WO2007075896A2 - Heterocyclic cytokine inhibitors - Google Patents

Abstract

The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory, anti-pain or anti-cancer agents. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions mediated by cytokines.

Description

HETEROCYCLIC CYTOKINE INHIBITORS

FIELD OF THE INVENTION

[0001] The present invention relates to low molecular weight compounds and compositions thereof, useful, e.g., as cytokine inhibitors, and their preparation. The invention further relates to methods of prevention and treatment of cytokine-mediated disorders.

BACKGROUND OF THE INVENTION

[0002] The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation and are called pro-inflammatory cytokines, whereas other cytokines suppress the activity 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, 1 18: 503-508).

[0003] Unregulated activities of these mediators can lead to the development of serious inflammatory conditions. For example, autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers. One hypothesis is that lymphocytes recognize at some point an antigen which mimics the "self and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders.

[0004] Tumor necrosis factor-α (TNF- a) and interleukin-1 (IL-I) are proinflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-I and TNF-oπs believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure, and psoriasis among others (Dinarello, CA. et al., Rev. Infect. Diseases 1984, 6, 51 ; Salituro et al., Curr. Med. Chem. 1999, 6, 807; Henry et al., Drugs Fut. 1999, 24,1345). Recent data from clinical trials support the use of protein antagonists of cytokines, for example soluble TNFa receptor fusion protein (etanercept) (Moreland et al., Ann. Intern. Med. 1999, 130, 478) or the monoclonal TNFa antibody (Enbrel), for the treatment of rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis and psoriatic arthritis (Rankin et al., Br. J. Rheumatol. 1995, 34, 334; Galadari et al. Int J Dermatol. 2003, 42,231; Reimold, Am J Med Sci. 2003, 325(2), 75). Thus, the reduction of pro-inflamrnatory cytokines such as TNF-α(also referred to as TNFa) and interleukin-1/3 (IL-Ib) has become an accepted therapeutic approach for potential drug intervention in these conditions.

SUMMARY OF THE INVENTION

[0005] The present invention provides low molecular weight compounds and pharmaceutical compositions thereof. In_.particular, compounds of the invention are useful as cytokine release inhibitory agents. There are further provided methods for the preparation of such compounds and for the use of these compounds alone, in mixtures thereof, or in mixtures with other therapeutic agents in the preparation of medicaments for use in treating various disease states. For example, methods are provided for the use of compounds of the invention in the prevention and treatment of various disorders mediated by cytokines such as inflammatory disorders, cancer, pain, and others.

[0006] Thus, there are provided in accordance with one aspect of the invention compounds comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with a target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with a target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety (L), wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP -binding pocket of the target protein,

wherein the compound is a cytokine inhibitor.

[0007] In this aspect of the invention, cytokine inhibitors have the structure

PEM-TM-OM-L-AM. At a concentration of 10 μM, such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%.

[0008] The targeting moiety can hydrogen bond to residues at the binding site of the target protein. Typically the targeting moiety is an amide group.

[0009] The pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein. Such moieties include 6 membered aryl and heteroaryl groups, for example, phenyl, pyridyl, or the like, substituted by bulky moieties. Bulky moieties fill a large volume of space in comparison to, for example, a methyl group, and include groups such as substituted or unsubstituted C₂^ alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec- butyl groups; substituted or unsubsituted €₃.₉ cycloalkyl groups, for example substituted or unsubstituted cyclohexyl or norbornyl groups; or substituted or unsubstituted heterocyclyl groups, such as substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidyl, 8-oxa-3-aza- bicyclo[3.2.1]octan-3-yl, oxazepanyl, thiazolyl, or thiomorpholinyl groups.

[0010] 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, phenyl, pyridyl or pyridazinyl, substituted by small hydrophobic moieties, exemplified by halogens, methyl, trifluoromethyl, and the like.

[001 1] Typically, the linker moiety, L₅ comprises an oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl group. [0012] 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 a substituted or unsubstituted amide, hydrazide or urethane group, and may further comprise a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group, such as substituted or unsubstituted phenyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, tetrahydropyranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, or neopentyl group.

[0013] In another aspect, the invention provides compounds of Formula I

stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein

X and Y are each independently CH or N;

A is F, Cl, Br, I, NR₂, or a Ci_₃ alkyl or -O(Ci.₃ alkyl) group, wherein the alkyl group is optionally partially or fully halogenated;

B, D and E are each independently N, NR, O₅ S or CR; wherein B, D, and E are selected such that the ring containing B, D, and E is aromatic;

G is an aryl or heteroaryl group, wherein G is substituted by one or more R¹, R² or R³;

L¹ is -C(O)NH-;

L² is -(CR'₂)_n-C(OHCR'₂)p-, -(CR'₂)_n-NR-(CR'₂)_p-, -(CR'₂)_n-C(O)NR-(CR'₂)_p-, -(CR'₂)_n-C(O)NRNR-(CR'₂)_P-, or -(CR'₂)_n-O-C(O)NR-(CR'₂)_p-;

Q is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group; each R¹ 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, Cl₅ 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, -NRC(O)R", -NR⁵C(O)OR", -NR⁵SO₂R", -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(Ci_-4 alkyl) group, wherein the C_]-4 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, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; each m is independently O, 1 or 2; and n and p are each independently O, 1, 2 or 3.

[0014] Thus, in some embodiments, compounds of Formula I are also cytokine inhibitors having the formula PEM-TM-OM-L-AM. For example, in some embodiments, G is PEM, L¹ is TM, the 6-membered ring is OM, the 5-membered heteroaryl is L, and -L²-Q is

AM.

[0015] AU of the following compounds are contemplated by Formula I:

IA-I IA-2 IA-3

IA-5 IA-6

IA-IO IA-11 IA-12

IB-I IB-2 IB-3

IC-I IC-2 IC-3

IC-IO IC-Il IC-12

[0016] As those of skill in the art will appreciate, all orientations of divalent linkers such as L¹ and L² are contemplated for use in compounds of the invention. Thus, in some embodiments, the compound of Formula I is the compound of Formula II:

[0017] In others, the compound of Formula I is

[0018] In some embodiments of compounds of the invention, including compounds of

Formula I or II, B is N. In others, D is NH, O or S. In still others, E is CH or O. In some other embodiments of compounds of Formula I, A is F, — CH3, or -CFj.

[0019] In some embodiments of compounds of the invention, including compounds of

Formula I or II, G is a phenyl, pyrimidyl or pyridyl group. In other embodiments, G is a phenyl or pyridyl group. For example, G is

[0020] In some embodiments of compounds of the invention, including compounds of

Formula 1 or II, L² is -C(OMCR'₂)p-₅ -(CH₂)_n-C(O)NR-(CH₂)p-, or -(CH₂)_n-C(O)NRNR-(CH₂)p-. For example, L² is -C(O) -, -C(O)CH₂- -C(O)CH₂CH₂-, -C(O)CH₂CH₂CH₂-, -C(O)NHNH-, -C(O)N(CH₃)NH-, -C(O)N(CH₃)NH-CH₂-, -C(O)N(CH₃)NH-CH₂CH₂-, -C(O)N(CH₃)NH-CH₂CH₂CH₂-, -C(O)NHNH-CH₂-, -C(O)NHNH-CH₂CH₂- or -C(O)NHNH-CH₂CH₂CH₂-, C(O)NH-, -C(O)N(CH₃)-, -C(O)N(CH₃)-CH₂~, -C(O)N(CHa)-CH₂CH₂- -C(O)N(CH₃)^H₂CH₂CH₂-, -C(O)NH-CH₂-, -C(O)NH-CH₂CH₂- or -C(O)NH-CH₂CH₂CH₂-.

[0021] In others, the compound is

[0022] In still others, the compound is

Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group.

[0023] In other embodiments of compounds of the invention, including compounds of

Formula I or II, Q is H, or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, pyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidyl, or piperazinyl group. For example, Q is a substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, moφholinyl, , 8-oxa-3-aza- bicyclo[3.2.1]octanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, or neopentyl group.

[0024] In yet other embodiments of compounds of the invention, including compounds of Formula I or II, R¹ is F, -CN, -NR₂, or a substituted or unsubstituted Q_-4 alkyl, C₃.₉ cycloalkyl, aryl, heterocyclyl, or heterocyclyl alkyl group. In some such embodiments, R¹ is F, -CN, -N(Ci_-3 alkyl)₂ wherein each Cj_-3 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted isopropyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, phenyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, thiazolyl, CH₂-thiazolyl, CH₂CH₂-thiazolyl, pyrrolidinyl, CH₂-pyrrolidinyl, CEbCHa-pyrrolidinyl, piperidyl, CH₂-piperidyl, CH₂CH ₂-piperidyl, morpholinyl, CH₂-morpholinyl, CH₂CH₂-morpholinyl, thiomorpholinyl, CH₂-thiomorpholinyl, CH2CH2-thiomorpholinyl, piperazinyl, CH₂-piperazinyl, CH₂CH₂-piperazinyl, oxazepanyl, CH₂-oxazepanyl, or CH₂CH₂-oxazepanyl group.

[0025] Also contemplated are compounds of the invention, including compounds of

Formula I or II, wherein R² is a substituted or unsubstituted Ci_-4 alkyl or heterocyclylalkyl group, F, Cl, -CN, -NO₂, -OR', -C(O)OR', -C(O)NRZ₂, -NRC(O)R", -NRC(O)OR", -NR⁵SO₂R", -NR'C(O)NR'₂, or -SO₂NR'₂. In some such embodiments, the alkyl group is substituted with NRR. In others, the heterocyclylalkyl group is a substituted or unsubstituted -(Ci-₃ alkyl)-pyrrolidinyl, -(Ci_-3 alkyl)-piperidyl, -(Ci_-3 alkyl)-piperazinyl, or -(C1-3 alkyl)- morpholinyl group. In still other embodiments, R² is F, -CF₃, -CN, -NO2, -O(Ci_₆ alkyl), -C(O)O(Ci_-6 alkyl), -C(O)NH₂, -C(O)NH(C,_-6 alkyl), -C(O)NH(aryl), -C(O)N H(aralkyl), - NHC(O)(C_1-5 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO₂(Ci_-5 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(C_1-6 alkyl), -SO₂NH(aryl), or -SO₂NH(aralkyl), wherein each Ci_-6 alkyl, aryl, or aralkyl group is substituted or unsubstituted.

[0026] In still other embodiments of compounds of the invention, including compounds of Formula I or II, R³ is a substituted or unsubstituted Ci_-4 alkyl or -0(Ci_-4 alkyl) group, or is a partially or fully halogenated -Q(Ci_-2 alkyl) group. [0027] In some embodiments of compounds of the invention, including compounds of

Formula I or II, G is phenyl and R¹ is F, Cl, -CN, -N(Ci_3 alkyl)2 wherein each C1-3 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted morpholinyl, thiomorpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, or cyclohexyl group. For example, R¹ is F, Cl, a substituted or unsubstituted morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, tert-butyl, or cyclohexyl group. In some such embodiments, R² is a substituted or unsubstituted Q.₄ alkyl or heterocyclylalkyl group, F, - CN, -NO₂, -0(C_1-6 alkyl), -C(O)O(C_-6 alkyl), -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(C_1-6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO₂(C_1-6 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(Ci_-6 alkyl), -SO₂NH(aryl) or -Sθ₂NH(aralkyl), wherein each Cj_-6 alkyl, aryl, or aralkyl group is substituted or unsubstituted. In some such embodiments^', the alkyl group is substituted with NRR. In others, the heterocyclylalkyl group is a substituted or unsubstituted -(C ₁-₃ alkyl)-pyrrolidinyl, -(C|_3 alkyl)-piperidyl₅ -(C1-₃ alkyl)-piperazinyl, Or -(Ci_-3 alkyl)-morpholinyl group. Typically, R² is F, -CF₃, -CN, -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -NHSO₂(C₆ alkyl), or -SO₂NH(Ci_-6 alkyl), wherein each Ci_-6 alkyl is substituted or unsubstituted. In some such embodiments, R³ is a substituted or unsubstituted C_1-4 alkyl or -0(C_1-4 alkyl) group, or is a partially or fully halogenated -0(C_1-2 alkyl) group.

[0028] In some embodiments of compounds of the invention, -L²-Q is

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

[0030] In some embodiments of compounds of the invention such as compounds of

Formula I, the compound is

[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 groupings. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents of Formulas I and Il as described herein. Thus, e.g., combination 1047 describes those embodiments in which the 5-membered B, D, E containing aromatic ring is pyrazol-3,5-diyl and G is phenyl.

[0032] Table 1 : Exemplary combinations of the B, D₃ E containing aromatic ring and

G for Formulas I and II.

[0033] Table 2 sets forth various combinations of substituents L² and Q of Formulas I and II. Thus, e.g., combination 1692 describes those embodiments in which L² is -C(O)- and Q is t-butyl. 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 the B, D, E containing ring and G, may be combined with any combination from Table 2, describing L² and Q. For example, combination 1047 from Table 1 and combination 1692 from Table 2 describe those embodiments of Formulas I and II in which the 5 membered B, D, E containing aromatic ring is pyrazol-3,5-diyl, G is phenyl, L is -C(O)- and Q is t-butyl. 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, NR₂, or Cj_-3 alkyl or— O(Ci-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 1692 describes those embodiments in which A is -F, L² is -C(O)- and Q is t-butyl, as well as those where A is — CH₃, L² is -C(O)- and Q is t-butyl, etc.

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

15

C088i70/900ZSfl/13d 968S/.0/-.00Z OΛV Table 2 (Cont.)

17

C088i70/900ZSfl/13d 968S/.0//.00Z OΛV -C(O)N(

-C(O)N(CH

-C(O

-C(O)N ⁸ ₉₆₀₆ ^{055 207 205 2}0_{5 20 20606 2063 204 20 267} ^{56 205} _{1 22660 5902} -C(

-C

-C(O

-C(

-C(O

-C(O)N

[0035] 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 III

F

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; under conditions suitable to provide a compound of Formula I; wherein A, B, D, E, X, Y, L², Q and G are as defined herein, and Z is an activating moiety, which may be displaced by, e.g., an amine.

[0036] Typical coupling agents include EDC, PyBOP, and the like. The activating moiety is typically F, Cl, Br, I, N₃, N-hydroxysuccinimido, 1 -oxybenzotriazole, pentafluorophenoxy, pentachlorophenoxy, para-nitrophenoxy, or -OC(O)-OR^y, wherein R^y is a substituted or unsubstituted Ci_-6 alkyl group. Suitable bases include sodium bicarbonate or a suitable organoamine, such as pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine.

[0037] In another aspect of the invention, there is provided a method of preparing a compound of Formula IV

For

the method comprising contacting a compound of Formula V

Formu with H-CMIl-L', under conditions suitable to provide a compound of Formula IV, wherein L' is -L²-Q, -(CH₂)_n-C(O)OPco, or -(CH₂)_PNR-P_N5 wherein Pco is a carboxy protecting group, P_N is an amine protecting group, and A, X, Y, L², n, p and Q are as defined herein. Typically Pco is an ester moiety, while P_N is typically a urethane protecting group as described herein.

[0038] In yet another aspect of the invention, there are provided compounds of

Formula VI

wherein V is an alkyl or cycloalkyl group, optionally partially or fully halogenated; T is -CN, -SO₂NR'_2j -C(O)NR'₂₎ or -NR⁵SO₂R"; U is-O(C,.₆ alkyl), and R' and R" are as defined herein.

[0039] In yet another aspect of the invention, there are provided compounds of

Formula VII,

F

wherein K is a C_2-6 alkyl or a cycloalkyl group, optionally partially or fully halogenated; J is -CN, -SC»₂NR'₂, or -NR'SO₂R"; 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 R_p is H or a substituted on unsubstituted alkyl, aralkyl or heterocyclalkyl group. [0040] In yet another aspect of the invention, there are provided compounds of

Formula VIII

wherein R_n, is hydrogen or a substituted or unsubstituted Ci -6 alkyl group; and m is 0, 1 or 2. In some embodiments, R_n, is H.

[0041] In some embodiments, the compound of Formula I at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.

[0042] The invention further provides compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.

[0043] In yet another aspect, the invention provides methods of treating disorders mediated by cytokines, including but not limited to inflammatory 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 disease. Such 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, musculoskeletal 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.

[0044] 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 others 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, Huntingdon'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.

[0045] 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.

[0046] In one aspect of the invention, there is provided a method of treating a disorder mediated by one or more cytokines, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, 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 of the invention, the disorder is 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, 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, degenerative joint disease, dermatitis, diarrhea, 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, 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, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis.

[0047] 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 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 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%, or at least 90%. In some embodiments the subject suffers from a cytokine mediated disorder, as described herein. In some embodiments, the cytokine is selected from TNFa, IL- 1 , 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., a bodily fluid 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.

[0048] 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 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 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%, 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, IFN-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.

[0049] 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 cytokine inhibitor effective to inhibit p38 activity, the phosphorylation of p38, or both, wherein the cytokine inhibitor 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%, or at least 90%. In some other embodiments, the p38 is in a subject. In some embodiments, the subject suffers from a cytokine mediated disorder as described herein.

[0050] 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 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 as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the reduction in proinflammatory mediator activity is at least 10%, at least 30%, at least 50%, or at least 90%._t In other embodiments, the subject suffers from 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 cytokine inhibitor. In some such embodiments, the decrease in circulating pro- inflammatory mediator level is at least 10%, at least 30%, at least 50%, or at least 90%. In some such embodiments, the pro-inflammatory mediator is a prostaglandin or a leukotriene, or a combination of two or 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%, 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.

[0051] 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 eomrise 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 as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiements, the reduction in circulating level is at least 10%, at least 30%, at least 50%, or at least 90%.

[0052] In yet another aspect of the invention, there are provided methods of reducing at least one indicia of rheumatoid arthritis. The methods comprise administering to a subject exhibiting one or more indicia of rheumatoid arthritis, an amount of 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 cytokine inhibitor, wherein the indicia is selected from erythrocyte sedimentation rate (ESR), joint redness, joint pain, joint tenderness, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, and/or circulating C-reactive protein level, and wherein the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof.

[0053] Also provided methods of reducing the number or severity of clinical signs of psoriasis. The methods comprise administering to a subject exhibiting one or more clinical signs of psoriasis an amount of a cytokine inhibitor effective to reduce the number or severity of clinical signs of psoriasis relative to those present in the subject prior to the administration of the cytokine inhibitor, 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.

[0054] In another aspect of the invention, there are provided methods of increasing the HDL-levels of a subject. The methods comprise administering to a subject an amount of a cytokine inhibitor effective to increase the HDL-level of the subject relative to the level prior to the administration of the cytokine inhibitor. In some embodiments, the cytokine inhibitor is a p38 inhibitor. In others, the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. 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 other embodiments, the subject has an LDL level less than about 150 mg/ml.

[0055] In some embodiments of methods 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 cytokine inhibitor. In still other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or Metabolic Syndrome.

[0056] In some embodiments of the invention, the methods additionally comprise administration of Atorvastatin (Lipitor, Torvast), Fluvastatin (Lescol), Lovastatin (Mevacor, Altocor), Mevastatin, Pitavastatin (Livalo, Pitava), Pravastatin (Pravachol, Selektine, Lipostat), Rosuvastatin (Crestor), Simvastatin, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, clinofibrate, Cholestyramine (Questran), Colestipol (Colestid), Ezetimibe (Zetia), niacin, or combinations of two or more thereof. In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, or by at least about 10%. For example, the HDL level of the subject is increased by at least about 7%.

[0057] 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 an amount of a cytokine inhibitor effective to decrease the triglyceride-level of the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor 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 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 cytokine inhibitor. In some embodiments of the invention, the method additionally comprises administration of Atorvastatin (Lipitor, Torvast), Fluvastatin (Lescol), Lovastatin (Mevacor, Altocor), Mevastatin, Pitavastatin (Livalo, Pitava), Pravastatin (Pravachol, Selektine, Lipostat), Rosuvastatin (Crestor), Simvastatin, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, clinofibrate, Cholestyramine (Questran), Colestipol (Colestid), Ezetimibe (Zetia), niacin, or combinations of two or more thereof. 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.

[0058] 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%.

[0059] 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 an amount of a cytokine inhibitor effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor 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 still 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 cytokine inhibitor.

[0060] 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 an amount of a cytokine inhibitor effective to decrease the HbAIc value in the subject relative to the level prior to the administration of the cytokine inhibitor, 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 HbAl c level is decreased to between about 4% and about 6.5%. 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 cytokine inhibitor.

[0061] 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 an amount of a cytokine inhibitor effective to decrease the insulin-level in the subject relative to the level prior to the administration of the cytokine inhibitor, 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 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 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 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 cytokine inhibitor.

[0062] 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 an amount of a cytokine inhibitor effective to decrease the HOMA Insulin Resistance Index in the subject relative to the Index prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor 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 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 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 cytokine inhibitor.

[0063] In yet another aspect of the invention, there are provided methods of increasing the indirect bilirubin level in a subject. The methods comprise administering to a subject an amount of a cytokine inhibitor effective to increase the indirect bilirubin level in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor 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.

[0064] 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 cytokine inhibitor.

[0065] Combination therapy employing cytokine inhibitors of the invention in combination with additional ingredient(s) (hereinafter referred to as "ingredient A") 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 as described herein, and in particular in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and in the other methods described herein. Thus, in one aspect, the invention provides methods that further include administering to a subject one or more, typically one, of the ingredients A described herein together with one or more, typically one, cytokine inhibitor of the invention. 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 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 A being an injectable, especially a biological agent, other benefits of adding the cytokine inhibitor may be seen. For example, cost reduction by way of interval and/or dose reduction.

[0066] A variety of ingredients A are contemplated for use in the combinations of the invention. For example, non-steroid 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.

[0067] Angiogenesis inhibitors may serve as ingredient A, such as compounds directed against VEGF, taxol, pentoxyfylline and/or thalidomide.

[0068] 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 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, IL1-6, LFA-I, or C5.

[0069] Also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and 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, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone. Among vitamin D3 derivatives are calcipotriol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, lθ!,2,5-dihydroxyvitamin D3, and parathyroid hormone-related peptide. [0070] Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with cytokine inhibitors of the invention. 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, DAB₃₈₉, CTLA-4Ig, anti-CD80, for example IDEC- 1 14 or ABX-IL8, DAB-IL-2, IL-10, anti-TAC, basiliximab and daclizumab. In addition, agents or therapies which act on other targets or immune mediated products are suitable as the ingredient 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.

[0071] Retinoid therapy can also be used as ingredient A. Thus, for example, bexarotene, acitretin, etretinate and tazarotene, and hydroxyurea, 6-thioguanine and phototherapies are suitable additional ingredients. (Orfanos C E., 1999, Cutis 64(5):347-53; see also Saurat J H., 1999, J.Am.Acad.Derm. 41(3 Pt 2):S2).

[0072] 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 .

[0073] Statins and HMG-CoA reductase inhibitors may also be employed as ingredients A, including, e.g. Atorvastatin (Lipitor, Torvast), Fluvastatin (Lescol), Lovastatin (Mevacor, Altocor), Mevastatin, 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, Gemfibrozil (e.g. Lopid®), or Fenofibrate; ezetimibe; nicotinic acid; bile acid sequestrants, such as Cholestyramine (Questran®) and Colestipol (Colestid®); and/or plant sterol-containing products and ω3-fatty acids. [0074] In another aspect, there are provided the above-mentioned combinations comprising ingredient A and one or more cytokine inhibitors of the invention, typically in therapeutically effective amounts, for use as pharmaceutical compositions with an anti- cytokine activity. Moreover, combinations comprising ingredient A and a cytokine inhibitor 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 cytokine inhibitor of the invention may further include the pharmaceutically acceptable derivatives thereof, and may be optionally combined with a conventional excipient, carrier, or combination thereof.

[0075] For therapeutic use, the pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention 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.

[0076] The pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention 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 cytokine inhibitor may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. The ingredient A and/or the cytokine inhibitor may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereroisomer or mixtures of stereoisomers, including racemates.

