00324] Another family of antiproliferative agents which may be used in combination with the present invention includes farnesyltransferase inhibitors. Suitable farnesyltransferase inhibitors that may be used in the present invention include, but are not limited to arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).

[00325] An additional family of antiproliferative agents which may be used in combination with the present invention includes pump inhibitors. Suitable pump inhibitors - that may be used in the present invention include, but are not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).

[00326] An alternative family of antiproliferative agents which may be used in combination with the present invention includes histone acetyltransferase inhibitors. Suitable histone acetyltransferase inhibitors that may be used in the present invention include, but are not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).

[00327] Another family of antiproliferative agents which may be used in combination with the present invention includes metalloproteinase inhibitors. Suitable metalloproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).

[00328] Also, the family of antiproliferative agents which may be used in combination with the present invention includes ribonucleoside reductase inhibitors. Suitable the DNA antagonists that may be used in the present invention include, but are not limited to gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).

[00329] Another family of antiproliferative agents which may be used in combination with the present invention includes endothelin A receptor antagonists. Suitable endothelin A receptor antagonists that maybe used in the present invention include, but are not limited to atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).

[00330] Yet another family of antiproliferative agents which may be used in combination with the present invention includes retinoic acid receptor agonists. The family of retinoic acid receptor agonists includes compounds which are natural and synthetic analogues of retinol (Vitamin A). The retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development, bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision. Retinoids are required to maintain normal differentiation and proliferation of almost all cells and have been shown to reverse/suppress carcinogenesis in a variety of in vitro and in vivo experimental models of cancer, see (Moon et al., Ch. 14 Retinoids and cancer. In The Retinoids, Vol. 2. Academic Press, Inc. 1984). Suitable retinoic acid receptor agonists that may be used in the present invention include, but are not limited to fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD-1 550 (Ligand).

[00331] Another family of antiproliferative agents which may be used in combination with the present invention includes imrnunornodulators. Suitable immunomodulators that may be used in the present invention include, but are not limited to interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CD154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), D-alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax).

[00332] An additional family of antiproliferative agents which may be used in combination with the present invention includes hormonal agents. Suitable hormonal agents that may be used in the present invention include, but are not limited to an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fiuoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutamide, or leuporelin.

[00333] Yet another family of antiproliferative agents which may be used in combination with the present invention includes photodynamic agents. Suitable photodynamic agents that may be used in the present invention include, but are not limited to talaporfin (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.

[00334] Yet another family of antiproliferative agents which may be used in combination with the present invention includes angiogenesis inhibitors. Suitable angiogenesis inhibitors that may be used in the present invention include, but are not limited to neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Sugen).

[00335] Another family of antiproliferative agents which may be used in combination with the present invention includes Tyrosine Kinase Inhibitors. Suitable Tyrosine Kinase Inhibitors that may be used in the present invention include, but are not limited to imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX- H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panitumumab (Abgenix), IMC-ICl 1 (ImClone), sorafenib (Bayer) or trastuzumab (Genentech).

[00336] Additional anti-proliferative agents which may be used in combination with the present invention include melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, paclitaxel (Taxol®), and the like.

[00337] hi the context of pain treatment, the cytokine inhibitors of the invention can be used in methods and compositions together with additional active ingredients or agents. Typically, the additional active agents are capable of relieving pain, inhibiting inflammatory reactions, providing a sedative effect or an antineuralgic effect, or ensuring patient comfort. Examples of the additional active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, anti-infiammatories, COX-2 inhibitors, α-adrenergic receptor agonists or antagonists, k tamine, anesthetic agents, NMDA antagonists, α2δ ligands, immunomodulatory agents, immunosuppressive agents, antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, corticosteroids, hyperbaric oxygen, other therapeutics known to relieve pain, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs and pharmacologically active metabolites thereof.

[00338] Opioids can be used to treat severe pain. Examples of opioid analgesics include, but are not limited to, oxycodone (OxyContin™), morphine sulfate (MS Contin™, Duramorph™, Astramorph™), meperidine (Demerol™), and fentanyl transdermal patch (Duragesic™) and other known conventional medications [See, e.g., Physicians 1Desk Reference, 594-595, 2851 and 2991 (57th ed., 2003)]. Oxycodone (OxyContin™) is a long- acting form of an opioid and may be used usually in initial and later stages of CRPS. Morphine sulfate may be used for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate is sold in the United States under the trade name MS Contin™, Duramorph™, or Astramorph™ [See, e.g., Physicians' Desk Reference, 594-595 (57th ed., 2003)]. Fentanyl transdermal patch (Duragesic™) is a potent narcotic analgesic with much shorter half-life than morphine sulfate. Meperidine (Demerol™) and hydromorphone (Dilaudid™) may also be used for pain management [See, e.g., Physicians 1Desk Reference, 2991 (57th ed., 2003)].

[00339] Non-narcotic analgesics and antiinflammatories are preferably used for treatment of pain during pregnancy and breastfeeding. Antiinflammatories such as non¬ steroidal anti-inflammatory drugs (NSAIDs) and cbx-2 inhibitors typically inhibit inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis. NSAIDs may provide pain relief in the early stage of pain syndrome. Examples of anti-inflammatories include, but are not limited to, salicylic acid acetate (Aspirin™), ibuprofen (Motrin™, Advil™), ketoprofen (Oruvail™), rofecoxib (Vioxx™), naproxen sodium (Anaprox™, Naprelan™, Naprosyn™), ketorolac (Acular™), and other known conventional medications. A specific cox-2 inhibitor is celecoxib (Celebrex™) [See, e.g., Physicians' Desk Reference, 1990, 1910-1914 and 2891 (57th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 5 11, 667 and 773 (23rd ed., 2002)].

[00340] Antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. Some antidepressants also have sodium channel blocking ability to reduce the firing rate of injured peripheral afferent fibers. Examples of antidepressants include, but are not limited to, nortriptyline (Pamelor™), amitriptyline (Elavil™), imipramine (Tofranil.), doxepin (Sinequan™), clomipramine (Anafranil™), fluoxetine (Prozac™), sertraline (Zoloft™), nefazodone (Serzone™), venlafaxine (Effexor™), trazodone (Desyrel™), bupropion (Wellbutrin™) and other known conventional medications [See, e.g., Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57th ed., 2003)].

[00341 ] Anticonvulsant drugs may also be used in embodiments of the invention. Examples of anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (Neurontin™), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine [See, e.g., Physicians' Desk Reference, 2563 (57th ed., 2003)].

[00342] Corticosteroids (e.g., prednisone, dexamethasone or hydrocortisone), orally active .class Ib anti-arrhythmic agents (e.g., mexiletine), calcium channel blockers (e.g., nifedipine), beta-blockers (e.g., propranolol), α-blockers (e.g., phenoxybenzamine), and α.2- adrenergic agonists (e.g., clonidine) can also be used in combination with a cytokine inhibitor [See, e.g., Physicians' Desk Reference, 1979, 2006 and 2190 (57th ed., 2003)].

[00343] The specific amount of the additional active agent will depend on the specific agent used, the type of pain being treated or managed, the severity and stage of pain, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the patient.

[00344] Hydromorphone (Dilaudid™) is typically administered in an initial dose of about 2 mg orally, or about 1 mg intravenously to manage moderate to severe pain [See, e.g., Physicians' Desk Reference, 2991 (57th ed., 2003)]. Morphine sulphate (Duramorph™, Astramorph™, MS Contin™) is typically administered in an initial dose of about 2 mg IV/SC/IM, depending on whether a patient has already taken narcotic analgesics [See, e.g., Physicians' Desk Reference, 594-595 (57th ed., 2003)]. No intrinsic limit to the amount that can be given exists, as long as a patient is observed for signs of adverse effects, especially respiratory depression. Various IV doses may be used, commonly titrated until a desired effect is obtained. For patients not using long-term agents, as little as 2 mg IV/SC may be sufficient. Larger doses are typically required for patients taking long-term narcotic analgesics. Morphine sulphate is also available in oral form in immediate-release and timed- release preparations. The long-acting oral form may be administered twice per day. An immediate-release form may be needed for periods of pain break-through, with the dose dependent on previous use. Oxycodone (OxyContin™) is a long-acting form of an opioid and may be used in initial and later stages of pain syndrome. Oxycodone (OxyContin™) is usually administered in an amount of about 10-160 mg twice a day [See, e.g., Physicians' Desk Reference, 2851 (57th ed., 2003)]. Meperidine (Demerol™) is typically administered in an amount of about 50-150 mg PO/IV/IM/SC every 3-4 hours. A typical pediatric dose of meperidine (Demerol™) is 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC every 3-4 hours [See, e.g., Physicians' Desk Reference, 2991 (57th ed., 2003)]. Fentanyl transdermal patch (Duragesic™) is available as a transdermal dosage form. Most patients are administered the drug in 72 hour dosing intervals; however, some patients may require dosing intervals of about 48 hours. A typical adult dose is about 25 mcg/h (10 cm2), 50 mcg/h (20 cm2), 75 mcg/h (75 cm2), or 100 mcg/h (100 cm2) [See, e.g., Physicians' Desk Reference, 1775 (57th ed., 2003)].

[00345] Non-narcotic analgesics and anti-inflammatories such as NSAIDs and cox-2 inhibitors may be used to treat patients suffering from mild to moderate pain. Ibuprofen (Motrin™, Advil™) is orally administered in an amount of 400-800 mg three times a day [See, e.g., Physicians' Desk Reference, 1900-1904 (57th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 511, 667 and 773 (23rd ed., 2002)]. Naproxen sodium (Anaprox™, Naprelan™, Naprosyn™) may also be used for relief of mild to moderate pain in an amount of about 275 mg thrice a day or about 550 mg twice a day [See, e.g., Physicians' Desk Reference, 1417,2193 and 2891 (57th ed., 2003)].

[00346] Antidepressants, e.g., nortriptyline (Pamelor™), may also be used in the invention to treat patients suffering from chronic and/or neuropathic pain. The oral adult dose is typically in an amount of about 25-100 mg, and usually does not exceed 200 mg/d. A typical pediatric dose is about 0.1 mg/kg PO as initial dose, increasing, as tolerated, up to about 0.5-2 mg/d. Amitriptyline (Etrafon™) is typically used for neuropathic pain in an adult dose of about 25-100 mg PO [See, e.g., Physicians' Desk Reference, 1417 and 2193 (57th ed., 2003)].

[00347] Anticonvulsants such as gabapentin (Neurontin™) may also be used to treat patients suffering from chronic and neuropathic pain. Typically, gabapentin is orally administered in an amount of about 100-1,200 mg three times a day [See, e.g., Physicians' Desk Reference, 2563 (57th ed., 2003)]. Carbamazepine (Tegretol™) is used to treat pain associated with true trigeminal neuralgia. The oral adult dose is typically in an amount of about 100 mg twice a day as initial dose, increasing, as tolerated, up to about 2,400 mg/d [See, e.g., Physicians' Desk Reference, 2323-25 (57th ed., 2003)].

[00348] For the treatment of pemphigus, other agents which may be used in combination with the novel compounds of the invention include, but are not limited to, anti-inflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, alkylating agents, immunoglobulins, or a combination of two or more thereof. Examples of anti-inflammatory agents include corticosteroids, COX-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAID), TNFa antagonists, and IL-I antagonists. For example, the corticosteroid can be prednisone, prednisolone, or methylprednisolone. Corticosteroids such as these may also be administered with either chlorambusil or mycophenylate mofetil. Examples of TNFa antagonists are infliximab, etanercept, and adalimumab. An example of an IL-I antagonist is anakinra. Examples of immunosuppressants are mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituximab, anti-interferon gamma, and cyclophosphamide, while anti-infectives include dapsone and hydroxychloroquine. In some instances, the gold salt can be myochrysine, or solganal. An example of an alkylating agent is lukeran. Antibiotics useful in combinations are tetracycline, minocycline, and doxycycline, sometimes in combination with nicotinamide, or niacinamide.

[00349] Treatment of pemphigus can also include plasmapherisis therapy or photophoresis therapy to the subject.

[00350] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

[00351] The following abbreviations are used throughout the application with respect to terminology: AcN: Acetonitrile AcOH or HOAc: Acetic acid aq.: Aqueous BOP: Benzotriazol-1-yloxy-tris-(dimethylamino) phosphonium hexafluorophosphate Bu: Butyl

CDI: N5N'-Carbonyldiimidazole DCC: Dicyclohexylcarbodiimide DCM: Dichloromethane DEPBT: (3-(Diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)- one) DIEA: N,N-Diisopropylethylamine DMF: N-Dimethylformamide PPA- Diphenylphosphoryl azide . dppb: 1,4-Diphenylphosphinobutane dppf: 1,1'-Bis(diphenylphosphino)ferrocene EDC: 1-Ethyl-3 -(3-dimethyllaminopropyl) carbodiimide hydrochloride eq.: Equivalent EtOAc: Ethyl acetate EtOH: Ethanol HATU: 2-(7-Aza-lH-benzotriazole-l-yl)-l , 1,3,3- tetramethyluronium hexafluorophosphate HBTU: 2-( 1H-Benzotriazole- 1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate HCTU: 2-(6-Chloro- 1H-benzotriazole- 1-yl)- 1,1,3,3- tetramethylaminium hexafluorophosphate Hex: Hexanes HOBt: , Hydroxybenzotriazole HPLC: High Pressure Liquid Chromatography hr: Hour(s) HV: - High vacuum IC50 value: The concentration of an inhibitor that causes a 50 % reduction in a measured activity. LC-MS: Liquid chromatography- mass spectroscopy MeOH: Methanol min: Minute(s) MTBE: Methyl-t-butyl ether NMM: N-methylmorpholine NMR: Nuclear magnetic resonance PE: Petroleum ether PyBOP: Benzotriazole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate PyBrOP: Bromo-tris-pyrrolidinophosphonium- hexafluorophosphate RP-HPLC: Reverse phase HPLC r.t.: Room temperature sat.: Saturated TATU: O-CV-Azabenzotriazole-l-yO-N.N.N^N'- tetramethyluronium tetrafluoroborate TBTU: 2-(l H-Benzotriazole-l -yl)-l 1,3,3-tetramethyluronium tetrafluoroborate TDBTU: N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo- 1,2,3- benzotriazin-3-yl)uranium tetrafluoroborate TFA: Trifluoroacetic acid THF: Tetrahydrofuran TSTU: O-(N-Succinimidyl)- 1,1,3,3-tetramethyl uranium tetrafluoroborate

[00352] Compounds are named using the automatic name generating tool provided in Chemdraw Ultra (CambridgeSoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry.

Synthesis of Intermediates

[00353] 5-Morpholinoisophthalonitrile. A mixture of 5-fluoroisophthalonitrile ( 1.00 g, 6.84 mmol, 1.0 eq.), morpholine ( 1 192 µl, 13.69 mmol, 2.0 eq.), and DMSO (2.0 ml) was stirred overnight at 500C. The mixture was diluted with 2% aq. HCl (30 ml), the solid was separated by filtration, washed with 2% aq. HCl, water, and dried in HV to give pure target product (white solid, 1.35 g, 92% yield, 99% pure by LCMS - no mass observed). 1H-NMR δ (DMSO-d 6) (ppm) 7.69 (s, 3H), 3.71 (m, 4H), 3.28 (m, 4H). [00354] Methyl 3-carbamoyl-5-morpholinobenzoate (A). In a 50 ml round- bottomed flask were placed 5-morpholinoisophthalonitrile (336 mg, 1.27 mmol) and DCM (3 ml). To this solution was added a solution prepared from DCM (26 ml), MeOH (6 ml) and acetyl chloride (2 ml). The solution was capped tightly and allowed to sit at r.t. for 18 hr. The solvent was removed and the residue refluxed in MeOH (80 ml) for 1 hr 45 min. The solvent was removed and the residue triturated with ether. The residue was dried to afford 257 mg of the methyl 3-carbamoyl-5-morpholinobenzoate A (CaIc. mass: 264, obs. mass: 265).

[00355] Methyl S-cyano-S-morpholinobenzoate. Methyl 3-carbamoyl-5- morpholinobenzoate A (257 mg, 0.97 mmol) was dissolved in DCM (15 ml) in a 100 ml round-bottomed flask. Pyridine (851 µl, 9.7 mmol) and phosphorous oxychloride (445 µl, 4.9 mmol) were added and the solution was allowed to sit at r.t. for 1 hr. The solvent was removed and the residue was purified on silica gel eluting with 0-50% EtOAc/Hex to afford 197 mg of the methyl 3-cyano-5-morpholinobenzoate (82% yield) (CaIc. mass: 246, obs. mass: 247).

[00356] 3-Cyaπo-S-niorpholinobenzoic acid (B). Methyl 3-cyano-5- morpholinobenzoate (197 mg, 0.8 mmol) was dissolved in MeOH (7 ml) and THF (7 ml). A NaOH solution (2 M, 0.60 ml) was added and the solution was heated to 500C for 75 min. The solvent was removed and the residue suspended in THF. 2M HCl (0.60 ml) was added and the solvent was removed. The residue was suspended in THF, the solution was filtered and the solvent was removed in vacuo to afford 281 mg of the target compound, which contained some sodium chloride (CaIc. mass: 232, obs. mass: 233). It was used in subsequent reactions without further purification.

[00357] 5-tert-Butyl-isophthalic acid monomethyl ester (C). To a solution of 5-tert- butylisophthalic acid (50 g, 0.225 mol) in MeOH (700 ml) was added 2 ml of concentrated H SO . The reaction was heated and stirred overnight. After cooling down to r.t., solid θ NaHC 3 was added to neutralize the reaction mixture. Excess NaHCO 3 was removed by filtration. The filtrate was evaporated and the residue was purified by column chromatography (using DCM and MeOH as eluents) to obtain the desired monoester C (32 g 1 δ 60%). H-NMR (DMSO-d 6) (ppm) 13.3 (s, IH), 8.35 (s, IH), 8.20 (s, IH), 8.24 (s, IH) 3.90 (s, 3H), 1.38 (s, 9H).

[00358] Methyl 3-tert-butyl-S-carbamoylbenzoate. To a suspension of C (19 g, 80.42 mmol) in DCM (600 ml) was added oxalyl chloride (39 ml, 0.45 mol) and 0.8 ml of DMF. The mixture was stirred at r.t. for 2 hr. The solvent was removed under vacuum to dryness. The residue was reacted at r.t. with ammonia (79 ml, 1.3 M in dioxane) in the presence of DIEA (46 ml) in DCM (150 ml). The mixture was stirred at r.t. overnight. The solution was evaporated and the residue was purified by column chromatography, using Hex/EtOAc to obtain the target compound (15 g, 79%) as a white solid. (CaIc. mass: 235.2, obs. mass: 276.6 (M-HAcN)+).

[00359] Methyl 3-tert-butyl-5-cyanobenzoate (D). To a suspension of the compound obtained above (6 g, 25.5 mmol) in chloroform (130 ml) was added a solution of POCU (3.03 ml, 33.15 mmol) in chloroform (20 ml). The mixture was stirred at r.t. for 3 hr. TEA was added at 0 °C. The mixture was stirred at r.t. overnight. The reaction mixture was evaporated under vacuum, and the residue was purified by column chromatography (Hex/EtOAc) to obtain the target compound (4.12 g, 75%) as a white solid. 1H-NMR δ (CDCl3) 8.31 (m, IH), 8.17 (m, IH), 7.86 (m, IH), 3.98 (s, 3H), 1.39 (s, 9H). [00360] 3-tert-Butyl-S-cyanobenzoic acid (E). Methyl 3-tert-butyl-5-cyanobenzoate (4.35 g, 20 mmol) obtained as described above was dissolved in THF (150 ml), MeOH (100 ml), and 2N NaOH ( 15 ml) was added. The solution was stirred for 130 min at r.t., then the mixture was concentrated and extracted with MTBE (50 ml) to remove unreacted starting material. The aqueous layer was neutralized with 12 M aq. HCl (3 ml) and a white solid precipitated. The solid was filtered, washed with water, air-dried and dried in HV at 80°C for 1 δ 2 hr to yield 3.88 g of the target material. H-NMR (DMSO-d 6) (ppm) 13.50 (bs, IH), 8.20 (m, IH), 8.13 (m, IH), 8.11 (m, IH), 1.32 (s, 9H).

[00361] 3-tert-Butyl-5-cyanobenzoyl chloride (F). To a suspension of the acid E (3.88 g, 19 mmol) in DCM (10 ml), oxalyl chloride (14.55 g, 115 mmol) and a catalytic amount of 5% DMF/DCM solution (0.5 ml.) were added. The reaction was stirred at r.t. for 80 min and the solvent was evaporated. The residue was purified by Kugelrohr distillation (HV, 140-1600C), to afford pure product as a yellow oil that slowly formed a crystalline 1 δ solid. H-NMR (CDCl 3) (ppm) 8.25 (m, IH), 8.18 (m, IH), 7.89 (m, IH), 1.32 (s, 9H). [00362] 3-(Bromomethyl)-5-tert-butylbenzoic acid- To a solution of intermediate C (0.5 g, 2.1 mmol) and NMM (0.64 g, 6.4 mmol) in THF (50 ml) at -78°C was added isobutyl chloroformate (0.35 g, 2.5 mmol). The mixture was stirred at -78°C for 15 minutes. Excess sodium borohydride (0.4 g) was dissolved in water (30 ml) and the solution was then added to the THF solution of the mixed anhydride. The mixture was allowed to warm to r.t. and was then added to 200 ml of water. The mixture was extracted with DCM. The organic fractions were dried over MgSO . The drying agent was removed by filtration, and the filtrate was concentrated under vacuum to give the benzyl alcohol intermediate. The intermediate was taken up into a THF/DCM mixture (50 ml of a 3:1 mixture) and was cooled to 00C. To this solution phosphorous tribromide (2.12 ml of a 1.0 M solution in DCM) was added and the reaction was stirred at 00C for 1 hr and then at r.t. for 4 hr. The mixture was added to 200 ml of water and was extracted with DCM. The organic fractions were dried with MgSO . The drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified via column chromatography (4: 1 Hex/EtOAc) to give the target 1 δ compound as a clear oil (0.3 g). H NMR (500 MHz, CDCl3) (ppm) 8.02 (s, IH), 7.90 (s, IH), 7.60 (s, IH), 4.53 (s, 2H), 3.93 (s, 3H), 1.36(s, 9H).

[00363] 3-(Bromomethyl)-5-tert-butylbenzoic acid (D). To a solution of the compound obtained above (0.1 g, 0.35 mmol) in DCM (3 ml) at 00C was added boron tribromide (0.5 ml of a 1.0 M solution in DCM) and the reaction was stirred at 00C for 1 hr and then at r.t. for 2 hr. The mixture was then added to 20 ml of water. The mixture was extracted with DCM. The organic fractions were dried with MgSO The drying agent was removed by filtration, and the filtrate was concentrated under vacuum to give the title 1 δ compound D as a clear oil (0.088 g). H NMR (500 MHz, CDCl3) (ppm) 8.01 (s, IH), 7.93 (s, IH), 7.74 (s, IH), 4.54 (s, 2H), 1.38 (s, 9H). [00364] S-tert-Butyl-l-methoxy-S-bromobenzoic acid (E). NBS (1.7 1 g, 9.6 mmol) was added to a solution of 5-tert-butyl-2-methoxybenzoic acid (1.0 g, 4.8 mmol) in glacial acetic acid ( 15 ml) and the mixture was heated to 1000C for 16 hr. The reaction was allowed to cool and was diluted with 10 ml water and then extracted with DCM. The combined organic layers were washed with water, dried over MgSO and concentrated to give intermediate E (1.2 g, 87%) as a pale yellow solid in > 90% purity. 1H-NMR (500 MHz δ CDCl 3) (ppm) 8.01 (s, IH), 7.78 (s, IH), 4.00 (s, 3H), 1.33 (s, 9H). [00365] Methyl 3-bromo-5-tert-butyl-2-methoxybenzoate (F). To a solution of 5-tert- butyl-2-methoxy-3-bromobenzoic acid E (0.63 g, 2,2 mmol) in DCM (18 ml), oxalyl chloride ( 1.0 ml, 11.5 mmol) and six drops of DMF were added. The mixture was stirred at r.t. for 1 hr, concentrated, the residue was dissolved in MeOH (10 ml) and further stirred at r.t. for 15 min. The solvent was evaporated to give a viscous yellow oil (quantitative) in >90% 1 δ purity. H-NMR (500 MHz, CDCl 3) (ppm) 7.75 (s, IH), 7.73 (s, IH), 3.95 (s, 3H), 3.92 (s, 3H), 1.33 (s, 9H).

[00366] Methyl 5-tert-butyl-3-cyano-2-methoxybenzoate (G). To a solution of 5-tert- butyl-2-methoxy-3-bromobenzoic acid methyl ester (0.15 g, 0.5 mmol) in a 1:1 DMF/dioxane

(5 ml) mixture, KCN (65 mg, 1 mmol), Pd(OAc) 2 (12 mg, 10 mol%), CsCO 3 (0.49 g, 1.5 mmol) and BINAP (62 mg, 20 mol%) were added. The mixture was stirred at 1500C for 40 miή. in the microwave, filtered over Celite, and the solids were washed with DCM. The filtrate was concentrated and the residue purified on reverse phase using 50-99% ACN in water to give the intermediate cyano ester (49 mg, 40%) as a pale yellow solid. 1H-NMR (500

MHz, CDCl3) 6 (ppm) 8.00 (s, IH), 7.72 (s, IH), 4.04 (s, 3H), 3.94 (s, 3H), 1.32 (s, 9H). [00367] 5-tert-Butyl-3-cyano-2-methoxybenzoic acid (H). To a solution of 5-tert-

butyl-2-methoxy-3-cyanobenzoic acid methyl ester (40 mg, 0.16 mmol) in 1:1 THFTMeOH (1 ml) mixture, 2N NaOH (0.35 ml) was added. The mixture was stirred at r.t. for 1 hr, neutralized with IN HCl and extracted with approx. 20 ml of EtOAc. The organic layer was dried over MgSθ 4and concentrated to give intermediate H (quantitative) as a white solid which was used in the next step without further purification.

[00368] Heterocyclylbenzoic acid derivatives (I). Method A. (method as described in WO00/55153) and exemplified for morpholino derivatives. Step 1. 3-Fluoro-5- morpholinobenzoπitrile (X = F). A mixture of 3,5-difluorobenzonitrile (5.00 g,

35.95 mmol, 1.0 eq.)5morpholine (22.0 ml, 7.0 eq.) and anhydrous DMSO (7.5 ml) was heated to 60-650C for 24 hr. After cooling, the mixture was diluted with chloroform (100 ml) and washed with water (500 ml). The organic layer was dried (Na SO ), concentrated and dried in HV to give 3-fluoro-5-morpholinobenzonitrile as a white solid (7.02 g, 94% yield, 99% pure by LC-MS). (CaIc. mass: 207, obs. mass: 248 (M +AcN)+).