[0077] The proportions in which the two components, ingredient A and the cytokine inhibitor, may be used in the combinations according to the invention are variable. Ingredient A and the cytokine inhibitor are optionally present in the form of their solvates or hydrates. Depending on the choice of the ingredient A and the cytokine inhibitor of the invention, 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 cytokine inhibitor, and are within the skill in the art.

[0078] 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) plus retinoids; methotrexate, or the combination of cyclosporin and retinoids.

[0079] A typical combination for treating psoriasis is the cytokine inhibitor compound in combination with immunotherapy drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LFA3TIP, DAB₃₈Q, CTLA-4Ig, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher E. M., 1998 Hospital Medicine, VoI 59 No 7, and the obvious variants thereof. Another typical combination for treating psoriasis is the cytokine inhibitor compound 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 the cytokine inhibitor compound 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 cytokine inhibitor and cyclosporine, followed by continuation with cytokine inhibitor after decrease of dosing and discontinuation of cyclosporine. Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with retinoids. Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, and this would be alleviated by continuation therapy with the cytokine inhibitor. Yet another typical combination for treating psoriasis is the cytokine inhibitor compound, in combination with ingredients A selected from steroids, such as glucocortico steroids, 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 cytokine inhibitor compound with vitamin D derivatives, most typically calcipotriol or tacalcitol. Another typical combination for treating psoriasis is the cytokine inhibitor compound 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 the cytokine inhibitor compound in combination with cell adhesion molecules 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-CD 11 monoclonal antibodies, efalizumab, and the obvious variants thereof. Cell adhesion molecules inhibitors appear to provide an acceptable response rate with limited tolerability problems. Combination with a cytokine inhibitor could 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 cytokine inhibitor and CAM inhibitors, followed by maintenance treatment with the cytokine inhibitor alone and retreatment with CAM inhibitors in case of significant relapse.

[0080] Another typical combination for treating psoriasis is the cytokine inhibitor compound with another anti-TNFa ingredient. A typical embodiment is one wherein the other anti-TNFa ingredient is selected from infliximab or etanercept, typically infliximab. Infliximab is believed to have a higher rate of response for induction of remission, which recently was suggested to be maintained on the long term. 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 the cytokine inhibitor compound with anti-CD4, anti-CD80 (IDEC-114 or ABX- IL8), DAB IL-2, DAB₃₈₉ IL-2, CTLA4-Ig, ILlO, the IL2 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(11), 1539; Salim, et. al., "Targeting interleukin-2 as a treatment for psoriasis," Current Opinion in Investigational Drugs, 2001 , 2(11), 1546). [0081 ] The combinations described above can also be used to reduce the number or severity of the clinical inidicia of psoriasis.

[0082] Any of the above 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, VoI 112. No. 4, 405-410.

[0083] 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). Apart from the combinations listed below, combination of the cytokine inhibitor, with one or more agents classified as DMARD/S AARD or NSAID and/or steroids, are contemplated in this invention.

[0084] A typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D- penicillamine, sulfasalazine, auranofϊn, 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 the cytokine inhibitor compound 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 the cytokine inhibitor compound in combination with inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I.

[0085] Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound 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 the cytokine inhibitor is combined with infliximab and methotrexate. Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound in combination with IL-I receptor antagonists, such as Kineret. Yet another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with NSAIDs, including acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, difiunisal, 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 the cytokine inhibitor compound combined with steroids, such as glucocorticosteroids, for example betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort.

[0086] The combinations described above can also be used to reduce at least one of the indicia of rheumatoid arthritis.

[0087] Any of the above 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, 5.8.1-5.8.6. Mosby, London, Philadelphia, St. Louis, Sydney, Tokio).

[0088] In Crohn's disease, the following groups of drugs combined with the cytokine inhibitor may be effective: 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 the cytokine inhibitor compound with one or more of the following: steroids including all those listed herein, 5-ASA₃ methotrexate and azathioprine. Another typical combination for treating Crohn's disease is the cytokine inhibitor compound combined with IL-I receptor antagonists, such as Kineret®. Yet another typical combination for treating Crohn's disease is the cytokine inhibitor compound 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 the cytokine inhibitor is combined with infliximab and methotrexate. More typically, the cytokine inhibitor is combined with infliximab. Another typical combination for treating Crohn's disease is the cytokine inhibitor compound combined with IL-IO, alicaforsen (anti ICAM 1), or Antegren (VCAM receptor antagonist).

[0089] It has been found that cytokine inhibitors possess inhibitory effects on the procoagulant and profibrinolytic responses during human endotoxemia. 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 patient in need thereof a pharmaceutically effective amount of the cytokine inhibitor. This administration may be of benefit given either prophylactically to patients at risk or therapeutically for patients who have developed complications related to these pathways.

[0090] Also within the scope of the invention is combination therapy of the cytokine inhibitor and 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, dipyrirnidamole, aggrennox, ticlopidine, clopidogrel (Plavix), abciximab, RheoPro, integrilin, aggrestat, and the like. Particular dosages, formulations and methods of administration either alone or combined is within the skill in the art.

[0091 ] In another aspect of the invention, there is provided a method comprising administering to a subject a combination of a cytokine inhibitor as described herein 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 A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorders. 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, lypodystrpohy, osteoarthritis, arthritis deformans, lumbodynia, emmcniopathy, obstructive sleep apnea, cholelithiasis, gallstones, nonalcoholic steatohepatitis, heart disease, abnormal heart rhythms and abnormal heart arrythmias, 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 lipoplasty, gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty.

[0092] In some embodiments, both the cytokine inhibitor and ingredient A are administered orally. In others, both the cytokine inhibitor and ingredient A are administered intravenously, subcutaneously or by inhalation. In still others, the cytokine inhibitor is administered orally and the ingredient A is administered intravenously, subcutaneously, or by inhalation. Alternatively, the cytokine inhibitor may be administered intravenously, subcutaneously, or by inhalation and the ingredient(s) A may be administered orally.

[0093] Examples of agents useful in the treatment of obesity or an obesity— related condition or disorders as ingredients A include an insulin sensitizer, an insulin or insulin mimetic, a sulfonyl urea, an α-glucosidase inhibitor, a cholesterol lowering agent, a PPARδ 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 /S-HSD-I 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, CP741952, zonisamide, IDl 101, BDC03, S2367, AOD9604, fluasterone, GT389255, QCBT16, MK0916, MK0493, MK0364, PD6735, c2735, adiponectin, or a combination of two or more thereof. In some such embodiments, ingredient A is an insulin sensitizer, an insulin or insulin mimetic, a sulfonyl urea, an of-glucosidase inhibitor, or a glucose transporter inhibitor. In others, ingredient A is a cholesterol lowering agent, or a PPARδ agonist. In still others, ingredient 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 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 A is rimonabant, sibutramine, fluoxetine, phentermine, bupropion, radafaxine, orlistat, cetilistat, oxyntomodulin, or oleoyl-estrone.

[0094] Typical examples of ingredients A, and combinations of any 2 or more thereof, that may be combined with the cytokine inhibitors as described herein, for the treatment or prevention of obesity, diabetes and/or obesity-related disorders, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:

[0095] (a) insulin sensitizers including (i) peroxisome proliferator activated receptors

(PPAR) y agonists, such as glitazones (e.g.isaglitazone; pioglitazone; rosiglitazone; rivoglitazone, netoglitazone), naveglitazar, farglitazar, metaglidasen, GW6779542, CS038, MBX2044, AZD6610, PLX204, LBM642, AMG131 , AVE0847, AVE5376, ONO5129, TAK654, CLX0921, and the like); (ii) biguanides such as metformin and phenformin;

[0096] (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.

[0097] (c) sulfonylureas, such as acetohexamide; chlorpropamide; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide;

[0098] (d) cfc-glucosidase inhibitors, such as alglucosidase alfa, voglibose, celgosivir, miglitol, acarbose, and the like;

[0099] (e) cholesterol lowering agents such as (i) 3 -hydroxy-3 -methyl glutaryl-

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) PPARα agonists such as fenofibric acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fenofibrate and benzafibrate), GW677954, CS038, ABT335, LY674, GFTl 4, PLX204, Kl 11, 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;

[00100] (f) PPARδ agonists, such as GW677954, CS068, RWJ800025, GW501516, and CKD501; and

[00101 ] (g) other therapeutic agents, including anti-obesity and anti-diabetic agents, such as [00102] (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, WO00/10968, 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;

[00103] (2) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, DOVl 02677, zimeldine, and sibutramine;

[00104] (3) adrenoceptor agonists, including j83-adrenoreceptor agonists, such as solabregon, YM 178, amibregon, tesofensince, fenfluramine, amphetamine, phenmetrazine, phentermine, and N5984;

[00105] (4) pancreatic lipase inhibitors, such as orlistat, cetilistat, and GT389255;

[00106] (5) apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-

B/MTP) inhibitors, such as ISIS301012, ISIS301012, JTT130, and SLx4090;

[00107] (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;

[00108] (7) neuropeptide Y (NPY) antagonists, such as NPYl antagonists, for example, BIBP3226, Jl 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 0248152, and WO 02/49648;

[00109] (8) peptide YY (PYY) agonists, such as PYY, PYY 3-36, peptide YY analogs, and PYY agonists, for example, ACl 62352, N-Acetyl [Leu(28,31)]NPY 24-36, and PYY(3-36)NH₂, 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;

[001 10] (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;

[00111] (10) glucagon-like peptide (GLP)-I agonists, including GLP-I, GLP-I analogs and derivatives, such as exenatide, exenatide-LAR, liraglutide, CJCl 134PC, LY548806, 716155, and AVEOOlO;

[00112] (1 1) melanocortin (MC) agonists, including MC4 agonists and MC4R agonists, such as Melanotan II, PTl 5, BL3020, AP1030, or those described in PCT Application Nos. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, 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;

[00113] (12) ghrelin receptor antagonists, such as NOXB 11 , CYT009GhrQb, TZP300,

EPOl 492, and those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250;

[00114] (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;

[00115] (14) cholecystokinin (CCK) agonists, such as ARR15849, GI181771,

JMV180, A71378, A71623, SRl 46131, UCL2000, and A71378, and those described in U.S. Pat. No. 5,739,106;

[001 16] (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;

[00117] (16) growth hormone (GH) secretagogues, growth hormone secretagogue receptor modulators, such as SUNl 1031, RC 1291, tesamorelin, sermorelin, examorelin, NN703, hexarelin, MK677, SM-130686, CP-424,391, L-692,429 and L-163,255;

[001 18] (17) dipeptidyl peptidase IV (DP-IV or DPP-IV) inhibitors, such as denagliptin, sitagliptin, SYR322, RO0730699, TS021, ALS20426, vidagliptin, GRC8200, MP513, PHXl 149, 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 ;

[001 19] (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;

[00120] (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;

[00121] (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 ;

[00122] (21) dopamine agonists, for example dopamine D2 agonists, such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACPI 04, quinagolide, nolomirole, NHOOl , SLV308, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol;

[00123] (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;

[00124] (23) diacylglycerol acyl transferase (DAG) inhibitors, such as BAY744113;

[00125] (24) glucose transporter inhibitors, for example, sodium glucose cotransporter

(SGLT) inhibitors, such as, KGTl 251, 189075, AVE2268, and SGLOOlO;

[00126] (25) 1 1/3-hydroxy steroid dehydrogenase- 1 (_/8-HSD-I) inhibitors, such as

INCB 13739, and AMG221;

[00127] (26) cholesterol ester transfer protein (CETP) inhibitors, such as torcetrapib,

CETiI, JTT705, B AY60552 l,and JTT302;

[00128] (27) squalene synthase inhibitors, for example, lapaquistat;

[00129] (28) glucocorticoid antagonists, for example, mifepristone, Org34511 , and

Org34850;

[00130] (29) phosphodiesterase (PDE) inhibitors, including phosphodiesterase-3B

(PDE3B) inhibitors, for example, tetomilast, tadalafil, atopik, vardenafil, tipelikast, HT0712, QADl 71 A, 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;

[00131] (30) antiplatelet agents, such as, limaprost, clopidogrel, felbinac, eptifibatide,

NCX4016, ticagrelor, tirofiban, abcixmab, sarpogrelade, DA697B, argatroban, SCH53O348, cilostazol, YSPSL, parogrelil, asasantin, DG041, prasugrel, ramatroban, cangrelor, epoprostenol, beraprost, aspirin, Kl 34, triflusal, YY280, xemilofiban, ozagrel, alprostadil alfadex, TP9201 , procainamide, ATI 015, Z335, BGC728, glyrofam, EF5077, SH529, and ME3229;

[00132] (31) angiotensin converting enzyme (ACE) inhibitors, such as peridopril, enalapril, ramipril, fosinopril, quinapril, lisinopril, imidapril, benazepril, ilepatril, captopril, trandolapril, temcapil, cilazapril, MC4232, CHFl 521, omapatrilat, spirapril, moexipril, zofenopril, delapril, alacepril, S5590, and fasidotril;

[00133] (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;

[00134] (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)- 1 -propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123;

[00135] (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; [00136] (35) cyclo-oxygenase (COX)-2 inhibitors such as etoricoxib, G W4063 S 1 , meloxicam, lumiracoxib, diclofenac, valdecoxib, parecoxib, PMIOOl, 6444784, SVT2016, nimesulfide, CS706, cimicoxib, LR3001, LAS34475, P54, rofecoxib, celecoxib, and arcoxia;

[00137] (36) monoamine reuptake inhibitors, such as those disclosed in PCT

Application No. WO 01/27068, and WO 01/62341 ;

[00138] (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 al. (2003) Bioorg. Med. Chem. Lett. 13(3):351-4; and Anderson et al. (2002) J. Pharmacol. Exp. Ther. 303:1044-1051;

[00139] (38) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001);

[00140] (39) fatty acid synthase (FAS) inhibitors, such as Cerulenin, and C75;

[00141] (40) acetyl-CoA carboxylase-2 (ACC2) inhibitors;

[00142] (41) corticotropin-releasing hormone agonists;

[00143] (42) galanin antagonists;

[00144] (43) bombesin receptor subtype 3 (BRS3) agonists;

[00145] (44) protein tyrosine phosphatase- 1 B (PTP-I B) inhibitors;

[00146] (45) fatty acid transporter inhibitors;

[00147] (46) dicarboxylate transporter inhibitors;

[00148] (47) phosphate transporter inhibitors;

[00149] (48) urocortin binding protein antagonists and urocortin ligands, such as urocortin II;

[00150] (49) human agouti-related proteins (AGRP); [00151] (50) neuromedin U receptor agonists;

[00152] (51) topiramate, oxyntomodulin, tagatose, CP741952, zonisamide, IDl 101,

BDC03, S2367, AOD9604, fluasterone, GT389255, QCBTl 6, MK0916, MK0493, MK0364, PD6735, c2735, and adiponectin.

[00153] Examples of other anti-obesity agents that can be employed in combination with the cytokine inhibitors as 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).

[00154] Obesity and weight loss treatments also include surgery. Typically the weight loss surgical procedure is liposuction or lipoplasty. Surgical obesity treatments include gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty.

[00155] In another aspect, there is provided a method comprising administering 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 or an obesity- related condition or disorder, and wherein the cytokine inhibitor 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 ingredient A used in combination as relative to the use of either agent alone.

[00156] In another aspect of the invention, there is provided a method comprising administering to a subject a cytokine inhibitor as described herein and an ingredient 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 cytokine inhibitor and ingredient A, wherein ingredient 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.

[00157] In yet another aspect of the invention, there is provided a method of treating a cancer, which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00158] In some embodiments of the invention, the method of treating cancer further comprises treating the subject with surgery, radiation, cryotherapy, or one or more antiproliferative 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 acctyltransferase 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 (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-1 1), 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 amonafide. 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 109881 A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS)₅ epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinflum^'ne (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-methylenetetrahydrofblate (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-1550 (Ligand). In some embodiments, the immuno-modulator is interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CD 154 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). 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, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofme, flutamide, goserelin, nilutamide, or leuporelin. In yet others, the photodynamic agent is talaporfin (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), 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-6515S2 (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-I CI l (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^®).

[00159] 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, Hp 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.

[00160] 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.

[00161] 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.

[00162] 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.

[00163] In some embodiments, the cancer is breast, lung, kidney or prostate cancer metastasis. In some such embodiments, the neoplasm is bone metastasis.

[00164] In yet another aspect of the invention, there is provided a method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00165] In some embodiments of the invention, the composition further comprises an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, α-adrenergic receptor agonist, α-adrenergic receptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, α2δ 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 α-adrenergic receptor agonist is clonidine or midodrine. In yet others, the ot-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, trirnethadione, 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 α2δ 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- (1 H-Tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1 -Aminomethyl-3,4-dimethyl- cyclopentyl)-acetic acid, (lα,3α,5α)(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. [00166] 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; musculo-skeletal 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, and 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; temperomandibular 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.

[00167] 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.

[00168] 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 burn, 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 some such embodiments, 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.

[00169] In yet another aspect of the invention, there is provided a method of treating pemphigus, which comprises administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the pemphigus is pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, paraneoplastic pemphigus, or cicatricial pemphigoid. In another aspect, there are provided methods comprising administering to a subject in need thereof a combination of (i) an effective amount of a cytokine inhibitor 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 A when used alone. Also provided are methods comprising administering to a subject exhibiting one or more clinical indicia of pemphigus an amount of a cytokine inhibitor of the invention 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 IL6 levels, skin TNFa-mRNA levels, skin IL6 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 Ingredients A, useful in the treatment of pemphigus, as described herein. In some such embodiments, the effective amount of Ingredients A is less than the effective amount of Ingredient A when used alone.

[00170] 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.

[00171] 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 antiinflammatory 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.

[00172] In other embodiments, the immunosuppressant is mycophenylate mofetil, cyclosporin, azathioprine, methotrexate, alefacept, rituximab, anti -interferon gamma, or cyclophosphamide. [00173] 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.

[00174] 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.

[00175] In some embodiments of the methods of the invention, the dosage of

Ingredient A is reduced by from about 10% to about 90% in comparison to the dosage used to achieve the same therapeutic effect with Ingredient 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 A is a corticosteroid, for example, prednisone or prednisolone. In some other embodiments, Ingredient A comprises a corticosteroid and either chlorambusil or mycophenylate mofetil. In some embodiments, the dosage of prednisone is reduced to less than about 10 mg/day, less than about 15 mg per day, less than about 20 mg/day, less than about 30 mg/day, less than about 50 mg/day or less than about 70 mg/day.

[00176] In yet other embodiments, the cytokine inhibitor is administered orally or topically. In some embodiments, Ingredient A is a corticosteroid or antibiotic and is administered orally, topically, in a mouthwash or in a mouth spray.

[00177] In accordance with yet another aspect of the invention there are provided the following compounds of List 1, including representative examples of compounds of Formula

I:

List 1.

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole-

5-carboxamide;

3-(5-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide; 5-tert-butyl-N 1 -methyl-N3 -(4-methyl-3 -(5-(neopentylcarbamoyl)isoxazol-3- yl)phenyl)isophthal amide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-acetamido-5-tert-butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide; methyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3- yl)phenylcarbamoyl)phenylcarbamate;

5-(3-(5-tert-butyI-2-methoxybenzamido)phenyl)-N-(pyridin-3-ylmethyl)isoxazole-3- carboxamide;

5-(3-(5-tert-butyl-2-methoxybenzamido)phenyl)-N-(pyridin-2-ylmethyl)isoxazole-3- carboxamide; tert-butyl (3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methylcarbamate;

5-tert-butyl-2-methoxy-N-(4-methyl-3-(5-(pivalamidomethyl)isoxazol-3- yl)phenyl)benzamide;

5-tert-butyl-N-(3-(5-((3,3-dimethylbutanamido)methyl)isoxazol-3-yl)-4-methylphenyl)-2- methoxybenzamide;

N-(3-(5-(benzamidomethyl)isoxazol-3-yl)-4-methylphenyl)-5-tert-butyl-2- methoxybenzamide;

N-((3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5-yl)methyl)ftιran-2- carboxamide;

N-((3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)picolinamide;

N-((3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)nicotinamide;

N-((3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)isonicotinamide;

5-tert-butyl-2-methoxy-N-(4-methyl-3-(5-(mθφholine-4-carbonyl)-lH-pyrazol-3- yl )phenyl)b enzamide;

3 -(5-(5-tert-butyl-2-methoxybenzamido)-2-methytphenyl)-N-(tetrahydro-2H-pyran-4-yl)- 1 H- pyrazole-5-carboxamide; 3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-neopentyl-lH-pyτazole-5- carboxamide;

5-(3 -(3 -tert-butyl-5-cyanobenzamido)phenyl)- 1 -methyl-N-neopentyl- 1 H-pyrazole-3 - carboxamide;

5-(3 -(3-fluoro-5-morpholinobenzamido)phenyl)- 1 -isopropyl-N-neopentyl- 1 H-pyrazole-3- carboxamide;

5-(3 -(5-tert-butyl-3 -cyano-2-methoxybenzamido)phenyl)- 1 -methyl-N-neopentyl- 1 H- pyrazole-3 -carboxamide;

5-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-neopentyl-l,3,4- oxadiazole-2-carboxamide;

3-(5-(3 -fluoro-5-morpholinobenzamido)-2-methylpyridin-3 -yl)-N-neopentyl- 1 H-pyrazole-5- carboxamide;

3-(5-(3-fluoro-5-moφholinobenzamido)-2-methylpyridin-3-yl)-l-methyl-N-neopentyl-lH- pyrazole-5-carboxamide;

5-(5-(3 -fluoro-5-morpholinobenzamido)-2-methylpyridin-3 -yl)- 1 -methyl-N-neopentyl- 1 H- pyrazole-3 -carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-neopentylisoxazole-5- carboxamide;

N-benzyl-3-(5-(3-flxioro-5-morpholinobenzamido)-2-methylpyridin-3-yl)isoxazole-5- carboxamide;

N-benzyl-3-(5-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2- methylρhenyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methylphenyl)-N-

(pyridin-2-ylmethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methylρhenyl)-N-

(pyridin-3-ylmethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methylρhenyl)-N-

(pyridin-4-ylmethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-(2-morpholinoethyl)isoxazole-

5-carboxamide; 3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-(2-(pyridin-4- yl)ethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-(2-(pyridin-3- yl)ethyl)isoxazole-5-carboxamide;

S-CS-CS-fluoro-S-morpholinobenzamido^-methylphenyO-N-neopentylisoxazole-S- carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pyridin-4- yl)ethyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole-

5-carboxamide;

3-(5-(5-tert-butyl-2-methoxyben2amido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-morpholinobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3 -cyano-5-(piperidin- 1 -yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3 -tert-butyl-5-(piperazin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-(2-(4-methylpiperazin-l-yl)ethoxy)benzamido)-2- methylphenyl)-N-neopentylisoxazole-5-carboxamide;

5-tert-butyl-3-cyano-2-methoxy-N-(4-methyl-3-(5-(3-phenylpropanoyl)isoxazol-3- yl)phenyl)benzamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole-

4-carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-τnethylphenyl)-N-neopentyl-lH-pyrazole-5- carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-neopentyl-lH-pyrazole-5- carboxamide; 3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzainido)-2-methylphenyl)-N-((tetrahydro-2H-ρyran-4- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pyrrolidin-l- yI)ethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylρhenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole-5- carboxamide;

3-(2-methyl-5-(3-morpholinobenzamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(3-morpholinobenzamido)phenyl)-N-(pyridin-3-ylmethyl)isoxazole-5- carboxamide;

3-(5-(3-cyanobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(5-tert-butyl-2-raethoxybenzamido)-2-methylphenyl)-N-(cyclohexylmethyl)isoxazole-5- carboxamide;

3-[5-(5-tert-Butyl-2-methoxy-benzoylamino)-2-τnethyl-phenyl]-isoxazole-;

5-carboxylic acid (adamantan-l-ylmethyl)-amide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)- 1 H-pyrazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)-

1 H-pyrazole-5-carboxamide;

3-(5-(5-tert-butyl-2-methoxybenzamido)-2-methylphenyl)-N-(cyclohexylmethyl)-lH- ρyrazole-5-carboxamide;