[00369] Step 2. 3-Fluoro-5-morpholinobenzoic acid (X=F) (I-a). A mixture of the compound obtained above (4.93 g, 23.92 mmol) and 6 M aq. HCl (100 ml) was heated overnight to 1000C. After cooling to 00C, the mixture was carefully neutralized with 50% aq. NaOH solution until a solid precipitate formed (pH ~l-2). The solid was separated by filtration, washed with water, air-dried, and dried in HV to give 3-fluoro-5- morpholinobenzoic acid I-a as a white solid (4.79 g, 88% yield, 97% pure by LC-MS). (CaIc. mass: 225, obs. mass: 267 (M + AcN)+).

[00370] Method B. (3-Fluoro-5-morpholinophenyl)(morpholtno)methanone (X=F). Morpholine (4 ml, 46 mmol) was added to methyl 3,5-difluorobenzoate (2.53 g, 15 mmol) and the mixture was heated to 1600C for 5 days, providing a mixture of target compound (CaIc. mass: 225, obs. mass: 266.9) and the bis-morpholino derivative. (CaIc. mass: 295.0, obs. mass: 294.0). The reaction mixture was allowed to cool to r.t., 6 N aq. HCl was added (15 ml) and the mixture was heated at 125°C for 3 hr. After cooling to r.t. the reaction mixture was diluted with water (50 ml) and the pH was adjusted to 2 using aq. NaHCC«3. The precipitated product was filtered, washed with water and dried. A second crop of 3-fluoro-5- morpholinobenzoic acid I-a was recovered from the combined washes after a reduction of the volume. (CaIc. mass: 225, obs. mass: 267). 1H-NMR (500 MHz, DMSO-d ) δ (ppm) 13.15

(bs, IH), 7.285 (t, IH), 7.05 (d, IH) 5 7.03 (s, IH), 3.73 (t, 4H), 3.18 (t, 4H). [00371] The above methods were used for the synthesis of the following substituted benzoic acids:

[00372] 3-Fluoro-5-(piperidin-l-yl)benzoic acid (I-b). (Step 1 reaction temperature: 400C). CaIc. mass: 224, obs. mass: 224.

[00373] 3-Fluoro-5-(pyrrolidin-l-yl)benzoic acid (I-c). (Step 1 reaction temperature: r.t.). CaIc. mass: 210, obs. mass: 251.

[00374] 3-(2,6-Dimethylmorpholino)-5-fIuorobenzoic acid (I-d). (Step 1 reaction temperature: 700C). CaIc. mass: 254, obs. mass: 254.

[00375] 3-FIuoro-5-(l,4-oxazepan-4-yI)benzoic acid (I-e). (Step 1 reaction temperature: 1000C). CaIc. mass: 240, obs. mass: 240.

[00376] 3-Fluoro-5-thiomorpholinobenzoic acid (I-f). (Step 1 reaction temperature: 700C). CaIc. mass: 242, obs. mass: 283.

[00377] 3-Morpholino-5-(trifluoromethyl)benzoic acid (I-g). (Step 1 reaction temperature: 600C). CaIc. mass: 276, obs. mass: 317.

[00378] 3-(Piperidin-l-yl)-5-(trifluoromethyl)benzoic acid (I-h). (Step 1 reaction temperature: 400C). CaIc. mass: 274, obs. mass: 315.

[00379] 3-(Pyrrolidin-l-yl)-5-(trifluoromethyl)benzoic acid (I-i). (Step 1 reaction temperature: r.t.). CaIc. mass: 260, obs. mass: 301. [00380] Ethyl 3,5-difluoro-2-methoxybenzoate. To the mixture of 3,5-difiuoro-2- methoxybenzoic acid (18.8 g, 100 mmol) in EtOH (200 ml) in an ice-bath, was added SOCl (35.7 g, 300 mmol) dropwise. After the addition was complete, the reaction mixture was heated to reflux overnight. TLC was used to detect completion of the reaction. The mixture was evaporated to give ethyl 3,5-difluoro-2-methoxybenzoate as a white solid (21.5 g, 99.5%), which was used as such in the next step.

[00381] Ethyl 3-fluoro-2-methoxy-5-morpholin-4-ylbenzoate. The compound obtained above (10.5 g, 48.6 mmol) and morpholine (42.3 g, 486 mmol) were added to DMSO (50 ml). The resulting mixture was heated to 100°C for 24 hr. After the reaction mixture was cooled, water ( 150 ml) was added. The resulting mixture was extracted with

DCM and the organic phase was dried over anhydrous MgSO4 and evaporated. The residue was purified by column chromatography (EtOAc/PE = 1:9 (v:v)) to provide the unreacted ethyl 3,5-difiuoro-2-methoxybenzoate (8.0 g), ethyl 5-fluoro-2-methoxy-3-morpholin-4- ylbenzoate (535 mg, 3.89%) and ethyl 3-fluoro-2-rnethoxy-5-morpholin-4-ylbenzoate 1 δ (187mg, 1.36%). H-NMR (300 MHz, CDCl3) : (ppm) 7.02 - 7.04 (q, IH), 6.76 - 6.82 (dd, IH), 4.34 - 4.41 (q, 2H), 3.82 - 3.89 (m, 7H) 3.09 - 3.13 (m, 4H), 1.37-1.42 (t, 3H).

[00382] 3-Fluoro-2-methoxy-5-morpholin-4-ylbenzoic acid (J). To the mixture of ethyl 3-fluoro-2-methoxy-5-morpholin-4-ylbenzoate (1.3 Ig, 4.63 mmol) in 40 ml of MeOH/THF (v:v = 1:1) was added 6 ml of 2N NaOH solution. The resulting mixture was heated to 50°C for 2 hr. TLC was used to detect completion of the reaction. The solvent was evaporated and the water phase was extracted with EtOAc (20 ml). The water phase was acidified to pH = 5 and extracted by EtOAc. The organic phase was dried over anhydrous MgS θ 4 and evaporated to provide 3-fluoro-2-methoxy-5-morpholin-4-ylbenzoic acid 1 δ (800mg, 67.8%). H-NMR (300 MHz, DMSOd 6) (ppm) 13.05 (s, IH), 7.03 - 7.09 (dd,

IH) 5 6.92 - 6.93 (q, IH), 3.68 - 3.73 (m, 7H), 3.05 - 3.28 (t, 4H). (CaIc. mass: 255; obs. mass: 254.0).

[00383] Methyl 3-amino-5-tert-butyl-2-methoxybenzoate. To a solution of 5-tert- butyl-2-methoxy-3-nitro-benzoic acid (1.8 g, 7.1 mmol) (obtained as described in US2005/01 07399) and DMF (0.5 ml) in DCM (50 ml), oxalyl chloride (3.1 ml, 35.5 mmol) was added dropwise and the mixture was stirred at 2O0C for 16 hr. The solvent was evaporated and the residue was taken up in MeOH (50 ml). To this solution, a spatula of PdVC (10 wt. %) was added and the suspension was stirred at 200C under an H atmosphere for 60 hr. The mixture was filtered (Celite), the solid washed with MeOH and the filtrate evaporated to give the target compound (1.5 g, 90%) as a brown oil, which was used in the next step without further purification. (CaIc. mass: 237.3; obs. mass: 237.5).

[00384] Methyl S-tert-butyI-2-methoxy-3-methylsulfonamido)-benzoate. To a solution of the compound obtained above (1.5 g, 6.3 mmol) and TEA ( 1.3 ml, 9.5 mmol) in DCM (10 ml), methanesulfonyl chloride (0.74 ml, 9.5 mmol) was added dropwise and the 0 mixture was stirred at 20 C for 16 hr. The mixture was washed with H O5 dried (MgSO ), evaporated and the brown residue was chromatographed on silica gel (0-50% EtOAc in Hex) to give the target compound (1.1 g, 55%) as a white solid.

[00385] 5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzoic acid (K). A suspension of the compound obtained in step 3 (1.1 g, 3.5 mmol) in 6 N HCl (50 ml) was heated at 800C for 72 hr. The mixture was allowed to cool, the precipitate collected under suction, washed with H2O and dried to give intermediate K (0.83 g, 79%) as a white solid. [00386] (E)-Methyl 3-tert-butyl-5-(T>T-hydroxycarbamimdoyI)benzoate. Intermediate D (1.5 g, 6.90 nrmol), ammoniumhydroxide hydrochloride ( 1.679 g,

24.16 mmol), and NaHCO 3 (2.059 g, 24.51 mmol) were dissolved in MeOH (20 ml) and 2 drops of water were added. The mixture was stirred at r.t. overnight and 40 ml EtOAC was added. The organic layer was washed with NaHCO 3 and water, and evaporated. The residue was dried overnight in HV to yield 1.8032 g of target compound. (CaIc. mass: 250.3, obs. mass: 251).

[00387] (E)-Methyl 3-(N'-acetoxycarbamimidoyl)-5-tert-butylbenzoate. The compound obtained above ( 116 mg, 0.464 mmol) was dissolved in DCM ( 1.5 ml) and acetyl µ µ chloride (39.5 l, 0.556 mmol) and, DIEA (161.6 l, 0.928 mmol) were added. The solution was stirred at r.t. for 3 days, then diluted with DCM. The organic solution was washed with NaHCO and water, dried over Na SO , filtered and evaporated. The target compound was obtained in 115.3 mg yield (CaIc. mass: 292.3, obs. mass: 233).

[00388] Methyl 3-tert-butyl-5-(5-methyl-l,2,4-oxadiazoI-3-yl)benzoate. The compound obtained above ( 115.3 mg) was dissolved in dioxane (2 ml) and acetic acid (3 drops) was added. The reaction mixture was stirred at 100°C for 24 hrs, then at r.t. overnight. The dioxane was removed by evaporation, and the residue was purified by preparative HPLC, to afford 67.5 mg of the target compound (CaIc. mass: 274.3, obs. mass: 233).

[00389] 3-tert-Butyl-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzoic acid. The compound obtained in the previous step (67.5 mg, 0.246 mmol) was dissolved in a mixture of THF µ (1 ml), MeOH (1 ml) and H2O (0.2 ml), and 2N NaOH (246 l, 0.492 mmol) was added. The reaction was stirred at r.t. overnight, neutralized with 1 M HCl (pH ~ 7) and the solvent was evaporated. After drying in HV, 83.9 mg of the target material was obtained (containing NaCl).

[00390] 3-tert-butyl-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzoyl chloride (L). The compound obtained in the previous step (83.9 mg, 0.246 mmol) was dissolved in DCM (3 ml) and oxalyl chloride (208 µl, 2.46 mmol) was added, followed by a catalytic amount of DMF. The reaction was stirred at r.t. for 2 hr, and then evaporated. The residue was dried in HV and used as such in the next step.

F M [00391] 5-tert-Butyl-3-(lH-imidazol-l-yl)-2-methoxybenzoic acid (R=H) (M-a). A mixture of intermediate F (120.5 mg, 0.4 mmol), imidazole (68 mg, 1.0 mmol), N N- dimethylglycine (8.2 mg, 0.08 mmol), CuI (7.6 mg, 0.04 mmol) and K2CO3 (165.6 mg, 1.2 mmol) in DMSO (2 ml) was heated at 1200C for 64 hr. The reaction was filtered and purified via LC-MS to yield 40.9 mg of the desired product. (CaIc. mass: 274.3, obs. mass: 275.1).

[00392] 5-tert-Butyl-2-methoxy-3-(4-mthyI-lH-imidazoI-l-yl)-benzoic acid (R=Me) (M-b) was similarly prepared (CaIc. mass: 288.3, obs. mass: 289.1).

[00393] 3-tert-Butyl-5-(aIkyloxycarbonylamino)benzoic acid. To a solution of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid B (0.465 g, 2.0 mmol) in DCM (10 ml) was added oxalyl chloride ( 1 ml, 6 eq.) and 2 drops of DMF. The mixture was heated to 400C until homogeneous and then at r.t. for 2 hr. The solvent was evaporated, the residue dissolved in toluene and evaporated again to give the crude acid chloride derivative a. The compound was dissolved in toluene (12 ml) and excess sodium azide (600 mg, 9.2 mmol), catalytic tetrabutylammonium chloride (20 mg, 0.09 mmol), and water (3 ml) were added and the mixture was vigorously stirred. Progress of the reaction was followed by IR, by tracking of the disappearance of the COCl carbonyl stretch at 1752 cm" 1 . Typically the reaction took less then 60 min to completion. The aqueous layer was removed, the toluene layer was washed with water and dried with MgSO4. This toluene solution of the intermediate azide b was heated to 105°C until the evolving of gas seized. Progress of reaction was again monitored by IR, by monitoring the disappearance of the CO-N3 carbonyl stretch at 1688 cm 1 and N 3 at 2137 cm 1. To the toluene solution of the isocyanate obtained, the alcohol of interest was then added (e.g. MeOH or t-BuOH) and the reaction was heated until completion (for MeOH, to 8O0C, for t-BuOH to 1100C) as indicated by the disappearance of the NCO carbonyl stretch at 2253 cm 1 in the IR spectrum. The solution was evaporated, the residue dissolved in MeOH and 1 M aq. NaOH was added (3 ml). The mixture was heated for 2 hr at 6O0C. The MeOH was evaporated, and the solution was acidified with 1 M HCl (4 ml). The product was extracted into a DCM-EtOAc mixture, the organic layer was dried over MgSO4, and evaporated to give the target products, which were used without further purification.

[00394] Methyl 3-tert-butyl-5-(methoxycarbonylamino)benzoate (N-a) (Ri = R2 = 1 δ Me). H-NMR (500 MHz, CDCl3) (ppm) 7.81 (s, 2H), 7.75 (s, IH), 6.66 (bs, IH), 3.93 (s, 3H), 3.81 (s, 3H), 1.36 (s, 9H).

[00395] 3-tert-Butyl-5-(Methoxycarbonylamino)benzoic acid (N-b) (Ri = Me, 1 δ R2 = H). H-NMR (500 MHz, DMSO-d 6) (ppm) 7.88 (s, IH), 7.84 (s, IH), 7.28 (s, IH), 6.78 (bs, IH), 3.83 (s, 3H), 1.38 (s, 9H).

[00396] 3-(tert-Butoxycarbonylamino)-5-tert-butylbenzoic acid (N-c) (Ri = t-Bu, 1 δ R 2 = H). H-NMR (500 MHz, CDCl3) (ppm) 7.87 (s, IH), 7.84 (s, IH), 7.74 (bs, IH), 6.64 (bs, IH), 1.56 (s, 9H), 1.37 (s, 9H).

[00397] Methyl 3-amino-5-tert-butylbenzoate. Methyl 3-(tert- butoxycarbonylamino)-5-tert-butylbenzoate (Intermediate A-c) (1.14 g, 3.71 mmol) was dissolved in TFA and stirred for 10 min at r.t. The solvent was evaporated and the intermediate was suspended in a minimum amount of water. Sulfuric acid (250 µ\) was added and the mixture was cooled in an ice/water bath. An aqueous sodium nitrite solution (14.15 mmol dissolved in minimum amount of water) was added dropwise and the reaction was mixed at 00C for 30 min. The reaction mixture was added to boiling 10% aq. sulfuric acid (40 ml, 47.27 mmol) over 10 min, and after 20 min the reaction was allowed to cool down. The product was extracted into DCM. One half of the solution was purified by chromatography over silica gel in DCM - 5% MeOH, resulting in two fractions. A first fraction contains the target phenol only (yield, 150 mg), while a second fraction contains a mixture of the target phenol and the aniline intermediate (yield: 110 mg). 1H NMR δ (500 MHz, CDCl3) (ppm) 7.68 (t, IH), 7.34 (dd, IH), 7.10 (t, IH), 3.92 (s, 3H), 1.34 (s, 9H).

[00398] 3-tert-Butyl-5-hydroxybenzoic acid (O). Methyl 3-tert-butyl-5- hydroxybenzoate B (140 mg, 0.672 mmol) was dissolved in MeOH (3 ml) and 1 M aq. NaOH (1 ml, 1 mmol) was added. The reaction mixture was heated at 600C for 75 min and then allowed to stir at r.t. overnight. The mixture was acidified IM aq. HCl (2 ml) and the product was extracted into DCM/ The DCM layer was separated, dried over MgSO , and evaporated to yield 90 mg of the target compound. 1H NMR (500 MHz, DMF) δ (ppm) 13.06 (bs, IH), 9.75 (2, IH), 7.57 (t, IH), 7.35 (t, IH), 7.15 (t, IH), 1.30 (s, 9H).

[00399] Methyl 3-tert-butyl-5-methoxybenzoate. Methyl 3-tert-butyl-5- hydroxybenzoate B (190 mg, 0.912 mmol), K2CO3 (440 mg, 3.184 mmol) and MeI (456 mg, 3.21 3 mmol) were dissolved in acetone (5 ml) and heated at 800C for 24 hr. The reaction mixture was evaporated, and the residue was triturated with diethylether. The ether solution was evaporated to give the target product as a red oil, which was used in the next step without 1 δ purification. H NMR (500 MHz, CDCl3) (ppm) 7.71 (t, IH), 7.39 (dd, IH), 7.16 (dd, IH), 3.93 (s, 3H), 3.87 (s, 3H), 1.35 (s, 9H).

[00400] 3-tert-Butyl-5-methoxybenzoic acid (P). The compound obtained above was dissolved in MeOH (3 ml), 1 M aq. NaOH ( 1 ml) was added and the mixture was heated to 800C. Reaction completion was monitored by TLC. The solvent was evaporated, the residue was acidified with IM aq. HCl, and the product was extracted into DCM. The DCM solution was dried over MgSO4, filtered, and evaporated to yield 105 mg of the target compound. 1 δ H NMR (500 MHz, CDCl3) (ppm) 7.79 (t, IH), 7.45 (dd, IH), 7.21 (dd, IH), 3.89 (s, 3H), 1.36 (s, 9H). [00401] Methyl 5-tert-butyl-3-cyano-2-(2-methoxy-2-oxoethoxy)benzoate. In a 50 ml round-bottomed flask were placed methyl 5-tert-butyl-3-cyano-2-methoxybenzoate (3.16 g, 12.8 mmol) (obtained as above) and DCM (10 ml) with magnetic stirring. To this was added a IM BBr3 solution in DCM (12.3 ml) and the reaction was stirred for 1 hr at r.t. The reaction was quenched with water,and the organic layer was separated. The aqueous layer was extracted with DCM and the combined layers were dried over Na SCv The solvent was removed, the crude material was dissolved in acetone and treated with methyl bromoacetate

(3.85 ml, 42 mmol), K2CC>3 (5.80 g, 42 mmol), and the reaction mixture was heated at reflux for lhr. The solvent was removed in vacuo and the residue was purified on silica gel, eluting with 0-30% EtOAc/Hex to afford 1.552 g (40% yield) of methyl 5-tert-butyl-3-cyano-2-(2- 1 δ methoxy-2-oxoethoxy)benzoate. H NMR (500 MHz5 CDCl3) (ppm) 8.04 (d, J 2.5 Hz, IH), 7.74 (d, = 2.5 Hz, IH), 4.79 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 1.33 (s, 9H).

[00402] Methyl 5-tert-butyl-3-cyano-2-(2-hydroxyethoxy)benzoate. In a 250 ml round-bottomed flask in an ice bath were placed the compound obtained above (1.55 g, 5.08 mmol), THF (10 ml) and MeOH (10 ml). To this stirred mixture was added 2M NaOH (2.80 ml, 5.59 mmol). After 30 min 2M HCl ( 1.53 ml) was added and the solvent was removed in vacuo. The residue was diluted in THF (100 ml) and further 2M HCl (1.27 ml) was added. The solvent was concentrated so that only water remained. EtOAc (50 ml) was added and the organic layer was separated and dried over Na SO4 to afford 1.56 g of 5-tert- butyl-3-cyano-2-(2-methoxy-2-oxoethoxy)benzoic acid. This acid was dissolved in THF (70 ml) in a 250 ml round-bottomed flask and treated with carbonyldiimidazole (1.05 g, 6.5 mmol). The reaction was stirred at r.t. for 2 hr after which time it was added to a solution of sodium borohydride (756 mg, 20 mmol) in water (50 ml) stirred in a 500 ml round- bottomed flask in an ice bath. The organic solvents were removed in vacuo after 1 hr stirring in the ice bath. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na SO , the solvent removed in vacuo and the residue purified on silica gel eluting with 0-50% EtOAc/Hex to afford 364 mg of methyl 5-tert-butyl-3-cyano-2-(2- 1 δ hydroxyethoxy)benzoate (26 % yield). H NMR (500 MHz, CDCl3) (ppm) 8.04 (d, J =

3.0 Hz5 IH), 7.74 (d, J = 3.0 Hz, IH), 4.45 (t, J = 4.0, 2H), 3.94 (s, 3H) 3.93 (t, J = 4.0 Hz,

2H) 5 1.33 (s, 9H). [00403] Methyl 5-tert-butyl-3-cyano-2-(2-(4-methylpiperazin-l-yI)ethoxy)benzoate. In a 50 ml round-bottomed flask were placed methyl 5-tert-butyl-3-cyano-2-(2- hydroxyethoxy)benzoate (364 mg, 1.31 mmol) and DCM (3 ml). To this reaction was added Dess-Martin reagent (668 mg, 1.58 mmol). The reaction was capped and stirred at r.t. for θ 25 min. The reaction mixture was treated with saturated NaHCO 3 (5 ml) and IM Na2S2 3 (5 ml) and stirred for 15 min. The reaction was diluted with DCM (20 ml) and extracted with DCM. The combined org'anic layers were dried over Na SO . The solvents were removed and concentrated to ~8 ml. Half of the solution was placed in a 16mm test tube and treated with acetic acid (728 µl, 13.1 mmol) followed by N-methyl piperazine (131 µl, 1.31 mmol), and then sodium triacetoxyborohydride (277 mg, 1.31 mmol). After stirring 18 hr additional sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added. After stirring for an additional 5 hr the reaction was quenched with saturated Na CO and the mixture was diluted with DCM (20 ml). The aqueous layer was extracted with DCM (5 ml) and the combined organic layers were dried over Na SO . The solvent was evaporated and the residue was purified on silica gel, eluting with 0-20% MeOH/DCM to afford 76 mg (32% yield) of methyl 5-tert-butyl-3-cyano-2-(2-(4-methylpiperazin-l-yl)ethoxy)benzoate. (CaIc. mass: 359.2; obs. mass: 359.0).

[00404] 5-tert-Butyl-3-cyano-2-(2-(4-methylpiperazin-l-yl)ethoxy)benzoic acid (Q). In a 50 ml round-bottomed flask in an ice bath were placed methyl 5-tert-butyl-3-cyano-2-(2- (4-methylpiperazin-l-yl)ethoxy)benzoate (76 mg, 0.21 mmol) and MeOH (3 ml), followed by 2 M NaOH (189 µl, 0.38 mmol). After stirring 2.5 hr in an ice bath the reaction was heated to 600C for 1.5 hr during which time the solvent evaporated. The residue was suspended in THF (5 ml), and treated with 2N HCl (189 µl), and the solvent was evaporated to afford the target compound which was used without further purification. (CaIc. mass: 345.2; obs. mass: 345.0).

[00405] 3-tert-Butyl-5-(chlorosulfonyl)benzoic acid. 3,5-Di-tert-butylbenzoic acid

(1273 g, 5.43 mmol) was dissolved in ClSO3H (5 ml, 75.22 mmol) at r.t.. The mixture was stirred at 1000C for 150 min, poured on ice and the resulting mixture was centrifuged. The water layer was decanted, the solid was washed with water and dried to give the target compound ( 1.3 g).

[00406] 3-tert-Butyl-5-(N-methylsuIfamoyl)benzoic acid (R=H, Me) (R-a). The intermediate compound (0.26 g, 0.94 mmol) was dissolved in a 2 M solution of methylamine in THF (4 ml, 8 mmol) at r.t. (alternatively, an EtOH solution of the amine can be added to a THF solution of the intermediate compound). The mixture was stirred for 30 min. and evaporated. The residue was dissolved in DCM, which was washed with IM aq. HCl, and dried over anhydrous MgSO4 filtered and evaporated, to give the target product in 220 mg 1 δ yield. H NMR (500 MHz, CDCl3) (ppm) 8.31 (m, 2H), 8.13 (m, IH), 7.56 (m, IH) 3 2.57 (s, 3H), 1.40 (s, 9H).

[00407] 3-tert-Butyl-5-(N,N-dimethylsulfamoyl)benzoic acid. (R=Me, Me) (R-b). - 3-tert-Butyl-5-(chlorosulfonyl)benzoic acid (0.26 g, 0.94 mmol) was dissolved in a 2 M solution of dimethylamine in THF (4 ml, 8 mmol) at r.t.. The mixture was stirred for 30 min. and evaporated. The residue was dissolved in DCM, which was washed with IM aq. HCl, and dried over anhydrous MgSO filtered and evaporated, to give the target product in 220 mg yield. [00408] Methyl 3-azido-5-tert-butyl-2-methoxybenzoate. Methyl 3-amino-5-tert- butyl-2-methoxybenzoate (0.387 mg, 1.6 mrnol) was dissolved in 10% H2SO4 (10 ml) and 0 cooled to O C. To this mixture NaNO 2 (159 mg, 2.31 mmol) and NaN 3 (202 mg, 3.1 1 mmol) were added, and the reaction mixture was allowed to warm to r.t. After 30 min, the mixture was extracted with DCM and the organic layer was dried over Na SO , filtered and 1 δ evaporated to afford 0.361 g of the target compound. H NMR (500 MHz, CDCl3) (ppm) 7.55 (d, J = 2.5, IH), 7.18 (d, J = 2.5, IH), 3.93 (s, 3H), 3.89 (s, 3H), 1.31 (s, 9H).

[00409] 3-Azido-5-tert-butyl-2-methoxybenzoic acid (S). The compound obtained above (0.264 mg, 1.00 mmol) was dissolved in MeOH (3 ml). A 2 N solution of NaOH (0.6 ml, 1.20 mmol) was added, and the reaction was heated to 500C for 90 min. The solvents were evaporated and the residue was diluted with THF and treated with 2 N HCl (0.6 ml). The solvents were evaporated, the residue dissolved in EtOAc and dried over

Na2SO4ZMgSO4.

[00410] Heterocyclylisonicotinate derivatives (T). Step 1. tert-Butyl 2- chloroisonicotinate. To a solution of 2-chloroisonicotinic acid (2.36 g, 15 mmol) in DCM (40 ml) and THF (10 ml) was added oxalyl chloride (6.5 ml) followed by addition of one drop of DMF. The mixture was stirred at r.t. for 3 hr before evaporation of solvent. The freshly made acid chloride was dissolved in THF (40 ml) and cooled to 4°C. After addition of a solution of potassium -butoxide (3.4 g, 30 mmol) in THF (10 ml), the reaction mixture was slowly warmed up to r.t. and stirred overnight. The dark red suspension was evaporated and the residue was partitioned between DCM and water. The organic phase was washed with aqueous sodium bicarbonate. The DCM phase was dried over Na2SO4 and evaporated to give 1.658 g of tert-butyl 2-chloroisonicotinate as a red oil (purity ca. 90%), which was used in the 1 δ next step without further purification. H NMR (500 MHz, DMSO-d 6) (ppm) 8.62 (d, IH), 7.81 (s, IH), 7.79 (d, IH), 1.52 (s, 9H).

[0041 1] Step 2. tert-Butyl 2-morpholinoisonicotinate. A solution of tert-butyl 2- r. W ni r n nate f427 mg, 2 mmol) and morpholine (5.2 ml, 60 mmol) in DMSO ( 1 ml) was heated at 800C for 60 hr. Morpholine was evaporated and the residue was dissolved in EtOAc/ aqueous NaHCU3. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, and dried over Na2SO4. After evaporation the crude product was subjected to silica gel column chromatography (40 g silica gel column) using DCM/EtOAc as eluents. t-Butyl 2-morpholinoisonicotinate was isolated as a thick brown oil δ (525 mg, purity >95%). 1H NMR (500 MHz, DMSO-d6) (ppm) 8.24 (d, IH), 7.18 (s, IH), 7.00 (d, IH), 3.74 (t, 4H), 3.52 (t, 4H), 1.54 (s, 9H).

[00412] Step 3. 2-Morpholinoisonicotinic acid (T-a). A mixture of t-butyl 2- morpholinoisonicotinate (525 mg) in 4N HCl dioxane solution (3 ml) and water (0.5 ml) was stirred overnight at r.t.. After evaporation of dioxane and water the solid residue was dried at 8 O0C under vacuum to give a pale yellow solid (421 mg). LC-MS showed the target compound as a major component (purity >90%). The crude product was used without further purification. (CaIc. mass: 208, obs. mass: 209).

[0041 3] Using similar procedures as illustrated for preparation of T-a, the following compounds were made:

[00414] 2-(Pyrrolidin-l-yl)isonicotinic acid (T-b). CaIc. mass: 192, obs. mass: 193.

[00415] 2-(Piperidin-l-yl)iso ήicotinic acid (T-c). CaIc. mass: 206, obs. mass: 207.

Aniline intermediates

[00416] 3-Amino-5-tert-butyl-2-methoxybenzonitrile (AA). To a suspension of 5-tert- butyl-2-methoxy-3-nitrobenzamide (prepared as described in US20050107399) (125 mg, µ 0.5 mmol) in 4 ml chloroform was added a solution of POCI3 (69 l, 0.75 mmol) in 0.5 ml chloroform. After stirring at r.t. for 3 hr, the reaction mixture was cooled to 00C, and TEA (500 µl) was added. The resulting mixture was stirred at r.t. overnight, and poured into 20 ml of 1 N HCl. The compound was extracted into chloroform. After washing with water, the organic phase was concentrated to give 160 mg of the crude intermediate as a brown solid. This intermediate was stirred with tin(II) chloride dihydrate (678 mg, 3 mmol, 6 eq.) in 4 ml DMF overnight at r.t. Preparative reverse phase HPLC purification furnished the title product (98 nag) as a brown solid. (CaIc. mass: 204.3; obs. mass: 245.9 (M+41)). (Purity >95%).

[00417] Step 1. tert-Butyl-S-tert-butyl-S-cyanophenylcarbamate. To a solution of 3-tert-butyl-5-cyanobenzoic acid H ( 1.0 g, 4.9 mmol, prepared as above) in t-BuOH, DPPA (1.4 ml, 6.4 mmol) and NMM (slight excess) were added. The mixture was stirred at reflux overnight, extracted with DCM, the organic layer was washed with brine, dried (MgSO-O evaporated. The residue was purified by chromatography on silica gel (gradient: 5 to 100% EtOAc in Hex). (CaIc. mass: 274.4, obs. mass: 275.1).

[00418] Step 2. 3-Amino-5-tert-butylbenzonitrile. (BB) To a solution of the compound obtained above in DCM (10 ml), TFA ( 1.5 ml) was added and the mixture was stirred at r.t. overnight. The solvent was evaporated and the residue used in the next step without further purification. (CaIc. mass: 174.2, obs. mass: 215.8 (M+AcN) +).

EE 3-Amino-5-morpholinobenzonitrile (CC). 3-Fluoro-5-nitrobenzonitrile (350 mg, 2.11 mmol) was treated with morpholine ( 1 ml) in a 40 ml vial. The reaction was capped and stirred at 700C overnight. The solvent was evaporated and the residue triturated twice with MeOH. The residue was suspended in DMF (0.5 ml), treated with tin chloride dihydrate (2.38 g, 10.5 mmol) and heated at 750C for 40 min. The reaction was quenched θ with saturated Na CO (7 ml) and solid Na2C 3 (3 g). The organic layer was diluted with DCM, filtered, washed with saturated Na Cθ 3 and dried over solid anhydrous Na SO . The solvents were removed and the residue was purified on silica gel to afford the target 1 δ compound (282 mg, 65%). HNMR (500 MHz, acetone-d 6) (ppm) 6.53 (s, IH), 6.52 (s, IH), 6.45 (s, IH), 3.75 (t, J = 5.0 Hz, 4H), 3.123 (t, J = 5.0 Hz, 4H), 2.73 (s, 2H). [00420] 3-Amino-5-(piperidin-l-yI)benzonitrile (DD) was prepared under the same conditions as above, using piperidine as the amine component. 1H NMR (500 MHz, δ 10% CD3OD/CDC13) (ppm) 6.47 (dd, J = 2.5 and 1.0 Hz, IH), 6.34 (t, J = 2.0 Hz, IH), 6.30 (t, J = 1.5 Hz, IH), 3.40 (bs, 2H), 3.05 (t, J =l l Hz, 4H), 1.58 (q, J = 6.0 Hz, 4H), 1.50 (m, 2H).

[00421] 3-Amino-5-(pyrrolidin-l-yl)benzamide (EE). The same conditions as above starting from pyrrolidine as the amine component resulted in formation of the corresponding 1 δ pyrrolidine benzamide derivative. H NMR (500 MHz, CD3OD/CDCI 3) (ppm) 6.37 (t, J = 1.5 Hz, IH), 6.34 (t, J = 1.5 Hz, IH), 3.5 (bs, 4H), 3.19 (q, J = 3.5Hz, 4H), 1.91 (q, J = 3.5 Hz, 4H).

Central Core Intermediates

a [00422] 2-Methyl-5-nitro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine salt (a). In a 40 ml vial were placed bis(pinacolato)diboron (687 mg, 2.72 mmol), Pd(dppf)2 (94 mg, 0.115 mmol), 3-bromo-2-methyl-5-nitropyridine (500 mg, 2.30 mmol) and anhydrous potassium acetate (733 mg, 7.48 mmol). DMSO (7 ml) was added, the vial was flushed with nitrogen, capped and stirred magnetically at 8O0C for 3h. The reaction mixture was partitioned between DCM and water and the mixture was filtered to remove the solids. The solids were washed with DCM and the organic layer was collected, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified on silica gel, eluting with 0-30% EtOAc/Hex to afford 336 mg (37% yield) of the 2-methyl-5-nitro-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine as a boronate salt. 1H NMR (500 MHz) δ (ppm) 9.32 (d, J = 3.0 Hz, IH), 8.80 (d, J = 3.0 Hz, IH), 2.88 (s, 3H), 1.38 (s, 6H), 1.27 (s, 6H), 1.26 (s, 6H), 1.24 (s, 6H). [00423] 3-Azido-2-methyl-5-nitropyridine (b). tert-Butyl 2-methyl-5-nitropyridin-3- ylcarbamate (2.03 g, 8.00 mmol), or alternatively, 2-methyl-5-nitropyridin-3 -amine (1.23 g,

8.00 mmol), and 12 M aq. HCl (5.84 ml) were stirred at r.t. for 10 min. H2O (29.2 ml) was added and the yellow solution was cooled to 00C. A solution of sodium nitrite (662 mg, 9.60 mmol, 1.2 eq.) in H O (2.66 ml) was added dropwise and the mixture was stirred at 00C for 8 min. Then a solution of sodium azide (572 mg, 8.8 mmol, 1.1 eq.) in H O (2.66 ml) was added dropwise at 00C and the mixture was allowed to warm up to r.t. within 4 h. Solids were removed by filtration, the filtrate was neutralized with sat. aq. NaHCO solution, and the product was extracted with DCM. The organic layers were dried (Na2SO.*) and concentrated to give 3-azido-2-methyl-5-nitropyridine (1.335 g, 93% yield, 97% pure by LC- MS —no mass detected) as a volatile yellow liquid that crystallized upon cooling. 1H-NMR (500 MHz, DMSO-d ) δ (ppm) 9.03 (d, J = 2.3 Hz, IH), 8.36 (d, J = 2.3 Hz, IH), 2.48 (s, 3H).

[00424] Ethyl 5-azido-6-methylnicotinate (c). A mixture of ethyl 5-(tert- butoxycarbonylamino)-6-methylnicotinate (obtained as in International application PCT/US06/042679) (643 mg, 2.29 mmol, 1.0 eq.) and 12 M aq. HCl (2.0 ml) was stirred at r.t. for 30 min. Water ( 10.0 ml) was added and the solution was cooled to 00C. A solution of sodium nitrite (194 mg, 2.81 mmol, 1.2 eq.) in water (783 µl) was added dropwise and the mixture was stirred at 00C for 7 min. Then a solution of sodium azide (168 mg, 2.58 mmol, 1.1 eq.) in water (783 µl) was added dropwise at 00C and the mixture was allowed to warm up to r.t. within 3 hr. The solids were removed by filtration, the filtrate was neutralized with sat. aqueous NaHCC>3 solution and the product was extracted with DCM. The organic layers were dried (Na SO4) and concentrated to give c (460 mg, 97% yield, 90% pure by LC-MS) as an oil, which was used without purification in the next step. (CaIc. mass: 206, obs. mass: 1 δ 192). H NMR (500 MHz, DMSOd 6) (ppm) 8.75 (d, IH, J = 1.8 Hz), 7.99 (d, IH, J = 1.8 Hz), 4.38 (q, 2H, J = 7.1 Hz), 2.44 (s, 3H), 1.35 (t, 3H, = 7.1 Hz).

[00425] Ethyl S-amino- -methylnicotinate. Ethyl 5-(tert-butoxycarbonylamino)-6- methylnicotinate (841 mg, 3 mmol) was added to a solution of TFA (9.5 ml) and water (0.5 ml) and the solution was stirred at r.t. for 65 min. The solvent was removed in vacuo and the residue was dried in HV. A saturated aq. NaHCCb solution (30 ml) was added and the aqueous solution was extracted with DCM. The organic layer was separated, dried over Na SO , filtered, and cone in vacuo. The residue was dried in HV to yield 551 mg of the 1 δ target compound (CaIc. mass: 180.2, obs. mass: 181). H-NMR (DMSCMl6) (ppm) 8.21 (d, IH, J = 1.9 Hz), 7.44 (d, IH, J = 1.9 Hz), 5.39 (bs, 2H), 4.29 (q, 2H, J = 7.1 Hz), 2.33 (s, 3H), 1.31 (t, 3H, J = 7.1 Hz).

[00426] Ethyl 5-iodo-6-methylnicotinate (d). The compound obtained above was µ dissolved in a solution of cone. H SO4 (195 l) and water (3 ml) at r.t. Separately sodium nitrite (217 mg, 3.15 mmol) was dissolved in water (450 µl) and potassium iodide (598 mg, 3.6 mmol) and copper iodide (81.6 mg, .428 mmol) were dissolved in water (600 µl) with sonication. The compound solution was cooled to 0°C in an ice bath, and the sodium nitrite solution was added dropwise within 3 min. The mixture was stirred at 00C for 8 min, then µ more cone. H2SO (60 l, 1.103 mmol) was added. The mixture was added dropwise to the cold potassium iodide solution (00C, vigorous stirring), and a dark precipitate formed. The resulting mixture was allowed to warm up to r.t., was sonicated, and was quickly warmed up to 600C (10 min). The mixture was neutralized with saturated aq. NaHCO solution, and

Na2SO was added to remove iodine. The precipitated solid was filtered, washed with water, DCM, and the filtrate was extracted with DCM. The organic layers were washed with aq.

Na SO3 solution., dried over Na SO4, concentrated in vacuo, and dried in HV to yield 681.7 mg of a dark solid, which was purified by silica gel chromatography (Gradient: 0-20% EtOAc/ DCM), to afford the target product as a white crystalline solid.. (CaIc. mass: 291.09, 1 δ obs. mass: 292). H-NMR (DMS0-d 6) (ppm) 8.92 (d, IH, J = 1.9 Hz), 8.55 (d, IH, J 1.9 Hz), 4.34 (q, 2H, J = 7.1 Hz), 2.72 (s, 3H), 1.34 (t, 3H, J = 7.1 Hz).

Example 1: Synthesis of Target Compounds of Formula I. Route A: Via coupling of G-C(O)OH -to the protected core template.

[00427] N-(5-Bromo-6-methylpyridin-3-yl)-3-tert-butyl-5-cyanobenzamide. To the acid chloride F in DCM 15 ml), 2-methyl-3-bromo-5-nitropyridine (164.4 mg, 0.6 mmol) and DIEA (0.4 ml, 5 eq.) were added. The mixture was stirred overnight at r.t., filtered, washed with H2O, dried (over MgSO ) and concentrated. The resulting product was used in 1 δ the next step without further purification. H-NMR (500 MHz, CDCl3) (ppm) 8.72 (d, J = 2.27 Hz, IH), 8.55 (d, J = 2.21 Hz, IH), 8.26 (t, J = 1.79 Hz, IH), 8.10 (t, J = 1.54 Hz, IH), 7.83 (t, J = 1.61, IH), 2.65 (s, 3H), 1.37 (s, 9H).

[0042 8] Methyl 3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3- yl)benzoate (2). A mixture of the N-(5-bromo-6-methylpyridin-3-yl)-3-tert-butyl-5-

cyanobenzamide (135 mg, 0.4 mmol), toluene (2.7 ml), DMF (0.3 ml), K2CO3 (284 mg, 2 mmol), Pd(dppb)Cl2 (8.2 mg, 0.01 mmol) and 3-(methoxycarbonyl)phenylboronic acid (100 mg, 0.6 mmol) was heated at 1500C for 10 min under microwave irradiation. The suspension was filtered (celite) and the solids were washed with DCM. The filtrate was

concentrated and the residue was purified by RP-HPLC (gradient of 30 to 99% AcN in H2O).

A second purification was performed by RP-HPLC (gradient of 35 to 50% AcN in H2O) to yield the target compound in sufficient purity. (CaIc. mass: 428, obs. mass: 428).

[00429] 3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)benzoic acid. To a solution of the benzoate obtained above (129 mg, 0.3 mmol) in THF/MeOH (10 ml, 1-n T C4mπ was added. The mixture was stirred at r.t. overnight, neutralized with IN HCl and evaporated. The obtained product was used in the next step without further purification. (CaIc. mass: 414, obs. mass: 414).

[00430] 3-tert-Butyl-5-cyano-N-(6-methyl-5-(3-(neopentylcarbamoyl)phenyl)- pyridin-3-yl)benzamide. To a solution of the above acid (85 mg, 0.2 mmol) in DCM/DMF (6 ml, 1:1) neopentyl amine (0.15 ml, 1.3 mmol), PyBOP (245.4 mg, 0.5 mmol) and DIEA (0.2 ml, 1.2 mmol) were added. The mixture was stirred at r.t. and monitored by LC-MS until complete. The solvent was evaporated and the residue subjected to RP- HPLC (gradient:

35 to 50% AcN in H2O) to give the product (24.8 mg) as a pale yellow solid. (CaIc. mass: 483 obs. mass: 484).

[0043 1] N-(5-(4-(Beftzyloxy)phenyI)-6-methylpyridin-3-yl)-3-tert-butyl-5- cyanobenzamide. In a glass vial N-(5-bromo-6-methylpyridin-3-yl)-3-tert-butyl-5- cyanobenzamide (20 mg, 0.05 mmol) (obtained as above), 4-(benzyloxy)phenylboronic acid

(12.3 mg, 0.05 mmol), K2CO3 (20 mg, 0.15 mmol), and Pd(dppb)Cl2 (1.5 mg, 0.0025 mmol) were added. Anhydrous toluene ( 1 ml) and anhydrous DMF ( 1 ml) were then added. The reaction mixture was purged with nitrogen and then sealed. The sealed tube was heated to 800C and stirred for 12 hr. The reaction was concentrated and the residue was purified via LC-MS to yield 1lmg of the target product. (CaIc. mass: 475, obs. mass: 476).

[00432] 3-tert-Butyl-5-cyano-N-(5-(4-(3,3-dimethyl-2-oxobutoxy)phenyl)~6- methylpyridin-3-yl)benzamide In a glass vial N-(5-bromo-6-methylpyridin-3-yl)-3-tert- butyl-5-cyanobenzamide (20 mg, 0.05 mmol), 3,3-dimethyl-l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)butan-2-one (16 mg, 0.05 mmol), K2CO3 (20 mg, 0.15 mmol), and Pd(dppb)Cl2 (1-5 mg, 0.0025 mmol) were added. Anhydrous toluene ( 1 ml) and anhydrous DMF (1 ml) were then added. The reaction mixture was purged with nitrogen and then sealed. The sealed tube was heated to 800C and stirred for 12 h. The reaction was concentrated and the residue was purified via LC-MS to yield 8 mg of the target product. (CaIc. mass: 427, obs. mass: 428).

[00433] 4-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylpyridin-3-yl)phenyl acetate. In a glass vial N-(5-bromo-6-methylpyridin-3-yl)-5-tert-butyl-2-methoxybenzamide, 4-acetoxyphenylboronic acid (9 mg, 0.05 mmol) (obtained by the methods described above) ρ (19 mg, 0.05mmol), K2CO3 (20 mg, 0.15 mmol). and Pd(dp b)Cl 2 (1.5 mg, 0.0025 mmol) was added. Anhydrous toluene ( 1 ml) and anhydrous DMF ( 1 ml) were then added. The reaction mix was purged with nitrogen and then sealed. The sealed tube was heated to 800C and stirred for 12 h. The reaction was concentrated and purified via LC-MS to yield 13 mg of product (CaIc. mass: 432, obs. mass: 433).

Route B : Via cross-coupling of L2-Q to the protected core template.

[00434] 3-(4-Methoxyphenyl)2-methyl-5-nitropyridine. A mixture of 2-methyl-3- bromo-5-nitropyridine ( 115.3 mg, 0.5 mmol), 2-methyl-4-methoxyphenyl-boronic acid

(91.2 mg, 0.5 mmol), Pd(dppb)Cl 2 (16.3 mg, 0.03 mmol) and K2CO3 (359 mg, 2.6 mmol) in toluene/DMF (4 ml, 9:1) was heated at 1500C for 10 min under microwave irradiation. The mixture was filtered (celite), the solids were washed with DCM and the filtrate was concentrated. The residue was chromatographed on silica gel using Hex/EtOAc (gradient: 0 to 80% EtOAc) as eluents to afford the target compound. 1H-NMR (500 MHz, δ CD3OD) (ppm) 9.27 (d, J = 2.59 Hz, IH), 8.28 (d, J = 2.62 Hz, IH), 7.09 (d J = 8.37 Hz, IH), 6.94 (d, J = 2.56 Hz, IH), 6.89 (dd, J = 2.64 and 8.00 Hz, IH), 3.85 (s, 3H), 2.41 (s, 3H), 2.07 (s, 3H). [00435] 5-(4-Methoxy-2-methylphenyl)-6-methoxypyridin-3-amine. To a solution of the nitropyridine obtained above in MeOH, a spatula of Pd/C (10 wt. %) was added and the suspension stirred at r.t. under H atmosphere overnight. The mixture was filtered (celite), the solid was washed with MeOH and the filtrate was evaporated to give the target compound, which was used in the next step without further purification.

[00436] 3-tert-butyl-5-cyano-N-(5-(4-methoxy-2-methyIphenyl)-6-methylpyridin-3- yl)benzamide. A solution of the compound obtained above (85.6 rag, 0.2 mmol), 3-tert- butyl-5-cyanobenzoic acid E (40.6 mg, 0.2 mmol), PyBOP (2eq.) and DIEA (5eq.) in DCM was stirred at r.t. overnight. The mixture was concentrated and the residue was chromatographed on silica gel (Hex/EtOAc, gradient: 0 to 100%), followed by RP-HPLC (gradient: AcN/ H O, 10 to 95%) to give the target product as a pale yellow solid (5.9 mg). (CaIc. mass: 414, obs. mass: 414).

[00437] Methyl 4-(2-methyI-5-nitropyridin-3-yl)benzoate. Method A. In a 40 ml vial with a magnetic stir bar were placed 4-carboxymethylphenyl boronic acid (414 mg, 2.30 mmol), 3-bromo-2-methyl-5-nitropyridine (500 mg, 2.30 mmol) and tetrakϊs(triphenylphosphine) palladium(O) (664 mg, 0.58 mmol). Dimethoxyethane (18 ml), toluene (2 ml) and EtOH (2 ml) were added, and the solution was sonicated until the solids were dissolved. A 2M Na COs solution (3.6 ml) was added while stirring rapidly under N . The vial was capped and stirred at 900C for 7 h. The solvents were removed in vacuo and the residue was partitioned between H2O and DCM. The organic layer was extracted with DCM and dried over Na SO4. The solvents were removed and the residue was purified on silica gel chromatography eluting with 0-50% EtOAc/Hex to afford 381 mg (61% yield) of methyl 4- (2-methyl-5-nitropyridin-3-yl)benzoate. (CaIc. mass: 272, obs. mass: 314 (M + AcN)+). [00438] Method B. A mixture of 3-bromo-2-methyl-5-nitropyridine ( 100 mg, 0.5 mmol), 4-carboxymethylphenyl boronic acid (90 mg. 0.5 mmbl), Pd(dppb)Cl (10 mol%) 0 and K2CO3 (3 eq.) in toluene/DMF (2 ml, 9:1) was heated at 135 C for 5 hr under microwave irradiation. The mixture was filtered (celite), the solids were washed with DCM and the filtrate was concentrated. The residue was chromato graphed on silica gel, eluting with EtOAc/Hex (gradient: 0-50%) to afford the target compound. (CaIc. mass: 272, obs. mass: 314 (M + AcN)+).

[00439] Methyl 4-(5-amino-2-methylpyridin-3-yl)benzoate. In a 40 ml vial were placed methyl 4-(2-methyl-5-nitropyridin-3-yl)benzoate (380 mg, 1.40 mmol), EtOAc θ (10 ml) and SnC.2 2H2 ( 1.58 g, 7 mmol). The vial was capped and the mixture was stirred magnetically at 6 O0C for Ih. The reaction was quenched with saturated NaHCO3 and EtOAc. The organic layer was basified to pH 11 with 1 M NaOH and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na SO4, the solvent was removed and methyl 4-(5-amino-2-methylpyridin-3-yl)benzoate residue (369 mg) was used without further purification. (Cafc. mass: 242, obs. mass: 243).

[00440] Methyl 4-(5-(3-tert-butyl-5-cyanobenzamido)-2-methyIpyridin-3- yl)benzoate. In a 50 ml round-bottomed flask were placed 3-tert-butyl-5-cyanobenzoic acid E (95 mg, 440 µmol) suspended in DCM (2 ml) and DMF (one drop). Oxalyl chloride (2 ml of a 2 M solution) was added and the reaction was allowed to sit overnight. The solvent was removed in vacuo and the residue was coevaporated from DCM and THF. The obtained acid chloride I, dissolved in DCM, was added to a solution of methyl 4-(5-amino-2- methylpyridin-3-yl)benzoate (149 mg, 0.61 mmol) and NMM (87 µl) in DCM (total volume, 15 ml) After 2 hr the solvent was removed and the residue was purified on silica gel eluting with 0-100% ethyl acetate/hexanes to afford 177 mg (95% yield) of the target product. 1 δ H NMR (500 MHz, CDCl3) (ppm) 8.78 (s, IH), 8.36 (bs, IH), 8.28 (s, IH), 8.23 (s, IH), 8.15 (dd, = 2.5, 8 Hz, 2H), 8.03 (s, IH), 7.87 (s, IH), 7.47 (dd, J 2.5, 8 Hz, 2H), 3.98 (s, 3H), 2.53 (s, 3H), 1.39 (s, 9H).

[00441] 4-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)benzoic acid. The compound obtained above (177 mg, 0.41 mmol) was dissolved in MeOH (2 ml) and THF (2 ml) and treated with solid NaOH (48.3 mg, 1.2 mmol). The solution was heated to 500C for 3 hr, and then was allowed to stir overnight at r.t. The solvent was removed in vacuo and the residue was diluted with THF. The solution was treated with IM HCl ( 1.20 ml) and the solvent was removed in vacuo. The compound obtained was used without further purification. (CaIc. mass: 413, obs. mass: 414).

[00442] 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyI)- pyridin-3-yl)benzamide. The compound from the previous step was dissolved in DMF ( 1 ml) and treated with PyBOP (487 mg, 0.94 mmol) and HOBt (144 mg, 0.94 mmol). The reaction was treated with a solution of NMM (171 µl, 1.56 mmol) in DCM (3 ml), followed by addition of neopentylamine (72 µl, 0.61 mmol). The solution was stirred at r.t. for 4 hr, during which time the solution went from heterogeneous to homogeneous. The solvent was removed in vacuo and the residue was purified on silica gel, eluting with 0-70% EtOAc/Hex. The residue was lyophilized from dioxane/HzO to afford 90 mg (46% yield over two steps) of 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide as a white fluffy powder. (CaIc. mass: 482; obs. mass: 484).

[00443] 4-(2-Methyl-5-nitropyridin-3-yl)benzoic acid (Y). To a solution of methyl 4- (2-methyl-5-nitropyridin-3-yl)benzoate (132 mg, 0.5 mmol) (obtained as above) in THF/MeOH (20 ml, 1:1) 2N NaOH (2 eq.) was added and the mixture was stirred at r.t. overnight. The mixture was neutralized with IN HCl, concentrated and used in the next step without further purification. (CaIc. mass: 258, obs. mass: 300 (M + AcN)+).

[00444] 4-(2-Methyl-5-nitropyridin-3-yl)-N-neopentylbenza ιnide. To a solution of the compound obtained above (130 mg, 0.5 mmol) in DCM, neopentylamine (excess), PyBOP (2 eq.) and DIEA (5 eq.) were added. The mixture was stirred at r.t. overnight, washed with H2O, dried (MgSO ) and evaporated. The residue was chromatographed over silica gel with EtOAc/Hex (gradient: 0 - 100%) as eluent. (CaIc. mass: 327, obs. mass: 369 (M + AcN)+). [00445] 4-(5-Amino-2-methylpyridin-3-yI)-N-neopentylbenzainide. To a solution of the compound from the previous step (160 mg, 0.5 mmol) in MeOH, a spatula of Pd/C

(10 wt. %) was added and the suspension was stirred at r.t. under H2 atmosphere overnight. The mixture was filtered (celite), the solids were washed with MeOH, the combined organics were concentrated and the residue was used in the next step without further purification. (CaIc. mass: 297, obs. mass: 298).

[00446] 3-Fluoro-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-5- morpholinobenzamide. To a solution of the compound above in DCM (3.5 ml), 3-fiuoro-5- morpholinobenzoic acid I-a (24.1 mg, 0.1 mmol), a few drops of DMF, PyBOP (2 eq.) and DIEA (5 eq.) were added and the mixture was stirred at 400C overnight. The mixture was washed with H O, dried (MgSO ) and the solvent was evaporated. The residue was purified by RP-HPLC (gradient: 10 - 70% AcN in H2O5), followed by chromatography over silica gel (gradient: 0-100% EtO Ac/Hex,), to yield the final product. (CaIc. mass: 505, obs. mass: 505).