5-[5-(5-tert-Butyl-2-methoxy-benzoylamino)-2-methyl-phenyl]-2H-pyrazol; e-3-carboxylic acid (adamantan-1-yl; methyl)-amide;

3-(5-(3-fluoro-5-moφholinobenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)- 1 H-pyrazole-5-carboxamide;

3-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-methoxybenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-chlorobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3,5-bis(trifluoromethyl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-fluorobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)-

1 H-pyrazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobcnzamido)-2-methylphenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH- pyrazole-5-carboxamide;

3 -(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)- 1 H- pyrazole-5-carboxamide;

N-(cyclohexylmethyl)-3-(5-(3-flυoro-5-morpholinobenzamido)-2-methylphenyl)-lH- pyrazole-5-carboxamide;

5-[5-(3-Fluoro-5-morpholin-4-yl-benzoylamino)-2-methyl-phenyl]-2H-pyrazole-3-carboxylic acid (adamantan-1 -ylmethyl)-amide;

N-(cyclohexylmethyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)isoxazole-5- carboxamide;

3-[5-(3-Fluoro-5-morpholin-4-yl-benzoylamino)-2-methyl-phenyl]-isoxazole-5-carboxylic acid (adamantan-1 -ylmethyl)-amide;

3-(5-(3-fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-fluoro-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

N-benzyl-3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-methylisoxazole-5- carboxamide;

N-benzyl-3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N- methylisoxazole-5-carboxamide; N-benzyl-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-methylisoxazole-5- carboxamide;

3-(5-(3-fluoro-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-neopentylisoxazole-

5-carboxamide;

3-(2-methyl-5-(3-morpholino-5-(tri£luoromethyl)benzamido)phenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-butylbenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole-5- carboxamide;

3-(2-methyl-5-(3-moφholino-5-(trifluoromethyl)benzamido)phenyl)-N-(tetrahydro-2H- pyran-4-yl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(4-tert-butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)ben2amido)phenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(pyrτolidin-l-yl)-5-(trifliαoromethyl)benzamido)phenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaρhthalene-2-carboxamido)ρhenyl)-N- neopentylisoxazole-5-carboxamide;

N-(3,4-dimethoxybenzyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N- methylisoxazole-5-carboxamide;

3-(5-(3-fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(4-methylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide; 3-(5-(3-fluoro-5-(4-methylpiperazin-l-yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3,3-dimethyl-2,3-dihydrobenzofuran-5-carboxamido)-2-methylp]ienyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(tetrahydro-2H- pyran-4-yl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(tetrahydro-2H- pyran-4-yl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-biphenyl-3-ylcarboxamido-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-methylisoxazole-5- carboxamide;

N-ethyl-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-propylisoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2,2,3,3,3- pentafluoropropyl)isoxazoIe-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2,2,2-trifluoroethyl)isoxazole-

5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(3₅3,3-trifluoropropyl)isoxazole-

5-carboxamide;

3-(2-methyl-5-(5-phenylnicotinamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(5-(piperidin-l-yl)nicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-methyl-5-(5-(pyrrolidin-l-yI)nicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-methyl-5-(5-moφholinonicotinamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(5-(pyrrolidin-l-yl)nicotinamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxarnide; 3-(2-methyl-5-(5-(piperidin-l-yl)nicotinamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(5-(pyrrolidin-l-yl)nicotinamido)phenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(2 -methyl -5-(5-(piperidin-l-yl)nicotinamido)phenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(2-methyl-5-(5-morpholinonicotinamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2,3- dimethoxybenzyl)-N-methylisoxazole-5-carboxamide;

3-(5-(3-isopropylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2-methoxybenzyl)-N- methylisoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(3-methoxybenzyl)-N- methylisoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(3,5- dimethoxybenzyl)-N-methylisoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-((l-ethylpyπOlidin-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(3- methoxybenzyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(3-methoxybenzyl)isoxazole-5- carboxamide;

N-(2,3-dimethoxybenzyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

N-((l-ethylpyrrolidin-2-yl)methyl)-3-(5-(3-fluoro-5-moφholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

N-benzyl-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)isoxazole-5-carboxamide; N-(3,5-dimethoxybenzyl)-3-(5-(3-fluoro-5-moφholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

N-(benzo[d] [ 1 ,3] dioxol-5-ylmethyl)-3 -(5-(3 -fluoro-5-morpholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2,3- dimethoxybenzyl)isoxazole-5-carboxamide;

3-(5-(3-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-acetylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(3-methoxybenzyl)isoxazole-5- carboxamide;

3-(5-(3-(2-methoxypropan-2-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3 -(5-(3 -tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-(( 1 -ethylpyrrolidin-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-morpholinobenzamido)-2-methylphenyl)-N-((l -ethylpyrrolidin-2- yl)methyl)isoxazole-5-carboxamide;

N-((l-ethylpyrrolidin-2-yl)methyl)-3-(2-methyl-5-(3-morpholino-5-

{trifluoromethyl)benzamido)phenyl)isoxazole-5-carboxamide;

3-(5-(3-(2-ethoxypropan-2-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(l-methylpiρeridin-4- yl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(l-methylpiperidin-4- yl)isoxazole-5-carboxamide;

3 -(2-methyl-5-(3 -morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-( 1 -methylpiperidin-4- yl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-moφholino-5-(trifluoromethyl)benzamido)phenyl)-N-((l-methylpiperidin-

4-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-morpholinobenzamido)-2-methylphenyl)-N-((l-methylpiperidin-4- yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-((l-methylpiperidin-4- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-moφholinobenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-((tetrahydroflιran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3 -cyano-S-Cpyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-((tetrahydrofiιran-2- yl)methyl)isoxazole-5-carboxamide;

2-methoxyethyl 3 -tert-butyl-5 -(4-methyl-3 -(5-(neopentyl carbamoyl)! soxazol-3 - yl)phenylcarbamoyl)phenylcarbamate; methyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3- yl)phenylcarbamoyl)benzoate;

3-(5-(3-tert-butyl-5-(2-methylthiazol-4-yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-flυoro-5-thiomorpholinobenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-thiomorpholinobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-(2,6-dimethylmorpholino)-5-fluorobenzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-fluoro-5-(l,4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-(l-hydroxy-2,2-dimethylpropyl)benzamido)-2-methylphenyl)-N-πeopentylisoxazole-

5-carboxamide;

3-(5-(3-amino-5-tert-butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-isobutylbenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5- carboxamide;

3-(2-methyl-5-(3-neopentylbenzamido)phenyl)-N-((tetrahydrofhran-2-yl)methyl)isoxazole-5- carboxamide;

3-(5-(3-(2,6-dimethylmoφholino)-5-fluorobenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide; 3-(5-(3-RuOrO-S-(1, 4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N-(pyτidin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-thiomorpholinobeπzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-(2,6-dimethylmorpholino)-5-fluorobenzamido)-2-methylphenyl)-N-((tetrahydrofuran-

2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-fluoro-5-(l,4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(hydroxymethyl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-methyl-5-(3-neopentylbenzamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(2-morpholinoisonicotinamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-methyl-5-(2-(pyrrolidin-l-yl)isonicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-methyl-5-(2-(piperidin-l-yl)isonicotinamido)ρhenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-cyano-5-moφholinobenzamido)-2-methylphenyl)-N-(pyridiπ-3-ylmethyl)isoxazole-

5-carboxamide;

3-(5-(3-cyano-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-(pyridin-2-yImethyl)isoxazole-5- carboxamide;

3-(5-(3-fluoro-5-(pyτrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluorornethyl)benzarnido)phenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-(2-methyl-5-(3-(ρyridin-2-yl)benzamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-cyano-5-moφholinobenzamido)-2-methylphenyl)-N-(pyridiπ-2-ylmethyl)isoxazole-

5-carboxamide;

3-(5-(3-cyano-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-{5-[3-Fluoro-5-(l-oxo-l X4-; thiomorρholin-4-yl)-benzoylamino]-2;

-methyl-phenylJ-isoxazole-S-carboxylic acid (2,2-dimethyl-propyl)-amide;

N-((l -methyl- 1 ,2,5,6-tetrahydropyridin-3-yl)methyl)-3-(2-methyl-5-(3-(pyrrolidin- 1 -yl)-5-

(trifluoromethyl)benzamido)phenyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(morpholinomethyl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-

5-carboxamide;

3-(5-(3-tert-butyl-5-(pyrrolidin-l-ylmethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(piperidin-l-ylmethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-teit-butyl-5-(moφholinomethyl)benzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-bυtyl-5-((dimethylamino)methyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(piperazin-l-ylmethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-bυtyl-5-(pyrrolidin-l-ylmethyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(piperidin-l-ylmethyl)benzamido)-2-methylphenyl)-N-((tetrahydrofuran-

2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-((dimethylamino)methyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-tert-butyl-5-(piperazin-l-ylmethyl)benzamido)-2-methylphenyl)-N-((tetrahydrofuran-

2-yl)methyl)isoxazole-5-carboxamide;

3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3-yl)phenylcarbamoyl)benzoic acid;

5-tert-butyl-Nl-(2-(dimethylamino)ethyl)-N3-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-

3-yl)phenyl)isophthalamide;

3-(5-(3-tert-butyl-5-(piperidin-l-ylmethyl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

(pyridin-3-ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(morpholinomethyl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3 -tert-butyl-5-((4-(2-hydroxyethyl)piperazin- 1 -yl)methyl)benzamido)-2-methylphenyl)-

N-((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-(((3S,5R)-3,5-dimethylpiperazin-l-yl)methyl)benzamido)-2- methylphenyI)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-((4-acetylpiperazin-l-yl)methyl)-5-tert-butylbenzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxainide;

3 -(5-(3-tert-butyl-5-((3-methylpiperazin-l-yl)methyl)benzamido)-2 -methyl phenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-cyclohexylisoxazole-5- carboxamide;

3-(5-(3-cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-cyclohexylisoxazole-5- carboxamide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-(piperidin-l-yl)isoxazole-5- carboxamide;

3-(5-(3-cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(piperidin-l-yl)isoxazole-5- carboxamide;

3-(5-(3-tert-butyl-5-cyanobenzamido)-2-methylphenyl)-N-morpholinoisoxazole-5- carboxamide;

3-(5-(3 -cyano-5-(pyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-morpholinoisoxazole-5- carboxamide; 3-(5-(3-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)-5-fluorobenzamido)-2-methylphenyl)-N- neoρentylisoxazole-5-carboxamide;

N-(3-(5-(8-oKa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)isoxazol-3-yl)-4-methylphenyl)-3-tert- butyl-5-cyanobenzamide;

N-(3-(5-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)isoxazol-3-yl)-4-methylphenyl)-5-tert- butyl-3-cyano-2-methoxybenzamide;

3-tert-butyl-5-cyano-N-(4-methyl-3-(5-(2,2,6,6-tetramethylmoφholine-4-carbonyl)isoxazol-

3-yl)phenyl)benzamide;

5-tert-butyl-3-cyano-2-methoxy-N-(4-methyl-3-(5-(2,2,6,6-tetramethylmorpholine-4- carbonyl)isoxazol-3-yl)phenyl)benzamide;

3-(5-(3-tert-butyl-5-((4-methylρiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N- cyclohexylisoxazole-S-carboxamide;

3-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-((6-

(trifluoromethyl)pyridin-3-yl)methyl)isoxazole-5-carboxamide;

3-tert-butyl-N-(4-methyl-3-(5-(piperidine- 1 -carbonyl)isoxazol-3 -yl)phenyl)-5-((4- methylpiperazin- 1 -yl)methyl)benzamide;

3-(5-(3 -tert-butyl-5-((4-methylpiperazin- 1 -yl)methyl)benzamido)-2-methylphenyl)-N-

(piperidin- 1 -yl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

(pyridin-4-ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N- cyclopentylisoxazole-S-carboxamide.

DETAILED DESCRIPTION OF THE INVENTION

[00178] The following terms are used throughout as defined below.

[00179] 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.

[00180] 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 carbon(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, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like.

[00181] 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.

[00182] 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.

[00183] 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 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.

[00184] 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[2.1.1]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, bornyl, 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.

[00185] 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.

[00186] 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(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CHaCHs)=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.

[00187] 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 cycloalkylalkenyl 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.

[00188] 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), -C=C(CH₂CH₃), -CH₂C=CH, -CH₂C=C(CH₃), and -CH₂C≡C(CH₂CH₃), 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.

[00189] 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, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 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.

[00190] 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 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.

[00191] 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, tetrahydrofuranyl, 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, quimiclidyl, 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-, A-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.

[00192] 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, 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, imidazopyridy], 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 substiruents such as those listed above. [00193] 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.

[00194] 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.

[00195] Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the invention are designated by use of the suffix, "ene." For example, divalent alkyl groups are alkylene groups, divalent aryl groups are arylene groups, divalent heteroaryl groups are divalent heteroarylene groups, and so forth. Substituted groups having a single point of attachment to the compound of the invention are not referred to using the "ene" designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene.

[00196] 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. [00197] 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.

[00198] The term "carboxylate" as used herein refers to a -COOH group.

[00199] The term "carboxylic ester" as used herein refers to -COOR³⁰ groups. R³⁰ is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[00200] The term "amide" (or "amido") includes C- and N-amide groups, i.e.,

-C(O)NR³¹R³², and -NR³¹C(O)R³² groups, respectively. R³¹ 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).

[00201] 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.

[00202] 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 NH₂, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[00203] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,

-SO₂NR³⁸R³⁹ and -NR³⁸SO₂R³⁹ groups, respectively. R³⁸ and R³⁹ 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 (-SO₂NH₂). [00204] The term "thiol" refers to -SH groups, while sulfides include -SR⁴⁰ groups, sulfoxides include -S(O)R⁴¹ groups, sulfones include -SO₂R⁴² groups, and sulfonyls include -SO₂OR⁴³. R⁴⁰, R⁴¹, R⁴², and R⁴³ are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00205] The term "urea" refers to -NR⁴⁴-C(O)-NR⁴⁵R⁴⁶ 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.

[00206] The term "amidine" refers to -C(NR⁴⁷)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.

[00207] The term "guanidine" refers to -NR⁵⁰C(NR⁵¹JNR⁵²R⁵³, wherein R⁵⁰, R⁵¹, 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.

[00208] The term "enamine" refers to -C(R⁵⁴)=C(R⁵⁵)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.

[00209] The term "ϊmide" refers to -C(O)NR⁵⁸C(O)R⁵⁹, wherein R⁵⁸ and R⁵⁹ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00210] The term "imine" refers to -CR⁶⁰(NR⁶¹) and -N(CR⁶⁰R⁶¹) groups, wherein R⁶⁰ and R⁶¹ 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 R⁶¹ are not both simultaneously hydrogen.

[00211] 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, tri ethyl chlorosilane; 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 trifluoracetate.

[00212] 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 -methyl ethoxycarbonyl, cx,Q!-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). [00213] 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.

[00214] Representative carboxy protecting groups are Cj to C₈ 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, cyclopentylmethyl 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)-l -ethyl, 1 -(pivaloyloxyl)- 1 -ethyl, 1 -methyl- 1 -(propionyloxy)- 1 -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, cyclohexyl oxycarbonylmethyl, 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.

[00215] 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.

[00216] "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, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[00217] 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 having Formula I are within the scope of the present invention.

[00218] 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.

[00219] ^' Compounds of the invention may be readily synthesized by techniques well known to those of skill in the art. For example, compounds of Formula IA, wherein B is N, D is O, E is CH, L' is a precursor to L² (see below), and X, Y, A, G, L², n, p, and Q are as defined herein (Formula IA), may be prepared as shown in Scheme 1.

Scheme 1

[00220] A suitably derivatized phenyl (X, Y= C), pyridine (X=N, Y=C, or X=C, Y=N) or pyridazine (X, Y=N), containing a nitro and aldehyde moiety, is reacted with hydroxylamine to form the intermediate oxime. Reaction with a derivatized alkyne (H-C s€- L') in an aprotic solvent, such as, for example DCM, ether, or toluene, in the presence of, for example, sodium hypochlorite and a base such as TEA, or NBS, or lead tetraacetate, leads to formation of the isoxazole-containing compound a, wherein L' is L²-Q, or wherein L' is a precursor for L²-Q. For example, when L' contains a urethane or carbonyl moiety, L' can be L²-Q, wherein L² is -(CH₂)_n-OC(O)NR-(CH₂)p- or -C(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-(CH₂)_P-Q to form compound b, wherein L² is -(CH₂)_π-C(O)NR-(CH₂)_q-.

[00221] Coupling with the amine-containing moiety may be effected, for example, by the use of typical amide-bond-forming reagents such as EDC, PyBOP, and the like, or by introduction of an activating moiety. The activating moiety is typically F, Cl, Br, I, N₃, N-hydroxysuccinimide, 1 -hydroxybenzotriazole, pentafluorophenol, pentachlorophenol, para- nitrophenol, or OC(O)-OR^y, wherein R^y is a Ci-6 alkyl group. Suitable bases include sodium bicarbonate or a suitable organoamine, such as pyridine, N-methylmorpholine, diisopropylethylamine or tri ethyl amine. Thus, any suitable amide-bond forming procedure may be used, such as those described in Bodanszky, M. and Bodanszky, A., Tke Practice of Peptide Synthesis, Springer- Verlag (1984); or Jones, J. Amino Acid and Peptide Synthesis Ed. Steven G. Davies, Oxford Science (1992). Alternatively, when L' contains a protected amine, it can be similarly deprotected and coupled with Q-(CH₂)_n-COOH by the methods described above, leading to compounds b, wherein L² is -(CH₂)_n-C(O)NR-(CH₂)_q-. In a next step, the nitro group of compound b is reduced to the amine, for example via hydrogenation in a solvent such as MeOH, EtOH, or the like, using Raney nickel or Pd/C as a catalyst, or reaction with SnCl₂ in a solvent such as DMF at room temperature. Target compounds of Formula IA are finally obtained by coupling with a G-COOH moiety, by one of the coupling methods described above. Alternatively, the nitro group in compound a is reduced first, followed by coupling with G-COOH, and finally conversion of L' to L²-Q, using the methods described above.

Scheme 2

[00222] Scheme 2 depicts an alternative route to the aryl-isoxazole derivatives. A suitably derivatized phenyl, pyridine or pyridazine, bearing an acetylene and amine moiety, is coupled to G-COOH by the methods described above to form compound d. Subsequently the aryl-isoxazole derivative e, wherein L' is COOR/, is formed by reaction with phenyl isocyanate and alkyl nitroacetate (NO₂CH₂COOR^y), or an oxime derivative (L 'C(NOH)H) as above. As before, the ester can be deprotected and the resulting acid coupled with NH₂(CH₂VQ to provide L²-Q, wherein L² is -C(O)NH(CH₂)_q-.

[00223] Yet another approach to compounds of Formula I is shown in Scheme 3. A suitably derivatized phenyl, pyridine, or pyridazine is nitrated by reaction with, for example, ammonium nitrate or fuming nitric acid in a solvent such as trifluoroacetic anhydride or concentrated sulfuric acid, respectively, at a temperature between 0° and 50⁰C to form intermediate f. In one approach, the ester and nitro group of intermediate f are reduced to the alcohol and amine respectively, for example, via reduction with LiAlH₄ in an organic solvent such as THF, ether, or the like. Coupling with a G-COOH moiety is achieved by one of the coupling methods described above. Subsequently the alcohol is oxidized to the aldehyde moiety via Dess-Martin oxidation. This intermediate can then be further derivatized as described above to generate the target compounds. In a second approach, the nitro group of intermediate f is selectively reduced by treatment with hydrogen gas in the presence of Raney nickel or Pd/C. The amine is coupled to G-COOH as described above. The ester moiety can be reduced to the aldehyde directly via DIBAL reduction, or converted into the aldehyde via the alcohol, using LiAlHU reduction followed by Dess-Martin oxidation as before. The compound thus obtained can be subjected to the reactions described above for aryl-isoxazole formation and futher derivatization.

[00224] Synthetic approaches to additional aryl-heterocycles are described below.

Compounds wherein B=D=N and E=CH, aryl-pyrazole derivatives (Scheme 4), can be obtained from intermediate a, by ring opening via for example, reduction with hydrogen using Pd/C, followed by recyclization with hydrazine to form the target pyrazole intermediate. Futher derivatization proceeds as described above for the isoxazole derivatives.

[00225] An exemplary synthesis of other aryl-heterocyclyl derivatives is shown in

Scheme 5. Treatment of intermediate f with hydrazine (Bioorg. Med. Chem. Lett., 2005, 15, 1863, Bioorg. Med. Chem. Lett. 2005, 15, 1311), followed by cyclization with ethyl 2- ethoxy-2-iminoacetate (Tetrah. Letters, 1982, 23, 3357) leads to the aryl-triazole derivative, wherein A, X, and Y are as defined herein and L' is COOEt. Alternatively, treatment of the intermediate hydrazine with the ethyl 2-ethoxy-2-iminoacetate HCl salt provides the aryl oxadiazole derivative. As before the ester can be deprotected and the resulting acid coupled with NH₂(CH₂)_q-Q to provide L²-Q, wherein L² is -C(O)NH(CH₂)_q-. Intermediate f can also be reacted with ammonia to form amide derivative g, which is converted to the nitrile and reacted with hydroxylamine, to generate the cyclization precursor h. Cyclization to the aryl- oxadiazole derivative can be achieved by treatment with ethyl 2-chloro-2-oxoacetate (J. Med. Chem., 1995, 38, 1355; J. Med. Chem., 1985, 28, 1234), again providing an intermediate wherein L' contains an ester group that can be further derivatized to afford L²-Q as before. Silmilarly, intermediate g can be reacted with chlorocarbonylsulfenyl chloride in the presence of ethyl carbonocyanidate (J. Chem. Soc, Perkin Trans. I₃ 1987, 2339) to afford the arylthiadiazole intermediates, wherein L' is COOEt, which can be further derivatized as before.

[00226] Scheme 6 shows an exemplary synthesis route towards aryl-thiazole derivatives. The aldehyde function of a suitably derivatized aryl precursor is converted into the epoxide moiety, which upon treatment with bromide anion (generated from NaBr, KBr and other bromide salts) and oxidation of the resulting β-bromohydrin yields the α- bromoketone derivative i. Treatment of this intermediate with ethyl 2-amino-2-thioxoacetate yields the ester containing aryl-thiazole intermediate (J.Med. Chem., 2002, 45, 3865), which can be derivatized further as before.

[00227] Compounds with the alternate orientation of L¹ can be obtained, e.g., as shown in Scheme 7. An appropriately derivatized phenyl, pyridine or pyridazine-3,5-dicarboxylic acid diester (R^y is as defined before) is deprotected by acid or base hydrolysis, to provide the carboxylic acid precursor, which in turn is coupled with G-NH₂ using the methods described above. Reduction of the ester group by the methods above again provides the aldehyde precursor for further derivatization.

[00228] 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, 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 modification or extension of those methods.

[00229] Pyridazine precursors can be obtained, e.g., as shown in Scheme 8, wherein A is as defined before, X=Y=N, and R^y is Ci.6 alkyl. Chlorination of a 3-methyl-6-oxo-l,6- dihydro-pyridazine-4-carboxylic acid ester (obtained as described in J.Am.Chem.Soc, 1955, 77, 3376), by, for example, reaction with POCI₃, is followed by displacement of the chlorine with 3,4-dimethoxy-benzylamine. Deprotection of the amine by treatment with an acid such as HCl or TFA, optionally in a cosolvent, provides the precursor, which can be coupled to G-COOH as above. Reduction of the ester moiety by the methods described above again provides the aldehyde precursor for further derivatization.

[00230] 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. [00231 ] The association of cytokine mediated disorders with imbalances in specific cytokine levels is well known in the art, as documented by the references in Chart I.

CHART I. References describing cytokine mediated processes and disorders.

[00232] 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). 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.

[00233] Assessment of these levels is associated with assessing the risk of cardiovascular and/or cerebrovascular disease. Lipoproteins 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.

[00234] 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.

[00235] 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 postprandial (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.

[00236] Glycosylated (or glycated) hemoglobin (hemoglobin Al c, HbIc, HbAl c 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 HbAl c. 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 HbAl c represents poor glucose control.