[00447] Methyl 4-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3- yl)benzoate. To a solution of 3-tert-butyl-5-cyanobenzoic acid E (120 mg, 0.6 mmol) and methyl 4-(5-amino-2-methylpyridin-3-yl)benzoate (126 mg, 0.5 mmol) (obtained as above) in DCM, a few drops of DMF, PyBOP (2 eq.) and DIEA (3 eq.) were added and the mixture was stirred at r.t. overnight. The mixture was washed with H O, dried (MgSO 0 and the solvent was evaporated. The residue was chromatographed on silica gel with EtOAc/Hex (gradient: 0-100%) as eluent. (CaIc. mass: 428, obs. mass: 428).

[00448] 4-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylpyridi π-3-yI)benzoic acid. To a solution of the compound from the previous step (130 mg, 0.3 mmol) in THF/MeOH (4 ml, 1:1), 2N NaOH (2 eq.) was added and the mixture was stirred at r.t. for 2 days. The mixture was neutralized with IN HCl, evaporated, and used in the next step without further purification. (CaIc. mass: 414, obs. mass: 414).

[00449] Methyl 4-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylpyridin-3- yl)benzoate. To a solution of the compound from -above (20 mg, 0.05 mmol) in DCM (2 ml), tetrahydro-2H-pyran-4-amine (2 eq.), a few drops of DMF, PyBOP (2 eq.) and DIEA (3 eq.) were added, and the mixture was stirred at r.t. overnight. The mixture was washed with H2O, dried (MgSO ) and the solvent was evaporated. The residue was chromatographed on silica gel with EtOAc/Hex (gradient: 0 - 100%) as eluent. (CaIc. mass: 497, obs. mass: 498).

[00450] 3-Fluoro-N-(5-(4-methoxyphenyl)-6-methylpy ridin-3-yl)-5- morpholinobenzamide. A solution of the 5-(4-methoxyphenyl)-6-methylpyridin-3-amine (obtained as above) (30 mg, 0.14 mmol) (prepared by the methods described above), 3-fluoro-5-morpholinobenzoic acid I-a (37 mg, 0.14 mmol), PyBOP (2 eq.) and DIEA (5 eq.) in DCM/DMF (3.5 ml, 6:1) was stirred at r.t. overnight. The mixture was concentrated and the residue was subjected to RP-HPLC (gradient: 5 to 90% AcN in H2O) followed by chromatography on silica gel (Hex/EtOAc, gradient: 0 to 100%) affording 10.1 mg of the final compound. (CaIc. mass: 422, obs. mass: 422). [00451] Methyl 6-bromonicotinate. In a 100 ml round-bottomed flask were placed 6-bromonicotinic acid (540 mg, 2.7 mmol), DCM (20 ml), and DMF ( 1 drop). Oxalyl chloride (1 ml) was added, resulting in vigorous gas evolution. The reaction was stirred for 1 hr after which the solvent was removed in vacuo. The residue was treated with MeOH and the solvent removed in vacuo. The residue was partitioned between DCM and saturated θ NaHC 3and the organic layer was dried over Na2SO . The solvent was removed to afford 369 mg (55% yield) of the methyl 6-bromonicotinate. 1H NMR (500 MHz) δ (ppm) 9.00 (dd, J = 2.0, 0.5 Hz, IH), 8.25 (dd, J = 8.5, 2.5 Hz, IH), 7.42 (dd, J = 8.5, 0.5 Hz, IH), 3.96 (s, 3H).

[00452] Methyl 21-methyl-5'-nitro-2,3'-bipyridine-5-carboxylate. In a 2 dram vial were placed 2-methyl-5-nitro-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine pinacolatoboronate a (130 mg, 0.33 mmol), methyl 6-bromonicotinate (as prepared above) (80 mg, 0.37 mmol), palladium tetrakis(triphenylphosphine) (38 mg, 0.03 mmol), DME (4.5 ml), ethanol (0.5 ml), and toluene (0.5 ml). Saturated Na COs (0.5 ml) was added while stirring rapidly. The reaction was flushed with nitrogen and capped tightly, then heated to 800C for 8.5 h. The solvents were removed in vacuo and the residue was purified on silica gel to afford 68 mg (75% yield) of the methyl 2l-methyl-5'-nitro-2,3'-bipyridine-5-carboxylate. 1 δ ' H NMR (500 MHz) (ppm) 9.39 (s, IH) 59.352 (s, IH), 8.57 (s, IH), 8.47 (d, J = 8.0 Hz, IH), 7.61 (d, J = 8.0 Hz, IH), 4.02 (s, 3H), 2.75 (s, 3H).

[00453] 2'-methyl-5'-nitro-N-((tetrahydrofuran-2-yl)methyl)-2,3'-bipyridine-5- carboxamide. In a 100 ml round-bottomed flask were placed methyl 2'-methyl-5'-nitro-2,3'- bipyridine-5-carboxylate (67 mg, 0.25 mmol), THF (4 ml), methanol (4 ml) and 2N sodium hydroxide ( 184 µl, 368 µmol). After stirring at r.t. for 2h the reaction was heated to 500C overnight. The solvent was removed and the residue was suspended in THF, treated with 2M HCl (184 µl, 368 µmol) and the solvent removed in vacuo. The residue was dissolved in DMF (0.5 ml) and treated with PyBOP (312 mg, 0.6 mmol) and N-methylmo φ holine (82 µl, 0.75 mmol). After 20 min, one third of this solution was treated with furfurylarnine (152 µl) and heated to 400C overnight. The residue was purified on silica gel, eluting with 0-1 00% EtOAc/Hex to afford the 2'-methyl-5'-nitro-N-((tetrahydrofuran-2-yl)methyl)-2,3'-bipyridine- 5-carboxamide. (CaIc. mass: 342, obs. mass: 343).

[00454] 5'-(3-tert-butyl-5-cyanobenzainido)-2'-methyl-N-((tetrahydrofuran-2- yl)methyl)-2,3'-bipyridine-5-carboxamide. 2'-Methyl-5l-nitro-N-((tetrahydrofuran-2- yl)methyl)-2,3'-bipyridine-5-carboxamide was dissolved in EtOAc (2 ml) and MeOH (0.5 ml) 0 in a 2 dram vial, treated with SnCl2-2H2O (90 mg, 0.4 mmol) and heated at 70 C for Ih. The θ solvent was evaporated and the residue was partitioned between DCM and saturated Na2C 3. The organic layer was dried and the solution filtered. The solution was treated with 3-cyano- 5-t-butylbenzoyl chloride F (160 µmol) and NMM (240 µmol). The solvent was evaporated and the residue purified on RP-HPLC to afford 2.5 mg of 5'-(3-tert-butyl-5- cyanobenzamido)-2'-methyl-N-((tetrahydrofuran-2-yl)methyl)-2,3'-bipyridine-5- carboxamide. (CaIc. mass: 497, obs. mass 499).

[00455] 5'-(3-tert-butyl-5-cyanobenzaπύdo)-2'-methyl-N-((tetrahydrofuran-2- yl)methyl)-3,3'-bipyridine-6-carboxamide was prepared by essentially the same methods. (CaIc. mass: 497, obs. mass 499).

[00456] 3-tert-Butyl-5-cyano-N-(6-methyi-5-(4-(piperidin-l- ylcarbamoyl)phenyl)pyridine-3-yl)benzamide. A mixture of 4-(5-(3-tert-Butyl-5- cyanobenzamido)-2-methylpyridin-3-yl)benzoic acid (26 mg, 0.06 mmol), 1-aminopiperidine (13 µl, 2 eq.), BOP (41 mg, 1.5 eq.) and DIEA (42 µl) in 1 ml DMF was stirred overnight at r.t. The reaction mixture was diluted with DMF and subjected to preparative LC-MS purification (20-50% ACNZH2O), which afforded 12.1 mg of the title compound. (CaIc. mass: 496, obs. mass 497). [00457] 4-Bromo-N-neopentylbenzenesulfonamide. To a solution of sulfonylchloride (4 g, 1.6 mmol) and DIEA (3 eq., 0.048 mol) in 50 ml of DCM was added neopentylamine ( 1.3 eq., 2.13 mmol). The solution was stirred for 2 hr at r.t. and then added to 200 ml of water (pH 2.0). The resulting mixture was extracted with DCM. The organic fractions were combined, dried (MgSO ), filtered and concentrated in vacuo to yield 5.6 g of the target 1 δ compound. H NMR (500 MHz, CDCl3) (ppm) 7.73 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 4.63 (t, J = 7.0 Hz, IH), 2.69 (d, J = 7.0 Hz, 2H), 0.89 (s, 9H).

[00458] N-Neopentyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzenesulfonamide. The compound obtained above (0.5 g, 0.0016 mol), bispinacolatodiboron (1.5 eq., 0.62 g), potassium acetate (3 eq., 0.48 g) and PdC^dppf (10 mol %, 120 mg) were dissolved in 3 ml DMSO. The solution was stirred at 800C for 2 hr under nitrogen. The mixture was added to water and extracted with DCM. The organic fractions were combined, dried (MgSO ), filtered and concentrated. Column chromatography 1 (SiO2; 1:1 DCM: EtOAc) yielded 0.415 g of the target compound. H NMR (500 MHz, δ CDCl3) (ppm) 7.94 (d, J' = 7.5 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 4.37 (bt, IH), 2.67 (d, J = 6.0 Hz, 2H), 1.36 (s, 12H), 0.87 (s, 9H).

[00459] 4-(2-Methyl-5-nitropyridin-3-yl)-N-neopentyIbenzenesulfonamide. The compound obtained above (30 mg, 0.085 mmol), 3-bromo-5-nitro-2-methylpyridine (1.0 eq.,

18 mg), K2CO3 (3 eq., 35 mg) and Pd(PPh3)4 (10 mol %, 10 mg) were dissolved in 3 ml DMErEtOH (9: 1). The solution was stirred at 800C for 24 hr under nitrogen. The mixture was concentrated in vacuo. Column chromatography (SiOa; 3:1 Hex: EtOAc) yielded 20 mg of the target compound. (CaIc. mass: 364, obs. mass 364).

[00460] 4-(5-Amino-2-methyIpyridin-3-yl)-N-neopentylbenzenesulfonamide. The compound obtained above (20 mg, 0.055 mmol) and 10 % Pd/C (10 mg) were added to 3 ml

MeOH. The solution was stirred for 2 hr at r.t. under 1 atm of H2. The mixture was filtered and concentrated in vacuo to yield 18 mg of the target compound. (CaIc. mass: 334, obs. mass 334).

[0046 1] 3-tert-butyI-5-cyano-N-(6-methyl-5-(4-(N-neopentylsulf amoyl)phenyl)- pyridin-3-yl)benzamide. The compound obtained above (20 mg, 0.06 mmol) and excess DIEA (0.2 ml) were added to a solution of 3-cyano-5-tertbutylbenzoylchloride F (1.0 eq., 13 mg) in 3 ml DCM. The solution was stirred for 1 hr at r.t. and then concentrated in vacuo. RP-HPLC purification (10 to 90% AcN in H2O with 0.1 % TFA) yielded 7.0 mg of the target 1 δ compound. (CaIc. mass: 519, obs. mass: 519). H NMR (500 MHz, CD3OD) (ppm) 8.85 (s, IH), 8.32 (s, IH), 8.16 (m, 2H), 7.99 (m, 3H), 7.63 (d, J = 7.5 Hz, 2H), 2.67 (s, 2H), 2.48 (s, 3H), 1.42 (s, 9H), 0.91 (s, 9H).

Route C: Via formation of the pyridine central core.

Y [00462] Step 1. 4-(2-Methyl-5-nitropyridin-3-yl)benzonitrile. To a mixture of 4-(2- oxopropyl)benzonitrile (162 mg, 1.0 mmol, 1.0 eq.), 2-nitromalonaldehyde (prepared as in Org. Synth. Coll., 4, 844, 1963) (210 mg, 1.5 mmol, 1.5 eq.) and ammonium acetate (395 mg, 5.1 mmol, 5.1 eq.) was added 50% aq. EtOH (2 ml) and the mixture was stirred overnight at 600C. The reaction mixture was diluted with water and the product was extracted in to DCM. The organic layer was dried (MgSO_i), evaporated and the residue was purified by chromatography on silica gel using 0 - 3% MeOH/DCM as eluent, providing 75 mg (30% 1 δ yield) of the target product. H-NMR (500 MHz, DMSO-d 6) (ppm) 9.33 (d, IH), 8.42 (d, 1 δ IH), 8.02 (d, 2H), 7.75 (d, 2H), 2.57 (s, 3H). H-NMR (500 MHz, CDCl3) (ppm) 9.40 (d, IH), 8.34 (d, IH), 7.85 (d, 2H), 7.52 (d, 2H), 2.65 (s, 3H). (CaIc. mass: 239.1, obs. mass: 280.9 (M+AcN+H +)).

[00463] 4-(2-MethyI-5-nitropyridin-3-yl)benzoic acid (Y). 4-(2-Methyl-5- nitropyridin-3-yl)benzonitrile (55 mg, 0.23 mmol) was dissolved in EtOH (1.2 ml) and 6 M aq. HCl (2.5 ml) was added. The mixture was stirred overnight at 1100C. The reaction mixture was evaporated providing 59 mg (100% yield) of the product. 1H-NMR (500 MHz, δ DMSO-d 6) (ppm) 10.34 (s, IH), 9.31 (d, IH), 8.39 (d, IH), 8.08 (d, 2H), 7.65 (d, 2H), 2.58 (s, 3H). (CaIc. mass: 258.1, obs. mass: 299.9 (M+AcN+H +)).

[00464] Intermediate Y was further derivatized using the methods described above. Route D : Alternate orientation of amide linker

[00465] N-Neopentyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (339 mg, 1.366 mmol) was dissolved in DCM (3 ml). Oxalyl chloride (3 ml) was added, followed by a catalytic amount of DMF and the mixture was stirred overnight at r.t. The mixture was concentrated in vacuo, and the residue was dried in HV. The pale yellow solid was dissolved in DCM (3 ml), and was added to a mixture of neopentylamine (131.0 mg, 1.503 mmol) and saturated aq.

NaHCC«3 solution. The reaction was vigorously stirred at r.t. for 45 min. The organic layer was separated, and the aq. layer was washed with DCM. The combined organic layers were dried over Na SO,*, filtered, concentrated in vacuo, and the residue was dried in HV. The crude compound was purified by column chromatography (silica gel, 0-50% EtOAc/DCM) to 1 δ afford the pure target product. (CaIc. mass: 317.23, obs. 318). H-NMR (DMSO-d 6) (ppm) 8.41 (t, IH, J = 6.4 Hz), 7.86 (d, 2H, J 8.2 Hz), 7.75 (d, 2H, J = 8.2 Hz), 3.1 1 (d, 2H, J = 6.4 Hz), 1.32 (s 12H), 0.91 (s, 9H).

[00466] Ethyl 6-methyl-5-(4-(neopentyIcarbamoyl)phenyl)nicotinate. A mixture of intermediate d ( 117.4 mg, 0.403 mmol) and the compound from above ( 153.5 mg, 0.484 mmol), cesium carbonate (394.2 mg, 1.21 mmol), triphenylarsine (18.5 mg, 0.06 mmol) in dioxane (9.6 ml) and water (0.4 ml) was degassed. Solid PdCl (PhCN) (7.7 mg, 0.02 mmol) was added, and the mixture was again degassed. The reaction was stirred at 700C under nitrogen gas for 135 min. The reaction was filtered over celite and MgSO , and the filtrate was Iyophilized. The residue was purified by column chromatography (silica gel, gradient: 0-50% EtOAc/ DCM) to gave pure target product. (CaIc. mass: 354.4, obs. mass: 355).

[00467] 6-Methyl-5-(4-(neopentylcarbamoyl)phenyl)nicotinic acid. Aqueous 2 N NaOH (212 µl, 0.424 mmol) and water (212 µl) were added to a solution of the compound obtained above in THF-EtOH (2 ml/2 ml). The mixture was stirred at 500C for 6.5 hr and concentrated and dried in vacuo. Aqueous IN HCl (424 µl, 0.424 mmol) and water (3 ml) were added, the mixture was sonicated, and filtered. The solid was washed with water, air dried, and dried in HV to yield 42.8 mg of the target compound. (CaIc. mass: 326.4, obs. mass: 327).

[00468] N-(3-tert-butyI-5-cyanophenyl)-6-methyl-5-(4-( πeopentylcarba ιnoyl)- phenyl)nicotinamide. A mixture of the crude compound above (20 mg, 0.061 mmol), intermediate BB (19.4 mg, 0.092 mmol), BOP (54.2 mg, 0.123 mmol), NMM (26.9 µl, 0.245 mmol) and DMF ( 1 ml) was stirred at r.t. for 3 hr 30, then heated to 500C overnight. The crude compound was purified by RP LC-MS (gradient: 30-80% AcN/water) to give the target compound in 24.4 mg yield. CaIc. mass: 482.6, obs. mass: 483).

Example 2: Synthesis of Target Compounds of Formula II. Synthesis of advanced intermediates.

b [00469] tert-Butyl l-(2-methyl-5-nitropyridin-3-yl)-lH-l,2,3-triazole-4-carboxylate (Z). A solution of 3-azido-2-methyl-5-nitropyridine b ( 1.12 g, 6.25 mmol, and tert-butyl

propiolate (1.72 ml, 12.5 mmol, 2.0 eq.) in AcN/H 2O (10:1, 23 ml) was stirred overnight at 800C in the presence of copper wire. The solution was concentrated and dried in HV to give crude product Z (1.91 8 g, quant, yield, >90% purity) as a brown solid. Column chromatography (silica gel, 0-10% MeOH in DCM or 0-50% EtOAc in DCM) yielded product Z as a white solid (1.861 g, 97% yield, >99% pure by LC-MS). (CaIc. mass: 305, obs. mass: 291 (MH-tBu + AcN)+). [00470] 3-Methyl-l-(l-(2-methyl-5-nitropyridin-3-yl)-lH-l,2,3-triazoI-4-yl)butan-l- ol (R = CH(OH)CH 2CH(CEb) 2). A solution of b (97.5 mg, 0.544 mmol, 1.0 eq.) and 5-methyl- l-hexyn-3-ol (244 mg, 2.18 mmol, 4.0 eq.) in AcN/water (10:1, 4 ml) was stirred overnight at 80 C in the presence of copper wire. The solution was concentrated and dried in HV to give crude target product (118 mg, 80% pure by LC-MS) which was used for the next step without further purification. (CaIc. mass: 291, obs. masses: 206, 246).

[00471] The above method was also used for the synthesis of benzyl 2-methyl-2-(l-(2- π methyl-5-nitropyridin-3-yl)-lH-l,2,3-triazol-4-yl)propa oate (R = C(CH 3)2COOBn). (CaIc. mass: 381, obs. mass: 382).

[00472] Propiolic acid. Potassium 3-carboxypropiolate (200 g, 1.32 mol) was added to 550 ml of water. The mixture was heated to reflux for 4 hr, then cooled to r.t. (NHU) SO (25 g) and IN HCl (100 ml) were added. The mixture was extracted with EtOAc and the θ combined organic layers were dried over MgS 4 and concentrated. The residue was distilled in vacuo [90- 1000C/ 100mm Hg] to provide the target compound (24 g, 26% yield) as a 1 δ colorless liquid. H-NMR (CDCl 3, 300 MHz) (ppm) 9.59 - 9.64 (d, IH), 3.02(s, IH). [00473] N-Neopentylpropiolamide. To a mixture of the compound above ( 11.2 g, 0.16 mol) and DCC (41 g) in DCM (650 ml) was added a solution of 2,2-dimethylpropan-l- amine (13 g in 20 ml DCM) dropwise at 00C. The mixture was stirred for 1 hr, then allowed to warm to room temperature for 1 hr. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (PE:EtOAc = 2:1) to give 1 δ the target compound V ( 17.6 g, 84.4% yield) as an oil. H-NMR (CDCl 3, 300 MHz) (ppm) 6.66 (s, IH), 3.01 - 3.03 (d, 2H), 2.79 (s, IH), 0.84 (s, 9H). Route A : Via coupling of G-C(O)OH to the protected core template.

[00474] tert-ButyI-l-(5-amino-2-methylpyridin-3-yl)-lH-l,2,3-triazole-4- carboxylate. Raney nickel (-300 mg) was added to a solution of Z (682 mg, 2.23 mmol) in MeOH (55 ml). The mixture was stirred under H atmosphere overnight at r.t., and filtered through celite. The filtrate was concentrated and the product was dried in HV at 800C for 3 hr to give the target compound as a white solid foam (465 mg, 75% yield, >99% pure by LC-MS). (CaIc. mass: 275, obs. mass: 191 (M-tBu-Nz) ).

[00475] tert-Butyl l-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)- lH-l,2,3-triazole-4-carboxylate. Step 1. A mixture of 3-fluoro-5-morpholinobenzoic acid I-a (762 mg, 3.38 mmol, 2.0 eq.), oxalyl chloride (10 ml), DCM (5 ml), and DMF (-10 µl) was stirred at 400C for 2-3 h. The clear solution was concentrated and dried at 800C in HV to give the solid 3-fluoro-5-rnorpholinobenzoyl chloride.

[00476] Step 2. A solution of this compound (3.38 mmol, 2.0 eq.) in DCM (5 ml) was added dropwise to a stirred solution of tert-butyl l-(5-amino-2-methylpyridin-3-yl)-lH-l,2,3- triazole-4-carboxylate (465 mg, 1.69 mmol), DIEA (1.77 ml, 10.13 mmol, 6 eq.) and DCM (10 ml). The mixture was stirred overnight at r.t., then aq. NaOH solution (25%, 50 ml) was added and the product was extracted with DCM. The organic layers were dried (Na SO ) and concentrated. The crude product was purified using column chromatography (silica gel, gradient: 0-3% MeOH in DCM) to give the target compound (749 mg, 91% yield, 98% pure by LC-MS) as a brown solid foam. (CaIc. mass: 483, obs. masses: 399, 483). [00477] l-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-lH-l,2,3- triazoIe-4-carboxylic acid. A solution of the compound from above (749 mg, 1.55 mmol) in TFA —H O (95:5, 10 ml) was stirred for 2 hr at r.t. and concentrated. The residue was dissolved in AcN (10 ml), concentrated, and the obtained residue was dried in HV. The crude product was stirred with diethyl ether (40 ml), the solid was separated by filtration, washed with diethyl ether, and dried in HV to give the target compound (582 mg, 88% yield, >99% pure by LC-MS) as a brown solid. (CaIc. mass: 426, obs. mass: 355 (MH-CO 2-N2)*). [00478] l-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N- ((tetrahydrofuran-2-yl)methyl)-lH-l,2,3-triazole-4-carboxamide. Tetrahydrofurfuryl amine (93 µl, 0.90 mmol, 2.4 eq.) was added to a mixture of 36 (162 mg, 0.38 mmol), BOP (53 1 mg, 1.20 mmol, 3.2 eq.), and DCM (5 ml) followed by addition of DIEA (41 8 µl, 2.40 mmol, 6.3 eq.). The mixture was stirred at r.t. for 3 hr, then TFA (46 ml, 0.60 mmol, µ 1.6 eq.), H2O (100 l), and MeOH (2 ml) were added and the mixture was stirred overnight at r.t. to hydrolyze the excess of BOP. The mixture was concentrated and the residue was purified using preparative RP-HPLC (gradient: 30-50% AcN in H2O). The concentrated fractions were neutralized with 2 M aq. K2CO3 (50 ml) and DCM extraction provided the free base of the target product (137 mg, 70% yield, >99% pure by LC-MS). (CaIc. mass: 510, obs. masses: 482, 510).

[00479] Using similar methods, the following compounds were prepared:

N-(5-(4-tert-Butyl-lH-l,2,3-triazoI-l-yl)-6-methylpyridin-3-yl)-3-fluoro-5- morpholinobenzamide (CaIc. mass: 439; obs. mass: 4 11, 439);

3-fluoro-N-(6-methyl-S-(4-(pyridin-2-yl)-lH-l,2,3-triazoI-l-yl)pyridin-3-yl)-5- morpholinobenzamide (CaIc. mass: 459.5; obs. mass: 432, 460);

3-fluoro-N-(5-(4-(methoxymethyI)-lH-l,2,3-triazol-l-yl)-6-methyIpyridin-3-yl)-5- morpholinobenzamide (CaIc. mass: 426; obs. mass: 399, 427). Route B: Via coupling of L -Q to the protected core template.

[00480] l-rø-Methyl-S-nitropyridin-S-yO-lH-l^S-triazoLe^-carboxylic acid. A solution of Z (843 mg, 2.76 mmol) in TFA - H2O (95:5, 10 ml) was stirred for 2 hr at r.t., concentrated, dissolved in AcN (10 ml), concentrated, and dried in HV. The crude product was stirred with diethyl ether (40 ml), the solid was separated by filtration, washed with diethyl ether, and dried in HV to give the target compound (639 mg, 92% yield, >95% pure 1 δ by LC-MS - no mass detected) as a brown solid. H-NMR (500 MHz, DMSOd 6) (ppm) 13.42 (bs, 1H).9.48 (d, J = 2.5 Hz, IH), 9.24 (s, IH) 8.89 (d, J = 2.5 Hz, IH), 2.54 (s, 3H).

[00481] l-(2-Methyl-5-nitropyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4- carboxamide. Neopentylamine (358 µl, 3.00 mmol, 2.1 eq.) was added to a mixture of the compound above (363 mg, 1.46 mmol), BOP (1.77 g, 4.00 mmol, 2.7 eq.), and DCM (12 ml) followed by the addition of DIEA ( 1.39 ml, 8.00 mmol, 5.5 eq.). The mixture was stirred at r.t. for 30 min, then aq. 2 M NaOH (20 ml) was added, the product was extracted with DCM, the organic layers were dried (Na2SO_) , and concentrated. The crude product was purified using column chromatography (silica gel, gradient: 0-10% MeOH in DCM). In order to remove the residual BOP, the purified product was suspended in hot MeOH (20 ml) and a solution of ammonium acetate (2.0 g) in H O (5 ml) was added. After stirring at r.t. for 1 hr, the solid was separated by filtration, washed with H_O, air dried, and dried in HV to give pure target compound (377 mg, 81% yield, >99% pure by LC-MS) as a white solid. (CaIc. + + mass: 318, obs. masses: 291 (MH - N2) , 360 (MH + AcN) ). [00482] l-(5-Amino-2-methylpyridin-3-yl)-N-neopentyHH-l,2,3-triazole-4- carboxamide. Raney nickel (-300 mg) was added to a solution of the compound above (375 mg, 1.18 mmol) in a mixture of EtOAc (40 ml) and EtOH (40 ml). The mixture was stirred under H2 atmosphere overnight at r.t., and filtered through celite. The filtrate was concentrated and the product was dried in HV to give the target compound as a white solid (284 mg, 83% yield, >99% pure by LC-MS). (CaIc. mass: 288, obs. masses: 261, 289, 330, 352).

[00483] l-(5-(3-tert-Butyl-5-cyanobenzaimdo)-2-methyIpyridin-3-yI)-N-neopentyl- lH-l,2,3-triazole-4-carboxamide. A solution of 3-tert-butyl-5-cyanobenzoyl chloride F (0.60 mmol, 1.5 eq.) in DCM (5 ml) was added dropwise to a stirred solution of the compound above ( 115 mg, 0.40 mmol), DIEA (279 µl, 1.60 mmol, 4.0 eq.) and DCM (5 ml). The mixture was stirred overnight at r.t., then 2 M aq. NaOH solution (50 ml) was added and the product was extracted with DCM. The organic layers were washed with H O (100 ml) dried (Na SO- ) and concentrated. The crude product was purified using preparative

RP-HPLC (gradient: 50-80% AcN in H2O). The concentrated fractions were neutralized with

2 M aq. K2CO3 (50 ml) and DCM extraction provided the free base of the target product (118 mg, 62% yield, >99% pure by LC-MS). (CaIc. mass: 474, obs. masses: 446, 474).

[00484] 3-Methyl-l-(l-(2-methyl-5-nitropyridin-3-yl)-lH-l,2,3-triazol-4-yl)butan-l- one. Dess-Martin periodinane (167 mg, 0.398 mmol, 1.2 eq.) was added to a solution of 3-methyl-l-(l-(2-methyl-5-nitropyridin-3-yl)-lH-l,2,3-triazol-4-yl)butan-l-ol W-a (99 mg, 0.340 mmol, 1.0 eq.) in DCM (5 ml) and the mixture was stirred overnight at r.t. Diethyl ether (50 ml) was added and the organic layer was washed with aq. Na2S O (2 M, 50 ml), aq.

K2CO3 (2 M, 50 ml), and water (50 ml). The combined organic layers were dried (Na SO ), concentrated in vacuo and dried in HV to give the crude target product (96 mg, 94 % pure by 1 δ LC-MS). (CaIc. mass: 289, obs. mass: 206). H NMR (500 MHz, DMSO-d6) (ppm) 9.48 (d, J = 2.4 Hz, IH), 9.31 (s, IH) 8.90 (d, J 2.4 Hz, IH), 2.97 (d, J = 7.0 Hz 2H), 2.55 (s, 3H), 2.26 (m, IH), 0.97 (d, J = 6.7, 6H).

[00485] l-(l-(5-Amino-2-methylpyridin-3-yl)-lH-l,2,3-triazol-4-yl)-3-methylbutan- 1-one. Raney nickel (~300 mg) was added to a solution of the compound obtained above

(96 mg, 0.332 mmol) in MeOH (4 ml). The mixture was stirred under H2 atmosphere at r.t. for 2 hr, and filtered through celite. The filtrate was concentrated and dried in HV to give the target product (75 mg, 94% pure by LC-MS). (CaIc. mass: 259, obs. mass: 232).

[00486] 3-tert-Butyl-5-cyano-N-(6-methyl-5-(4-(3-methylbutanoyl)-lH-l,2,3-triazol- l-yl)pyridin-3-yl)benzamide. 3-tert-Butyl-5-cyanobenzoyl chloride F (70.5 mg, 0.318 mmol, 1.1 eq.) was added to a stirred solution of the compound obtained above (75 mg, 0.289 mmol, 1.0 eq.), and DIEA (121 µl, 0.694 mmol, 2.4 eq.) in DCM (2 ml). The mixture was stirred at r.t. for 2 hr, then 2 M aq. K2CO3 solution. (5 ml) was added and the product was extracted with DCM (50 ml). The organic layer was washed with water (100 ml), dried (NaiSC , and concentrated. The crude product was purified using preparative RP-HPLC

(40-80% AcN in H2O) to give pure product (31.7 mg, 99% pure by LC-MS). (CaIc. mass: 444, obs. masses: 417, 445).

[00487] 2-(l-(5-Amino-2-methylpyridin-3-yl)-lH-l,2,3-triazol-4-yl)-2- methylpropanoic acid. Palladium on carbon (10%, ~500 mg) was added to a solution of benzyl 2-methyl-2-(l-(2-methyl-5-nitropyridin-3-yl)-lH-l,2,3-triazol-4-yl)propanoate W-b

(277 mg, 0.726 mmol) in MeOH (7 ml). The mixture was stirred under H2 atmosphere at 500C for 3 days, and filtered through celite. The filtrate was concentrated and dried in HV to give the target product (110 mg). (CaIc. mass: 261, obs. mass: 234).

[00488] 2-(l-(5-Amino-2-methylpyridin-3-yl)-lH-l,2,3-triazoI-4-yl)-2-methyl-N- neoperttylpropanamide. Neopentylamine (478 µl, 4.00 mmol, 9.5 eq.) was added to a mixture of the compound obtained above (110 mg, 0.421 mmol, 1.0 eq.), BOP (442 mg, 1.00 mmol, 2.4 eq.), and DCM (5 ml). The mixture was stirred at r.t. for 1.5 hr, then concentrated in vacuo to remove the excess amine, hi order to remove the residual BOP, the residue was dissolved in DCM (5 ml) and a solution of ammonium acetate ( 1.26 g) in water (5 ml) was added. After stirring at r.t. for 30 min, the organic layer was washed with water, dried (Na2SO ), concentrated and dried in HV to give the target product ( 1 16 mg, 93% pure by LC-MS). (CaIc. mass: 330, obs. mass: 303 (MH-Na)+).

[00489] 3-tert-Butyl-5-cyano-N-(6-methyl-5-(4-(2-methyI-l-(neopentylamino)-l- oxopropan-2-yl)-lH-l,2,3-triazol-l-yI)pyridin-3-yI)benzamide. 3-tert-Butyl-5- cyanobenzoyl chloride Fj(56 mg, 0.250 mmol, 1.4 eq.) was added to a stirred solution of the compound obtained above (58 mg, 0.176 mmol, 1.0 eq.), DIEA (87 µl, 0.500 mmol, 2.8 eq.) and DCM (5 ml). The mixture was stirred overnight at r.t., then 2 M aq. K2CO3 solution (20 ml) was added and the product.was extracted with DCM (50 ml). Organic layer was washed with water (100 ml), dried (Na SO ), and concentrated. The crude product was purified using preparative RP-LC-MS (50-60% AcN in H2O) to give pure target product + (30.6 mg, 98% pure by LC-MS). (CaIc. mass: 515, obs. mass: 488 (MH-N2) ). Route C: Via formation of the pyridine ring.

[00490] Method A. l-Azidopropan-2-ol. 2-Methyloxirane (4.5 ml, 3.2 g, 55 mmol, 0.7 eq.) was added to a solution of sodium azide (5.15 g, 79 mmol, 1.0 eq.) and the mixture was stirred for 40 minutes. Another portion of 2-methyloxirane ( 1.0 ml, 0.7 g, 12 mmol, 0.16 eq.) was added and the solution was left at r.t. overnight. The product was then extracted into EtOAc, dried (MgSO-O an evaporated to provide 3.7 g (55% yield) of a thick 1 oil, which solidified upon standing. H-NMR (500 MHz, DMSO-d 6) (ppm) 4.98 (d, IH), 1 δ 3.79 (m, IH), 3.14 (dd, IH), 3.09 (dd, IH), 1.06 (d, 3H); H-NMR (CDCl 3) (ppm) 3.97 (m, IHX 3.35 (dd, IH), 3.23 (dd, IH), 1.23 (d, 3H).

[0049 1] Methyl l-(2-hydroxypropyl)-lH-l,2,3-triazole-4-carboxylate. l-Azidopro ρan-2-ol (2.81 g, 28 mmol, 1.0 eq.) was dissolved in AcN (40 ml) and water (8 ml). Methylpropiolate was added in two portions (90 % first and 10 % at 2 hr) (3.0 g, 36 mmol, 1.3 eq.) and the mixture was stirred at 600C in the presence of Cu wire. After 4 hr the reaction was complete. The Cu wire was removed and the residue was evaporated to yield 3.63 g (70%) of a green oil, which was used in the next reaction without further 1 δ purification. H-NMR (500 MHz, DMSO-d 6) (ppm) 8.64 (s, IH), 5.07 (d, IH), 4.40 (dd, IH), 4.26 (dd, IH), 4.02 (m, IH), 3.83 (d, 3H), 1.07 (d, 3H). [00492] l-(2-Hydroxypropyl)-N-neopentyI-lH-l,2,3-triazole-4-carboxamide. Methyl l-(2-hydroxypropyl)-lH-l,2,3-triazole-4-carboxylate (3.63 g, 20 mmol, 1.0 eq.) was dissolved in MeOH (12 ml). Neopentylarnine (2.1 g, 24 mmol, 1.2 eq.) was added and the mixture was heated in a closed tube at 1000C overnight. The reaction was monitored by LC- MS and was complete at that time. The reaction mixture was evaporated and dried in high vacuum to yield 4.53 g (96%) of a green oil, which was used in the next reaction without 1 δ further purification. H-NMR (500 MHz5 DMSO-d6) (ppm) 8.42 (s, IH), 8.24 (t, IH), 5.08

(bs, IH), 4.38 (dd, IH) 5 4.25 (dd, IH) 5 4.02 (bs5 IH) 5 3.08 (d5 2H), 1.07 (d, 3H), 0.88 (s, 9H).

[00493] N-Neopentyl-l-(2-oxopropyl)-lH-l,2,3-triazole-4-carboxamide. 1-(2- hydroxypropyl)-N-neopentyl-lH-l,2,3-triazole-4-carboxamide (600 mg5 2.5 mmol, 1.0 eq.) was dissolved in DCM (8 ml). Dess Martin periodinane was added ( 1.17 g, 2.8 mmol, 1.1 eq.) and the mixture was stirred until the reaction was complete (~2 hr). The reaction was monitored by TLC and was complete at that time. The reaction mixture was diluted with

EtOAc and was washed with 25 ml of a mixture of IM Na2S O and saturated aq. NaHCOa

(1:1), saturated aq. NaHCO 3 and with brine, dried (MgSO ), evaporated and dried in high 1 δ vacuum to yield 390 mg (66%) of product. H-NMR (500 MHz, DMSO-d 6) (ppm) 8.38 (s,

IH) 5 8.29 (t, IH), 5.54 (s, 2H), 3.31 (s, 2H), 3.09 (d, 2H), 1.98 (s, 3H), 0.88 (s, 9H).

[00494] Method B. l-Azidopropan-2-one was prepared from chloroacetone according to reported procedures. See J. Chem. Soc. 1908, 93, 72 or Eur. J. Org. Chem. 2005, 4141.

To a concentrated aqueous solution of sodium azide (78 g, 1.2 mol), was added chloroacetone . (74 g, 0.8 mol) and a few drops of glacial acetic acid at 0°C. The resulting mixture was stirred at r.t. for 24hr. After the reaction was complete, the mixture was extracted with diethylether. The combined ether layers were dried over anhydrous Na2SO4 and evaporated to provide the crude target product (64 g, 81%) as an oil, which was used for the next step without further

1 δ 13 purification. H NMR (500 MHz 5 CD2Cl2) (ppm) 3.97 (s, 2H)5 2.19 (s, 3H). C NMR δ (CD2Cl2) (ppm) 202.1, 58.1, 27.2.

[00495] N-neopentyl-l-(2-oxopropyl)-lH-l,2,3-triazole-4-carboxamide. A solution of the compound above (46.5 g, 47 mmol) and N-neoρentylpropiolamide V (51 g, 36 mmol) in a mixture of AcN (1200 ml) and water (120 ml) was heated to reflux for 6 hr in the presence of a catalytic amount of Cu powder. After the reaction was complete, the reaction mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography eluted by EtOAc:PE=l:l to provide the target compound as a white solid (70 g, 82%).

[00496] l-(2-methyl-5-nitropyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4- carboxamide. A mixture of the compound from the previous step (84 g, 0.353 mol), nitromalondialdehyde sodium salt (88 g, 0.635 mol), ammonium acetate (244 g, 3 mol), EtOH (1200 ml) and water (1200 ml) was heated to 80°C with stirring for 18 hr. After the reaction was complete, the mixture was filtered to collect the solid. The filtrate was evaporated to remove EtOH and the residue was extracted with EtOAc. The combined EtOAc layers were dried over anhydrous Na SO and evaporated. The residue and the obtained solid were purified by column chromatography, eluting with EtOAc:PE=l :3 to provide the target compound as a white solid (33g, 30%).

[00497] [l-(5-amino-2-methyl(3-pyridyl))(l,2,3-triazol-4-yl)]-N-(2,2-dimethylpropyl) carboxamide. To the solution of the compound from the previous step (33 g, 0.104 mol) in

MeOH (1.2 1) was added '10% pd/C (16 g). The mixture was allowed to react under H atmosphere for 3 hr at r.t. After the reaction was complete, the mixture was filtered. The filtrate was evaporated to provide the crude target compound (28.8 g, 96%) which was used for the next step without further purification.

[00498] l-(5-(3-tert-butyI-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-neopentyl- lH-l,2,3-triazole-4-carboxamide. To a solution of the compound E (20.7 g, 102 mmol) in DCM (400 ml) was added oxalyl chloride (48.7 ml) dropwise and a catalytic amount of DMF at 00C. The mixture was stirred at r.t. for 2 hr, then evaporated. The residue was again dissolved in DCM (200 ml) and added to a mixture of the compound obtained above (28.8 g, 100 mmol) and DIEA (87 ml) in DCM (400 ml) at 00C. The mixture was allowed to stir at r.t. for 3 hr. The solvent was removed in vacuo and the residue was purified by column chromatography (PE:EtOAc=4:l) to give the target compound (30.5g, 64%) as a yellow 1 δ solid. H NMR (CDCl 3, 300 MHz) (ppm) 8.86 -8.90 (d, 2H)3 8.45 - 8.46 (d, IH), 8.26 -

8.28 (m, 2H)5 8.13 - 8.14 (t, IH), 7.85 - 7.86 (t, IH), 7.35 - 7.40 (t, IH), 3.26 - 3.28 (d, 2H), 2.45 (s, 3H), 1.36 (s, 9H), 0.98 (s, 9H). (CaIc. mass: 473.6, obs. mass: 474.2).

[00499] Method C. Acetol tosylate. A mixture of acetol (6.86 ml, 7.41 g, 0.100 mol, 1.0 eq.) and pyridine (30 ml) in a 500 ml flask was cooled to < 00C in an ice-salt bath. A solution of p-toluenesulfonyl chloride (20.74 g, 0.109 mol, 1.1 eq.) in pyridine (70 ml) was added dropwise to the flask over ~2 hr at an internal temperature < O0C. The mixture was stirred at < O0C for 30-40 min, and then cold water (250 ml) and 6 M aq. HCl. (250 ml) were added. The mixture was extracted with DCM, the combined organic layers were washed with IM H2SO4, water, dried (Na2SC»4), and concentrated in vacuo. The crude product (9.281 g, 41% yield), 96% pure by LC-MS, 1H NMR) was an amber oil, which darkened upon standing 1 δ at r.t., and which could be purified by vacuum distillation. H NMR (500 MHz, CD2Cl2) (ppm) 7.82 (d, J = 8 Hz, 2H), 7.42 (d, J = 8 Hz, 2H), 4.52 (s, 2H), 2.48 (s, 3H), 2.18 (s, 3H).

[00500] l-Azidopropan-2-one. Two solutions were prepared as follows: Solution A: acetol tosylate (4.71 g, 20.6 mmol, 1.0 eq.) in EtOH (21 ml) and acetic acid (2.36 ml, 41.3 mmol, 2.0 eq.), and Solution B: sodium azide (2.68 g, 41.3 mmol, 2.0 eq.) in water (8.2 ml). Solutions A and B were cooled to 00C, combined, and maintained at 00C (in the refrigerator) for 3 days. The disappearance of starting material was followed by analytical LC-MS. Water (500 ml) was added, and the product was extracted with diethyl ether. The combined organic layers were washed with sat. aq. NaHCC*3, dried (Na SO ), and concentrated in vacuo. The crude product was distilled at 500C using high-vacuum in a Kugelrohr distillation apparatus. The collection bulb was cooled using a acetone - dry ice mixture. Pure product (0.791 g, 39% yield, >95% pure by 1H NMR) was a volatile colorless

1 δ 13 to amber liquid. H NMR (500 MHz, CD2Cl2) (ppm) 3.97 (s, 2H), 2.19 (s, 3H). C NMR δ (CD2Cl2) (ppm) 202.1, 58.1, 27.2.

[00501] N-Neopentyl-l-(2-oxopropyl)-lH-l,2,3-triazole-4-carboxamide. A solution of l-azidopropan-2-one obtained above (442 mg, 4.47 mmol, 1.2 eq.) and N- neopentylpropiol-amide (500 mg, 3.59 mmol, 1.0 eq.) in a mixture of AcN (10 ml) and water (1.0 ml) was stirred and heated to 6 O0C in a closed vial for 4 hr in the presence of copper wire. After cooling to r.t., the copper was removed, the mixture was concentrated in vacuo and dried in HV to give the crude product as an off-white solid (907 mg, quant, yield, >95% pure by LC-MS and 1H NMR). (CaIc, mass: 238, obs. mass: 2 11, 239). 1H NMR (500 MHz, δ DMSO-d 6) (ppm) 8.38 (s, IH), 8.29 (t, = 6.6 Hz, IH), 5.54 (s, 2H), 3.09 (d, J = 6.6 Hz, 1 δ 2H), 2.23 (s, 3H), 0.88 (s, 9H). H NMR (500 MHz, CD2Cl2) (ppm) 8.1 1 (s, IH), 7.25 (bs, 13 IH), 5.30 (s, 2H), 3.26 (d, J = 6.6 Hz, 2H), 2.30 (s, 3H), 1.00 (s, 9H). C NMR (CD2Cl2) δ (ppm) 198.6, 160.0, 144.0, 127.0, 58.9, 50.3, 32.3, 27.2. The crude product contained traces of azidoacetone (1H NMR), which could be removed by extended drying in HV at elevated temperature or by crystallization.

[00502] l-(2-Methyl-5-nitropyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4- carboxamide. A mixture of the compound obtained above (106 mg, 0.445 mmol, 1.0 eq.), nitromalondialdehyde sodium salt (prepared as above) (62 mg, 0.445 mmol, 1.0 eq.), ammonium acetate (171 mg, 2.224 mmol, 5.0 eq.), EtOH (0.5 ml), and water (0.5 ml) was stirred and heated for 8 hr at 800C in a closed vial. A deep red solution formed, and a solid product precipitated. After cooling to 0°C, the precipitated solid was filtered, washed with cold EtOH-water (1:1) MeOH, air dried, and dried in HV. The gray solid was pure target product (30.8 mg, 22% yield), >98% pure by LC-MS and 1H NMR). Alternatively, 1.5 eq. of nitromalondialdehyde sodium salt was used, and the reaction was run at 600C overnight. After cooling, the reaction mixture was diluted with water (50 ml), and the product was extracted with DCM. The combined organic layers were dried (Na SO4), concentrated in vacuo and the residue was purified by column chromatography (SiO2, 0-50% EtOAc/DCM) to give pure product as a pale yellow solid. Also, the product can be purified by crystallization from MeOH or MeOH/water. (CaIc. mass: 318, obs. mass: 204, 219, 245, 1 δ 262). H NMR (500 MHz, DMSO-d6) (ppm) 9.47 (d, J = 2.4 Hz, IH), 9.1 1 (s, IH), 8.88 (d, J = 2.4 Hz, IH), 8.53 (t, J = 6.6 Hz, IH), 3.14 (d, 6.6 Hz, 2H), 2.56 (s, 3H), 0.92 (s, 9H).

[00503] l-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylpyridin-3-yl)-N-neopentyl- . lH-l,2,3-triazole-4-carboxamide was synthesized as before. Route D: Alternate orientation of amide linker.

[00504] Ethyl 5-(4-(tert-butoxycarbonyI)-lH-l,2 3-triazoI-l-yl)-6-niethylnicotinate. A solution of c (458 mg, 2.22 mmol, 1.0 eq.) and tert-butyl propiolate (458 µl, 3.33 mmol, 1.5 eq) in AcN/water (10:1, 8.8 ml) was stirred overnight at 800C in a closed vial in a presence of copper wire. The solution, was concentrated, dried in HV, and the crude product was purified by column chromatography (SiO , 0 - 50% EtOAc/DCM) to give pure target compound (665 mg, 90% yield, 99% pure by LC-MS) as a dark oil. (CaIc. mass: 332, obs. 1 δ mass: 318). H NMR (500 MHz, acetone-d 6) (ppm) 9.21 (d, J = 2.0 Hz, IH), 8.91 (s, IH), 8.45 (d, J = 2.0 Hz, IH), 4.44 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.63 (s, 9H), 1.41 (t, J = 7.1, 3H).

[00505] l-(5-(Ethoxycarbonyl)-2-methylpyridin-3-yl)-lH-l,2,3-triazole-4-carboxylic acid. A solution of the compound obtained above (664 mg, 2.00 mmol) in TFA —water (95:5, 10 ml) was stirred for 1 hr at r.t., concentrated, dissolved in AcN (10 ml), concentrated, and dried in HV. The crude product was stirred with diethyl ether (40 ml), the solid was separated by filtration, washed with diethyl ether, and dried in HV to give the target compound (523 mg, 94% yield, 99% pure by LC-MS) as a light brown solid. (CaIc. mass: 1 δ 276, obs. mass: 277). H NMR (500 MHz, DMSOd 6) (ppm) 9.23 (s, IH), 9.17 (d, J = 2.0 Hz, IH), 8.45 (d, J = 2.0 Hz, IH), 4.39 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[00506] Ethyl 6-methyl-5-(4-(neopentylcarbamoyl)-lH-l,2,3-triazoI-l-yI)nicotinate. Neopentyl amine (239 µl, 2.00 mmol, 2.0 eq.) was added to a mixture of the compound obtained above (276 mg, 1.00 mmol, 1.0 eq.), BOP (885 mg, 2.00 mmol, 2.0 eq.), and DCM (5.0 ml), followed by addition of DIEA (697 µl, 4.00 mmol, 4.0 eq). The mixture was stirred at r.t. for 3 hr, then aq. NH OAc (2.8 g in 10 ml water) was added and the mixture was stirred at r.t. for 2 hr to hydrolyze the excess of BOP. The mixture was concentrated, dried in HV, θ and the crude product was purified by column chromatography (Si 2, 0-10% MeOH in DCM) to give pure target compound (330 mg, 95% yield, 99% pure by LC-MS) as an off- + + + white solid. (CaIc. mass: 345, obs. mass: 318 (MH -N2), 346 (MH ), 387 (MH -I-AcN), 409 (MNa++AcN)).

[00507] 6-MethyI-5-(4-(neopentylcarbamoyl)-lH-l,2,3-triazol-l-yl)nicotinic acid. 2M Aqueous NaOH (1.0 ml, 2.00 mmol, 2.1 eq) was added to a solution, of the compound obtained above (326 mg, 0.942 mmol, 1.0 eq.) in EtOH (5.0 ml) and THF (5.0 ml). The mixture was stirred at r.t. for 2 hr, cone in vacuo, and neutralized with IM aq. HCl (3.0 ml). The precipitated solid was sonicated, filtered, washed with water, air dried, and dried in HV to give the target compound (271 mg, 90% yield, 99% pure by LC-MS) as a white solid. (CaIc. mass: 317, obs. mass: 176, 202, 243, 262, 289, 318, 359). 1H NMR (500 MHz, δ DMSO-d 6) (ppm) 13.72 (s, IH), 9.15 (d, J = 2.0 Hz, IH), 9.09 (s, IH), 8.50 (t, J = 6.6 Hz, IH), 8.38 (d, J = 2.0 Hz, IH), 3.15 (d, J - 6.6 Hz, 2H), 2.49 (s, 3H), 0.93 (s, 9H).

[00508] N-(3-tert-butyl-5-cyanophenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-lH- l,2,3-triazol-l-yl)nicotinamide. A mixture of the compound obtained above (31.7 mg, 0.100 mmol, 1.0 eq.), 3-amino-5-tert-butylbenzonitrile (34.8 mg, 0.200 mmol, 2.0 eq.), BOP (88.5 mg, 0.200 mmol, 2.0 eq.), DIEA (70 µl, 0.400 mmol, 4.0 eq.), and DCM ( 1.0 ml) was stirred at r.t. for 2 hr, then heated to 500C for 0.5 hr in a closed vial. After cooling, the mixture was diluted with DCM (50 ml) and the organic layer was washed with water, dried

(Na 2SO4), concentrated in vacuo, and dried in HV. The crude product was purified by column θ chromatography (Si 2, 0-50% EtOAc in DCM) to give pure target compound (42.1 mg, 88% + yield, 88-97% pure by LC-MS as a white solid. (CaIc. mass: 473, obs. mass: 446 (MH -N2), 474 (MH+)). Example 3: Additional derivatization reactions.

[00509] 3-(Aminomethyl)-5-tert-butyl- Λ-(5-(4-(l-hydroxymethyl)phenyI)-6- methylpyridin-3-yl)-2-methoxybenzamide. A spatula of Pd/C (10 wt. %) was added to a solution of iV-(5-(4-acetylphenyl)-6-methylpyridin-3-yl)-5-tert-butyl-3-cyano-2- methoxybenzamide ( 10 mg, 0.023 πunol) (obtained by the methods described above) in EtOH (2 ml). The mixture was stirred under H atmosphere overnight at r.t., and filtered through celite. The filtrate was concentrated and the residue purified using preparative

RP-HPLC (gradient: 10-95% AcN in H2O) to give the title compound (6.8 mg, 67% yield, >95% pure by LC-MS) as an off-white solid. (CaIc. mass: 448, obs. mass: 448).

[005 10] 5-tert-Butyl-3-(4-(hydroxymethyl)-lH-l,2,3-triazoH-yl)-2-methoxy-N-(6- methyl-5-(4-(neopentylcarbamoyI)phenyl)pyridin-3-yl)benzamide. 3-Azido-5-tert-butyl- 2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide (obtained from intermediate S using the methods described herein) (0.226 g, 0.43 mmol) was dissolved in AcN (2 ml). Prop-2-yn-l-ol (0.24 g, 4.28 mmol), copper wire and water (200 µl) were added and the vial was capped and heated to 1000C overnight. The mixture was portioned between EtOAc and brine, and the organic layer was dried over Na2SO , filtered and evaporated. The residue was purified using silica gel chromatography, affording the target compound in 125 mg yield. (CaIc. mass: 584.7, obs. mass: 585.2).

[005 11] 5-tert-Butyl-3-(4-formyl-lH-l,2,3-triazoI-l-yl)-2-methoxy-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yI)benzamide. The compound from the previous step (0.125 g 0.21 mmol) was dissolved in DCM (5 ml) and Dess-Martin reagent (0.136 g, 0.32 mmol) was added. The reaction was stirred for 48 min. and saturated aq. NaHCO (2 ml), and 10% Na S O (2ml) were added. Stirring was continued for 20 min and the layers were separated. The aqueous layer was extracted with DCM and the combined DCM phases containing the intermediate aldehyde were divided in 2 ml aliquots (8 aliquots), which were subjected to reductive amination as exemplified below.