[00237] 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

Θδ 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.

[00238] 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 phosphorylated 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.

[00239] 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. [00240] "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. For example, within the context of cancer, successful treatment may include an alleviation of symptoms or slowing or halting the progression of the disease, as measured by a reduction in the growth rate of a tumor, a halt in the growth of the tumor, a reduction in the size of a tumor, partial or complete remission of the cancer, or increased survival rate or clinical benefit. 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 of 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. A subject is any animal that can benefit from the administration of a cytokine inhibitor, hi 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 mammal is a human.

[00241] 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/fibrin generation markers. Such markers include, but are not limited to, Creatine Kinase with Muscle and/or Brain subunits (CKMB), D-Dimer, F 1.2, 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).

[00242] 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.

[00243] 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.

[00244] 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 rumors, 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.

[00245] 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. [00246] The term "neuropathic pain" includes, but is not limited to, CRPS (Complex

Regional Pain Syndrome) type I, CRPS type II, reflex sympathetic dystrophy (RSD)₅ 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.

[00247] 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.

[00248] 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.

[00249] 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.

[00250] 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 1 1 hours 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.

[0025 IJ 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.

[00252] 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.

[00253] 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.

[00254] 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.

[00255] 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.

[00256] 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.

[00257] 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).

[00258] 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 Enzymology 7/2:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 6:165-182 (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.

[00259] 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.

[00260] 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.

[00261] 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. [00262] 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 nonvolatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[00263] 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.

[00264] 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.

[00265] 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, ρolyoxyethylene-9- lauryl ether, glycocholate and deoxycholate. Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.

[00266] 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.

[00267] 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 dichlorodifiuoromethane, 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.

[00268] 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.

[00269] 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.

[00270] 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.

[00271] 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.

[00272] 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).

[00273] 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.

[00274] 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.

[00275] 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.

[00276] 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. [00277] 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.

[00278] 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.

[00279] 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. US20050129729.

[00280] 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.

[00281 ] 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.

[00282] 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 anti-proliferative 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.

[00283] 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.

[00284] 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.

[00285] 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 acetyl transferase 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.

[00286] 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.

[00287] 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.

[00288] 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), fludarabine, gemcitabine, raltitrexed, or capecitabine. [00289] Another family of antiproliferative 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-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-11), or topotecan.

[00290] 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.

[00291] Another family of antiproliferative agents which may be 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 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS)₅ epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabuIin(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 djsodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatin-10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKline), docetaxel, vinorelbine, or vincristine.

[00292] 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.

[00293] 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).

[00294] Yet another 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).

[00295] 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).

[00296] 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).

[00297] 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).

[00298] Another family of antiproliferative agents which may be used in combination with the present invention includes metalloproteinase inhibitors. Suitable metal loproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), παetastat (CollaGenex), or marimastat (British Biotech).

[00299] 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).

[00300] 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 may be 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).

[00301] 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-1550 (Ligand).

[00302] Another family of antiproliferative agents which may be used in combination with the present invention includes immunomodulators. 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), CDl 54 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), |8-alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax).

[00303] 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, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutamide, or leuporelin.

[00304] 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.

[00305] 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).

[00306] 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).

[00307] 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.

[00308] In 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-inflammatories, cox-2 inhibitors, α-adrenergic receptor agonists or antagonists, ketamine, 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,

[00309] 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' Desk Reference, 594-595, 2851 and 2991 (57^th 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 (57^lh 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' Desk Reference, 2991 (57^th ed., 2003)).

[00310] Non-narcotic analgesics and antiinflammatories are preferably used for treatment of pain during pregnancy and breastfeeding. Antiinflammatories such as nonsteroidal anti -inflammatory drugs (NSAIDs) and cox-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 (57^th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 511, 667 and 773 (23^rd ed., 2002)).

[00311] 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 (Tofranill), 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 (57^th ed., 2003)).

[00312] 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 (57^th ed., 2003)).

[00313] 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 α2- 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 (57^th ed., 2003)).

[00314] 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 subject.

[00315] 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 (57^th 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 subject has already taken narcotic analgesics (See, e.g., Physicians' Desk Reference, 594-595 (57^th ed., 2003)). No intrinsic limit to the amount that can be given exists, as long as a subject 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 subjects not using long-term agents, as little as 2 mg IV/SC may be sufficient. Larger doses are typically required for subjects 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 (57^th 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 (57^th ed., 2003)]. Fentanyl transdermal patch (Duragesic ) is available as a transdermal dosage form. Most subjects are administered the drug in 72 hour dosing intervals; however, some subjects 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 (57^th ed., 2003)].

[00316] Non-narcotic analgesics and antiinflammatories such as NSAIDs and cox-2 inhibitors may be used to treat subjects 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 (57^th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 51 1, 667 and 773 (23^rd 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 (57^th ed., 2003)].

[00317] Antidepressants, e.g., nortriptyline (Pamelor™), may also be used in the invention to treat subjects 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 (57^th ed., 2003)].

[00318] Anticonvulsants such as gabapentin (Neurontin™) may also be used to treat subjects 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 (57^th 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 (57^th ed., 2003)].

[00319] 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, antiinflammatory agents, immunosuppressants, anti-infectives, antibiotics, gold salts, alkylating agents, immunoglobulins, or a combination of two or more thereof. Examples of antiinflammatory agents include corticosteroids, COX-2 inhibitors, non-steroidal antiinflammatory 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.

[00320] Treatment of pemphigus can also include plasmapherisis therapy or photophoresis therapy to the subject.

[00321] 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

[00322] The following abbreviations are used throughout the application with respect to terminology:

AcN: Acetonitrile

AcOH: Acetic acid

AIBN: Azobisisobutyronitrile

BTNAP: 2,2'-Bis(diphenylphosphino)- 1 , 1 '-binaphthyl

Boc: N-tert-Butoxycarbonyl

BOP: benzotriazol- 1 -yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate

Bu: Butyl

BzI: Benzyl

DIEA: N,N-Diisopropylethylamine

DCM: Dichloromethane

DIBAL: Diisobutylaluminium hydride

DIC: Diisopropyl carbodiimide DMAP: N₅N-dimethyl-4-aminopyπdine

DMF: N,iV-Dirnethylformamide

DMSO: Dimethylsulfoxide

EDC or EDCI: l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Eq.: Equivalent

Et: Ethyl

EtOAc: Ethyl acetate

EtOH: Ethanol

Hex: Hexanes

HPLC: High Pressure Liquid Chromatography

HV: High vacuum

IC50 value: The concentration of an inhibitor that causes a 50 % reduction in a measured activity.

IR: Infrared spectroscopy

LC-MS: Liquid chromatography- mass spectroscopy

LPS: Lipopolysaccharide

Me: Methyl

MeOH: Methanol

NBS: N- bromosuccinimide

NMM: N-Methylmorpholine

NMR: Nuclear Magnetic Resonance

PTSA: p-Toluene sulfonic acid

PyBOP: Benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate

RP: Reverse phase rt: Room temperature

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

TLC: Thin layer chromatography [00323] 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, or using the naming program Autonom2000 (Elsevier MDL, San Leandro, CA).

Synthesis of Intermediates

[00324] Intermediate A: 3-tert-Butylbenzoic acid. l-tert-Butyl-3-methylbenzene (205 mg, 250 μl, 1.4 mmol) was mixed with water (1 ml) and concentrated HNO₃ (1 ml) was added. The mixture was heated at 135°C for 3 hr and at 150⁰C for 3 hr. The mixture was allowed to cool, the precipitate was collected by decantation, washed with H₂O, and dissolved in DCM. The organic layer was washed with water and dried over MgSU₄ to give intermediate A (0.21 g, 85%). ¹H-NMR (CDCl₃) δ (ppm) 8.17 (s, IH), 7.95 (d, IH), 7.68 (d, IH), 7.43 (t, IH), 1.39 (s, 9H).

[00325] Intermediate B: 3,3-Dimethyl-2,3~dihydrobenzofuraπ-5-carboxylic acid.

Step 1: To a suspension of 3-bromo-4-hydroxybenzoic acid a_(2.86 g, 13.2 mmol) in DCM (80 ml) was added oxalyl chloride (2.9 ml, 2.5 eq.) and DMF (50 μl). The mixture was stirred overnight until it became homogeneous. The solvents were evaporated to give 3- bromo-4-hydroxybenzoyl chloride.

[00326] Step 2. The compound obtained above was dissolved in EtOH, the mixture was heated for 1.5 hr and the solvent was evaporated to yield ethyl 3-bromo-4- hydroxybenzoate (3.24 g, 100%). ¹H-NMR (CDCl₃) δ (ppm) 8.17 (s, IH), 7.95 (d, 1 H), 7.68 (d, IH), 4.29 (q, 3H), 1.32 (t, 2H). [00327] Step 3: The compound obtained above (3.23, 13.2 mmol) was dissolved in acetone (50 ml), 3-chloro-2-methylprop-l-ene (1.6 ml, 1.25 eq.) and K₂CO₃ (2.73 g, 1.5 eq.) were added, and the mixture was refluxed overnight. After cooling, the solids were filtered and the solution was evaporated. The residue was dissolved in DCM and the organic layer was washed with water, dried over MgSO₄ and evaporated to give 1.75 g (44%) of ethyl 3- bromo-4-(2-methylallyloxy)benzoate. ¹H-NMR (CDCl₃) δ (ppm) 8.12 (s, IH), 7.86 (d, IH), 6.98 (d, IH)₅ 5.17 (s, IH)₅ 5.04 (s, IH), 4.57 (s, 2H), 4.35 (q, 2H), 1.87 (s, 3H)₃ 1.39 (t, 3H).

[00328] Step 4: A solution of ethyl 3 -bromo-4-(2 -methyl allyloxy)benzoate (305 mg,

1.05 mmol), tributyl tin hydride (600 mg, 2 eq.) and AIBN (12 mg, 0.07 eq.) in toluene was heated at 7O⁰C for 3 hr. The solvent was evaporated and the residue was chromatographed on silica gel using Hex/DCM, affording the desired product ethyl 3,3-dimethyl-2,3- dihydrobenzofuran-5-carboxylate (130 mg, 56%). ¹H-NMR (CDCl₃) δ (ppm) 7.90 (dd, IH), 7.81 (d, IH), 6.80 (d, IH), 4.36 (q, 2H), 4.32 (s, 2H), 1.40 (t, 3H), 1.38 (s, 6H).

[00329] Step 5: Ethyl 3,3-dimethyl-2,3-dihydrobenzofuran-5-carboxylate (130 mg, 59 mmol) was dissolved in MeOH (3 ml) and 1 M aq. NaOH (1.2 ml) was added. The solution was heated for 3 hr at 70⁰C. The MeOH was evaporated and the solution was acidified with 1 M HCl (1.4 ml). The precipitate was filtered off and washed with water. After drying the product 3,3-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid B was obtained (90 mg, 79%). ¹H-NMR (CDCl₃) δ (ppm) 7.97 (d, IH), 7.88 (s, IH), 6.84 (d, IH), 4.35 (s, 2H), 1.39(s, 6H).

[00330] Intermediate C. Method A: 3-Isopropylbenzoic acid (C-a). To a solution of l-bromo-3-isopropylbenzene (1.24 g, 6.23 mmol) in THF (18 ml) was added magnesium wire (0.151 g, 1 eq.). The mixture was heated to 50 to 60⁰C until the magnesium was dissolved. To this solution was added an excess of solid CO₂ and after 40 min the reaction mixture was acidified with IM aq. HCl. The product was extracted into DCM, the organic layer was dried over MgSO₄ and evaporated, yielding the target product (1.07 g (quantitative)). ¹H-NMR (CDCl₃) δ (ppm) 8.00 (s, IH), 7.95 (d, IH), 7.49 (d, IH), 7.41 (t, IH), 3.00 (m, IH), 1.30 (d, 6H).

[00331] Method B: Ethyl 3-isopropyIbenzoate (C-b). To a solution of l-bromo-3- isopropylbenzene (2.43 g, 12.5 mmol) in THF (18 ml) was added magnesium wire (0.296 g, 1 eq.). The mixture was heated to 50 to 60⁰C until the magnesium was dissolved. To this was added a THF solution of ethyl chloro formate (1.3 ml, 1.1 eq.) at -78°C and the mixture was allowed to warm up to room temperature . The reaction mixture was diluted with IM aq. HCl. The product was extracted into DCM, the organic layer was dried over MgSO₄ and evaporated. Column chromatography (silica gel) using hexanes afforded the desired ethyl ester (1.04 g, 43 %). ¹H-NMR (CDCl₃) δ (ppm) 7.94 (s, IH), 7.89 (d, IH), 7.44 (d, IH), 7.38 (t, IH), 4.41 (q, 2H), 3.00.(m, IH), 1.42 (t, 3H), 1.30 (d, 6H).

[00332] Intermediate C-b can be easily converted into intermediate C-a by standard methods, using alkaline hydrolysis with aqueous NaOH in MeOH.

[00333] Intermediates D and E: 3-(2-Hydroxypropan-2-yi)benzoic acid (D) and ethyl 3-acetylbenzoic acid (E). To a solution of intermediate C-b (370 mg, 1.9 mmol) in acetic acid (5 ml) was added chromium trioxide (0.46 g). The mixture was stirred overnight at rt. The acetic acid was evaporated and the residue was dissolved in DCM. The organic layer was washed with water, dried over MgSO₄ and evaporated to give a mixture of starting material and both products in a ratio of approximately 3:1 :1. The mixture of esters was hydrolyzed by dissolving the residue in MeOH (5 ml), adding 1 M aq. NaOH (3 ml) and heating for 2 hr at 100⁰C. The MeOH was evaporated, and the remaining solution was acidified with 1 M HCl (4 ml). The product was extracted into DCM, the organic layer was dried over MgSO₄ and evaporated. The mixture of acids was used as such in subsequent reactions and the products obtained were separated by chromatography.

[00334] Intermediate F: 3-(2-Methoxypropan-2-yI)benzoic acid (F-a) . Step 1: A solution of ethyl 3-isopropylbenzoate C-b (236 mg, 1.23 mmol) NBS (250 mg, 1.14 eq.) and dibenzoylperoxide (22 mg, 0.07 eq.) in tetrachloromethane was heated to 80⁰C for 3 hr. The solvent was evaporated to yield the target compound. ¹H-NMR (CDCI3) δ (ppm) 8.28 (s, IH), 7.98 (d, IH), 7.87 (d, IH), 7.45 (t, IH), 4.42 (q, 2H), 2.24 (s, 6H), 1.43 (t, 3H).

[00335] Step 2: Ethyl 3-(2-bromopropan-2-yl)benzoate was dissolved in MeOH and the mixture was heated to 55°C for 2 hr. To the methanolic solution was added 1 M aq. NaOH (2 ml). The resulting mixture was heated overnight to 55°C. The MeOH was evaporated, and the resulting solution was acidified with 1 M HCl (4 ml). The product was extracted into DCM, the organic layer was dried over MgSO-*, and the solvent was evaporated. The product F-a was used without purification in subsequent reactions. H- NMR (CDCl₃) δ (ppm) 8.18 (s, IH), 8.05 (d, IH), 7.74 (d, IH), 7.50 (t, IH), 3.13 (s, 3H), 1.60 (s, 6H).

[00336] 3-(2-Ethoxypropan-2-yl)benzoic acid (F-b) was prepared similarly, using

EtOH instead of MeOH. ¹H-NMR (CDCl₃) δ (ppm) 8.18 (s, IH), 8.03 (d, IH), 7.74 (d, IH), 7.50 (t, IH), 3.25 (q 2H), 1.60 (s, 6H), 1.21 (t, 3H).

[00337] Intermediate G : 5-(Pyrrolidin-l-yl)nicotinic acid. Step 1: 5-

Bromonicotinonitrile (367 mg, 2 mmol) was dissolved in pyrrolidine (1.5 ml) and DMSO (1.3 ml). The mixture was heated overnight at 140°C. The reaction mixture was diluted with chloroform, washed with water and dried over Na₂SO₄. The product was chromatographed on silica gel using MeOH/DCM (3:97) to give the pyiτolidin-l-yl(5-(pyrrolidin-l-yl)pyridin- 3-yl)methanone intermediate (320 mg, 65 %).

[00338] Step 2: The amide was dissolved in 6 N aq. HCl (3 ml) and heated to 120⁰C for

3 hr. The mixture was allowed to cool and the product was filtered, washed with 0.5 ml of 6N HCl and dried to yield 150 mg (50 %) of the target product HCl salt. ¹H-NMR (CDCl₃) δ (ppm) 8.31 (s, IH), 8.22 (d₅ IH), 7.83 (dd, IH), 3.40 (m, 4H), 2.00 (m, 4H).

[00339] The following intermediates were similarly prepared:

[00340] S-CPiperidin-l-yrjnicotinic acid (G-2). ¹H-NMR (CDCl₃) δ (ppm) 8.55 (d,

IH), 8.44 (d, IH), 8.00 (s, IH), 3.38 (m, 4H), 1.60 (bs, 6H).

[00341] 5-(Morpholin-l-yl)nicotinic acid (G-3). ¹H-NMR (CDCl₃) δ (ppm) 8.61 (d,

IH), 8.41 (d, IH), 7.92 (dd, IH), 3.86 (m, 4H), 3.28 (m, 4H).

[00342] Intermediate H: 3-tert-ButyI-5-(alkyloxycarbonylamino)benzoic acid. To a solution of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (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 rt for 2 hr. The solvent was evaporated, the residue dissolved in toluene and evaporated again to give the crude acid chloride derivative. 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 IR₃ 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 was heated to 105⁰C 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 N₃ 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 80⁰C, 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.

[00343] Methyl 3-tert-butyI-5-(methoxycarbonylamino)benzoate (H-a) (Rj = R₂ =

Me). ¹H-NMR (CDCl₃) δ (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).

[00344] 3-tert-Butyl-5-(MethoxycarbonyIamino)benzoic acid (H-b) (Rj = Me, R₂ =

H). ¹H-NMR (DMSO) δ (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).

[00345] 3-(tert-ButoxycarbonyIamino)-5-tert-butyIbenzoic acid (H-c) (Ri = t-Bu,

R₂ = H). ¹H-NMR (CDCl₃) δ (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).

[00346] Intermediate I: 3-tert-ButyI-5-(2-methyIthiazol-4-yl)benzoyI derivatives.

To a solution of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (0.295 g, 1.3 mmol) in DCM (5 ml) was added oxalyl chloride (0.5 ml, 4.5 eq.) and 2 drops of DMF. The mixture was heated at 40⁰C until homogeneous and than at rt for 2 hr. The solvent was evaporated, the residue dissolved in toluene and the solvent was evaporated again to give crude methyl 3-tert- butyl-5-(chlorocarbonyl)benzoate. The compound was dissolved in THF (5 ml) and added to excess diazσmethane in ethyl ether until yellow color persisted. After stirring for 1.5 hr at rt the reaction was complete, as verified by TLC. The reaction solvent was evaporated and the residue was dissolved in 4M HCl in dioxane. After 10 min the solvent was evaporated, providing methyl 3-tert-butyl-5-(2-chloroacetyl)benzoate. ¹H-NMR (CDCl₃) δ (ppm) 8.40 (s, 2H)₃ 8.34 (s, IH), 8.23 (s, IH), 4.77 (s, 2H), 3.99 (s, 3H), 1.40 (s, 9H).

[00347] Methyl 3-tert-butyI-5-(2-methyIthiazoI-4-yI)benzoate (I-a). A mixture of the compound obtained above (61 mg, 0.23 mmol), thioacetamide (20 mg, 1.2 eq.) and NMM (50μl, 2.0 eq) in dioxane (1 ml) was heated to 80⁰C overnight and evaporated. The residue was partitioned between DCM and IM HCl, the organic portion was washed with IM HCl, water and dried over MgSO₄ to provide methyl 3-tert-butyl-5-(2-methylthiazol-4-yl)benzoate I-a. ¹H-NMR (CDCl₃) δ (ppm) 8.33 (m, IH), 8.21 (m, IH), 8.07 (m, IH)₅ 7.42 (s, IH), 3.97 (s, 3H), 2.84 (s, 3H), 1.43 (s, 9H).

[00348] 3-tert-Butyl-5-(2-methylthiazoI-4-yl)benzoic acid (I-b). Compound I-a was dissolved in MeOH (1 ml) and 1 M aq. NaOH was added (0.5 ml). The mixture was heated for 1 hr at 80⁰C. The solvent was evaporated, the solution was acidified with 1 M HCl (1 ml), and the compound precipitated as a yellow solid, which was filtered, washed with water and dried to give the target product I-b (46 mg, 73 %). ¹H-NMR (CDCl₃) δ (ppm) 8.423 (m, IH), 8.24 (m, IH), 8.13 (m, IH), 7.45 (s, IH)₅ 2.88 (s, 3H), 1.44 (s, 9H).

[00349] Intermediates J; Heterocyclylbenzoic acid derivatives. (Methods as described in WO00/55153 and WO2006/010082.) Method A. Step 1: A mixture of 3,5- difluorobenzonitrile (X = F) (5.00 g, 35.95 mmol, 1.0 eq.), morpholine (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 (Na₂SO₄), 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)⁺). [00350] Step 2. A mixture of the compound obtained above (4.93 g, 23.92 mraol) 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 acid 3-fluoro-5-morpholinobenzoic acid J-a (X = F) as a white solid (4.79 g, 88% yield, 97% pure by LC-MS). (CaIc. mass: 225, obs. mass: 267 (M + AcN)⁺).

[00351] Method B. Morpholine (4 ml, 46 mmol) was added to methyl 3,5- difluorobenzoate (X=F) (2.53 g, 15 mmol) and the mixture was heated to 160⁰C for 5 days, providing a mixture of target compound (Calculated mass: 225, observed mass: 266.9) and the bis-morpholino derivative. (CaIc. mass: 295.0, obs. mass: 294.0). The reaction mixture was allowed to cool to rt, 6 N aq. HCl was added (15 ml) and the mixture was heated at 125°C for 3 hr. After cooling to rt the reaction mixture was diluted with water (50 ml) and the pH was adjusted to 2 using aq. NaHCO₃. The precipitated product was filtered, washed with water and dried. A second crop of 3-fluoro-5-morpholinobenzoic acid J-a (X = F) was recovered from the combined washes after a reduction of the volume. (CaIc. mass: 225, obs. mass: 267). ¹H-NMR (DMSO-d₆) δ (ppm) 13.15 (bs, I H), 7.285(t, IH), 7.05(d, IH), 7.03(s, 1 H), 3.73 (t, 4H)₅ 3.18 (t, 4H).

[00352] The above methods were used for the synthesis of the following substituted benzoic acids:

[00353] 3-Fluoro-5-(piperidin-l-yl)benzoic acid (J-b). (Method A: Step 1 reaction temperature: 40⁰C.) CaIc. mass: 224, obs. mass: 224.

[00354] 3-Fluoro-5-(pyrrolidin-l-yl)benzoic acid (J-c). (Method A: Step 1 reaction temperature: rt.) CaIc. mass: 210, obs. mass: 251.

[00355] 3-(2,6-DimethyImorpholino)-5-fluorobenzoic acid (J-d). (Method A: Step 1 reaction temperature: 70⁰C.) CaIc. mass: 254, obs. mass: 254. [00356] 3-Fluoro-5-(l,4-oxazepan-4-yl)benzoic acid (J-e). (Method A: Step 1 reaction temperature: 100⁰C.) CaIc. mass: 240, obs. mass: 240.

[00357] S-Fluoro-S-thiomorphoIinobenzoic acid (J-f)» (Method A: Step 1 reaction temperature: 70⁰C.) CaIc. mass: 242, obs. mass: 283.

[00358] 3-Morpholino-5-(trifluoromethyl)benzoic acid (J-g). (Method A: Step 1 reaction temperature: 60⁰C.) CaIc. mass: 276, obs. mass: 317.

[00359] 3-(Piperidin-l-yl)-5-(trifluoromethyl)benzoic acid (J-h). (Method A: Step 1 reaction temperature: 40⁰C.) CaIc. mass: 274, obs. mass: 315.

[00360] 3-(PyrroIidin-l-yl)-5-(trifluoromethyl)benzoic acid (J-i). (Method A: Step 1 reaction temperature: rt.) CaIc. mass: 260, obs. mass: 301.

[00361] Intermediate K: Heterocvclylisonicotinate derivatives. Step 1. 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 room temperature for 3 h 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 ϊ-butoxide (3.4 g, 30 mmol) in THF (10 ml), the reaction mixture was slowly warmed up to room temperature 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 Na₂Sθ₄and evaporated to give 1.658 g of tert-butyl 2-chloroisonicotinate as a red oil (purity ca. 90%), which was used in the next step without further purification. ¹H NMR (DMSO-dβ) δ (ppm) 8.62 (d, IH), 7.81 (s, IH), 7.79 (d, IH), 1.52 (s, 9H).

[00362] Step 2. A solution of tert-butyl 2-chloroisonicotinate (427 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 NaHCO₃. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, and dried over Na₂SO_-J. 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 (525 mg, purity >95%). ¹H NMR (DMSO-d₆) δ (ppm) 8.24 (d, I H), 7.18 (s, I H), 7.00 (d, IH), 3.74 (t, 4H), 3.52 (t, 4H), 1.54 (s, 9H).

[00363] 2-Morpholinoisonicotinic acid (K-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 rt. After evaporation of dioxane and water the solid residue was dried at 80⁰C 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).

[00364] Using similar procedures as illustrated for preparation of K-a, the following compounds were made:

[00365] 2-(Pyrrolidin-l-yl)isonicotinic acid (K-b). CaIc. mass: 192, obs. mass: 193.

[00366] 2-(Piperidin-l-yI)isonicotinic acid (K-c). CaIc. mass: 206, obs. mass: 207.

[00367] Intermediate L: S-Cyano-S-morpholinobenzoic acid. Step 1. 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 room temperature for 18 hr. The solvent was removed and the residue refluxed in MeOH (80 ml) for Ih 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 (CaIc. mass: 264, obs. mass: 265). [00368] Step 2. Methyl 3-cyano-S-morpholinobenzoate. Methyl 3-carbamoyl-5- morpholinobenzoate (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 room temperature for lhr. The solvent was removed and the residue was purified on silica gel eluting with 0-50% EtO Ac/Hex to afford 197 mg methyl 3-cyano-5-morpholinobenzoate (82% yield) (CaIc. mass: 246, obs. mass: 247).

[00369] Step 3. S-Cyano-S-morpholinobenzoic acid. Methyl 3-cyano-5- morpholinobenzoate (197 mg, 0.8 mmol) was dissolved in MeOH (7 ml) and THF (7 ml). A NaOH solution (2M, 0.60 ml) was added and the solution was heated to 50⁰C for 1 h 15 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 acid, which contained some sodium chloride (CaIc. mass: 232, obs. mass: 233). It was used in subsequent reactions without further purification.

[00370] Intermediate M: 5-tert-ButyI-2-methoxy-3-bromobenzoic acid. NBS (1.71 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 MgSO₄ and concentrated to give intermediate M (1.2 g, 87%) as a pale yellow solid in > 90% purity. ¹H-NMR (500 MHz, CDCl₃) δ (ppm) 8.01 (s, IH), 7.78 (s, IH)₃ 4.00 (s, 3H), 1.33 (s, 9H).

[00371 ] Intermediate N: S-tert-Butyl-Z-methoxy-S-cyanobenzoic acid. Step 1 : To a solution of 5-tert-butyl-2-methoxy-3-bromobenzoic acid M (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 rt for 1 hr, concentrated, the residue was dissolved in MeOH (10 ml) and further stirred at it for 15 minutes. The solvent was evaporated to give a viscous yellow oil (quantitative) in >90% purity. ¹H-NMR (500 MHz₅ CDCl₃) δ (ppm) 7.75 (s, IH), 7.73 (s, IH), 3.95 (s, 3H), 3.92 (s, 3H), 1.33 (s, 9H).

[00372] Step 2 : 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%), CsCO₃ (0.49 g, 1.5 mmol) and BINAP (62 mg, 20 mol%) were added. The mixture was stirred at 15O⁰C for 40 tnin. 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) δ (ppm) 8.00 (s, IH), 7.72 (s, IH), 4.04 (s, 3H), 3.94 (s, 3H), 1.32 (s, 9H).

[00373] Step 3: To a solution of 5-tert-butyl-2-methoxy-3-cyanobenzoic acid methyl ester (40 mg, 0.16 mmol) in 1 :1 THF/MeOH (1 ml) mixture, 2N NaOH (0.35 ml) was added. The mixture was stirred at room temperature for 1 hr, neutralized with IN HCl and extracted with approx. 20 ml of EtOAc. The organic layer was dried over MgSO₄ and concentrated to give intermediate N (quantitative) as a white solid which was used in the next step without further purification. ¹H-NMR (500 MHz, CDCl₃) δ (ppm) 7.81 (d, J= 2.43 Hz,lH), 7.64 (d, J= 2.44 Hz₅IH), 7.02 (br s, IH), 3.97 (s, 3H), 3.89 (s, 3H)₅ 3.03 (s, 3H)₅ 1.35 (s, 9H).

[00374] Intermediate O: 5-tert-Butyl-2-methoxy-3-(methyIsulfønamido)benzoic acid. Steps 1 and 2: Methyl 3-amino-5-tert-butyI-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 US2OO5/O107399) 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 20⁰C 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 H₂ 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).

[00375] Step 3: Methyl 5-tert-butyl-2-methoxy-3-methyIsulfonamido)-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 mixture was stirred at 20⁰C for 16 hr. The mixture was washed with H₂O, dried (MgSO₄), evaporated and the brown residue was chromato graphed on silica gel (0-50% EtOAc in Hex) to give the target compound (1.1 g, 55%) as a white solid.

[00376] Step 4: 5-tert-butyl-2-methoxy-3-(methyIsulfonamido)benzoic acid. 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 O (0.83 g, 79%) as a white solid. ¹H-NMR (500 MHz, CD₃OD) δ (ppm) 7.77 (d, J= 2.49 Hz₃IH), 7.68 (d, J = 2.50 Hz,lH), 3.88 (s, 3H), 3.05 (s, 3H), 1.35 (s, 9H).

[00377] Intermediate P: Method A. S-tert-Butyl-S-Cmethoxycarbony^benzoic acid. A solution of 5-tert-butyl-isophthalic acid (2.22 g, 10 mmol) and 2 drops cone, sulfuric acid in 30 ml MeOH was heated at 70⁰C overnight. After cooling down, the reaction solution was neutralized with solid Na₂CO₃. After filtration, the filtrate was concentrated to dryness. The solid residue was dissolved in DCM/water. The DCM phase was dried over Na₂SO₄Io give 801 mg the diester compound. ¹H-NMR (500 MHz, DMSO-d₆) δ (ppm) 8.36 (s, IH), 8.22 (s, 2H), 3.92 (s, 6H), 1.38 (s, 9H). The aqueous phase was concentrated and subjected to preparative HPLC purification, which afforded 816 mg of intermediate P as a white solid. ¹H- NMR (500 MHz, DMSO-d₆) δ (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). [00378] Method B. To a solution of 5-tert-butylisophthalic acid (3 g, 13.5 mmol) in

MeOH (50 ml) at rt was added PTSA (100 mg). The mixture was stirred at 5O⁰C for 2 days. The reaction was allowed to cool to rt. Solid NaOH (0.54 g, 13.5 mmol) and 100 ml of water were added and the mixture was stirred overnight. Most of the solvent was removed under vacuum. The residue was extracted with DCM. The aqueous residue was acidified to pH 2 with 6N HCl. The mixture was extracted with DCM. The organic fractions were dried over MgSO₄. The drying agent was removed by filtration, and the filtrate was concentrated under vacuum to give the title compound (analytically pure by LC-MS) as a white solid (1.84 g). ¹H NMR (CD₃OD) δ (ppm) 8.47 (s, IH), 8.31 (s, IH), 8.29 (s, IH), 3.95 (s, 3H), 1.40 (s, 9H).

[00379] Intermediate Q: Methyl S-tert-butyl-S-carbamovIbenzoate. A mixture of

5-tert-butyl-isophthalic acid monoester P (48 mg, 0.2 mmol), oxalyl chloride (5 eq.) and a catalytic amount of DMF in 1.5 ml DCM was stirred at rt for 2 hr. After concentrating to dryness, the resulting acid chloride was coupled with ammonia (0.4 ml 0.5 M in dioxane) in 1 ml DCM in the presence of DIEA (105 μ\, 3 eq.). The reaction was stirred at rt overnight, before being concentrated. Preparative HPLC purification afforded 39 mg product as a white solid. (CaIc. mass: 235.2; obs. mass: 276.6 (M+AcN)).

[00380] Intermediate R; Methyl 3-tert-butyl-5-(methylcarbamoyl)benzoate.

Intermediate R (41 mg) was prepared in a similar way as above starting from 0.2 mmol 5- tert-butyl-isophthalic acid monoester. (CaIc. mass: 249.3, obs. mass: 290.6 (M+AcN)).

[00381] Intermediate S: 3-tert-Butyl-5-eyanobenzoic acid. Step 1. To a suspension of methyl 3-tert-butyl-5-carbamoylbenzoate (97 mg, 0.41 mmol) in 2 ml chloroform was added a solution OfPOCl₃ (50 μl, 0.53 mmol) in 0.5 ml chloroform. After stirring at rt for 3 hr, the reaction mixture was cooled to 0⁰C, and TEA (345 μl, 0.246 mmol) was added. The resulting mixture was stirred at rt overnight, and poured into 20 ml of 1 N HCl. Extraction was done with chloroform. The organic phase was concentrated to give 145 mg of the crude orange-red oil, which was further purified by prep HPLC to give 26.5 mg target product. ¹H-NMR (500 MHz, CDCl₃) δ 8.31 (m, IH), 8.17 (m, IH), 7.86 (m, IH), 3.98 (s, 3H), 1.39 (s, 9H).

[00382] Intermediate S; 3-tert-Butyl-S-cyanobenzoic acid. Methyl 3-tert-butyl-5- cyanobenzoate (1 1 1.7 mg, 0.5 mmol) obtained above was dissolved in THF (1 ml), MeOH (1 ml), and 2N NaOH (0.5 ml) was added. The solution was stirred for 30 min., then the solvent was removed and the residue dried at 80⁰C under vacuum for 1 hr. The compound was used as such in the next step.

[00383] Intermediate T: 3-tert-ButyI-5-eyanobenzoyI chloride. To a suspension of the acid S (104.4 mg, 0.5 mmol) in DCM (15 ml), 4 drops of DMF and oxalyl chloride (5 eq.) were added. The reaction was monitored by LC-MS and the solvent evaporated upon completion. The residue was used in the next step without further purification.

[00384] Intermediate U: 3-fBromomethvn-S-tert-butvl benzoic acid. Step 1. To a solution of intermediate P (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 rt and was then added to 200 ml of water. The mixture was extracted with DCM. The organic fractions were dried over MgSO₄. 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 room temperature for 4 hr. The mixture was added to 200 ml of water and was extracted with DCM. The organic fractions were dried with MgSO₄. 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 title compound as a clear oil (0.3 g). ¹H NMR (CDCl₃) δ (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).

[00385] Step 2: 3-(Bromomethyl)-5-tert-butylbenzoic acid. 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 0°C for 1 hr and then at rt 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 MgSO₄. The drying agent was removed by filtration, and the filtrate was concentrated under vacuum to give the title compound as a clear oil (0.088 g). ¹H NMR (CDCU) δ (ppm) 8.01 (s, IH), 7.93 (s, IH), 7.74 (s, IH)₅ 4.54 (s, 2H), 1.38 (s, 9H).

[00386] Intermediate V: 5-tert-ButyI-3-cyano-2-(2-(4-methylpiperazin-l- yl)ethoxy)benzoic acid. Step 1. In a 50 ml round-bottomed flask were placed methyl 5-tert- butyl-3-cyano-2-methoxybenzoate (3.16 g, 12.8 mmol) 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 lhr at rt 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 Na₂SO₄.

The solvent was removed, the crude material was dissolved in acetone and treated with methyl bromoacetate (3.85 ml, 42 mmol), K2CO3 (5.80 g, 42 mrnol), and the reaction mixture was heated at reflux for Ihr. 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-methoxy-2-oxoethoxy)benzoate. ¹H NMR (CDCl₃) δ (ppm) 8.04 (d, J = 2.5 Hz, IH), 7.74 (d, J = 2.5 Hz₅ IH), 4.79 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 1.33 (s, 9H).

[00387] Step 2. 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 Na2SO₄ 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 rt 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 Na₂SO₄, 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-hydroxyethoxy)benzoate (26 % yield). ¹H NMR (CDCl₃) δ (ppm) 8.04 (d, J = 3.0 Hz, 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), 1.33 (s, 9H).

[00388] Step 3. 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 rt for 25 min. The reaction mixture was treated with saturated NaHCO₃ (5 ml) and IM NaZS₂O₃ (5 ml) and stirred for 15 min. The reaction was diluted with DCM (20 ml) and extracted with DCM. The combined organic layers were dried over Na₂SO₄. The solvents were removed and concentrated to ~8 ml. Half of the solution was placed in a 16 mm test tube and treated with acetic acid (728 μl, 13.1 mmol) followed byN-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 Na₂CO₃ 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 Na₂SO₄. 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).

[00389] Step 4. 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 1.5hr 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 5-tert-butyl-3-cyano-2-(2-(4-methylpiperazin-l-yl)ethoxy)benzoic acid which was used without further purification. (CaIc. mass: 345.2; obs. mass: 345.0).

[00390] The intermediates described above are used in the methods described for the following examples.

Example 1 : Synthesis of phenyl-isoxazoles. Method A.

[00391] l-Methyl-S-nitrobenzaldehyde oxime. To a solution of 2-methyl-5- nitrobenzaldehyde (2.3 g, 13 mmol) in MeOH (10 ml) at it was added hydroxylamine hydrochloride (4.86 g, 70 mmol). The mixture was stirred at rt for 2 hr. The solvent was removed under vacuum. The residue was dissolved in EtOAc (200 ml), washed with saturated NajCO₃ and dried over anhydrous Na₂SO₄. The drying agent was removed by filtration, and the filtrate was concentrated under vacuum to give the title compound (analytically pure by TLC) as an orange solid (1.76 g). ¹H NMR (CDCl₃) δ (ppm) 8.54 (s, IH), 8.42 (s, IH), 8.12 (d, IH)₅ 7.4 (b, IH)₃ 7.37 (d, IH), 2.53 (s, 3H).

[00392] tert-Butyl 3-(2-methyl-5-nitrophenyI)isoxazole-5-carboxylate. To a solution of 2 (3.4 g) and t-butyl propiolate (4.9 ml) in DCM (100 ml) at rt was added a solution of sodium hypochlorite (aq. 5.6%, 100 ml) at a rate of 1 drop per 3 seconds. The mixture was stirred at rt for 18 hr. The DCM layer was separated, washed with water, and dried over anhydrous Na₂SO₄. The drying agent was removed by filtration and the filtrate was concentrated under vacuum. The crude product was purified on a silica gel column using 3% EtOAc in Hex to give the target compound (white soft solid, 1.44 g) and tert-butyl 3-(2- methyl-5-nitrophenyl)isoxazole-4-carboxylate (yellow oil, 0.74 g).

[00393] tert-Butyl 3-(2-methyl-5-nitrophenyl)isoxazole-5-carboxylate: ¹H NMR

(CDCl₃) δ (ppm) 8.39 (s, IH)₅ 8.23 (d, IH), 7.51 (d, IH), 7.11 (s, IH), 2.62 (s, 3H), 1.65 (s, 9H).

[00394] 3-(2-MethyI-5-nitrophenyl)isoxazole-5-carboxylic acid. To a solution of the compound obtained above (0.51 g, 1.68 mmol) in DCM (5 ml) at rt was added TFA (5 ml). The mixture was stirred at rt for 1 hr, after which the solvent was removed under vacuum to dryness. The crude product (white solid, 0.42 g) was used without further purification.

[00395] 3-(2-Methyl-5-nitropheπyl)-iV-(pyridin-3-ylmethyl)isoxazoIe-5- carboxamide (Ri = (3-pyridyl)CH2-, R2 = H). To a solution of the compound from the previous step (0.145 g, 0.58 mmol) in DCM (5 ml) at rt was added 3-(arninomethyl)pyridine (0.58 ml, 5.8 mmol) and PyBop (0.60 g, 1.16 mmol). The mixture was stirred at rt for 17 hr, after which the solvent was removed under vacuum to dryness. The residue was dissolved in EtOAc (100 ml), washed with saturated Na₂CO₃ (100 ml) and dried over Na₂SO₄ to give the crude product as a brown oil (254 rag). LC-MS showed the target compound was the major component of the crude mixture. The crude product was used without further purification. CaIc. mass: 338, obs. mass: 338, 380. [00396] 3-(5-Amino-2-methylpheny])rN-(pyridinO-yImethyl)isoxazole-5- carboxamide (Ri = (3-pyridyl)CH2-, R2 = H) (W). To a solution of the compound above (0.58 mmol, crude product from the reaction above) in DMF (10 ml) at rt was added tin(II)chloride dihydrate (1.36 g, 5.8 mmol). The mixture was stirred at rt for 17 hr. The solvent was removed under high vacuum. The residue was dissolved in 2N NaOH (aq. 100 ml) and extracted with DCM. The combined DCM layers were dried over Na₂SO₄. After removing the drying agent and solvent, the crude product was obtained as a yellow oil (134 mg). LC-MS showed W was the major component. The crude product was used without further purification. CaIc. mass: 308, obs. mass: 309.

[00397] 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyI)-N-(pyridin-3- ylmethyI)isoxazoIe-5-carboxamide (Ri = (3-pyridyl)CH₂-, R₂ = H, R₃ = 5-tert-butyl-2- methoxyphenyl) (1). Method a. To a solution of W (0.58 mmol, crude product from the reaction above) in DCM (10 ml) at rt was added DIEA (0.54 ml, 3.48 mmol), 5-tert-butyl-2- methoxybenzoic acid (0.245 g, 1.16 mmol) and PyBop (0.6 g, 1.16 mmol). The mixture was stirred at rt for 18 hr. The solvent was removed under vacuum. The residue was dissolved in EtOAc (100 ml), washed with water, saturated Na₂CO₃ and dried over Na₂SO₄. The crude product was purified using RP-HPLC using AcN and water as eluents to give 1 as a white solid (31.8 mg). CaIc. mass: 498, obs. mass: 499. ¹H NMR (CD₃OD) δ (ppm) 8.96 (bs, IH), 8.43 (bs, I H), 8.64 (d, I H), 8.09 (bs, IH), 8.02 (s, IH), 8.01 (s, IH), 7.68 (dd, IH), 7.61 (dd, IH), 7.38 (d, IH), 7.33 (s, IH), 7.15 (d, IH), 4.82 (s, 2H) 4.04 (s, 3H), 2.48 (s, 3H), 1.36 (s, 9H).

[00398] Method b. To a solution of W (0.08 mmol, crude product from the reaction above) in DMF (0.3 ml) was added carboxylic acid R₃CO₂H (0.08 mmol), BOP (0.05 g, 0.12 mmol), and NMM (0.02 ml, 0.2 mmol). The mixture was stirred at 50⁰C until the reaction was complete (typically 30 to 90 min.). The reaction mixture was diluted with MeOH and purified by RP-HPLC using AcN and water as eluents to give the target compound as a white solid.

[00399] Using the procedures described above, the following exemplary compounds were prepared: [00400] 3-(5-(5-tert-Butyl-2-methoxy-3-(methyIsulfonanύdo)benzamido)-2- methyIphenyl)-Λ^r-neopentylisoxazole-5-carboxamide (2). CaIc. mass: 570, obs. mass: 571.

[00401] 5-tert-Butyl-N¹-methyl-N³-(4-methyl-3-(5-(neopentylcarbamoyl)-isoxazol-

3-yl)phenyl)isophthaIamide (3). CaIc. mass: 504, obs. mass: 505.

[00402] 3-(5-(3-tert-Butyl-S-cyanobenzamido)-2-methylphenyI)-iV- neopentyIisoxazoIe-5-carboxamide (4). CaIc. mass: 472, obs. mass: 473.

[00403] 3-(5-(3-Acetamido-5-tert-butylbenzamido)-2-methylphenyl)-N- neopentylisoxazoIe-5-carboxamide (5). CaIc. mass: 504, obs. mass: 506.

[00404] Methyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3- yl)phenylcarbamoyl)phenylcarbamate (6). CaIc. mass: 520, obs. mass: 522.

Method B.

[00405] 5-tert-Butyl-iV-(3-ethynyIphenyI)-2-inethoxybenzainide. To a solution of 5- tert-butyl-2-methoxybenzoic acid (0.42 g, 2.0 mmol) in DCM (10 ml) at rt was added PyBop (2.08 g, 4.0 mmol), DIEA (1.04 ml, 6.0 mmol) and 3-ethynylaniline (0.21 ml, 2.0 mmol). The mixture was stirred at rt for 18 hr. The solvent was removed to dryness. The residue was dissolved in EtOAc (100 ml), washed with IN HCl, water, saturated Na₂CO₃, brine and dried over Na₂SO₄. The crude product was purified on a silica gel column eluted using EtOAc in Hex (0 - 50% in 60 min.) to give the target compound as a white solid (0.519 g). CaIc. mass: 307, obs. mass: 308.

[00406] Ethyl 5-(3-(5-tert-butyI-2-methoxybenzamido)-phenyl)isoxazoIe-3- carboxylate. To a solution of the compound above (0.3 Ig, 1.0 mmol) in anhydrous toluene (3 ml) was added ethyl nitroacetate (0.22 ml, 2.0 mol), DIEA (0.52 ml, 3.0 mmol) and phenyl isocyanate (0.22 ml, 2.0 mmol). The mixture was stirred at 80^°C for 18 hr. Additional ethyl nitroacetate (1.1 ml, 10.0 mol), DIEA (2.6 ml, 15.0 mmol) and phenyl isocyanate (1.1 ml, 10.0 mmol) were added. The mixture was stirred for additional 72 hr at 80 C. The mixture was diluted with EtOAc (100 ml), washed with IN HCl, water, saturated Na₂CO₃, brine and dried over Na₂SO₄. The crude product was purified on a silica gel column eluted using EtOAc in Hex (0-50% in 80 min.) to give the target compound as a brown oil (134 mg). CaIc. mass: 422, obs. mass: 423.

[00407] 5-(3-(5-tert-Butyl-2-methoxybenzamido)phenyl)isoxazole-3-carboxylic acid. To a solution of the compound from the previous step (134 mg, 0.32 mmol) in MeOH (10 ml) at rt was added IN NaOH (aq. 3 ml). The mixture was stirred at rt for 2 hr. The solvent was removed to dryness. The residue was dissolved in IN HCl (10 ml) and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄. The drying agent was removed by filtration. The filtrate was concentrated to dryness to give the target compound as a yellow solid (128 mg). CaIc. mass: 394, obs. mass: 395.

[00408] 7V-BenzyI-5-(3-(5-tert-butyl-2-methoxybenzamido)phenyl)isoxazole-3- carboxamide (R — BzI) (7). To a solution of the compound above (25 mg, 0.06 mmol) in DCM (10 ml) at rt was added PyBop (65 mg, 0.12 mmol) and benzylamine (0.066 ml, 0.6 mmol). The mixture was stirred at rt for 18 hr. The solvent was removed under vacuum. The residue was purified using RP-HPLC to give 7 (9.2 mg). CaIc. mass: 483, obs. mass: 484.

[00409] Using the procedures illustrated above, the following compounds were prepared:

[00410] 5-(3-(5-tert-Butyl-2-methoxybenzamido)phenyl)-iV-(pyridin-3- ylmethyl)isoxazole-3-carboxamide (8). CaIc. mass: 484, obs. mass: 485.

[00411 ] 5-(3-(5-tert-Butyl-2-methoxybenzanudo)phenyl)-N-(pyridin-4- ylmethyI)isoxazole-3-carboxamide (9). CaIc. mass: 484, obs. mass: 485.