[005 12] 5-tert-Butyl-2-methoxy-N-(6-methyl-5-(4-(neopentyIcarbamoyl)phenyl)- pyridin-3-yI)-3-(4-(pyrroUdin-l-yImethyl)-lH-l,2,3-triazoI-l-yl)benzamide (R = H, pyrrolidinyl). To the aldehyde solution from above, acetic acid (30 µl, 0.534 mmol) was µ added, followed by pyrrolidine (24 l, 0.27 mmol), and NaBH(OAc) 3 (57 mg, 0.27 mmol). The mixture was sonicated and then shaken at r.t. overnight. The solvent was evaporated, and the residue was purified via preparative HPLC yielding 8.7 mg of the target compound. (CaIc. mass: 637.8, obs. mass: 638.2).

[00513] N-(5-(4-(2-An-ino-2-methylpropylcarbamoyl)phenyl)-6-methyIpyridin-3- yl)-3-tert-butyI-5-cyanobenzamide. 4-(5-(3-tert-Butyl-5-cyanobenzamido)-2- methylpyridin-3-yl)benzoic acid (obtained as described in Example 1) (74 mg, 0.18 mmol) was dissolved in DCM (3 ml). Oxalyl chloride (0.16 ml, 1.79 mmol) and DMF (2 drops) were added and the reaction was stirred for 80 min. The reaction was quenched with MeOH, the solvent was removed and the residue was dried in HV. 2-Methylpropane-l ,2-diamine (63 mg, 0.72 mmol) was dissolved in THF (3 ml) and DIEA (0.124 ml). A solution of the compound obtained above in THF (3 ml) was added and the reaction was stirred for 90 min. The solvent was evaporated, and the residue was purified by preparative HPLC. The combined fractions were partitioned between DCM and a small amount of saturated Na COa.

The organic layer was dried over Na2CO3, filtered and evaporated to yield 13.7 mg of the free base. (CaIc. mass: 483.6, obs. mass: 484.1).

[005 14] 3-tert-Butyl-5-cyano-N-(5-(4-(2-(dimethylamino)-2-methyIpropyl- carbamoyl)phenyl)-6-methylpyridin-3-yl)benzamide. The compound obtained above (6 mg, 0.01 mmol) was dissolved in DCM (0.5 ml). Formaldehyde (37% aqueous solution, 1.3 µl, 0.02 mmol) was added and the mixture was stirred for 15 min. Acetic acid (20 µl) and NaBH(OAc)3 (10 mg, 0.47 mmol) were added and stirring was continued for 70 min. The reaction mixture was evaporated and the residue was purified via preparative HPLC. (CaIc. mass: 5 11.7, obs. mass: 512.2).

[005 15] 3-tert-Butyl-5-(isoxazol-4-yl)-N-(6-methyl-5-(4-(neope πtylcarbamoyl)- phenyl)pyridin-3-yl)benzamide. 3-Bromo-5-tert-butyl-2-methoxy-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide (obtained by the methods described herein) (19 mg, 0.03 mmol) and isoxazol-4-ylboronic acid (6 mg, 0.05 mmol) were dissolved µ µ µ in DME (450 l), EtOH (50 l), and toluene (50 l), and Pd(PPh 3)4 (4 mg, 0.003 mmol) and µ a saturated aq. solution of Na CO (34 l) were added. The reaction was flushed with N2 and the vial was capped. The mixture was heated and stirred at 800C overnight. The reaction was allowed to cool to r.t. and the solvent was evaporated under a N stream. The residue was purified using silica gel chromatography, yieleding the target product in 2.3 mg yield. (CaIc. mass: 556.7, obs. mass: 557.1). [005 16] 5-(3-tert-Butyl-5-cyanobenzamido)-2-methyl-3-(4- (neopentylcarbamoyl)phenyl)pyridine 1-oxide. To a solution of 3-tert-butyl-5-cyano-N-(6- methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)benzamide (53.1 mg, 0.11 mmol) in

AcN/MeOH (2 ml, 1:1), H2O2 ( 1 ml, 30%) was added and the mixture stirred at r.t. After 10 min a precipitate formed and MeOH was added until the mixture cleared. The resulting solution was stirred at r.t. for 2 days, the solvent was evaporated and the residue was subjected to RP-HPLC (gradient: 25 to 95% AcN in H2O) to give the target product (8.0 mg, 15%) as a white crystalline solid. (CaIc. mass: 498.6, obs. mass: 501.1).

[005 17] 5-tert-butyl-3-(iV-hydroxycarbainimidoyl)-iV-(5-(4-(l- (hydroxyimino)ethyl)plvenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide. A solution of Λr-(5-(4-acetylphenyl)-6-methylpyridin-3-yl)-5-tert-butyl-3-cyano-2-methoxybenzamide (10 mg, 0.023 mmol), hydroxylamine hydrochloride (4.8 mg, 0.069 mmol, 3.0 eq.) and pyridine (2 drops) in EtOH (1 ml) was stirred at 700C overnight. The clear solution was concentrated and the residue purified using preparative RP-HPLC (gradient: 10-95% AcN in

H2O) to give the title compound (1.5 mg, 14% yield, >95% pure by LC-MS) as an off-white solid. (CaIc. mass: 490, obs. mass: 491).

[00518] l-(2-Methyl-5-(3-(4-methyl-lH-imidazoH-yl)-5-(trifluoromethyl)- benzamido)pyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4-carboxamide and l-(2-methyl- 5-(3-(5-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)benzamido)pyridin-3-yl)-N- neopentyHH-l,2,3-triazoIe-4-carboxamide. A solution of l-(5-(3-fluoro-5- (trifluoromethyl)benzamido)-2-methylpyridin-3-yl)-N-neopentyl-lH-l,2,3-triazole-4- carboxamide (38.4 mg, 0.08 mmol) and 4-methylimidazole (65.9 mg, 0.8 mmol) in DMF (2 ml) was heated in a microwave at 2200C for 3 hr. The solution was diluted with DMF and purified using preparative HPLC, providing a mixture of two isomers, that were not further separable (CaIc. mass: 540.5, obs. mass: 541.0).

[005 19] 3-tert-Butyl-5-cyano-N-(5-(4-(l-(hydroxyimino)-3-methylbutyl)-lH-l,2,3- triazol-l-yl)-6-methylpyridin-3-yl)benzamide. A solution of the compound above (18.9 mg, 42.5 µmol, 1.0 eq.), hydroxylamine hydrochloride (69.5 mg, 1.00 mmol, 23.5 eq.) and EtOH ( 1 ml) was stirred at r.t. for 2 days. A white precipitate formed during the reaction, which was collected by filtration, washed with cold EtOH and water. The solid was dried in HV to give pure target product (10.9 mg, 99% pure by LC-MS). (CaIc. mass: 459, obs. masses: 432, 460).

Biological Testing. Example 1: Inhibition of TNFaproduction in THP cells [00520] The inhibition of cytokine production can be observed by measuring inhibition of TNFa in lipopolysaccharide-stimulated THP-I cells (see Prichett et al. J. Inflammation, 1995, 45, 97). THP-I cells (ATCC TIB 202, American Type Culture Collection, Rockville,

MD) were maintained at 37°C, 5% CO2 in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/1 glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC. For the assay, the cells and compounds were diluted in the media above except with 1% fetal bovine serum (assay media). Test compound stocks in DMSO were diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of less than 0.3% in the assay. THP-I cells were plated at lxl θs/well in 96 well tissue culture plates. Diluted compounds (or DMSO control) were added and allowed to preincubate with the cells at 37°C, 5% CO2 for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 µg/ml. Cells were then incubated 18-20 hours at 37°C/5% CO . The assay was terminated by centrifuging the plates for 10 min at r.t. Supernatants were removed to clean culture plates and aliquots were removed for analysis for TNFa by a commercially available ELISA kit (R&D Systems #DY210, Minneapolis, MN). Data was analyzed by non linear regression using PRISM 4 software from Graphpad Software (San Diego, CA). The calculated IC50 is the concentration of the test compound that caused a 50% decrease in the maximal TNFa production.

[00521] Each of the compounds in List I was tested in the TNFa ELISA assay and was µ found to have activity therein, with most compounds having IC50Sbelow 10 M in this assay. Example 2: Inflammation models [00522] Methods for the testing of systemic lupus erythematosus (SLE) in susceptible mice are known in the art (Knight et al., J. Exp. Med., 1978, 147, 1653; Reinersten et al., New Eng. J. Med., 1978, 299, 515). Myasthenia Gravis (MG) is tested in SJL/J female mice by inducing the disease with soluble AchR protein from another species (Lindstrom et al., Adv. Immunol., 1988, 42, 233). Arthritis is induced in a susceptible strain of mice by injection of Type II collagen (Stuart et al., Ann. Rev. Immunol., 1984, 42, 233). A model by which adjuvant arthritis is induced in susceptible rats by injection of mycobacterial heat shock protein has been described (Van Eden et al., Nature, 1988, 331, 171). Thyroiditis is induced in mice by administration of thyro globulin as described (Maron et al., J. Exp. Med., 1980, 152, 1115). Insulin dependent diabetes mellitus (IDDM) occurs naturally or can be induced in certain strains of mice such as those described by Kanasawa et al., Diabetologia, 1984, 27, 113. Experimental autoimmune encephalomyelitis (EAE) in mouse and rat serves as a model for MS in human. In this model, the demyelinating disease is induced by administration of myelin basic protein (see Paterson, Textbook of Immuopathology, Mischer et al., eds., Grune and Stratton, New York, 1986, pp. 179-213; McFarlin et al., Science, 1973, 179, 478: and Satoh et al., J. Immunol., 1987, 138, 179). Examples are described in more detail below.

[00523] Collagen Induced Arthritis model in mice. Immunization of for example, DBA/1 mice with murine type II collagen induces a chronic relapsing polyarthritis that provides a strong model for human autoimmune arthritis. The model is described, for example, by Courtenay et al., Nature, 1980, 282, 666; Kato et al., Ann. Rheum. Dis., 1996, 55, 535; and Myers et al., Life ScL, 1997, 61, 1861-1878, each of which is incorporated herein by reference. Briefly, mice are quarantined for at least three days. On day 0, the mice are weighed and separated into treatment groups. The non-diseased control group animals receive no adjuvant (10 mice), in contrast to diseased mice (20 mice/treatment group). The mice are anesthetized, shaved at the base of tail, and injected (id) with adjuvant (50 µl/mouse; 100 µg/mouse collagen; lOOµg/mouse M. tuberculosis H37Ra), using a 1 ml syringe fitted with a 26 G needle. On day 2 1, the adjuvant is prepared by emulsifying (in an homogenizer) a 1:1 combination of collagen and M. tuberculosis H37Ra. The adjuvant is injected (id) (50 µl/mouse; 100 µg/mouse collagen; lOOµg/mouse M. tuberculosis H37Ra) using 1 ml syringe fitted with a 26 G needle. On days 22-27 the macroscopic signs of arthritis are scored daily. Each paw receives a score: 0 = no visible effects of arthritis; 1 edema and/or erythema of one digit; 2 = edema and/or erythema of two joints; 3 = edema and/or erythema of more than two joints; or 4 = severe arthritis of the entire paw and digits. The Arthritic Index is calculated by addition of all the individual paw scores, and recorded (maximum arthritic index = 16). On day 28 the mouse weights are recorded and the macroscopic signs of arthritis are scored. The mice are sorted into treatment groups (10 mice/group) based upon their arthritic index. Each treatment group is designed to have a similar average Arthritic Index and a similar range of arthritic indices. The dosing regimen by oral route is initiated. On day 29-42 the mice are dosed,and any adverse effects of test agent administration are recorded. The macroscopic signs of arthritis for each paw are scored daily. On day 43 the macroscopic signs of arthritis are scored, the mice are exsanguinated and their blood is collected in heparinized tubes. The hindlimbs and/or forelimbs are removed and immersed in four volumes of 10% buffered formalin. The paws are evaluated for decalcification and histology. Livers are removed and their weights are recorded.

[00524] Collagen Induced Arthritis model in rats. Female Lewis rats, (Charles River ref #7218419), weighing 125-150 g on arrival (8/group for arthritis, 4/group for normal control), are housed 4/cage, and are acclimated for 4-8 days after arrival. Acclimated animals are anesthetized with Isoflurane and given collagen injections (DO). On day 6 they are anesthetized again for the second collagen injection. Collagen is prepared by making a 4 mg/ml solution in 0.01 N acetic acid. Equal volumes of collagen and Freund's incomplete adjuvant are emulsified by hand mixing until a bead of this material holds its form when placed in water. Each animal receives 300 µl of the mixture each time spread over 3 subcutaneous sites on its back. Caliper measurements of normal (pre-disease) right and left ankle joints are collected on day 9. On days 10-1 1, the onset of arthritis occurs and the rats are randomized into treatment groups. Animals to be given vehicle or compound doses are enrolled and qd (24 hr. intervals) dosing is initiated for days 1-6 using a volume of 5 ml/kg for oral solutions. The rats are weighed on days 1-7 of arthritis; caliper measurements of ankles are taken every day. The final body weights are collected on day 7 of arthritis. On day 7, the animals are anesthetized for whole blood draw to exsanguinate (serum can be used for clinical chemistry) and then euthanized. Both hind paws and knees are removed, the hind paws are weighed and then (with knees) placed in formalin and processed for microscopy. Following 1-2 days in fixative and 4-5 days in decalcifier, the ankle joints are cut in half longitudinally, the knees are cut in half in the frontal plane, processed, embedded, sectioned and stained with toluidine blue. The arthritic ankles and knees are given scores of 0 (normal) -5 (severe effects) for inflammation, pannus formation and bone resorption. Percent inhibition of paw weight and AUC is calculated using the following formula:

% Inhibition^ A - B/A 100

with A = (Mean Disease Control —Mean Normal) and B = (Mean Treated - Mean Normal).

[00525] Inflammatory Bowel and Crohn's Disease Models. To evaluate the effectiveness of test compounds in Crohn's disease, the TNF∆ARE transgenic mouse model of Crohn's disease (originally described by Kontoyiannis et al., Immunity, 1999, 10, 387) is used (the DSS (dextran sodium sulfate) model can also be used in a similar fashion). The animals develop an IBD phenotype with similarity to Crohn's disease starting between 4 and 8 weeks of age. Test compounds are administered at either 3 weeks of age (to test prevention of disease) or 6 weeks of age (to test stabilization, prevention of progression or reversal of disease symptoms), and animals are scored by weight and histologically as described herein. Test compositions are administered either weekly or twice weekly, or can be administered continuously, for example, using an osmotic pump. Alternatively, oral delivery formulations can also be applied. The studies are continued for up to 7 weeks or more once initiated. Animals can be monitored for bowel disease according to a standard scale as described in Kontoyiannis et al., 2002, supra. Paraffin-embedded intestinal tissue sections of ileum are histologically evaluated in a blinded fashion according to the following scale: Acute and chronic inflammation are assessed separately in a minimum of 8 high power fields (hpf) as follows —acute inflammatory score: O=(O-I) polymorphonuclear (PMN) cells per hpf (PMN/hpf); l=(2-10) PMN/hpf within mucosa; 2=(ll-20) PMN/hpf within mucosa; 3=(21- 30) PMN/hpf within mucosa or ( 11-20) PMN/hpf with extension below muscularis mucosae; and 4=>30 PMN/hpf within mucosa or >20 PMN/hpf with extension below muscularis mucosae. Chronic inflammatory score: O=(O-IO) mononuclear leukocytes (ML) per hpf (ML/hpf) within mucosa; I=(1 1-20) ML/hpf within mucosa; 2=(21-30) ML/hpf within mucosa or ( 11-20) ML/hpf with extension below muscularis mucosae; 3=(31-40) ML/hpf within mucosa or (21-30) ML/hpf with extension below muscularis mucosae or follicular hyperplasia; and 4=>40 ML/hpf within mucosa or >30 ML/hpf with extension below muscularis mucosae or follicular hyperplasia. Total disease score per mouse is calculated by summation of the acute inflammatory or chronic inflammatory scores for each mouse.

[00526] Efficacy in the TNF∆ARE model of Crohn's disease is shown by any of: i) a failure to develop disease symptoms when administered to animals beginning at 3 weeks of age; ii) lessened severity of disease symptoms appearing when administered starting at 3 weeks of age, relative to control animals; iii) failure to progress to more severe disease or progression at a lower rate relative to control animals when administered beginning at 6 weeks of age; iv) reversal of symptoms at any of 7, 8, 9, 10, 11, 12, or 14 weeks when administered to an animal beginning at 6 weeks of age. In particular, treatment is considered effective if the average hfstopathological disease score is lower in treated animals (by a statistically significant amount) than that of a vehicle control group. Treatment is also considered effective if the average histopathological score is lower by at least 0.5 units, at least 1.0 units, at least 1.5 units, at ieast 2.0 units, at least 2.5 units, at least 3.0 units, or by at least 3.5 units relative to the vehicle-only control group. Alternatively, the treatment is effective if the average histopatholigical score remains at or is lowered to 0 to 0.5 throughout the course of the therapeutic regimen.

[00527] Other models of IBD include, for example, the DSS model of chronic colitis in BALB/c mice. The DSS model was originally described by Okayasu et al., Gastroenterology, 1990, 98, 694 and was modified by Kojouharoff et al., Clin Exp. Immunol. 1997, 107, 353 (see also WO 2004/041862, incorporated herein by reference). BALB/c mice weighing 21-22 g are treated to induce chronic colitis by the administration of DSS in their drinking water at 5% w/v in cycles of 7 days of treatment and 12 days recovery interval without DSS. The 4th recovery period can be extended from 12 to 2 1 days to represent a chronic inflammation status, rather than the acute status modeled by shorter recovery. After the last recovery period, treatment with a compound of the invention, optionally with one or more ingredient(s) A, is initiated. Weekly administration is recommended initially, but can be adjusted by one of skill in the art as necessary. At intervals during treatment, animals are killed, the intestine is dissected and histopathological scores are assessed as described herein or as described in Kojouharoff et al., 1997, supra. Other animal models of inflammatory bowel disease include the chronic intestinal inflammation induced by rectal instillation of 2,4,6-Trinitrobenzene sulfonic acid (TNBS; method described by Neurath et al., J. Exp. Med., 1995, 182, 1281; see also U.S. Patent No. 6,764,838, incorporated herein by reference). Histopathological scoring can be performed using the same standard described above.

Example 3: Clinical Inflammatory Disease Assessments [00528] Ex-vivo LPS challenge endotoxemia model. Ex-vivo treatment of blood from patients treated with anti-inflammatory compounds with endotoxin represents a safe, well-defined model of acute inflammation in humans. It is also an excellent tool to study the mechanisms contributing to inflammatory responses in man in vivo. Given the importance of the balance of inflammatory and anti-inflammatory cytokines and other factors in the etiology of inflammatory diseases such as rheumatoid arthritis and Crohn's disease, evaluation of cytokine inhibitors in a human LPS model could prove beneficial in elucidating potential effects of anti-inflammatory compounds in human inflammatory processes.

[00529] Compounds described herein are administered orally at different doses to human volunteers. After 1 to 24 hours, blood samples are collected via venepuncture into vacutainer tubes and heparinized. Prior to the stimulation assay, a monocyte count is performed for each individual's undiluted heparinized whole blood sample (Cell Dyn 3500 SL). For this purpose a small volume (100-200 µl) is aspirated directly form the whole blood sample into the analyzer. For each sample and for each subject the following stimulation assays are performed: a. Unstimulated control (only vehicle) and b. Stimulated: 10 ng/ml LPS (final concentration). The stimulation assays are performed within one hour after withdrawal of the whole blood samples. The stimulation assay procedure is as follows.

1. Dilute the whole blood sample 1 + 1 with RPMI- 1640 medium; mix gently by inversion. 2. Pipette the diluted whole blood into each of the two separate sterile tubes (one for each condition). 3. Add to each tube 200 µl of the appropriate LPS stock (or blank) to yield the above-listed final LPS concentrations. Mix gently by inversion. 4. From each tube, add gently 0.5 ml per well into multiple (e.g., eight) master block wells. 5. Any empty wells should be filled with 0.5 ml of PBS buffer. 6. Cover the master blocks with their specific covers. 0 7. Incubate for 24 hours at 37 C and 5% CO2. 8. At the end of the incubation period, centrifuge the blocks at 1000 x g for 10 minutes at r.t. 9. Collect the supernatants and pool the appropriate wells into their appropriate polypropylene tubes (expected yield at 1+1 whole blood dilution: 40-60% of volume). 10. Mix and aliquot into separate tubes; one for each cytokine to be analyzed (target supernatant volume per aliquot: 0.5 ml). 11. Store samples at -700C until analysis.

[00530] TNF- , IL-1& IL-6 or other cytokines are analyzed using validated ELISA methods.

[0053 1] Rheumatoid Arhritis disease assessment. Rheumatoid arthritis is clinically scored on the basis of several clinically accepted scales, such as those described in U.S. Patent No. 5,698, 195, which is incorporated herein by reference, and Aletaha et al., Clin. Exp. Rheumatol. 2005, 23 (suppl. 39), S 100. Disease activity and change effected with treatment can be evaluated using the disease activity score (DAS) and/or the chronic arthritis systemic index (CASI), see Carotti et al., 2002, Ann. Rheum. Dis. 61:877-882, and Salaffi et al., 2000, Rheumatology 39: 90-96. Briefly, clinical response studies can assess the following parameters: A. Number of tender joints ; B. Number of swollen joints (Both tenderness and swelling are evaluated for each joint separately); and C. Visual analog pain scale (0-10 cm). Clinical response is assessed using a subjective reporting system as follows: Without any difficulty, With some difficulty, With much difficulty, or Unable to do. The visual analog scale for pain is a straight line with the left end of the line representing no pain and the right end of the line representing the worst pain. Patients are asked to mark on the line where they think their pain is.

[00532] Additionally, blood chemistry analysis determines levels of CRP, Rheumatoid Factor, cytokines and other biomarkers.

[00533] Crohn's Disease assessment: Crohn's Disease Activity Index. The CDAI is a patient assessment form incorporating both objective and subjective information. Using established criteria the physician calculates the CDAI score. CDAI scores > 150 indicate active disease with a poorer prognosis than scores < 150. (See Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's disease activity index., National

Cooperative Crohn's Disease Study. Gastroenterology 1976; 70: 439-444; Winship DH5 Summers RW, Singleton JW, et al. National Cooperative Crohn's Disease Study: study design and conduct of the study. Gastroenterology 1979; 77: 829-842).

[00534] Psoriasis disease assessment. Efficacy of psoriasis treatment can be monitored by changes in clinical signs and symptoms of the disease, including Psoriasis Area and Severity Index (PASI) scores, physician's global assessment (PGA) of the patient compared with the baseline condition. A decrease in PASI score indicates a therapeutic effect. Psoriatic disease activity can also be determined based on Overall Lesion Severity (OLS) scale, percentage of total body surface area (BSA) affected by psoriasis, and psoriasis plaque thickness. Skin biopsies are studied for the effects of the drug on lymphocytes within psoriatic lesions. Histological analysis of skin biopsies can be performed to look for reduction in epidermal thickness arid T-cell infiltration and reversal of pathological epidermal hyperplasia. Immunological activity can be monitored by testing for the effects of treatment on cell-mediated immunity reactions (delayed hypersensitivity), tetanus antibody responses, and lymphocyte subpopulations (flow cytometry).

Example 4: Cardiovascular and. metabolic disease models [00535] Lipid determinations. The anti-atherosclerotic activity of compounds may be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain animals, for example marmosets (Crook et al. Arteriosclerosis 10, 625, 1990) or Golden Syrian Hamsters (Goulinet et al., J. Lipid Res., 34, 943, 1993), and others, that possess a plasma lipoprotein profile similar to that of humans.

[00536] Blood chemistry evaluation in Marmosets. Adult marmosets are assigned to treatment groups so that each group has a similar mean.+/-SD for total, HDL, and/or LDL plasma cholesterol concentrations. After group assignment, the marmosets are dosed daily with compound as a dietary admix or by intragastric intubation for from one to eight days. Control marmosets receive only the dosing vehicle. Plasma total, LDL VLDL and HDL cholesterol values may be determined at any point during the study by obtaining blood from an antecubital vein and separating plasma lipoproteins into their individual subclasses by density gradient centrifugation, and by measuring cholesterol concentration as previously described (Crook et al. Arteriosclerosis 10, 625, 1990).

[00537] Blood chemistry evaluation in cynomolgous monkeys. Sixteen male and 16 female cynomolgous monkeys are assigned to four dose groups. A compound is formulated in a suitable vehicle at low, medium, and high concentrations. The three dosages of the compound and vehicle alone are administered once daily by oral gavage for 90 consecutive days to all male and female monkeys in the corresponding dose group. Blood samples (4 to 6 ml) are collected from the femoral vein at days 0, 28, and 90. The blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol, triglyceride and total bilirubin levels, which are determined by standard methods.

[00538] Blood chemistry evaluation in Wistar rats. Eighty male and 80 female Wistar rats are assigned to four dose groups. A compound is formulated in a suitable vehicle at low, medium, and high concentrations. The three dosages of the compound and vehicle alone are administered once daily by oral gavage for 90 consecutive days to all male and female rats in the corresponding dose group. Blood samples (2 to 3 ml) are collected via the orbital sinus at days 0, 28, and 90. The blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol levels, which are determined by standard methods.

[00539] Blood chemistry evaluation in Golden Syrian Hamsters. Female Golden Syrian Hamsters (6-8 weeks old) were quarantined for 72 hours and then assigned to treatment groups. A sample bleed was taken by retro-orbital bleed on day 0, prior to dosing, and processed to 1 ml serum in pre-chilled EDTA-treated tubes. Each serum sample was aliquoted to 0.5 ml and 0.3 ml volumes and stored at -200C until shipment. Subsequently the test compound or vehicle was administered orally (typically 5 ml/kg, for a dose of 30 mg/kg). Once daily dosing at those doses was continued on days 1-13. On day 2, day 6 or 13, terminal bleeds were taken several hours after the final oral dose, and the sera were processed, aliquoted and stored as before. Lipid analysis and clinical chemistry panel analysis was performed on all bloodsamples.

[00540] Rabbit Atherosclerosis Assay. Anti-atherosclerotic effects of the compounds may be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta. Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar mean.+/-SD for total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration and/or cholesteryl ester transfer protein activity. After group assignment, rabbits are dosed daily with compound given as a dietary admix or on a small piece of gelatin based confection. Control rabbits receive only the dosing vehicle, be it the food or the gelatin confection. The cholesterol/coconut oil diet is continued along with the compound administration throughout the study. Plasma cholesterol values may be determined at any point during the study by obtaining blood from the marginal ear vein. After 3-5 months, the rabbits are sacrificed and the aortae are removed from the thoracic arch to the branch of the iliac arteries. The aortae are cleaned of adventitia, opened longitudinally and then analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42- 47). The percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System,(Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percent of lesioned surface area in the compound-receiving group in comparison with the control rabbits.