[00412] 5-(3-(5-tert-Butyl-2-methoxybenzamido)phenyl)-iV-(pyridin-2- ylmethyI)isoxazole-3-carboxamide (10). CaIc. mass: 484, obs. mass: 485. [00413] 5-(3-(5-tert-ButyI-2-methoxybenzamIdo)phenyl)--V-neopentylisoxazole-3- carboxamide (11). CaIc. mass: 463, obs. mass: 464.

[00414] tert-Butyl prop-2-ynylcarbamate. To a solution of propargyl amine (3.2 ml,

50 mmol) and DIEA (18 ml, 100 mmol) in DCM (150 ml) at rt was added dropwise a solution of (Boc)aO (16 g, 75 mmol) in DCM (20 ml). The mixture was stirred at rt for 18 hr, washed with 10% citric acid and dried over Na₂SO₄. The drying agent was removed by filtration. The filtrate was concentrated to give the target compound as a clear liquid (15 g, contains 1 eq. of tert-butanol).

[00415] tert-Butyl (3-(2-methyl-5-nitrophenyl)isoxazol-5-yl)methylcarbamate. To a solution of the compound above (5.0 mmol), 2-methyl-5-nitrobenzaldehyde oxime (prepared as described above) (0.90 g, 5.0 mmol) and DIEA (2.61 ml, 15 mmol) in DCM (20 ml) at rt was added an aqueous NaOCl solution (5%, 21 ml) via a syringe pump at the rate of 1 ml/hr. The mixture was stirred at rt for a total of 18 hr, diluted with DCM (50 ml), washed with water and dried over Na₂SO₄. The drying agent was removed by filtration. The filtrate was concentrated. The residue was purified on a silica gel column using EtOAc in Hex (0-50% in 70 min.) as eluents to give the target compound as a yellow solid (0.876 g). ¹H NMR (CDCl₃) δ (ppm) 8.35 (d, IH), 8.19 (dd, IH), 7.48 (d, IH), 6.45 (s, IH), 5.16 (bs, IH), 4.54 (d, 2H), 2.59 (s, 3H), 1.48 (s, 9H).

[00416] tert-Butyl (3-(5-amino-2-methylphenyl)isoxazol-5-yI)methylcarbamate. To a solution of the compound from the previous step (214 mg, 0.64 mmol) in MeOH (5 ml) at rt was added Raney-Ni (200 mg, wet weight). The mixture was stirred at rt under hydrogen atmosphere for 5 hr. The catalyst was filtered off. The filtrate was concentrated under vacuum to give the target compound as a light yellow oil (191 mg). Calc. mass: 303, obs. mass: 304.

[00417] tert-Butyl (3-(5-(5-tert-butyI-2-methoxybenzamido)-2- methylphenyl)isoxazol-5-yl)methylcarbamate (12).- To a solution of the compound obtained above (191 mg, 0.64 mmol) in DCM (10 ml) was added DIEA (0.033 ml, 1.92 mmol), 5-tert-butyl-2-methoxybenzoic acid (266 mg, 1.28 mmol), and PyBop (0.67 g, 1.28 mmol). The mixture was stirred at rt for 18 hr, diluted with DCM (50 ml) and washed with 10% citric acid (3x) and dried over Na₂SCv The drying agent was removed by filtration. The filtrate was concentrated. The residue was purified on a silica gel column using EtOAc in Hex (0-50% in 60 min.) as eluents to give the target compound as a clear oil (251 mg). CaIc. mass: 493, obs. mass: 494.

[00418] Λ^-(3-(5-(Aminomethyl)isoxazol-3-yl)-4-methylphenyl)-5-tert-butyl-2- methoxybenzamide. To a solution of the compound above (225 mg, 0.46 mmol) in DCM (5 ml) was added TFA (5 ml). The mixture was stirred at rt for 1 hr. The solvent was removed to dryness to give the target compound as clear oil. CaIc. mass: 393, obs. mass: 394.

[00419] 5-tert-Butyl-2-methoxy-iV-(4-methyI-3-(5-(pivaIamidomethyI)isoxazol-3- yl)phenyl)benzamide (Ri = tBu) (13). To a solution of the compound above (0.065 mmol, 1/7 of the crude product from the reaction above) in DCM (2 ml) at rt were added DIEA (0.11 ml, 0.65 mmol) and pivaloyl chloride (0.04 ml, 0.33 mmol). The mixture was stirred at rt for 18 hr, diluted with DCM (20 ml), washed with IN NaOH and dried over Na₂SO₄. The drying agent was removed by filtration. The filtrate was concentrated. The residue was purified using RP-HPLC to give 12 as a clear film (12.3 mg). CaIc. mass: 477, obs. mass: 478.

[00420] Using similar procedures, the following compounds were synthesized.

[00421 ] 5-tert-Butyl-A^(3-(5-((3,3-dimethylbutanamido)methyl)isoxazol-3-yl)-4- methylphenyI)-2-methoxybenzamide (13). CaIc. mass: 491, obs. mass: 492.

[00422] iV-(3-(5-(Benzamidoraethyl)isoxazol-3-yl)-4-methyIphenyl)-5-tert-butyl-2- methoxybenzamide (14). CaIc. mass: 497, obs. mass: 498. [00423] N-((3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)isoxazoI-5- yl)methyI)furan-2-carboxamide (15). CaIc. mass: 487, obs. mass: 488.

[00424] -V-((3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyI)isoxazol-5- yl)methyl)picolinamide (16). CaIc. mass: 498, obs. mass: 499.

[00425] Λ^-((3-(5-(5-tert-ButyI-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)nicotinamide (17). CaIc. mass: 498, obs. mass: 499.

[00426] N-((3-(5-(5-tert-ButyI-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)isonicotin amide (18). CaIc. mass: 498, obs. mass: 499.

Example 2. Synthesis of phenyl pyrazoles. Method A.

[00427] 4-(5-Amino-2-methylphenyI)-l-morphoIinobutane-l,2,4-trione (Ri-N-R₂ = morpholino). To a solution of (3-(2-methyl-5-nitrophenyl)isoxazol-5- yl)(morpholino)methanone (19 mg, 0.06 mmol) prepared as described for 1) in a mixed solvent of THF/MeOH (1/1, 3 ml) at rt was added Raney-Ni (60 mg, wet weight). The mixture was stirred under hydrogen atmosphere at rt for 3 hr. The catalyst was removed by filtration. The filtrate was concentrated to dryness to give the target compound (Rj-N-R₂ = morpholino). CaIc. mass: 290, obs. mass: 291.

[00428] 5-tert-Butyl-2-methoxy-ΛK4-methyl-3-(4-morpholmo-3,4-dioxobutanoyl)- phenyl)benzamide (R₁-N-R₂ = morpholino, R₃ = 5-tert-butyl-2-methoxyphenyl ). To a solution of 5-tert-butyl-2-methoxybenzoic acid (15 mg, 0.07 mmol) in DCM (1 ml) at rt was added oxalyl chloride (0.031 ml, 0.35 mmol) and a drop of DMF. The mixture was stirred at rt for 3 hr. The solvent was removed under vacuum to dryness. The residue was dissolved in DCM (1 ml). A solution of the compound obtained above (0.06 mmol, crude product from the reaction above) in DCM (1 ml), and DIEA (0.061 ml, 0.35 mmol) were added. The mixture was stirred at rt for 18 hr. The solvent was removed to dryness to give the target compound. CaIc. mass: 480, obs. mass: 481.

[00429] 5-tert-ButyI-2-methoxy-Λ'-(4-methyl-3-(5-(morpholine-4-carbonyl)-iJE-^r- pyrazoI-3-yI)phenyl)benzamide (R₁-N-R2 = morpholino, R₃ = 5-tert-butyl-2- methoxyphenyl). To a solution of the compound above (0.06 mmol, crude product from the reaction above) in EtOH (0.5 ml) at rt was added hydrazine (20 μl). The mixture was stirred at 70⁰C for 18 hr. The solvent was removed to dryness. The residue was purified using RP- HPLC to give 20 as a white solid (5.4 mg). CaIc. mass: 476, obs. mass: 477.

[00430] Using similar procedures as illustrated for 20, the following compounds were prepared:

[00431 ] 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-.V-(tetrahydro- 2/T-pyran-4-yl)-iH^r-pyrazole-5-carboxamide (21). CaIc. mass: 490, obs. mass: 491.

[00432] 3-(5-(5-tert-ButyI-2-methoxybenzamido)-2-methyIphenyI)-N-neopentyl- lH-pyrazole-5-carboxamide (22). CaIc. mass: 471, obs. mass: 472.

Method B.

[00433] Methyl 5-(3-(tert-butoxycarbonylamino)phenyI)-l-methyI-lH-pyrazole-3- carboxylate. In a 2 dram vial were placed methylhydrazine sulfate (47.6 mg, 0.33 mmol) and 2 M NaOH (340 μl, 0.68 mmol). To this rapidly stirred homogeneous solution was added acetic acid (53 μl, 0.93 mmol) followed by methyl 4-(3-(tert-butoxycarbonylamino)phenyI)- 2,4-dioxobutanoate (100 mg, 0.31 mmol) as a solution in dioxane (1 ml). The reaction was heated to 8O⁰C overnight. The solvent was removed and the residue purified on silica gel eluting with 0-50% EtOAc/Hex to afford 27 mg (26 % yield) of the target compound. ¹H NMR (CDCl₃) δ (ppm) 7.82 (s, IH), 7.46 (s, IH), 7.33 (s, 2H)₅ 7.13 (s, IH), 6.54 (s, IH), 4.22 (s, 3H), 3.90 (s, 3H), 1.53 (s, 9H).

[00434] 5-(3-(3-tert-ButyI-5-cyanobenzamido)phenyl)-l-methyl-N-neopentyl-lH- pyrazole-3-carboxamide (23). The compound obtained above (27.5 mg, 85 μmol) was dissolved in MeOH (4 ml) in a 50 ml round-bottomed flask and treated with IM NaOH (169 μl). The reaction was heated at reflux for 2hr 40 min. The solvent was removed, the residue diluted with THF and treated with IM HCl (169 μl). The solvents were removed in vacuo and the residue suspended in THF. The reaction was treated with a solution of neopentyl amine (30 μl, 25 μmol) and EDC (20 mg, 104 μmol) in DCM (1 ml). The solvents were removed after 1 hr and the residue was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaCl and dried over Na₂SO₄. The solution was filtered through silica gel and the solvent evaporated. The residue was treated with 20% TFA/DCM for 20 min and the solvents were removed in vacuo. One third of this residue (28 μmol) was dissolved in DCM and treated with 3-cyano-5-t-butylbenzoic acid (Intermediate S) (42 μmol) and EDC (42 μmol). After stirring overnight, the reaction mixture was directly purified on silica gel, eluting with 0-50% EtOAc/Hex to afford 4.3 mg (33% yield) of the target compound 23. CaIc. mass: 471, obs. mass: 473.

[00435] Using similar procedures, the following compounds were synthesized:

[00436] 5-(3-(3-Fluoro-5-morpholinobenzamido)phenyl)-l-isopropyI-N-neopentyl- lH-pyrazole-3-carboxamide (24). CaIc. mass: 521, obs. mass: 523.

[00437] 5-(3-(5-tert-Butyl-3-cyano-2-methoxybenzamido)phenyl)-l-methyI-N- neopentyl-lH-pyrazole-3-carboxamide (25). CaIc. mass: 501, obs. mass: 503.

Example 3: Synthesis of pyridyl-oxadiazoles.

[00438] 2-Methyl-5-nitronicotinohydrazide. To a solution of methyl 2-methyl-5- nitronicotinate (0.55 g, 2.8 mmol) in MeOH (3 ml) at rt was added hydrazine (0.5 ml). The mixture was stirred at rt for 3 days. The precipitated product was filtered off, washed with MeOH and dried under vacuum to give the title compound as an off-white solid (0.44 g, 80%). ¹H NMR (DMSO-d₆) δ (ppm) 9.82 (s, IH), 9.30 (d, I H), 8.44 (d, IH), 4.60 (d, 2H), 2.66 (s, 3H).

[00439] 5-(2-Methyl-5-nitropyridin-3-yl)-N-neopentyl-l,3,4-oxadiazole-2- carboxamide. To a solution of the compound obtained above (70 mg, 0.36 mmol) in EtOH (1 ml) was added ethyl 2-ethoxy-2-iminoacetate hydrochloride (65 mg, 0.36 mmol, 1.0 eq.). The mixture was stirred at 100⁰C for 2 hr, neopentyl amine was added (130 μl, 1.09 mmol, 3 eq.) and heating was continued for one more hr. The reaction mixture was evaporated, DCM was added (2 ml), the organic layer was washed with saturated aq. Na₂CO₃, and dried over anhydrous MgSO₄. The drying agent was removed by filtration and the filtrate was concentrated under vacuum to give the target product (119 mg). It was used without purification in the next reaction. ¹H NMR (CDCl₃) δ (ppm) 9.50 (d, IH), 9.15 (d, IH), 7.22 (bt, IH), 3.36 (d, 2H), 3.17 (s, 3H), 1.04 (s, 9H); CaIc. mass: 319, obs. mass: 320.

[00440] 5-(2-Methyl-5-nitropyridin-3-yl)-N-neopentyl-l,3,4-oxadiazole-2- carboxamide. To a solution of the compound obtained in the previous step (119 mg, 0.36 mmol) in MeOH (2.5 ml) at rt was added RaNi. The mixture was stirred under hydrogen atmosphere for 2 hr, after which the catalyst was removed by filtration and the solvent evaporated under vacuum to dryness. The crude product (white solid, 0.11 g) was used without further purification. ¹H NMR (CDCl₃) δ (ppm) 8.21 (bs, IH), 7.68 (bs, IH)₅ 7.20 (bt, IH), 3.33 (d, 2H), 2.89 (s, 3H),1.03 (s, 9H).

[00441 ] 5-(5-(3-FIuoro-5-morpholinobenzamido)-2-methylpyridin-3-yI)-N- neopentyI-l,3,4-oxadiazoIe-2-carboxamide (24). To a solution of the compound above (25 mg, 0.08 mmol) in DCM (2 ml) at rt was added 3-fluoro-5-morpholinobenzoyl chloride.HCl (25 mg, 0.10 mmol) (prepared from Intermediate J-a) and NMM (30 μ\, 0.27 mmol). The mixture was stirred at rt for 30 min, after which MeOH (1 ml) was added and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (2 ml), and purified by RP chromatography using a gradient of AcN/water. After evaporation the title compound was obtained as the TFA salt. CaIc. mass: 496, obs. mass: 498. ¹H NMR (DMSO-d₆) <5 (ppm) 10.36 (s, IH), 9.30 (s, IH), 9.08 (d, IH)₃ 8.79 (d, IH), 7.37 (s, IH), 7.19 (d, IH), 7.03 (d, IH), 4.84 (t, IH), 3.76 (t, 4H), 3.25 (t, 4H), 3.14 (d, 2H), 2.85 (s, 3H), 0.92 (s, 9H).

Example 4: Synthesis of pyridyl-pyrazoles. Method A.

XX

[00442] (3Z)-4-Aminopent-3-en-2-one. (Ref. B. Singh and G.Y. Lesher, J.

Heterocycl. Chem., 1990, 27, 2085). A mixture of pentane-2,4-dione (68 g, 0.679 mol), ammonium acetate (127.9 g, 1.66 mol), and toluene (500 ml) was heated under reflux with azeotropic removal of water for 5 hr. The solvent was removed under reduced pressure. The target compound, (Z)-4-aminopent~3-en-2-one, was obtained by distillation (106-1 10°C/13 mm Hg): 42.8 g; yield: 63.6%.

[00443] 2-Nitropropane-l,3-diaI sodium salt. (Ref. T.L.V. Ulbricht and CC. Price, J.

Org. Chem. 1957, 22, 235). Mucobromic acid (200 g, 0.776 mol) in EtOH (400 ml) was added to a solution of sodium nitrite (216 g, 3.13 mol) in water (400 ml) with stirring. The resulting mixture was kept at 60⁰C for 30 min. Stirring was continued for 60 min without external heating. The solution was put into the refrigerator overnight. The solid was filtered and dried to give the target compound (42.4 g; yield: 34.6%).

[00444] l-(2-Methyl-5-nitro-3-pyridyl)ethan-l-one. A solution of 2-nitropropane-

1,3-dial sodium salt (5 g, 0.036 mol) in DMF (20 ml) was dried over 4A molecular sieves (7 g) for 2 hr and filtered, and the sieves were washed with DMF. Pyridine (11 ml) was added to the filtrate under N₂, and the solution was cooled to -5°C. A solution of p-toluenesulfonyl chloride (6.2 g, 32.5 mmol) in DMF (12 ml) was added dropwise while the temperature was maintained below 0⁰C. The solution was warmed to rt. A solution of the previously prepared (3Z)-4-aminopent-3-en-2-one (3.6 g, 0.036 mol) in DMF (20 ml) was added dropwise and the solution was stirred for 2 hr. The solvent was removed under vacuum. The residue was dissolved in water and extracted into DCM. The organic layer was washed with 5% aq.Na₂Cθ₃ solution, dried (Na₂SO₄) and evaporated. The crude material was chromatographed on silica gel, eluting with EtOAc/PE (1 :10) to provide l-(2-methyl-5-nitro- 3-pyridyl)ethan-l-one (1.91 g, 29%) ¹H NMR (CDCl₃) δ (ppm) 9.40 (d, J - 2.4 Hz, IH), 8.71 (d, J = 2.7 Hz, IH), 2.87 (s, 3H), 2.69 (s, 3H); CaIc. mass: 180, obs. mass: 181.

[00445] l-(5-Amino-2-methylpyridin-3-yI)ethanone. To a solution of the compound obtained above (0.36 g, 2 mmol) in dioxane (5 ml) was added Raney Ni (100 mg). The mixture was stirred at rt under hydrogen atmosphere for 4 hr. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give l-(5-amino-2-methylpyridin-3- yl)ethanone in quantitative yield, which was used without further purification. CaIc. mass: 150 , obs. mass: 151. [00446] N-CS-Acetyl-ό-methylpyridin-S-yO-S-fluoro-S-morphoIinobenzamide. To a solution of the compound obtained above (2 mmol, crude from above reaction) in DCM (5 ml) was added 3-fluoro-5-morpholinobenzoic acid J-a (0.45 g, 2 mmol), DIEA (1.05 ml, 6 mmol), DIC (0.63 ml, 4 mmol) and catalytic amount of DMAP. The mixture was stirred at rt for 18 hr. The solvent was removed under vacuum. The residue was purified on a silica gel column eluted using 0 - 10% MeOH in DCM over 40 min. to give the target compound as a light brown solid (91 mg). CaIc. mass: 357, obs. mass: 358.

[00447] Methyl 4-(5-(3-fluoro-5-morpholinobenzamido)-2-methyIpyridin-3-yl)-2,4- dioxobutanoate (X). To a solution of the compound obtained above (91 mg, 0.25 mmol) in anhydrous toluene (5 ml) was added dimethyl oxalate (0.148 g, 1.25 mmol) and NaH (30 mg, 1.25 mmol). The mixture was stirred at 80⁰C for 4 hr. The reaction was cooled to rt and quenched with water. The solid was collected by filtration and dried under high vacuum to give the target compound X as a dark brown solid (62 mg). CaIc. mass: 443, obs. mass. 444.

[00448] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yI)-lH- pyrazoIe-5-carboxyIic acid. To a solution of X (62 mg, 0.14 mmol) in MeOH (5 ml) was added hydrazine monohydrochloride (200 mg, 2.9 mmol). The mixture was stirred at 80°C for 2 hr and cooled to rt. The solvent was removed under vacuum. The residue was purified by solid phase extraction using Cj₈ silica gel to give the target compound as a yellow solid (27 mg). CaIc. mass: 425, obs. mass: 426.

[00449] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N- neopentyl-lH-pyrazole-5-carboxamide (27). To a solution of the compound above (27 mg, 0.063 mmol) in DCM ( 5 ml) was added neopentylamine (55 mg, 0.63 mmol) and PyBop (99 mg, 0.19 mmol). The mixture was stirred at rt for 18 hr. The solvent was removed under vacuum. The residue was purified using RP-HPLC to give TFA salt of 27 as a white solid (8.8 mg). CaIc. mass: 494, obs. mass: 495. Method B.

[00450] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-l-methyI- lH-pyrazole-5-carboxyIic acid and S-(5-(3-fluoro-5-morpholinobenzamido)-2- methylpyridin-3-yl)-l-methyl-lH-pyrazole-3-carboxylic acid. To a solution of X (~ 0.3 mmol, crude product from reaction described above) in a mixture of MeOH/ AcOH (10/1, 5 ml) was added methylhydrazine (0.2 ml, 3.8 mmol). The mixture was stirred at 90⁰C for 17 hr. The solvent was removed under vacuum. The crude product was purified to give 3-(5- (3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-l-methyl-lH-pyrazole-5- carboxylic acid (9 mg; calc. mass: 439, obs. mass: 440) and 5-(5-(3-fluoro-5- morpholinobenzamido)-2-methylpyridin-3-yl)-l-m ethyl- lH-pyrazole-3-carboxylic acid (4.8 mg; calc. mass: 439, obs. mass: 440).

[00451] S-CS-CS-Fluoro-S-morpholinobenzamidoJ-Z-methylpyridin-S-ylJ-l-methyl-

N-neopentyl-lH-pyrazole-5-carboxamide (28). Compound 28 was prepared from 3-(5-(3- fiuoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)- 1 -methyl- 1 H-pyrazole-5-carboxylic acid using a procedure similar to that for compound 1. Calc. mass: 508, obs. mass: 509.

[00452] 5-(5-(3-FIuoro-5-morphoIinobenzamido)-2-methylpyridin-3-yl)-l-methyl-

N-neopentyl-lH-pyrazole-3-carboxamide (29): Compound 29 was prepared from 5-(5-(3- fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)- 1 -methyl- 1 H-pyrazole-3-carboxylic acid using a procedure similar to that for compound 1. Calc. mass: 508, obs. mass: 509. Example 5: Synthesis of pyridyl-isoxazoles. Method A.

[00453] Methyl 4-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-4-

(hydroxyimino)-2-oxobutanoate. To a solution of X (0.10 g, crude, ~ 0.15 nunol) in MeOH (5 ml) was added hydroxylamine hydrochloride (0.10 g). The mixture was stirred at rt for 18 hr. The solvent was removed under vacuum. The residue was purified by solid phase extraction to give the target compound as a solid (48.2 mg). CaIc. mass: 458, obs. mass: 459.

[00454] Methyl 3-(5-(3-fluoro-5-morpholinobenzamido)-2-methyIpyridin-3- yl)isoxazoIe-S-carboxyIate. A solution of the compound obtained above (48.2 mg, 0.105 mmol) in acetic acid (1 ml) was stirred at 80⁰C for 18 hr. The solvent was removed under vacuum. The crude product (contained about 30% target material) was used in the next step without further purification. CaIc. mass: 440, obs. mass: 441.

[00455] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)isoxazole-5- carboxylic acid. To a solution of the compound above (0.105 mmol, crude from above reaction) in MeOH (10 ml) was added IN NaOH (aq. 1 ml). The mixture was stirred at rt for 17 hr. The reaction was quenched with IN HCl (aq. 2 ml). The solvent was removed under vacuum. The residue was dried under high vacuum to give crude the target compound. CaIc. mass:, obs. mass:

[00456] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N- neopentylisoxazole-5-carboxamide (30): To a solution of the compound above (0.105 mmol, crude product from above reaction) in DCM (5 ml) was added neopentylamine (91 mg, 1.05 mmol) and PyBop (0.2 mmol). The mixture was stirred at rt for 17 hr. The solvent was removed under vacuum. The crude product was purified on RP-HPLC to give 30 (1.8 mg). CaIc. mass: 495, obs. mass: 496.

Method B.