[00541] Cuff induced accelerated atherosclerosis. The compounds are tested in a mouse model for restenosis and accelerated atherosclerosis based on cuff placement around the femoral artery in ApoE3 Leiden mice (Lardenόye et al. Circ Res. 2000, 87(3):248-53). The model is highly regulated by inflammatory factors (Pires et al. Cardiovasc Res, 68 (2005) 415 -424) including TNFa (Monraats et al. FASEB J 2005;19: 1998-2004) and MCP-I, as has been demonstrated by Egashira et al (Circ Res 2002; 90: 1167-72). Cuff placement in ApoE3 Leiden mice receiving a mild hypercholesterolemic diet results in a rapid adhesion and infiltration of monocytes, followed by a rapid induction of neointima formation, and in the induction in foam cell accumulation within the cuffed vessel segment.

[00542] Briefly, male ApoE3 Leiden mice (age 12 weeks) are fed a mildly hypercholesterolemic diet for 3 weeks prior to surgical cuff placement. After 3 weeks mice are divided in 3 groups, matched for plasma cholesterol levels. The mice either receive daily (from day-1 on) a control gavage solution or a gavage solution containing test compound (typically at a concentration of 30 mg/kg). On day 0 surgery is performed, i.e. a non- constricting cuff (2-3 mm in length) is placed around both the femoral arteries of the mice. Mice are sacrificed after 2 days for analysis of monocyte adhesion and infiltration, and additional mice are sacrificed after 2 weeks for histomorphometric analysis to quantify the (inhibition of) accelerated atherosclerotic lesions and neointima formation.

Example 5: Clinical Cardiovascular and Metabolic Disease Assessments [00543] Anti-obesity assay. The ability of compounds to cause weight loss may be assessed in obese human subjects with body mass index (BMI) ≥30 kg/m2. Doses of inhibitor are administered sufficient to result in an increase of ≥ l 5% in HDL cholesterol levels. BMI and body fat distribution, defined as waist (W) to hip (H) ratio (WHR), are monitored during the course of the 3-6 month studies, and the results for treatment groups compared to those receiving placebo.

[00544] Diagnostic methods for glucose and insulin disorders. Oral glucose tolerance testing (OGTT). During a glucose tolerance test, which may be used to diagnose diabetes mellitus, a fasted subject takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over the following 2 hours. Interpretation is based on WHO guidelines, but glycemia greater than or equal to 11.lmmol/1 at 2 hours or greater than or equal to 7.0mmol/L fasting is diagnostic for diabetes mellitus. OGTT can be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial (after the meal) peak in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip", which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

[00545] Hyperinsulinemic euglycemic clamp. The standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 10-120 mU per m2 per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol/1. The rate of glucose infusion is determined by checking the blood sugar levels every 5-10 minutes. Low dose insulin infusions are more useful for assessing the response of the liver whereas high dose insulin infusions are useful for assessing peripheral (i.e. muscle and fat) insulin action. The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the subject is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest "impaired glucose tolerance," an early sign of insulin resistance.

[00546] Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some subjects), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment (HOMA) [ Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9], and a more recent method is QUICKI (quantitative insulin sensitivity check index). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies.

[00547] Using a fasting blood sample, insulin resistance (IR) is quantified using the following formula: IR= Glucose (mg/dl)) x Insulin (µU/ml) / 405

[00548] In this equation, one should use the constant 22.5 instead of 405 if the glucose is reported in mmol/1. This model correlates well with estimates using the euglycemic clamp method.

[00549] HOMA IR values between 1.7 and 2.5 are seen in subjects with normal glucose tolerance [Tripathy D, Carlsson M, Almgren P, Isomaa Bo, Taskinen MR, Tuomi T, . Groop LC: Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes 49:975-980, 2000; Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M: Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 47:1643—1649, 1998; Juan F. Ascaso, MD, Susana Pardo, MD, Jose T. Real, MD, Rosario I. Lorente, MD, Antonia Priego, MD and Rafael Carmena, MD Diagnosing Insulin Resistance by Simple Quantitative Methods in Subjects With Normal Glucose Metabolism, Diabetes Care 26: 3320-3325, 2003].

Example 6: Analysis of biomarkers in clinical samples. [00550] Patients with low HDL-C and elevated TG levels, with or without concomitant lipid-lowering therapy (e.g., statins, bile acid sequestrants, or cholesterol absorption inhibitors), are treated with a compound as described herein, administered orally once daily for 6 weeks. A fasting lipid panel (total cholesterol, HDL-C, LDL-C, TG), CRP and general laboratory parameters (CBC, general chemistry panel) are assessed at baseline, every two weeks during dosing and 4 weeks after the end of dosing. At Week 1, patients have a general chemistry panel assessed. Weight, and waist and hip circumference are assessed at each visit, other than Week 1. Lipid/metabolic, inflammatory, and prothrombotic biomarkers are assessed at Baseline, Week 2, Week 4, Week 6 and Follow-up. Urinalysis and coagulation parameters are assessed at baseline and at the end of dosing.

Example 7: Cancer models [00551] Proliferation assay. Human non-small cell lung carcinoma cells A549 0 (ATCC# CCL-1 85), are grown at 37°C +/- 0.5 C and 5% CO2 in DMEM supplemented with 10% FBS, 2 mM glutamine, 1% penicillin, and 1% streptomycin. Anti-proliferation assays are performed in 384-well plates. 6.6 µL of 1Ox stock compound solutions is added to 40 µL of culture media in assay wells. The tumor cells are liberated from the culture flask using a solution of 0.25% trypsin'. Cells are diluted in culture media such that 3000 or 6000 cells are delivered in 20 µL of media into each assay well. Assay plates are incubated for 72-80 hours 0 at 37°C +/-0.5 C with 5% CO2. Twenty microliters of 20% Alamar Blue warmed to 37°C +/- 0.5 0C is added to each assay well following the incubation period. Alamar Blue metabolism is quantified by the amount of fluorescence intensity 3.5-5.0 hours after addition. Quantification, using an LJL Analyst AD reader (LJL Biosystems), is taken in the middle of the well with high attenuation, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 575 nm. For some experiments, quantification is performed using a Wallac Victor2 reader. Measurements are taken at the top of the well with stabilized energy lamp control; a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 590 nm. No significant differences between plate readers are measured.

[00552] The percent inhibition (% I) for each well is calculated using the following formula: % I= [(avg. untreated wells-treated well)/(avg. untreated wells)] x 100

[00553] The average untreated well value (avg. untreated wells) is the arithmetic mean of 40 wells from the same assay plate treated with vehicle alone. Negative inhibition values result from local variations in treated wells as compared to untreated wells. [00554] The anti-cancer effect that can be demonstrated with the tumor cell lines refered to herein can be similarly demonstrated using other cancer cell lines, such as, for example, NSC lung carcinoma, MCF7 mammary adenocarcinoma, PA-I ovarian teratocarcinoma, HT29 colorectal adenocarcinoma, H l 299 large cell carcinoma, U-2 OS osteogenic sarcoma, U-373 MG glioblastoma, U-1 18 MG glioblastoma, U-138 MG glioblastoma, LN-229 glioma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33A cervical carcinoma, HT-3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI- H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell lung carcinoma, HeLa, epithelial cervical adenocarcinoma, KB epithelial mouth carcinoma, HTl 080 epithelial fibrosarcoma, Saos-2 epithelial osteogenic sarcoma, PC3 epithelial prostate adenocarcinoma, SW480 colorectal carcinoma, CCL-228, MS-751 epidermoid cervical carcinoma, LOX IMVI melanoma, MALME-3M melanoma, M14 melanoma, SK-MEL-2 melanoma, SK-MEL-28 melanoma, SK-MEL-5 melanoma, UACC-257 melanoma, or UACC-62 melanoma cell lines. The specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells.

[00555] As will be recogonized by those of skill in the art, many more cancer cell lines, such as those available from American Type Culture Collection (ATCC) (P.O. Box 1549 Manassas, VA 201 08, USA), can be used similarly.

Example 8 [00556] Table 5 lists compounds of the invention prepared using the methods of Examples 1-2. Each compound was analyzed by LC-MS and displayed the expected molecular ion. The compounds of the invention can be assayed by one or more of the above methods and have or are expected to have activity in one or more of the above assays. For example, each of the compounds in Table 5 was tested in the TNFa ELISA assay (Example 3) and found to have activity therein, with some compounds having ICsos below 10 µM in this assay. TABLE 5.

Structure Cmpd Name

3-tert-butyl-5-cyano-N-(6-methyl-5- (3-(neopentylcarbamoyl)phenyl)- pyridin-3-yl)benzamide

N-(5-(4-(benzyloxy)phenyl)-6- methylρyridin-3-yl)-3-tert-butyl-5- cyanobenzamide

3-tert-butyl-5-cyano-N-(5-(4-(3,3- dimethyl-2-oxobutoxy)phenyl)-6- methylpyridin-3-yl)benzamide

4-(5-(5-tert-butyl-2- methoxybenz£imido)-2-methylpyridin- 3-yl)phenyl acetate

3-tert-butyl-5-cyano-N-(5-(4- methoxy-2-methylphenyl)-6- methylpyridin-3-yl)benzamide

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-(neopentylcarbamoyl)phenyl)- pyridin-3-yl)benzamide No. Structure Cmpd Name

3-fluoro-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)-5-morpholinobenzamide

3-tert-butyl-5-cyano-N-(6-methyI-5- (4-(tetrahydro-2H-pyran-4- 8 ylcarbamoyl)phenyl)pyridin-3- yl)benzamide

3-fluoro-N-(5-(4-methoxyphenyl)-6- methylpyridin-3-yl)-5- morpholinobenzamide

N-(5-(4-acetylphenyl)-6- 10 methylpyridin-3-yl)-5-tert-butyl-3- cyano-2-methoxybenzamide

3-(aminomethyl)-5-tert-butyl-N-(5-(4- (1-hydroxyethyl)phenyl)-6- 11 methylpyridin-3-yl)-2- methoxybenzamide

5-tert-butyl-3-(N- hydroxycarbamimidoyl)-N-(5-(4-( 1- 12 (hydroxyimino)ethyl)ρhenyl)-6- methylpyridin-3-yl)-2- methoxybenzamide

5'-(3-tert-butyl-5-cyanobenzamido)-2'- methyl-N-((tetrahydrofuran-2- 13 yl)methyl)-2,3'-bipyridine-5- carboxamide

Structure Cmpd Name

3-fluoro-N-(5-(4-(methoxymethyl)- lH-l,2,3-triazol-l-yl)-6- methylpyridin-3-yl)-5- morpholinobenzamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-neopentyl- 1H-1,2,3-triazole-4-carboxamide

3-tert-butyi-5-cyano-N-(6-methyl-5- (4-(3-methylbutanoyl)-l H-1 ,2,3- triazol- 1-yl)pyridin-3-yl)benzamide

(Z)-3-tert-butyl-5-cyano-N-(5-(4-( 1- (hydroxyimino)-3-methylbutyl)-IH- 1,2,3-triazol-1-yl)-6-methylpyridin-3- yl)benzamide

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-(2-methyl- 1-(neopentylamino)-1- oxopropan-2-yl)-lH-l,2,3-triazol-l- yl)pyridin-3-yl)benzamide

N-(3-tert-butyl-5-cyanophenyl)-6- methyl-5-(4-(neopentylcarbamoyl)- 1H-1 ,2,3-triazol-l -yl)nicotinamide

Structure Cmpd Name

l-(5-(3-fluoro-5- morpholinobenzamido)-2- methylpyridin-3 -yl)-N,N-dimethyl- IH-1 ,2,3-triazole-4-carboxamide

1-(2-methyl-5-(3-morpholino-5- (trifluoromethyl)benzamido)pyridin-3- yl)-N-neopentyl-lH-l,2,3-triazole-4- carboxamide

1-(2-methyl-5-(3-(pyrrolidin- 1-yl)-5- (trifluoromethyl)-benzamido)pyridin- 3-yl)-N-neopentyl-lH-l,2,3-triazole- 4-carboxamide

1-(S-CS-fluoro-S-føiperidin-1- yl)benzamido)-2-methylpyridin-3-yl)- N-neopentyl- IH-1 ,2,3-triazole-4- carboxamide

1-(5-(3-fluoro-5-(pyrrolidin- 1- yl)benzamido)-2-methylpyridin-3-yl)- N-neopentyl-lH-l,2,3-triazole-4- carboxamide

l-(5-(3-fluoro-5- morpholinobenzamido)-2- methylpyridin-3-yl)-N-(2- methylbutyl)-l H-1,2,3-triazole-4- carboxamide

Structure Cmpd Name

1-(5-(3-cyano-5-(piperidin-l- yl)benzamido)-2-methylpyridin-3-yl)- N-((tetrahydrofuran-2-yl)methyl)-1H- 1,2,3-triazole-4-carboxainide

1-(5-(3-cyano-5-(pyrrolidin-1- yl)benzamido)-2-methylpyridin-3-yl)- N-((tetrahydrofuran-2-yl)methyl)-l H- 1,2,3-triazole-4-carboxamide

N-(5-(4-((l -ethylpyrrolidin-2- yl)methylcarbamoyl)phenyl)-6- methylpyridin-3-yl)-3-fluoro-5- morpholinobenzamide

1-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-methylpyridin- 3-yl)-N-neopentyl-lH-l,2,3-triazole- 4-carboxamide

1-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-methylpyridin- 3-yl)-N-(pyridin-3-ylmethyl)-lH- 1,2,3-triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-((1- ethylpyrrolidin-2-yl)methyl)-l H-1 ,2,3- triazole-4-carboxamide Structure d Name

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-(4-methylpiperazine- 1-carbonyl)- 1H-1 ,2,3-triazol-l -yl)pyridin-3- yl)benzamide

1-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-methylpyridin- 3-yl)-N-((tetrahydrofuran-2- yl)methyl)-l H-1,2,3-triazole-4- carboxamide

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-(morpholine-4-carbonyl)-l H-1 ,2,3- triazol-l -yl)pyridin-3-yl)benzamide

1-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methyIpyridin-3-yl)-N-(l - methylpiperidin-4-yl)-l H-1 ,2,3- triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyτidin-3-yl)-N-(2- (pyrrolidin-1-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-(2- (dimethylamino)ethyl)- 1H-1 ,2,3- triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-(2- methoxyethyl)-l H-1 ,2,3-triazole-4- carboxamide Structure Cmpd Name

1-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-(quinuclidin- 3-yI)-IH-1 ,2,3-triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3~yl)-N-(piperidin-4- yl)-l H-1 ,2,3-triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanoben2:amido)- 2-methylpyridin-3 -yl)-N-(piperidin-3- yl)-l H-1 ,2,3-triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3 -yl)-N-(2- hydroxypropyl)- 1H-1 ,2,3-triazole-4- carboxamide

l-(5-(3-fluoro-5-(l ,4-oxazepan-4- yl)benzamido)-2-methylpyridin-3-yl)- N-((tetrahydrofiiran-2-yl)methyl)- 1H- 1,2,3-triazole-4-carboxamide

1-(5-(3-fluoro-S-Cpyrrolidin-1- yl)benzamido)-2-methylpyridin-3-yl)- N-((tetrahydrofυran-2-yl)methyl)- 1H- 1,2,3-triazole-4-carboxamide Structure Cmpd Name

l-(5-(3-cyano-5-(pyrrolidin-l- yl)benzamido)-2-methylpyridin-3-yl)- N-neopentyl-1 H-1,2,3-triazole-4- carboxamide

1-(5-(3-cyano-5-(piperidin- 1- yl)benzamido)-2-methylpyridin-3 -yl)- N-neopentyl-lH-l,2,3-triazole-4- carboxamide

l-(5-(3-cyano-5- morpholinobenzamido)-2- methylpyridin-3-yl)-N-neopentyl- 1H- 1,2,3-triazole-4-carboxamide

l-(5-(3-fluoro-5- thiomorpholinobenzamido)-2- methylpyridin-3-yl)-N-neopentyl-lH- 1,2,3-triazole-4-carboxamide

1- {5-[3-Fhioro-5-(l -oxo-1 λ4- thiomorpholin-4-yl)-benzoylamino]-2- methyl--pyridin-3-yl }-1H- [l,2,3]triazole-4-carboxylic acid (2,2- dimethyl-propyl)-amide

1-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-((l - methylpiperidin-4-yl)methyl)-l H- 1,2,3-triazole-4-carboxamide

Structure Cmpd Name

1-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-((l - methylpiperidin-2-yl)methyl)-l H- 1,2,3-triazole-4-carboxamide

1-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-methylpyridin- 3-yl)-N-((l -methylpiperidin-2- yl)methyl)-l H-1 ,2,3-triazole-4- carboxamide

1-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-cyclohexyl- 1H- 1,2,3-triazole-4-carboxamide

l-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-(piperidin-l- yl)- IH-1 ,2,3-triazole-4-carboxamide

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-((6-methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3- yl)benzamide

5-tert-butyl-3-cyano-2-methoxy-N-(6- methyl-5-(4-((6-methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3- yl)benzamide

Structure Cmpd Name

N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)-2-morpholinoisonicotinamide

3-cyano-N-(6-methyl-5-(4-((6- methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3- yl)-5-morpholinobenzamide

3-cyano-N-(6-methyl-5-(4-((6- methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3- yl)-5-(pyrrolidin- 1-yl)benzamide

3-cyano-N-(6-methyl-5-(4-((6- methylpyridin-2- yl)methylcarbamoyl)phenyl)pyridin-3- yl)-5-(piperidin-l -yl)benzamide

methyl 4-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-methylpyridin- 3-yl)benzoate

3-tert-b tyl-5-cyano-N-(5-(4~ (cyclohexylcarbamoyl)phenyl)-6- methylpyridin-3-yl)benzamide Structure Cmpd Name

3-tert-butyl-5-cyano-N-(5-(4-(2- (diethylamino)ethylcarbamoyl)- phenyl)-6-methylpyridin-3- yl)benzamide

3_-t.e_r.t.--butyl-5-cyano-N-(5-(4-(2- (diisopropylamino)ethylcarbamoyl)ph enyl)-6-methylpyridin-3-yl)benzamide

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-(2-methyl-2-(piperidin- 1- yl)propylcarbamoyl)phenyl)pyridin-3- yl)benzamide

3-tert-butyl-5-cyano-N-(6-methyl-5- (4-(( 1-(piperidin- 1- yOcyclohexyljmethylcarbamoyOpheny l)pyridin-3 -yl)benzamide

3-tert-butyl-5-(((2- methoxyethyl)(methyl)amino)methyl)- N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)benzamide

3-tert-butyl-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)pyridin- 3-yl)-5-(pyrrolidin-l- ylmethyl)benzamide

Structure Cmpd Name

3-tert-butyl-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)-5-(morpholinomethyl)benzamide

3-tert-butyl-N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridiπ- 3-yl)-5-((3-oxopiperazin-l - yl)methyl)benzamide

3-tert-butyl-N-(5-(4-(2-tert- butylhydrazinecarbonyl)- IH-1 ,2,3- triazol-l-yl)-6-methylpyridin-3-yl)-5- cyanobenzamide

3-tert-butyl-5-cyano-N-(5-(4-(2- cyclohexylhydrazinecarbonyl)- 1H- l,2,3-triazol-l-yl)-6-methylpyridin-3- yl)benzamide

1-(5-(3-tert-butyl-5-cyanobenzamido)- 2-methylpyridin-3-yl)-N-(2,6- dimethylpiperidin-1 -yl)-l H-1,2,3- triazole-4-carboxamide

N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)-2-(pyrrolidin-l - yl)isonicotinaraide

No. Structure Cmpd Name

1-(5-(3-fluoro-2-methoxy-5- morpholinobenzamido)-2- 188 methylpyridin-3-yl)-N-neopentyl-1H- 1,2,3-triazole-4-carboxamide

1-(5-(3-fluoro-2-methoxy-5- morpholinobenzamido)-2- 189 methylpyridin-3-yl)-N- ((tetrahydrofuran-2-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide

1-(5-(3-fluoro-2-methoxy-5- morpholinobenzamido)-2- 190 methylpyridin-3-yl)-N-(pyridin-3- ylmethyl)-IH-1,2,3-triazole-4- carboxamide

3-fluoro-2-methoxy-N-(6-methyl-5-(4- (pyridin-3- 191 ylmethylcarbamoyl)phenyl)pyridin-3- yl)-5-morpholinobenzamide

3-fluoro-2-methoxy-N-(6-methyl-5-(4- ((tetrahydrofuran-2- 192 yl)methylcarbamoyl)phenyl)pyridin-3- yl)-5-morpholinobenzamide

3-fluoro-2-methoxy-N-(6-methyl-5-(4- 193 (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)-5-morpholinobenzamide

8049

Structure Cmpd Name

5-tert-butyl-3-cyano-N-(6-methyl-5- (4-(neopentylcarbamoyl)phenyl)- pyridin-3-yl)-2-(2-(4-methylpiperazin- 1-yl)ethoxy)benzamide

3-cyano-N-(6-methyl-5-(4-(N- neopentylsulfamoyl)phenyl)pyridin-3- yl)-5-morpholinobenzamide

3-cyano-N-(6-methyl-5-(4-(N- neopentylsulfamoyl)phenyl)ρyridin-3- yl)-5-(pyrrolidin- 1-yl)benzamide

5-tert-butyl-3-cyano-2-methoxy-N-(6- methyl-5-(4-(N- neopentylsulfamoyl)phenyl)pyridin-3- yl)benzamide

N-(6-methyl-5-(4- (neopentylcarbamoyl)phenyl)-pyridin- 3-yl)isoxazole-3-carboxamide

3-tert-butyl-1-methyl-N-(6-methyl-5- (4-(neopentylcarbamoyl)phenyl)- pyridin-3-yl)-lH-pyrazole-5- carboxamide

5-tert-butyl-2-methyl-N-(6-methyl-5- (4-(neopentylcarbamoyl)- phenyl)pyridin-3-yl)fiiran-3- carboxamide

[00557] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[0055S] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

[00559] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. CLAIMS

What is claimed is:

1. A compound 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 or the NH 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 heteroaryl ring and attached to the NH or carbonyl 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 6-membered aryl or heteroaryl moiety; 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 1hydrogen bond interaction with an ATP-binding pocket of the target protein,

wherein the compound is a cytokine inhibitor.

2. The cytokine inhibitor of claim 1, wherein the targeting moiety is an amide group.

3. The cytokine inhibitor of claim 1, wherein the pocket-expanding moiety comprises a 6 membered aryl or heteroaryl moiety, substituted by a substituted or unsubstituted C2-4 alkyl, C3..9 cycloalkyl, or heterocyclyl group.

4. The cytokine inhibitor of claim 1, wherein the orienting moiety comprises a pyridyl, pyridyl-N-oxide, or pyridazinyl group, substituted by a halogen, methyl or trifluoromethyl group. 5. The cytokine inhibitor of claim 1, wherein the anchoring moiety comprises an amide, amine, carbonyl, alkoxy, urethane, sulfoxide, sulfonamide, or OC(O) group.

6. A compound of Formula I,

stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein X is CH, N, or NO; Y is CH, N, NO, provided that X and Y are not both CH or NO;

A is F, Cl, Br, I, NR2, or a C1-3 alkyl or -0(C 1- alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; G is an aryl or heteroaryl group, wherein G is substituted by one or more R1, R2 or R3; Ar is a 6-membered aryl or heteroaryl group; L1 is -C(O)NH-; 2 L is a covalentbond, (CR' 2)S, (CR' 2)nO(CR'2)t, (CR' 2)nNR(CR'2)t

(CR'2)πC(NOR), (CR' 2)πSO2NR(CR' 2)t, (CR' 2)nC(O)(CR' 2)t, O(CR' 2)tC(O)(CR' 2)n,

O(CR' 2)sNR(CR' 2)n, O(CR' 2)nC(O)NR(CR' 2)t, O(CR' 2)sNRC(O)(CR' 2)π>

(CR'2)nC(O)NR(CR' 2)t, (CR' 2)nC(O)NRNR(CR' 2)t, or (CR' 2)nNRC(O)O(CR' 2)t group; Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl group; 1 each R is independently F, Cl, Br, I, -NR2, -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heterocyclylalkyl group; each R2 is independently F, Cl, Br, I, -CN, -NO , a substituted or unsubstituted

alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR' 2, -C(NR)NR2, -C(NR)NROR, -NR' 2, -NRC(O)R", -NR' C(O)OR", -NR' SO2R",

-NR'C(O)NR' 2, -NR'C(S)NR 2, -S(O) mR", or -SO2NR' 2; each R3 is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an -0(C alkyl) group, wherein the C alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted Ci-e alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl or heterocyclylalkyl group;

each m is independently O, 1 or 2; n is 0, 1, or 2; s is 1, 2 or 3; and each t is independently 0, 1, or 2; provided the compound is not 5-(biphenyl-4-yl)-6-chloro-N-(6- methoxypyridin-3-yl)nicotinamide.

7. The compound of claim 6, wherein Ar is phenyl, pyridyl, pyrimidyl, or pyridazinyl.

8. The compound of claim 7, wherein Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

9. The compound of claim 6, wherein the compound is

10. The compound of claim 6, wherein the compound is 11. The compound of claim 6, wherein the compound is

12. The compound of claim 6, wherein the compound is

13. The compound of claim 6, wherein A is F, -CH 3, or -CF3.

14. The compound of claim 6, wherein G is a phenyl, pyrimidyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, or furanyl group.

15. The compound of claim 6, wherein G is a phenyl group.

16. The compound of claim 14, wherein G is

17. The compound of claim 6, wherein L2 is a covalent bond, O, NR,

C(O)(CH2)n, C(NOR), SO2NR, O(CH2)tC(O), C(O)NR, C(O)NRNR OrNRC(O)O group.

18. The compound of claim 6, wherein L2 is a covalent bond, O, OC(O),

C(NOH), SO2NH, OCH2C(O), C(O), C(O)CH2, C(O)CH2CH2, C(O)NHNH, or C(O)NH.

19. The compound of claim 6, wherein Q is a substituted or unsubstiruted alkyl, cycloalkyl, (C0-4 alkyl)phenyl, (C0- alkyl)pyridyl, (C0-4 alkyl)pyrimidinyl,

(Co-4 alkyl)morpholinyl, (Co-4 alkyl)thiomorpholinyl, (C0-4 alkyl)quinuclidinyl, 2 6 (C0-4 alkyl)(10-oxa-4-aza-tricyclo[5.2.1.0 ]decanyl), (C0-4 alkyl)(8-oxa-3-aza- bicyclo[3.2.1]octanyl), (C0-4 alkyl)tetrahydropyranyl, (Co- alkyl)tetrahydrofuranyl,

(Co-4 alkyl)pyrrolidinyl, (C0-4 alkyl)piperidinyl, or (C0.4 alkyl)piperazinyl group.