[00457] Ethyl 5-(tert-butoxycarbonylamino)-2-methyInicotinate. In a 2 dram vial were placed ethyl 2-methyl-5-nitronicotinate (259 mg, 1.23 mmol), EtOAc (2 ml) and SnCl₂*2H₂O (1.39 g, 6.15 mmol). The vial was capped and stirred at 60⁰C for lhr. The reaction was basifϊed with saturated Na₂Cθ₃ and diluted with EtOAc. The organic layer was dried and the solvents removed. The residue was diluted in DCM (3 ml) and treated with di- tert-butyl carbonate (436 mg, 2 mmol), DMAP (42 mg, 0.34 mmol), and NMM (207 μml, 1.85 mmol). The reaction was stirred overnight after which time additional di-tert-butyl carbonate (62 mg) was added. The solvents were removed and the residue was purified on silica gel eluting with 0-30 EtOAc/Hex to afford 241 mg (70% yield) of ethyl 5-(tert- butoxycarbonylamino)-2-methylnicotinate. ¹H NMR (CDCl₃) δ (ppm) 8.58 (d, J = 2.5 Hz₅ IH), 8.17 (d, J = 2.5 Hz, IH), 4.39 (q, J = 7.0, 14.0, 2H), 2.86 (s, 3H), 1.46 (s, 9H), 1.40 (t, J = 7.0Hz, 3H).

[00458] tert-Butyl S-formyl-ό-methylpyridin-S-ylcarbamate. Ethyl 5-(tert- butoxycarbonylamino)-2-methylnicotinate (241 mg, 0.86 mmol), obtained as described above, was dissolved in DCM (10 ml) in a 100 ml round-bottomed flask equiped with magnetic stirring under a nitrogen atmosphere, and was cooled in a dry ice/acetone bath. A IM DIBAL solution in DCM (1.81 ml) was added dropwise over five minutes. After stirring 1.5 hr in a dry ice/acetone bath, MeOH (1 ml) was slowly added by dripping down the side of the flask. The reaction was allowed to cool to rt and the organic layer was washed with saturated NaCl solution and dried over Na₂SO₄. The solvent was removed and the residue purified on silica gel, eluting with 0-100% EtOAc/Hex to afford 31 mg (15% yield) of the tert-butyl S-formyl-ό-methylpyridin-S-ylcarbamate. ¹H NMR (CDCl₃) δ (ppm) 10.28 (s, IH), 8.54 (d, J = 3.0 Hz, IH), 8.36 (s, IH), 6.62 (s, IH), 2.82 (s, 3H), 1.54 (s, 9H).

[00459] tert-Butyl 5-((hydroxyimino)methyl)-6-methylpyridin-3-ylcarbamate. tert-

Butyl S-formyl-ό-methylpyridin-S-ylcarbamate (75 mg, 0.29 mmol) was dissolved in MeOH (3 ml) in a 100 ml round-bottomed flask and treated with hydroxylamine hydrochloride (100 mg, 1.45 mmol). After stirring overnight at rt, the solvent was removed and the residue was partitioned between DCM and saturated Na₂CO₃. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na₂SO₄. The solvent was removed to afford 77 mg (98% yield) of tert-butyl 5-((hydroxyimino)methyl)-6-methylpyridin-3-yl carbamate as a mixture of E and Z isomers, which was used without further purification. ¹H NMR (CDCl₃) δ (ppm) 8.47 (d, J = 2.5 Hz, 0.5H), 8.44 (d, J = 2.0 Hz, 0.5H), 8.34 (s, 0.5H), 8.31 (s, 0.5 H), 6.80 (bs, IH), 2.66 (s, 1.5H), 2.61 (s, 1.5H), 1.51 (s, 4.5H)₃ 1.42 (s, 4.5H).

[00460J tert-Butyl 3-(5-(tert-butoxycarbonyIamino)-2-methylpyridin-3- yI)isoxazole-5-carboxylate. In a 100 ml round-bottomed flask were placed tert-butyl 5- ((hydroxyimino)methyl)-6-methylpyridin-3-yl carbamate (77 mg, 0.28 mmol), tert-butyl propiolate (384 μl, 2.8 mmol), and DCM (5 ml). To this stirred solution was added 5% sodium hypochlorite solution (2 ml) via syringe at a rate of 25 μl/min. After the addition was complete, the reaction was stirred for 2hr at rt. The reaction was diluted with water and DCM and the aqueous layer was extracted with DCM. The organic layer was dried over Na₂SO₄ and the solvents removed in vacuo. The residue was purified over silica gel, eluting with 0-50% EtO Ac/Hex to afford 13 mg (12% yield) of tert-butyl 3-(5-(tert- butoxycarbonylamino)-2-methylpyridin-3~yl)isoxazole-5-carboxylate. ¹H NMR (CDCl₃) δ (ppm) 8.40 (d, J = 2.5Hz, IH), 8.18 (bs, IH), 7.08 (s, IH), 6.58 (bs, IH), 1.63 (s, 9H), 1.52 (s, 9H).

[00461 ] 3-(5-Amino-2-methylpyridin-3-yl)-N-benzylisoxazole-5-carboxamide (31).

The compound obtained above (13 mg, 33 μmol) was dissolved in DCM (2 ml) and treated with 95% TF A/water (3 ml). After 1.5 hr the solvent was removed in vacuo. To this residue was added EDC (75 mg, 391 μmol), benzylarnine (68 μl, 0.64 mmol), DCM (2 ml), DIEA (18 μl) and DMF (600 μl), and the reaction was sonicated. After stirring overnight the reaction was quenched with water and extracted with DCM. The organic layer was dried over Na₂SO₄ and the solvents were removed in vacuo. The residue was purified on silica gel eluting with 0-20% MeOH/DCM. The residue was dissolved in DCM (1 ml) and treated with 3-morpholino-5-fluorobenzoic acid J-a (15 mg, 66 μmol) and EDC (13 mg, 66 μmol). After 1.5 hr at rt, the reaction was purified directly on silica gel, eluting with 0-100% EtOAc/Hex to afford 1.7 mg (9% yield) of the target compound 31. CaIc. mass: 515, obs. mass: 517.

Example 6: Additional derivatization reactions

[00462] tert-Butyl 3-(5-amino-2-methylphenyl)isoxazole-5-carboxylate. To a solution of tert-butyl 3-(2-methyl-5-nitrophenyl)isoxazole-5-carboxylate (65 mg, 0.21 mmol) (prepared as described above) in MeOH (5 ml) at rt was added Raney-Ni (60 mg, wet weight). The suspension was stirred at rt under hydrogen atmosphere for 5 hr. The catalyst was removed by filtration. The filtrate was concentrated to dryness under vacuum to give the target compound as a brownish oil (60 mg). CaIc. mass: 274, obs. mass: 275.

[00463] tert-Butyl 3-(5-(5-tert-butyl-2-methoxy-3-(methyIsuIfonamido)- benzamido)-2-methylphenyl)isoxazole-5-carboxyIate (R₃ = 5-tert-butyl-2-methoxy-3- (methylsulfonamido)phenyl). To a solution of the compound obtained above (0.21 mmol, crude product from the above reaction) in DCM (5 ml) at rt was added 5-tert-butyl-2- methoxy-3-(rnethylsulfonamido)benzoic acid (63 mg, 0.21 mmol) (Intermediate O), DIEA (0.11 ml, 0.63 mmol) and PyBop (218 mg, 0.42 mmol). The mixture was stirred at rt for 18 hr, diluted with DCM (10 ml), washed with IN HCl, IN NaOH, water and dried over Na₂SO₄ to give the crude product as a yellow oil (203 mg). The title compound was the major component. CaIc. mass: 557, obs. mass: 558.

[00464] 3-(5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2- methylphenyl)isoxazole-5-carboxyIic acid (R₃ = 5-tert-butyl-2-methoxy-3- (methylsulfonamido)phenyl). To a solution of the compound above (0.21 mmol, crude product from the above reaction) in DCM (5 ml) at rt was added TFA (5 ml). The mixture was stirred at rt for 1 hr. The solvent was removed under vacuum to give the crude product as a yellow oil (189 mg). The title compound was the major component. CaIc. mass: 501, obs. mass: 502.

[00465] iV-Benzyl-3-(5-(5-tert-butyl-2-inethoxy-3-(methylsulfonamido)benzamido)-

2-methylphenyl)isoxazoIe-5-carboxamide (Ri = benzyl, R₂ = H, R₃ = 5-tert-butyl-2- methoxy-3-(methylsulfonamido)phenyl) (32). To a solution of the compound above (0.05 mmol, crude product from the above reaction) in DCM (5 ml) at rt was added benzylamine (0.054 ml, 0.5 mmol) and PyBop (52 mg, 0.1 mmol). The mixture was stirred at rt for 18 hr. The solvent was removed under vacuum. The residue was purified using RP-HPLC to give 32 as a clear film (8.3 mg). CaIc. mass: 590, obs. mass: 591.

[00466] Using similar procedures as illustrated for the formation of 32, the following compounds were prepared:

[00467] 3-(5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2- methylphenyl)-Λ'-(pyridin-2-ylinethyI)isoxazoIe-5-carboxamide (33). CaIc. mass: 591, obs. mass: 592.

[00468] 3-(5-(5-tert-ButyI-2-methoxy-3-(methyIsulfonamido)benzamido)-2- methylphenyl)-.V-(pyridin-3-ylmethyI)isoxazole-5-carboxamide (34). CaIc. mass: 591, obs. mass: 592.

[00469] 3-(5-(5-tert-ButyI-2-methoxy-3-(mcthylsulfonamido)benzamido)-2- methylphenyl)-W-(pyridin-4-ylmethyI)isoxazole-5-carboxamide (35). CaIc. mass: 591, obs. mass: 592.

[00470] 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-iV- neopentylisoxazole-5-carboxamide (36). CaIc. mass: 477, obs. mass: 478.

[00471 ] 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-iV-(2- morpholinoethyl)isoxazole-5-carboxamide (37). CaIc. mass: 520, obs. mass: 521.

[00472] 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-iV-(2-(pyridin-4- yl)ethyl)isoxazole-5-carboxamide (38). CaIc. mass: 512, obs. mass: 513. [00473] 3-(5-(5-tert-ButyI-2-methoxybenzamido)-2-methylphenyl)-7V-(2-(pyridin-3- yl)ethyl)isoxazoIe-5-carboxamidc (39). CaIc. mass: 512, obs. mass: 513.

[00474] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-.V- neopentyIisoxazole-5-carboxamide (40). CaIc. mass: 494, obs. mass: 495.

[00475] 3-(5-(3-FIuoro-5-morpholinobenzamido)-2-methylphenyl)-Λ'-(pyridin-4- ylmethyl)isoxazole-5-carboxamide (41). CaIc. mass: 529, obs. mass: 530.

[00476] 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyI)isoxazole-5-carboxamide (42). CaIc. mass: 515, obs. mass: 516.

[00477] 3-(5-(5-tert-ButyI-2-methoxybenzamido)-2-methylphenyI)-N-(tetrahydro-

2H-pyran-4-yl)isoxazole-5-carboxamide (43). CaIc. mass: 491, obs. mass: 492.

44

[00478] 3-(5-(3-Cyano-5-fluorobenzamido)-2-methyIphenyI)-N-neopentyiisoxazole-

5-carboxamide. A mixture of 3-cyano-5-fluorobenzoic acid (41.3 mg, 0.25 mmol, 1.25 eq), oxalyl chloride (1.0 ml), DCM (1.0 ml), and 5% DMF in DCM (-30 μl) was stirred at 4O⁰C for 1-2 hr. The clear solution was concentrated and dried in HV to give 3-cyano-5- fluorobenzoyl chloride, which was used in the next step without further purification. A solution of this compound (0.25 mmol, 1.25 eq.) in DCM (2.0 ml) was added dropwise to a stirred solution of W (prepared as described for 1) (57.5 mg, 0.20 mmol, 1.00 eq.), DIEA (70 μl, 0.40 mmol, 2.00 eq.) and DCM (2.0 ml). The mixture was stirred overnight at rt, then 2M aq. K2CO3 solution (50 ml) was added and the product was extracted with DCM. The organic layers were dried (Na₂SO₄) and concentrated. The crude product was dried in HV to give the tareget compound as a white solid (92.1 mg, quantitative yield, 99% pure by LC- MS), which was used for the next step without further purification. CaIc. mass: 435, obs. masses: 435, 476.

[00479] 3-(5-(3-Cyano-5-morpholinobenzamido)-2-methyIphenyI)-N- neopentyIisoxazole-5-carboxamide (44). Morpholine (150 μl) was added to a solution of the compound above (30.5 mg, 0.07 mmol) in anhydrous DMSO (50 μl) and the mixture was stirred at 8O⁰C for 3-5 days. The mixture was concentrated and the residue was purified using preparative RP-HPLC (gradient: 50-70% AcN in H₂O). The concentrated fractions were dried in HV to give the title compound (12.0 mg, >99% pure by LC-MS). CaIc. mass: 502, obs. mass: 502.

[00480] 3-(5-(3-Cyano-5-(piperidin-l-yl)benzamido)-2-methyIphenyl)-N- neopentyIisoxazoIe-5-carboxamide (45). Piperidine (150 μl) was added to a solution of the compound above (30.5 mg, 0.07 mmol) in anhydrous DMSO (50 μl) and the mixture was stirred at 50⁰C for 2-3 days. The mixture was concentrated and the residue was purified using preparative RP-HPLC (gradient: 40-100% AcN in H₂O). The concentrated fractions were dried in HV to give the target compound (15.5 mg, >99% pure by LC-MS). CaIc. mass: 500, obs. mass: 500.

[00481 ] 3-(5-(3-Cyano-5-(pyrrolidin-l-yl)benzamido)-2-methyIphenyl)-N- neopentylisoxazoIe-5-carboxamide (46). Pyrrolidine (150 μl) was added to a solution, of 38 (30.5 mg, 0.07 mmol) in anhydrous DMSO (50 μl) and the mixture was stirred at rt for 2-3 days. The mixture was concentrated and the residue was purified using preparative RP-HPLC (gradient: 40-100% AcN in H₂O). The concentrated fractions were dried in HV to give 46 (6.4 mg, >99% pure by LC-MS). CaIc. mass: 486, obs. mass: 486.

[00482] 3-(5-(3-(Bromomethyl)-5-tert-butyIbenzamido)-2-methylphenyI)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-S-carboxamide (Ri = 2- methyltetrahydrofuran). To a solution of intermediate U (0.1 g, 0.38 mmol) in DCM (3 ml) at rt was added excess oxalyl chloride (0.2 ml) and a few drops of DMF. The mixture was allowed to stir for 15 minutes and was then concentrated under vacuum to yield the acid chloride intermediate. The intermediate was taken up in DCM (3 ml) and was added to a solution of 3-(5-amino-2-methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5- carboxamide (prepared as described for 1) (0.1 g, 0.34 mmol) and DIEA (0.1 ml) in DCM (3 ml). The resulting solution was stirred at rt for 30 minutes and was then concentrated under vacuum. The residue was purified via column chromatography (3:1 Hex/EtOAc) to give the title compound as a white solid (0.12 g), which was analytically pure via TLC and LC-MS. CaIc. mass: 554, obs. mass: 554.

[00483] 3-(5-(3-tert-ButyI-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2- methylphenyl)-N-((tetrahydrofuran-2-yl)methyϊ)isoxazole-5-carboxamide (Ri = 2- methyltetrahydrofuran, R₂ = 4-methylpiperazine) (47). To a solution of the compound above (0.12 g, 0.21 mmol) and K₂CO₃ (0.1 g, 0.77 mmol) in acetone (3 ml) at rt was added 1 -methylpiperazine (0.038 g, 0.38 mmol). The mixture was heated at 45°C for 10 min. The mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified via HPLC (water/AcN/TFA) to give the title compound as a white solid (0.06 g) which was analytically pure via TLC and LC-MS. CaIc. mass: 574, obs. mass: 574. ¹H NMR (CD₃OD) δ (ppm) 7.98 (s, IH), 7.95 (s, IH)₅ 7.79 (s, IH), 1.41 (s, 9H), 7.77 (d, J = 9.0 Hz, IH), 7.67 (s, IH), 1.71 (m, IH), 7.39 (d, J = 8.5 Hz, IH), 7.26 (s, IH), 4.14 (m, IH), 3.92 (m, IH), 3.87 (s, 2H), 3.79 (m, IH), 3.50 (m, 2H), 3.37 (b, 8H), 2.91 (s, 3H), 2.49 (s, 3H), 2.07 (m, IH), 1.97 (m, 2H).

[00484] 3-(5-(3-tert-Butyl-5-(piperazin-l-ylmethyl)benzamido)-2-methylphenyl)-N-

(pyridin-3-yImethyl)isoxazole-5-carboxamide (48). Intermediate U (180 mg, 0.66 mmol) was added to 5 ml of DCM. Oxalyl chloride (0.5 ml) and a catalytic amount of DMF were added. The reaction was allowed to stir at rt for 20 minutes and was then concentrated in vacuo to yield the acid chloride intermediate. 3-(5-amino-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide (205 mg, 0.66 mmol, 1.0 eq.) (prepared as described for 7) in a solution of 5 ml DCM and 0.1 ml DIEA was added to the acid chloride and the resulting mixture was stirred at rt for 1 hr and then concentrated in vacuo. Column chromatography (1:1 Hex/EtOAc) afforded 182 mg of a polymeric material. The polymeric material (20 mg) was subsequently added to 2 ml of acetone and K₂CO₃ (40 mg) and reacted with excess tert-butyl piperazine-1-carboxylate (50 eq.) at 100⁰C in a sealed vial for 1 hr. The reaction was filtered and concentrated in vacuo. TFA (1 ml) was added to the residue and the resulting solution was stirred at rt for 30 min and then concentrated in vacuo. Purification via LC-MS (10-90% AcN in H₂O with 0.1% TFA) yielded 3.0 mg of the target compound as the TFA salt. CaIc. mass: 567, obs. mass: 567. ¹H NMR (CD₃OD) δ (ppm) 8.88 (bs, IH), 8.76 (bs, IH), 8.51 (d, 7= 8.0 Hz₅ IH), 7.97 (m, 3H), 7.79 (s, IH), 7.73 (d, J= 8.0 Hz, IH), 7.68 (s, IH), 7.39 (d, J= 7.5 Hz, IH), 7.3 (s, IH), 4.78 (s, 2H), 3.89 (s, 2H), 3.34 (m, 4H), 2.92 (m, 4H), 2.48 (s, 3H), 1.40(s, 9H).

[00485] 3-(2-Methyl-5-nitrophenyl)isoxazole-5-carbonyl chloride hydrochloride. In a 50 ml round-bottomed flask were placed tert-butyl 3-(2-methyl-5-nitrophenyl)isoxazole-5- carboxylate (prepared as described for 1) (203 mg, 0.67 mmol) DCM (5 ml) and 95% TFA/H₂O (5 ml). After 1 hr the solvent was removed in vacuo and the residue reevaporated twice from EtOAc. The residue was treated with DCM (3 ml), oxalyl chloride (0.67 ml, 1.34 mmol) and DMF (1 drop). The flask was capped and the mixture was stirred, occasionally releasing pressure build up by releasing the cap. The solvent was removed after 4hr to afford 183 mg (91% yield) of the target HCl salt. ¹H NMR (CDCl₃) δ (ppm) 8.41 (d, J = 2.5 Hz, IH)₅ 8.27 (dd, J = 2.5, 8.5Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 7.43 (s, IH), 2.47 (s, 3H).

[00486] 5-tert-Butyl-3-cyano-2-methoxy-N-(4-methyl-3-(5-(3- phenyIpropioloyl)isoxazol-3-yl)phenyl)benzamide. In a 25 ml round-bottomed flask were placed the compound obtained above (50 mg, 165 μmol) and THF (2 ml) and phenyl acetylene (12 μl, 1 10 μmol). To this stirred solution was added bis(triphenylphosphine)palladium dichloride (12.6 mg, 16.5 μmol) and copper (I)iodide (8.6 mg, 50 μmol). After stirring for 10 min, TEA (52 μl, 371 μmol) was added. After stirring 30 min, diethylether (10 ml) was added and the solution was filtered. The solvents were removed in vacuo and the residue was dissolved in DCM and filtered through silica gel. The solvents were removed to afford 50 mg of crude l-(3-(2-methyl-5-nitrophenyl)isoxazol-5-yl)- 3-phenylprop-2-yn-l-one which was used without further purification. In a 2 dram vial were placed this material (39 mg, 1 18 μmol), EtOAc (3 ml), and SnCl₂ ^«2H₂O (144 mg, 0.64 mmol). The reaction was capped and stirred at 60⁰C for 4.5 hr. The reaction was quenched with 2M Na₂CO₃ and extracted with EtOAc. The solvents were removed and the residue dissolved in DCM (2 ml), and treated with EDC (21 mg, 110 μmol) and 3-cyano-5-t-butyl-2- methoxybenzoic acid (23 mg, 100 μmol) (Intermediate N). After 40 min at rt, the solvents were removed and the residue was purified on silica gel, eluting with 0-20% EtOAc/Hex to afford 2.6 mg of the target compound. CaIc. mass: 517, obs. mass: 518.

[00487] 5-tert-Butyl-3-cyano-2-methoxy-N-(4-methyI-3-(5-(3- phenylpropanoyl)isoxazol-3-yl)phenyI)benzamide (49). In a 2 dram vial were placed the compound from above (2.6 mg, 5 μmol), MeOH (1 ml), THF (1 ml) and palladium on carbon (10% dry w/w, Degussa type containing 50% water, 10 mg). The vial was fitted with a septum cap and hydrogen was introduced via syringe needle and balloon. The reaction was stirred for 2 hr 20 min, after which time the reaction was filtered and the solvent removed. The residue was purified using reverse-phase HPLC to afford 0.9 mg of the target compound 49. CaIc. mass: 521, obs. mass: 523.

Example 7: Inhibition of TNFa production in THP cells

[00488] 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/L 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 1.10⁵/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 hr at 37°C/5% CO₂. The assay was terminated by centrifuging the plates for 10 min at room temperature. Supernatants were removed to clean culture plates and aliquots 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.

Example 8: Inflammation models

[00489] 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 thyroglobulin 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. 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. [00490] Collagen Induced Arthritis model. 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 Sci., 1997, 61,1861-1878, each of which is incorporated herein by reference.

[00491] 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 21, 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.

[00492] Inflammatory Bowel and Crohn's Disease Models. To evaluate the effectiveness of test compounds in Crohn's disease, the TNF^ΔARE transgenic mouse model of Crohn's disease (originally described by Kontoyiannis et al., Immunity, 1999, 10, 387) is used (the DSS 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=(11-20) 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.

[00493] Efficacy in the TNF^ΔARE 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 histopathological 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 least 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.

[00494] Other models of IBD include, for example, the DSS (dextran sodium sulfate) 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., CHn 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 21 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 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. Pat. No. 6,764,838, incorporated herein by reference). Histopathological scoring can be performed using the same standard described above.

Example 9: Inflammatory Disease Assessments

[00495] 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 DH, Summers RW, Singleton JW, et al. National Cooperative Crohn's Disease Study: study design and conduct of the study. Gastroenterology 1979;77: 829-842).

[00496] 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 and 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).

[00497] Rheumatoid Arhritis disease assessment. Rheumatoid arthritis is clinically scored on the basis of several clinically accepted scales, such as those described in U.S. Pat. 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)₅ 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 and assessment of pain/tenderness (The following scoring is used: 0 - No pain/tenderness; 1 = Mild pain: the patient says it is tender upon questioning; 2 = Moderate pain: the patient says it is tender and winces; 3 = Severe pain: the patient says it is tender and winces and withdraws); B. Number of swollen joints (Both tenderness and swelling are evaluated for each joint separately); C. Duration of morning stiffness (in minutes); D. Grip strength; E. Visual analog pain scale (0-10 cm); F. Patients and blinded evaluators are asked to assess the clinical response to the drug. Clinical response is assessed using a subjective scoring system as follows: 5 = Excellent response (best possible anticipated response); 4 = Good response (less than best possible anticipated response); 3 = Fair response (definite improvement but could be better); 2 = No response (no effect); 1 = Worsening (disease worse).