20. The compound of claim 19, wherein Q is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, (CH2)-cyclopropyl, (C-Hfefe-cyclopropyl, (CH2)3-cyclopropyl, cyclobutyl,

(CH2)-cyclobutyl, (CH 2)2-cyclobutyl, (CH 2)3-cyclobutyl, cyclopentyl, (CH 2)-cyclopentyl,

(CH2)2-cyclopentyl, (CH 2)3-cyclopentyl 3 cyclohexyl, (CH 2)-cyclohexyl, (CH 2)2-cyclohexyl,

(CH2)3-cyclohexyl, bicyclo[2.2.1]heptanyl, (CH2)bicyclo[2.2.1]heptanyl,

(CH2)2bicyclo[2.2.1]heptanyl, (CH 2)3bicyclo[2.2.1]heptanyl, cycloheptyl, phenyl, benzyl, phenethyl, 2-pyridyl, (CH 2)-2-pyridyl, (CH 2)2-2-pyridyl, (CH 2)3-2-pyridyl, 3-pyridyl,

(CH 2)-3-pyridyl, (CH 2)2-3-pyridyl, (CH2)3-3-pyridyl, 4-pyridyl, (CH 2)-4-pyridyl 5 (CH2)2-4- pyridyl, (CH 2)3-4-pyridyl, tetrahydrofuranyl, (CH 2)-tetrahydrofuranyl,

(CH 2)2-tetrahydrofuranyl, (CH 2)3-tetrahydrofuranyl, tetrahydropyranyl,

(CH2)-tetrahydropyranyl, (CH 2)2-tetrahydropyranyl, (CH 2)3-tetrahydropyranyl, pyrrolidinyl,

(CH2)-pyrrolidinyl, (CH 2)2-pyrrolidinyl, (CH 2)3-pyrrolidinyl, 10-oxa-4-aza- 2 6 tricyclo[5.2.1.0 ' ]decanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, piperidinyl, (CH2)-piperidinyl,

(CH2)2-piperidinyl, (CH 2)3-piperidinyl, piperazinyl, (CH )- piperazinyl, (CH 2)2- piperazinyl,

(CH )3- piperazinyl, morpholinyl, (CH 2)-morpholinyl, (CH 2)2-morpholinyl, or

(CH2)3-morpholinyl group.

1 2 1. The compound of claim 6, wherein R is F, -CN, -NR 2, or a substituted or unsubstituted C 1-4 alkyl, C3..9 cycloalkyl, heterocyclyl or heterocyclylalkyl group.

1 22. The compound of claim 21, wherein R is F, -CN, -N(Ci_3 alkyl) 2 1 wherein each C 1.3 alkyl group is independently substituted or unsubstituted; or R is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3- dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, thiomorpholinyl,

(CH2)-pyrrolidinyl, (CH 2)-piperidinyl, (Ct^-oxazepanyl, (CH 2)-morpholinyl, or

(CH2)-piperazinyl group.

23. The compound of claim 6, wherein R2 is a substituted or unsubstituted

(Cu 6 alkyl) or heterocyclylalkyl group, F, Cl, -CN, -NO 2, -OR', -C(O)OR', -C(O)NR' 2, -(CH2XNRR", -C(NR)NR 2, -C(NR)NROR, -NRC(O)R", -NRC(O)OR", -NR SO2R",

-NR'C(O)NR' 2, or -SO2NR' 2.

2 24. The compound of claim 23, wherein R is F, -CN, -CF3, -NO2,

-0(Ci -6 alkyl), -C(O)O(Ci -6 alkyl), -C(O)NH2, -C(O)NH(Ci -6 alkyl),

-C(O)NH(C3-6 cycloalkyl), -C(0)NH(cycloalkylalkyl), -C(O)NH(aralkyl), -(CH2)NH(Ci-6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -C(NH)NH 2, -C(NH)NH(C L 6 alkyl), -C(NH)NHOH, -C(NH)NHO(C 6 alkyl), -NHC(O)(Ci -6 alkyl), -NHC(0)(

C3-6 cycloalkyl), -NHC(O)(cycloalkylalkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO2(C 1- alkyl), -NHSO2(C3 6 cycloalkyl), -NHSO2(cycloalkylalkyl), -NHSO 2(aryl), -NHSO2(araIkyl),

-SO2NH(C 1-6 alkyl), -SO2NH(C 3-6 cycloalkyl), -SO2NH(cycloalkylalkyl), -SO2NH(aryl), or

-SO2NH(aralkyl), wherein each Ci-6 alkyl, C -6 cycloalkyl, cycloalkylalkyl aryl, and aralkyl group is substituted or unsubstituted.

25. The compound of claim 6, wherein R3 is a substituted or unsubstituted

Ci-4 alkyl or -0(Ci - alkyr) group, or is a partially or fully halogenated -0(Ci -2 alkyl) group.

26. The compound of claim 6, wherein G is phenyl and R 1 is F, Cl, -CN,

-N(Ci 3 alkyl)2 wherein each Ci-3 alkyl group is independently substituted or unsubstituted; or R 1 is a substituted or unsubstituted morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)-oxazepanyl, (CH2)-morpholinyl,

(CH2)-piperazinyl, methyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, neopentyl, or cyclohexyl group.

27. The compound of claim 26, wherein R 1 is F, Cl, a substituted or unsubstituted morpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl,

(CH2)-morpholinyl, (CH2)-piperazinyl, methyl, tert-butyl, or cyclohexyl group.

2 28. The compound of claim 26, wherein R is F, -CN, -CF3, -NO2,

-O(d -6 alkyl), -C(O)O(C 6 alkyl), -C(O)NH2, -C(O)NH(Ci -6 alkyl),

-C(O)NH(C 6 cycloalkyl), -C(O)NH(cycloalkylalkyl), -C(O)NH(aralkyl), -NHC(O)(Ci-6 alkyl), -NHC(O)(C 6 cycloalkyl), -NHC(O)(cycloalkylalkyl),-NHC(O)(aryl),

-NHC(OXaralkyl), -(CH2)NH(C 1-6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C3 cycloalkyl), -NHSO2(cycloalkylalkyl), -NHSO2(aryl),

-NHSO2(aralkyl), -SO2NH(Ci -6 alkyl), -SO2NH(C3 cycloalkyl), -SO2NH(cycloalkylalkyl), θ -SO2NH(aryl) or -S 2NH(aralkyl), wherein each Ci- alkyl, C -6 cycloalkyl, cycloalkylalkyl aryl, or aralkyl group is substituted or unsubstituted.

2 29. The compound of claim 26, wherein R is F, -CN, -CF3, -C(O)NH2,

-C(O)NH(Ci - alkyl), -C(O)NH(C3-6 cycloalkyl), -C(O)NH(cycloalkylalkyl), -(CH2)NH(Ci -6 alkyl), -(CH2)NH(heterocyclylalkyl), -NHSO2(Ci- alkyl), Or-SO2NH(Ci -6 alkyl), wherein each Ci-6 alkyl, C 6 cycloalkyl and cycloalkylalkyl group is substituted or unsubstituted.

30. The compound of claim 26, wherein R3 is a substituted or unsubstituted C alkyl or -0(C alkyl) group, or is a partially or fully halogenated

-O(Ci-2 alkyl) group.

31. The compound of claim 6, wherein L2 is O, OC(O), C(O), C(O)NH,

C(O)NHNH, C(O)NMe, OCH2C(O), SO2NH, CH(OH), or C(NOH), and Q is 32. The compound of claim 31, wherein G is a phenyl group.

33. The compound of claim 6, wherein the compound at a concentration of 10 µM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.

34. A compound of Formula II,.

stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein X is CH, N or NO; Y is CH, N, or NO, provided that X and Y are not both CH or NO;

A is F, Cl, Br, I, NR , or a C1-3 alkyl or -0(Ci alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; B and D are each independently CR or N; G is an aryl or heteroaryl group, wherein G is substituted by one or more R1, R2 or R3; L1 is -C(O)NH-; 2 L is a covalent bond, CR' 2O, (CR' 2)mC(O)(CR' 2)t, (CR' 2)mC(O)NR(CR' 2)t,

(CR' 2)mC(O)NRNR(CR' 2)t, (CR' 2)mC(NOR) (CR' 2)t, or (CR' 2)mNRC(O)O(CR' 2)t group; Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl group; 1 each R is independently F, Cl, Br, I, -NR2, -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heterocyclylalkyl group; 2 each R is independently F, Cl, Br, I, -CN, -NO2, a substituted or unsubstituted alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR' 2, -NR' 2,

-(CR' 2)tNRR', -NRC(O)R", -NR C(O)OR", -NR' SO2R", -NR'C(O)NR' 2, -NR'C(S)NR' 2,

-S(O)1n R", or -SO2NR' 2; each R3 is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an -0(C 1 alkyl) group, wherein the C 1-4 alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted Ci. alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl or heterocyclylalkyl group; each m is independently 0, 1 or 2; and

t is O, l , or 2.

35. The compound of claim 34, wherein the compound is

36. The compound of claim 34, wherein the compound is

37. The compound of claim 34, wherein B is N.

38. The compound of claim 34, wherein D is N.

39. The compound of claim 34, wherein A is F, —CH3, or -CF3.

40. The compound of claim 34, wherein G is a phenyl, pyrimidyl or pyridyl group.

4 1. The compound of claim 34, wherein G is 42. The compound of claim 34, wherein L2 is a covalent bond, C(O),

CH2O, C(O)NHNH, C(NOH), or C(O)NH.

43. The compound of claim 34, wherein Q is a substituted or unsubstituted alkyl, cycloalkyl, 10-oxa-4-aza-tricyclo[5.2.1.0 2'6]decanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl,

(Co-4 alkyl)cycloalkyl, (C0-4 alkyl)phenyl, (C0-4 alkyl)pyridyl, (Co-4 alkyl)pyrimidinyl,

(Co alkyl)quinuclidinyl, (Co-4 alkyl)morpholinyl, (Co-4 alkyl)thiomorpholinyl,

(Co-4 alkyl)tetrahydropyranyl, (Co-4 alkyl)tetrahydrofuranyl, (C0-4 alkyl)pyrrolidinyl,

(Co-4 alkyl)piperidinyl s or (C0-4 alkyl)piperazinyl group.

44. The compound of claim 34, wherein Q is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, neopentyl, cyclopropyl, (CH 2)-cyclopropyl, (CH^-cyclopropyl, (CH^-cyclopropyl, cyclobutyl,

(CH 2)-cyclobutyl, (CH 2)2-cyclobutyl, (CH 2)3-cyclobutyl, cyclopentyl, (CH2)-cyclopentyl,

(CH 2)2-cyclopentyl, (CH 2)3-cyclopentyl, cyclohexyl, (CH 2)-cyclohexyl, (CH 2)2-cyclohexyl,

(CH 2)3-cyclohexyl, bicyclo[2.2.1]heptanyl, (CH 2)bicyclo[2.2.1]heptanyl,

(CH 2)2bicyclo[2.2.1]heptanyl, (CH 2)3bicyclo[2.2.1]heptanyl, cycloheptyl, phenyl, benzyl, ρ phenethyl, 2-pyridyl, (CH 2)-2- yridyl, (CH 2)2-2-pyridyl, (CH 2)3-2-pyridyl, 3-pyridyl, (CH2)- ρ 3-pyridyl, (CH 2)2-3-pyridyl, (CH 2)3-3- yridyl, 4-pyridyl, (CH 2)-4-pyridyl, (CH2)2-4-pyridyl,

(CH 2)3-4-pyridyl, quinuclidinyl, (CH 2)-quinuclidinyl, (CH 2)2-quinuclidinyl, 2 6 (CH 2)3-quinuclidinyl, 10-oxa-4-aza-tricyclo[5.2.1.0 ' ]decanyl, 8-oxa-3-aza- bicyclo[3.2.1]octanyl, tetrahydrofuranyl, (CH2)-tetrahydrofuranyl, (CH 2)2-tetrahydrofuranyl, τ (CH 2)3-tetrahydrofuranyl, tetrahydropyranyl, (CH 2)-tetrahydropy anyl,

(CH 2)2-tetrahydropyranyl, (CH 2)3-tetrahydropyranyl, pyrrolidinyl, (CH 2)-pyrrolidinyl, π (CH 2)2-py Olidinyl, (CH 2)3-pyrrolidinyl, piperazinyl, (CH 2)-piperazinyl, (CH 2)2-piperazinyl,

(CH 2)3-piperazinyl, piperidinyl, (CH 2)-piperidinyl, (CH 2)2-piperidinyl, (CH 2)3-piperidinyl, morpholinyl, (CH 2)-morpholinyl, (CH 2)2-morpholinyl, or (CH 2)3-morpholinyl group. 1 45. The compound of claim 34, wherein R is F, -CN, -NR2, or a substituted or uπsubstituted C alkyl, C3.9 cycloalkyl, heterocyclyl, or heterocyclylalkyl group.

1 46. The compound of claim 45, wherein R is F, -CN, -N(Ci - alkyl)2 1 wherein each C 1- alkyl group is independently substituted or unsubstituted; or R is a substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, sec-butyl, neopentyl, cyclohexyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3- dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, morpholinyl, thiomorpholinyl,

(CH 2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)-oxazepanyl, (CH2)-morpholinyl, or

(CH2)-piperazinyl group.

47. The compound of claim 34, wherein R2 is a substituted or unsubstituted (Ci 6 alkyl) or heterocyclylalkyl group, F, Cl, -CN, -NO 2, -OR', -C(O)OR',

-C(O)NR' 2, -(CH 2)tNRR", -NRC(O)R", -NRC(O)OR", -NR SO2R", -NR'C(O)NR' 2, or

-SO 2NR' 2.

2 48. The compound of claim 47, wherein R is F, -CN, -CF3, -NO2,

-0(C 1-6 alkyl), -C(O)O(C 1-6 alkyl), .-C(O)NH2, -C(O)NH(C 1-6 alkyl),

-C(O)NH(C 3-6 cycloalkyl), -C(O)NH(cycloalkylalkyl), -C(O)NH(aralkyl), -(CH2)NH(C 1-6 alkyl), -(CH 2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -NHC(O)(C L 6 alkyl),

-NHC(O)(C 3-6 cycloalkyl), -NHC(O)(cycloalkylalkyl), -NHC(O)(aryl), -NHC(O)(aralkyl),

-NHSO 2(Ci -6 alkyl), -NHSO 2(C3-6 cycloalkyl), -NHSO 2(cycloalkylalkyl), -NHSO 2(aryl),

-NHSO 2(aralkyl), -SO 2NH(C 1-6 alkyl), -SO 2NH(C 3-6 cycloalkyl), -SO 2NH(cycIoalkylalkyl),

-SO 2NH(aryl), or -SO 2NH(aralkyl), wherein each Ci-6 alkyl, C - cycloalkyl, cycloalkylalkyl, aryl, and aralkyl group is substituted or unsubstituted.

49. The compound of claim 34, wherein R3 is a substituted or unsubstituted C - alkyl or -0(Ci - alkyl) group, or is a partially or folly halogenated -O(Ci-2 alkyl) group.

50. The compound of claim 34, wherein G is phenyl and R 1 is F, Cl, -CN,

-N(Ci- 3 alkyl) 2 wherein each Ci-3 alkyl group is independently substituted or unsubstituted; or R1 is a substituted or unsubstituted morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, piperazinyl, oxazepanyl, (OH^J-pyrrolidinyl, (CH2)-piperidinyl, (CHa)-oxazepanyl, (CH2)-morpholinyl, (CH2)-ρiρerazinyl, methyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, or cyclohexyl group.

51. The compound of claim 50, wherein R 1 is F, Cl, a substituted or unsubstituted morpholinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, oxodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, piperidinyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)- φ mo holinyl, (CH2)-piperazinyl, methyl, tert-butyl, or cyclohexyl group.

2 52. The compound of claim 50, wherein R is F, -CN, -CF3, -NO2,

-0(C 1-6 alkyl), -C(O)O(C 1-6 alkyl), -C(O)NH2, -C(O)NH(C 1-6 alkyl),

-C(O)NH(C 3 6 cycloalkyl), -C(O)NH(cycloalkylalkyl), -C(O)NH(aralkyl), -NHC(O)(C 1-6 alkyl), -NHC(O)(C 3-6 cycloalkyl), -NHC(0)(cycloalkylalkyl), -NHC(O)(aryl),

-NHC(O)(aralkyl), -(CH2)NH(C 1-6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl),

-NHSO2(Ci -6 alkyl), -NHSO2(C3 6 cycloalkyl), -NHSO 2(cycloalkylalkyl), -NHSO2(aryl),

-NHSO2(aralkyl), -SO2NH(Ci -6 alkyl), -SO2NH(C 3-6 cycloalkyl), -SO2NH(cycloalkylalkyl),

-SO2NH(aryl) or -SO NH(aralkyl), wherein each C i-6 alkyl, C3-6 cycloalkyl, cycloalkylalkyl, aryl, and aralkyl group is substituted or unsubstituted.

2 53. The compound of claim 50, wherein R is F, -CN, -CF3, -C(O)NH2,

-C(O)NH(C -6 alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(0)NH(cycloalkylalkyl), -(CH2)NH(Ci -6

alkyl), -(CH2)NH(heterocyclylalkyl), -NHSO 2(CL 6 alkyl), or -SO2NH(Cu 6 alkyl), wherein each Ci-6 alkyl, C3-6 cycloalkyl, and cycloalkylalkyl group is substituted or unsubstituted.

54. The compound of claim 50, wherein R3 is a substituted or unsubstituted C1-4 alkyl or -0 (C - alkyl) group, or is a partially or fully halogenated

-O(Ci-2 alkyl) group. 55. The compound of claim 34, wherein L is a bond, CH O, C(O),

C(O)O, C(O)NH, C(O)NHNH, C(NOR), or C(CH3)2C(O)NH, and Q is

OH . + . . -

56. The compound of claim 55, wherein B and D are N.

57. The compound of claim 56, wherein G is a phenyl group.

58. The compound of claim 34, wherein the compound at a concentration of 10 µM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.

59. A composition comprising a compound of claim 6 or 34 and a pharmaceutically acceptable carrier. 60. A method of treating a disorder mediated by cytokines which comprises administering to a subject in need of such treatment a therapeutically effective . amount of a compound of claim 6 or 34.

6 1. The method of claim 60, wherein the cytokine-mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejection, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, atherosclerosis, allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obliterative bronchiolitis, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, respiratory tract inflammation, psoriasis, pemphigus, eczema, atopic dermatitis, contact dermatitis, acne, Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelinating diseases, viral meningitis, bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, epilepsy, diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia nervosa, bulimia nervosa, bone resorption diseases, osteopetrosis, osteoporosis, sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, or drug resistance.

62. The method of claim 60, wherein the cytokine-mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's Disease, ulcerative colitis, inflammatory bowel disease, diabetes, psoriatic arthritis, psoriasis, pemphigus, chronic obstructive pulmonary disease, pain, atherosclerosis, ischemia reperfusion, restenosis, acute coronary syndrome, heart failure, multiple myeloma, follicular lymphoma or osteosarcoma.

63. The method of claim 60, wherein the cytokine-mediated disorder is a neutrophil-mediated disorder.

64. The method of claim 63, wherein the neutrophil-mediated disorder is bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis.

65. The method of claim 60, wherein the cytokine is selected from TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma or a combination of any two or more thereof.

66. The method of claim 60, wherein the disorder is or results from abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphospholipid syndrome, arteriosclerotic dementia, arteritis temporal, arthropod- bome encephalitis, asphyxia, atopic hypersensitivity, atrial fibrillation, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy, cardiac surgery, cardiomegaly, carditis, carotid angioplasty, carotid endarterectomy, carotid stents, carotid ulcer, celiac disease, cirrhosis, colitis, colitis granulomatous, coronary artery bypass graft, coronary artery bypass surgery, cortical cataracts, corticosteroid-resistant asthma, degenerative joint disease, dermatitis, diarrhea, erectile neuropathy, erectile vasculopathy, dry eye, dyslipidemia, dyspnea, edema, end-stage renal disease, epsteϊ n-barr virus infections, fever, follicular thyroid carcinoma, gastroenteritis, heart attack, heart bypass surgery, heart surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, insulin resistance, kidney failure, kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacterial meningitis, myeloproliferative disorders, myopathies, myositis, neonatal-onset multisystem inflammatory disease, nephritis, neuromuscular disorders, neuropathy, obliterative bronchiolitis, oral cancer, percutaneous coronary intervention, periodontal bone loss, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, posterior capsular opafication, pruritus, pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, sympathetic opthalmia, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis.

67. A method comprising administering to a subject an amount of a cytokine inhibitor effective to reduce a level of a cytokine relative to the level prior to administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 6 or 34.

68. The method of claim 67, wherein the cytokine is selected from TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof.

69. A method comprising exposing a cell to an amount of a cytokine inhibitor effective to reduce the level of cytokine released from the cell in response to a pro¬ inflammatory stimulus relative to the level of released cytokine prior to contacting the cell with the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 6 or 34.

70. A method comprising contacting p38 with an amount of a cytokine inhibitor effective to inhibit p38 activity, the phosphorylation of p38, or both, wherein the cytokine inhibitor is a compound of claim 6 or 34.

7 1. A method comprising administering to a subject an amount of a cytokine inhibitor effective to reduce the activity of a pro-inflammatory mediator relative to the activity prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 6 or 34. 72. A method comprising administering to a subject an amount of cytokine inhibitor effective to reduce the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both, in blood relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 6 or 34.

73. A method comprising administering to a subject an amount of a compound effective to increase the HDL-level of the subject relative to the level prior to the administration of the compound, wherein the compound is a compound of claim 6 or 34.

74. A method comprising administering to a subject exhibiting one or more indicia of rheumatoid arthritis, an amount of a compound effective to reduce at least one of the indicia to a level below that which exists prior to the administration of the compound, wherein the compound is a compound of claim 6 or 34.

75. A method comprising administering to a subject an amount of a compound effective to increase the Apo-Al -level of the subject relative to the level prior to the administration of the compound, wherein the compound is a compound of claim 6 or 34.

76. A method of preparing a compound of claim 6, the method comprising contacting a compound of Formula III

Formula III with (i) G-COOH in the presence of a coupling agent and a base; or with (ii) G-CO-Z in the presence of a base; wherein said contacting occurs under conditions suitable to provide a compound of Formula I; wherein A, X, Y, R, L2, Q and G are as defined in Formula I, and Z is an activating moiety. 77. A method of preparing a compound of claim 6, the method comprising (i) contacting a compound of Formula IIIB

Formula IIIB with G-NH in the presence of a coupling agent and a base; or (ii) contacting a compound of Formula HIC

Formula IIIC with G-NH2 in the presence of a base, wherein said contacting occurs under conditions suitable to provide a compound of Formula I, wherein A, X, Y, R, L2, Q and G are as defined in Formula I, and Z is an activating' moiety.

78. A method of preparing a compound of claim 34, the method comprising contacting a compound of Formula IV

Formula IV with (i) G-COOH in the presence of a coupling agent and a base; or with (ii) G-CO-Z in the presence of a base; wherein said contacting occurs under conditions suitable to provide a compound of Formula II; wherein A, B, D, X Y, R, L2, Q and G are as defined in Formula II, and Z is an activating moiety. 79. A method of preparing a compound of claim 34, the method comprising (i) contacting a compound of Formula IVB

Formula IVB with G-NH2 in the presence of a coupling agent and a base; or (ii) contacting a compound of Formula IVC

Formula IVC with G-NH2 in the presence of a base, wherein said contacting occurs under conditions suitable to provide a compound of Formula II; wherein A, B, D, X, Y, R, L2, Q and G are as defined in Formula II, and Z is an activating moiety. 80. A method of preparing a compound of Formula V

Formula V, the method comprising contacting a compound of Formula VI

Formula VI with nitromalonaldehyde sodium salt wherein said contacting occurs under conditions suitable to provide a compound of Formula V; wherein Ar' is a 5 or 6-m.embered aromatic or heteroaromatic group, optionally substituted by L3-Q;

W is a Ci 6 alkyl or cycloalkyl group; 3 L is a covalent bond, CH2O C(O), C(O)O, (CR2)mC(O)NR, C(O)NRNR, C(NOR), or NRC(O)O group; Q is hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and each R is independently hydrogen or a substituted or unsubstituted Ci-6 alkyl group.

81. A compound of Formula VII

Formula VII wherein Hal is Cl, Br, or I;

T is O or (CH2)n;

Rm is H or a substituted or unsubstituted alkyl, aralkyl or heterocyclalkyl group; and n is O, 1 or 2.

82. A compound of Formula VIII wherein T is O or (CEb) ; 11

U is F, Cl, Br, CN, -SO2NR' 2, -C(O)NR' 2 or -NR SO2R";

V is -O(C,. 6 alkyl);

Rm is H or a substituted or unsubstituted alkyl, aralkyl or heterocyclalkyl group; each R' is independently hydrogen, or a substituted orunsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and

n is O, 1 or 2.

83. A compound of Formula IX

Formula IX wherein

T is an (C2-δ)alkyl or cycloalkyl group, optionally partially or fully halogenated; 5 U is -CN, -SO2NR Or-NR SO2R"; each R is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R 5 is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and

PN is H or an amine protecting group.

84. A compound selected from List 1. International application No. INTERNATIONAL SEARCH REPORT PCT/US07/18049 A. CLASSIFICATION OF SUBJECT MATTER IPC: C07D 213/75( 2006.01)

USPC: 546/309 According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S : 546/309

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. US 6,448,274 A (FRIESEN et al) 10 September 2002 (10.09.2002), see entire document. 11

D Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents "T" later document published after the international filing date or priority date and not ui conflict with the application but cited to understand the "A' document defining the general state of the art which is not considered to be of principle or theory underlying the invention particular relevance "X" document of particular relevance, the claimed invention cannot be "E" earlier application or patent published on or after the international filing date considered novel or cannot be considered to involve an inventive step when the document is taken alone "L" document which may throw doubts on pnontv claim(s) or which is cited to establish the publication date of another citation or other special reason (as "Y" document of particular relevance, the claimed invention cannot be specified) considered to involve an inventive step when the document is combined with one or more other such documents, such combination "O" document referring to an oral disclosure, use, exhibition or other means being obvious to a person skilled in the art

"P" document published pπor to the international filing date but later than the "&" document member of the same patent family priority date claimed Date of the actual completion of the international search Date of mailing of the internati search report 14 November 2007 (14,1 1 2007) L _ Name and mailing address of the ISA/US Authonzed offi cer / Mail Stop PCT, Attn ISA/US Patricia L. Morris / n Commissioner for Patents C P O Box 1450 Telephone No. (571) 272-1600 Alexandria, Virginia 22 313-1450 Facsimile No. (571) 273-3201 Form PCT/ISA/210 (second sheet) (April 2005) INTERNATIONAL SEARCH REPORT n erna ona app ca on o. PCT/US07/18049

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely:

2. [XJ Claims Nos.: 1-10 and 12-84 because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: Please See Continuation Sheet

3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:

As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. As all searchable claims could be searched without effortjustifying additional fees, this Authority did not invite payment of any additional fees. As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:

No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on Protest The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. No protest accompanied the payment of additional search fees.

Form PCT/ISA/210 (continuation of first sheet(2)) (April 2005) International application No. INTERNATIONAL SEARCH REPORT PCT/US07/18049

Continuation of Box II Reason 2: In these claims, the numerous variables and their voluminous, complex meanings and their seemingly endless permutations and combinations plus proviso clauses and functional language (claim 1), make it virtually impossible to determine the full scope and complete meaning of the claimed subject matter. Further, the compounds do not even belong to a recognized class of chemical compounds. As presented, the claimed subject matter cannot be regarded as being a clear and concise description for which protection is sought and as such the listed claims do not comply with the requirements of PCT Article 6. Thus it is impossible to carry out a meaningful search on same. A search will be made on the first discemable invention of claim 11, i.e., compound no. 1on page 230 of the specification.

Form PCT/ISA/210 (extra sheet) (April 2005)