[00498] Anti-Inflammatory evaluation during human endotoxemia. Intravenous administration of 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 antiinflammatory cytokines and other factors in the etiology of inflammatory diseases such as rheumatoid arthritis and Crohn's disease, administration of cytokine inhibitors in a human LPS model could prove beneficial in elucidating potential effects of the cytokine inhibitors in human inflammatory processes.

[00499] The cytokine inhibitors 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, 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.

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 room temperature.

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.

[00500] TNF-α, IL-IjS, IL-6 or other cytokines are analyzed using validated ELISA methods.

Example 10: Anti-Proliferation Assay

[00501 ] Human non-small cell lung carcinoma cells A549 (ATCC# CCL- 185), are grown at 37°C +/- 0.5⁰C 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 10x 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 at 37°C +/-0.5⁰C with 5% CO₂. Twenty microliters of 20% Alamar Blue warmed to 37°C +/- 0.5⁰C 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.

[00502] The percent inhibition (% I) for each well is calculated using the following formula:

% I=[(avg. untreated wells-treated well)/(avg. untreated wells)] x 100 [00503] 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.

[00504] 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 1299 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, Ml 4 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.

[00505] 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 20108, USA), can be used similarly.

Example 11: In vivo bone cancer models.

[00506] Method A. Experiments are performed on 39 adult male C3H mice (The

Jackson Laboratory, Bar Harbor, Maine), weighing 18—20 g. After induction of general anesthesia with sodium pentobarbital (50 mg/kg, i.p.), an arthrotomy is performed exposing the condyles of the distal femur. HBSS (Sigma, St. Louis, MO; sham, n = 8) or medium containing 105 osteolytic murine sarcoma cells (20 μl, NCTC 2472; American Type Culture Collection, Rockville, MD; tumor, n = 16) is injected into the intramedullary space of the mouse femur and the injection site sealed with dental amalgam.

[00507] Method B. The experiments use 36 adult male C3H/HeJmice (Jackson

Laboratories, Bar Harbor, Maine), 20-25 g in body weight. The mice are housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 22°C with a 12-hour alternating light-dark cycle, and are given food and water ad libitum. After induction of general anesthesia with sodium pentobarbital (a dose of 50mg/kg, at a concentration of 5 mg/ml, injected intraperitoneally), a superficial incision is made in the skin overlying the patella, using Mora scissors.The patellar ligament is then cut, exposing the condyles of the distal femur. A 30-gauge needle is inserted at the level of the intercondylar notch and into the medullary canal to create an initial core pathway. After the initial core is made, a 29-gaxige needle is used to make the final pathway into the bone. A 0.5-mm depression is then made using a halfround bur in a pneumatic dental high speed handpiece, to serve as mechanical retention for the amalgam plug. Then, 20 μL ominimum essential media (Sigma; sham injection; n = 12) or 20 μL media containing 1 x 10⁵ 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection; n = 24) is injected using a 29-gauge needle and a 0.25 cc syringe. To prevent leakage of cells outside the bone, the injection site is closed with dental grade amalgam, followed by copious irrigation with filtered water. Wound closure is achieved using autowound clips (Becton Dickinson, San Jose, California). Wound clips are removed at day 5 to prevent interference with behavioral testing.

[00508] For both methods above, cancer cells are introduced on day 0 of the protocol and compound/vehicle dosing is started the same day. After 14 days, cancer progression is evaluated by measurement of bone mineral density using DEXA (dual energy X-ray absorptiometry), measurement of bone loss by Faxitron (solid-state X-ray), histology, histomorphometry (essentially quantitative measurements of bone erosion and tumor progression), or osteoclast staining.

[00509] Alternatively, the animals can be monitored for metastatic growths or metastasis by MRI or other types of scanning or for mortality. [00510] Other cancer cell lines can also be used, in particular, prostate cancer cells or breast cancer cells. These cells are introduced directly into the bone as above and serve as a model for establishment and growth of metastatic tumors.

Example 12: Xenograft cancer models

[00511] Human cancer cell lines are injected into athymic nude mice. For cells maintained in vitro, tumors are generated by injecting precisely determined numbers of cells into mice. For tumors which are best propagated in vivo, tumor fragments from donor mice are implanted into small numbers of mice for maintenance, or larger numbers of mice for study initiation. A typical efficacy study design involves administering one or more drugs of unknown efficacy to tumor-bearing mice. Additionally, reference chemotherapeutic agents (positive control) and negative controls are similarly administered and maintained. Routes of administration can include subcutaneous (SC), intraperitoneal (IP), intravenous (IV), intramuscular (IM) and oral (PO). Tumor measurements and body weights are taken over the course of the study and morbidity and mortality are recorded. Necropsy, histopathology, bacteriology, parasitology, serology and PCR can also be performed to enhance understanding of disease and drug action.

[00512] Some of the typical human cancer cell lines that can be used in the above xenograft models are: the MDA MB-231, MCF7, MDA-MB-435, and T-47D cell lines for breast cancer; the KMl 2, HCT-15, COLO 205, and HT29 cell lines for colon cancer; the NCI-H460 and A549 cell lines for lung cancer; the CRW22, LNCAP, PCC-3, and DU-145 cell lines for prostate cancer; the LOX-IMVI cell line for melanoma; the SK-O V-3 cell line for ovarian cancer; and the CAKI-I, A498, and SN12C cell lines for renal cancer.

Example 13: Pharmacological assays for pain assessment

[00513] A variety of animal pain models are described in Hogan, Q., Regional

Anesthesia and Pain Medicine 27(4):385-401 (2002), which is incorporated by reference herein in its entirety. Examples of models are given below. The most commonly used neuropathic pain models are the Bennett, Selzer, and Chung models (Siddall, P. J. and Munglani, R., Animal Models of Pain, pp 377-384 in Bountra, C, Munglani, R., Schmidt, W. K., eds. Pain: Current Understanding, Emerging Therapies and Novel Approaches to Drug Discovery, Marcel Dekker, Inc., New York, 2003). A: Neuropathic pain models

[00514] Sciatic nerve ligation procedure. Nerve injury. Mice are anesthetized with a mixture of ketamine (50 mg/kg, i.m.) and medetomidine (1 mg/kg, i.in.)- An incision is made just below the hip bone, parallel to the sciatic nerve. The nerve is exposed and any adhering tissue removed from the nerve. A tight ligature with 6-0 silk suture thread around one-third to one-half of the diameter of the sciatic nerve is made (12). Muscles are closed with suture thread and the wound with wound clips. The response of the mice to mechanical stimulation is tested before and up to 15 days after nerve injury.

[00515] Spinal Nerve Ligation (SNL) (Chung model). L5/L6 SNL is performed as described by Kim and Chung (Kim, S. H. & Chung, J. M. (1992) Pain 50, 355-363). Animals are anesthetized with halothane. An incision is made lateral to the lumbar spine. The right L5 and L6 spinal nerves are isolated and tightly ligated distal to the dorsal root ganglion. The incision is closed, and animals are allowed to recover for 10 days. Sham-operated animals re prepared in an identical fashion except that the spinal nerves are not ligated.

[00516] Hyperalgesia model. C3H/HeJ mice receive an intratibial injection of 10⁵ NCTC 2472 cells. Thermal hyperalgesia is seen after recovery (about 7 days) vs. vehicle- injected mice.

B: Bone cancer pain models.

[00517] Method A. Experiments are performed on 39 adult male C3H mice (The Jackson Laboratory, Bar Harbor, Maine), weighing 18—20 g. After induction of general anesthesia with sodium pentobarbital (50 mg/kg, i.p.), an arthrotomy is performed exposing the condyles of the distal femur. HBSS (Sigma, St. Louis, MO; sham, n = 8) or medium containing 105 osteolytic murine sarcoma cells (20 μl, NCTC 2472; American Type Culture Collection, Rockville, MD; tumor, n = 16) is injected into the intramedullary space of the mouse femur and the injection site sealed with dental amalgam."

[00518] Method B. The experiments use 36 adult male C3H/HeJmice (Jackson Laboratories, Bar Harbor, Maine), 20-25 g in body weight. The mice are housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 22°C with a 12-hour alternating light-dark cycle, and are given food and water ad libitum. After induction of general anesthesia with sodium pentobarbital (a dose of 50mg/kg, at a concentration of 5 mg/ml, injected intraperitoneally), a superficial incision is made in the skin overlying the patella, using Mora scissors.The patellar ligament is then cut, exposing the condyles of the distal femur. A 30-gauge needle is inserted at the level of the intercondylar notch and into the medullary canal to create an initial core pathway. After the initial core is made, a 29-gauge needle is used to make the final pathway into the bone. A 0.5-mm depression is then made using a halfround bur in a pneumatic dental high speed handpiece, to serve as mechanical retentionfor the amalgam plug. Then, 20 μ\ α-minimum essential media (Sigma; sham injection; n = 12) or 20 μl media containing 1 x 10⁵ 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection; n = 24) is injected using a 29-gauge needle and a .25 cc syringe. To prevent leakage of cells outside the bone, the injection site is closed with dental grade amalgam, followed by copious irrigation with filtered water. Wound closure is achieved using autowound clips (Becton Dickinson, San Jose, California). Wound clips are removed at day 5 to prevent interference with behavioral testing.

C: Pain Measurements.

[00519] Measurement of Tactile Withdrawal Threshold (Von Frey model). Tactile withdrawal threshold is determined as described by Chaplan et al. (Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. (1994) J. Neurosci. Methods 53, 55-63. ). Animals are acclimated for 30 min in suspended cages with wire mesh bottoms. The hindpaw is probed with calibrated von Frey filaments (Stoelting) applied perpendicularly to the plantar surface. A positive response is indicated by a sharp withdrawal of the paw. The 50% paw withdrawal threshold is determined by the nonparametric method of Dixon (Dixon, W. J. (1980) Annu. Rev. Pharmacol. Toxicol. 20, 441-462.), in which the stimulus is incrementally increased until a positive response is obtained, then decreased until a negative result is observed. The protocol is repeated until three changes in behavior are determined.

[00520] Measurement of Thermal Withdrawal Latency. The method of Hargreaves et al. (Hargreaves, K. M., Dubner, R., Brown, F., Flores, C. & Joris, J. (1988) Pain 32, 77-88) is used. Animals re acclimated within Plcxiglas enclosures on a clear glass plate maintained at 30⁰C. A radiant heat source (high-intensity projector lamp) is focused onto the plantar surface of the paw. When the paw is withdrawn, a motion detector halts the stimulus and a timer. A maximal cut-off of 40 sec for rats and 30 sec for mice is used to prevent tissue damage.

[00521 ] Formalin Test for Measurement of Persistent Pain in Rats. Animals are injected with compound or vehicle (controls) followed by the injection of formalin into the dorsal surface of the paw. The animal is observed to determine the number of times it flinches the injected paw over a period of 60 minutes. This model allows for the evaluation of anti-nociceptive drugs in the treatment of pain (Abbott, F. et al. Pain 60:91-102 (1995)).

[00522] Hot Plate Test for Measurement of Acute Pain in Rats. Animals are injected with a selective cytokine inhibitory drug or vehicle (controls) and then placed on the hot plate one at a time. Latency to respond to the heat stimulus is measured by the amount of time it takes for the animal to lick one of its paws (Malmberg, A. and Yaksh, T., Pain 60:83- 90 (1995)). This model allows for the evaluation of anti-nociceptive drugs in the treatment of pain. Langerman et al., Pharmacol. Toxicol. Methods 34:23-27 (1995).

[00523] Tail-Flick Test for Measurement of Acute Pain in Rats. Animals are injected with compound or vehicle (controls) and then a light beam is focused on the tail. Latency to respond to the stimulus is measured by the amount of time it takes for the animal to flick its tail. This model allows for the evaluation of anti-nociceptive drugs in the treatment of pain (Langerman et al., Pharmacol. Toxicol. Methods 34:23-27 (1995)).

[00524] Model for Topical Capsaicin-Induced Thermal AUodynia. A model particularly useful for thermal allodynia is the topical capsaicin-induced thermal allodynia model (Butelman, E. R. et al., J. of Pharmacol. Exp. Therap. 306:1106-1114 (2003)). This model is a modification of the warm water tail withdrawal model (Ko₃ M. C. et al., J. of Pharmacol. Exp. Therap. 289:378-385 (1999)). Briefly, monkeys sit in a custom made chair in a temperature-controlled room (20-22°C). Their tails are shaved with standard clippers and tail withdrawal latencies are timed in 0.1 second increments up to a maximum of 20 seconds in both 38°C and 42°C water stimuli to provide a baseline. Following baseline determination, the tail is gently dried and degreased with an isopropyl alcohol pad. Approximately 15 minutes before use, capsaicin is dissolved in a vehicle composed of 70% ethanol and 30% sterile water for a final capsaicin concentration of either 0.0013 or 0.004 M. The solution (0.3 mL) is slowly injected onto a gauze patch, saturating the patch and avoiding overflow. Within 30 seconds of the capsaicin solution being added to the patch, capsaicin patch is fastened to the tail with tape. After 15 minutes, the patch is removed and tail withdrawal testing in both 38°C and 42°C water stimuli is performed as described above. Allodynia is detected as a decrease in tail withdrawal latency compared to the baseline measurements. To determine the ability of a compound to decrease allodynia, a single dose of the compound is administered prior to (e.g., 15 minutes prior, 30 minutes prior, 60 minutes prior or 90 minutes prior) the application of the capsaicin patch. Alternatively, the allodynia reversal properties of a compound can be determined by administering a single dose of the compound after application of the capsaicin patch (e.g., immediately after, 30 minutes after, 60 minutes after or 90 minutes after).

[00525] Other methods: Hyperalgesia measurements can use the same two readouts as above (thermal withdrawal latencies and tactile thresholds). Other methods include observations of spontaneous guarding behaviour, rotorod testing, weigh-bearing on limbs, etc.

Example 14: Assay models for pemphigus

[00526] The effectiveness of the compounds of the invention or its derivatives or salts in the treatment of any of the forms of pemphigus described above can be evaluated by one or more of the following methods: (a) in an established organ culture model where the degree of acantholysis can be measured, after introduction of exogenous pemphigus antibody; (b) in a neonatal mouse model where disease can be induced, and evidence of clearing can be monitored; and/or (c) in humans with pemphigus.

[00527] Experimental procedure for purification of pemphigus antibodies from human donors. The pemphigus antibodies to be used in the analysis are purified and prepared in the following manner (Anhalt, Till, Diaz, Labib, Patel and Eaglstein, J. Immunol. 1986, Vol. 137, pp. 2835-40). Serum is obtained from human patients with the clinical, histologic and immunologic features of pemphigus. The IgG fractions of the sera are purified by 40% ammonium sulfate precipitation, followed by ion exchange chromatography. IgG fractions prepared in this manner are free of significant protease contamination when assayed. Further or alternate purification regimens can include protein-A or protein-G binding and elution, and various chromatography schemes that exploit differences in the size and charge of the IgG, as known to those skilled in the art. The fractions are concentrated and sterilized via filtration. The pemphigus anti-body titer in the serum is then measured.

[00528] Organ Culture Model for Pemphigus. Production of acantholysis in vitro can be carried out as follows (Lever, J. Am. Acad. Dermatol. 1979, Vol. 1, pp. 2-31). Normal human skin is maintained in organ cultures to which sera of patients with pemphigus is added. Direct IF staining of the explants with fluorescein-labeled goat anti-human IgG shows that, after incubation, binding of the pemphigus IgG occurs in the intercellular cement substance of the epidermis. Suprabasal acantholysis is observed which progresses to extensive acantholysis. Complement is not required for the in vitro production of acantholysis since heating the pemphigus sera at 56°C for thirty minutes does not prevent acantholysis (Lever, J. Am. Acad. Dermatol. 1979, Vol. 1, pp. 2-31).

[00529] The ability of the compounds of the invention or derivatives or salts thereof to lessen or eliminate acantholysis in vitro caused by exposure to pemphigus-IgG can be evaluated as follows. Normal human skin is cultured according to the method described by Naito, et al., (Naito, Morioka, Nakajima, Ogawa, J. Invest. Dermatol. 1989, Vol. 93, 173-77). Skin is sliced into 2x2mm pieces thick. The skin is then floated on top of a total volume of 1.0 ml culture medium with the assistance of paraffin edged lens paper. The cultures are kept in humid atmosphere containing CO2 in air for 24, 48 and 72 hours. The culture medium should contain approximately 7 mg/mL of pemphigus IgG with or without the test compounds. After each culture period, the skin explants are examined by routine histologic (hemotoxylin and eosin staining) methods. The final concentration of test compound should range from 0.1 to 20 mg/ml. The skin can be preincubated (1 -24 hours) with the test compound prior to addition of pemphigus IgG. Acantholysis is evaluated on a scale of (-), (+), (++), or (+++), where (-) is no acantholysis, (+) is positive on 10-30%, (++) is positive on 30-70%, and (+++) is positive on 70-100% of the epidermis in the histologic section.

[00530] Neonatal Mouse Model for Pemphigus. The ability of the test compounds to reduce the symptoms of pemphigus in vivo can be evaluated in a neonatal mice model (Anhalt, Labib, Voorhees, Beals and Diaz, N. Engl. J. Med. 1982, Vol. 306, pp. 1 189-96). Purified IgG fractions are injected i.p. into neonatal mice using a 30 gauge needle in a single administration of 10 mg IgG per gram body weight according to an established model

(Takahashi, Patel, Labib, Diaz, Anhalt, J. Invest. Dermatol. 1985, Vol. 84, pp. 41-46). Skin and serum samples are obtained from animals receiving injections of either normal human IgG (control) or human pemphigus IgG. Skin samples from the flank region, where lesions most often occur are processed for direct immuno-fluorescence. Human pemphigus antibodies are also monitored in the animals' serum, to confirm transfer of the pemphigus antibodies. One group of mice is treated with topical administration of the test compound and monitored for disease improvement by sampling the skin and assessing its appearance by histology and/or by clinical appearance.

[00531] Specifically, within 30 minutes of pemphigus IgG injection, the neonatal mice receive injections of test compound prepared in PBS. The administered dosages of test compound range from 13 μg/g of mouse body weight to 2 mg/g mouse body weight. Each of the solutions to be injected is sterilized by filtration through an 0.45 μm millipore filter. Effects of inhibitors on epidermal acantholysis by pemphigus IgG in neonatal mice are evaluated visually (positive if the presence of Nikolsky sign is observed; i.e., apparently normal epidermis can be separated at the basal layer and rubbed off when pressed with a sliding motion on any part of the skin surface) as well as histologically (acantholytic changes are examined at five sites) 24 hours after pemphigus IgG is injected. To carry out biochemical analysis 24 hours after pemphigus IgG injection the mice are sacrificed and the whole skin of each animal removed. At least five different sites from each removed skin are then examined for histologic analysis.

[00532] In addition to acantholysis, the effect of the test compound on the level of a protease, plasminogen activator, in the neonatal mouse epidermis is determined. Skin samples are removed as described above at 3 and 24 hours after injection of pemphigus IgG with preinjection of the test compound. The skin is isolated by heating the skin at 56°C for 30 seconds and putting it through 2 freeze thaw cycles. It is then homogenized and spun at 4°C for 2 hours in 0.0 IM sodium monophosphate, pH 7.0 and centrifuged at 750 g for 10 min. The pellet is extracted with 2M potassium thiocyanate (KSCN) with 0.01% Triton X-100 4°C for 2 hours. The extracts are centrifuged at 750 g for 10 min, and the supernatant dialyzed against 0.12M glycine-NaOH, pH 8.5. Plasminogen activity is determined spectroscopically according to literature procedures (Naito, Morioka, Nakajima, Ogawa, H. J Invest Dermatol, 1989, vol. 93, 173-177). [00533] Methods for the evaluation of test compounds in humans with oral lesions.

The effectiveness of treatment of patients with oral lesions resulting from lichen planus, bullous pemphigoid, cicatricial pemphigoid, pemphigus or canker sores (aphthous uclers) with test compounds can be evaluated as described generally for treatment of lichen planus by Eisen, Ellis, Duell, Griffiths and Voorhees, in N. Engl. J. Med. 1990, Vol. 323, pp. 290-4. For example, patients with symptomatic oral lichen planus are given either placebo or a test compound formulation containing 1 to 50% test compound. The solutions are swished for several minutes and expectorated or swallowed several times daily.

[00534] Clinical evaluations are performed by the same physician for the duration of the experiment. Each patient's disease is measured on a scale of 1 to 4, with 1 indicating minimal disease, and 4 indicating severe lesions. The degree of erosion, erythema, and reticulation of each lesion is separately scaled over time for a period ranging from 1 day to 6 months, as desired. In addition, the patients evaluate lesion discomfort on a scale of 1 to 4.

[00535] Additional models for pemphigus are described in "Animal Models of Human

Inflammatory Skin Diseases", Ed. L.S. Chan, CRC Press, 2003.

Example 15: Cardiovascular and metabolic disease models

[00536] Plasma Lipids Assay. 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 mammals, for example marmosets that possess a plasma lipoprotein profile similar to that of humans (Crook et al. Arteriosclerosis 10, 625, 1990). 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] 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.

[00538] Anti-obesity assay. The ability of cytokine inhibitors to cause weight loss may be assessed in obese human subjects with body mass index (BMI) ΞSO 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.

[00539] 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 vessel 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.

[00540] 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.

[00541] Diagnostic methods for glucose and insulin disorders. Glucose tolerance testing (GTT). 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.^'

[00542] Hyperinsuliπemic 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.

[00543] 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.

[00544] Using a fasting blood sample, insulin resistance is quantified using the following formula:

IR= Glucose (mg/dl)) x Insulin (μU/ml) / 405

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. 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 J₅ 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, MD₃ 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 16. [00545] Table 3 lists compounds of the invention prepared using the methods of

Examples 1 -6. 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 3 was tested in the TNFa ELISA assay (Example 4) and found to have activity therein, with some compounds having IC₅₀S below 10 μM in this assay.

TABLE 3

Structure Compound Name

3-(5-(5-tert-butyl-2- methoxybenzamido)-2- methylphenyl)-N-neopentyl- 1 H- pyrazole-5-carboxamide

3-(5-(3-fluoro-5- morpholinobenzamido)-2- methylphenyl)-N-neopentyl- 1 H- pyrazole-5-carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2- raethylphenyl)-N- neopentylisoxazole-5-carboxamide

3-(5-(5-tert-butyl-2- methoxybenzamido)-2- methylphenyl)-N-((tetrahydro-2H- pyran-4-yl)methyl)isoxazole-5- carboxamide

3-(5-(3-fluoro-5- morpholinobenzamido)-2- methylphenyl)-N-((tetrahydro-2H- pyran-4-yl)methyl)isoxazole-5- carboxamide

3-(5-(3-fluoro-5- morpholinobenzamido)-2- methylphenyl)-N-(tetrahydro-2H- pyran-4-yl)isoxazol e-5- carboxamide

No. Structure Compound Name

3-(5-(3-cyanobenzamido)-2-

64 methylphenyl)-N- neopentylisoxazole-5-carboxamide

3-(5-(5-tert-butyl-2- metnoxybenzamido)-2-

65 methylphenyl)-N-

(cyclohexylmethyl)isoxazole-5- carboxamide

3-[5-(5-tert-Butyl-2-methoxy- benzoylamino)-2-methyl-phenyl]-

66 isoxazole-

5-carboxylic acid (adamantan-1- ylmethyl)-amide

3-(5-(5-tert-butyl-2- methoxybenzamido)-2-

67 methylphenyl)-N-((tetrahydro-2H- pyran-4-yl)methyl)- 1 H-pyrazole-5- carboxamide

3-(5-(5-tert-butyl-2- methoxybenzamido)-2-

68 methylphenyl)-N-

((tetrahydrofiiran-2-yl)methyl)-lH- pyrazole-5-carboxamide

3-(5-(5-tert-butyl-2- methoxybenzamido)-2-

69 methylphcnyl)-N-

(cyclohexylmethyl)- 1 H-pyrazole-5- carboxamide

No. Structure Compound Name

3-(5-(3-fluoro-5- morpholinobenzamido)-2-

115 methylphenyl)-N-(2,2,3,3 ,3- pentafluoropropyl)isoxazole-5- carboxamide

3-(5-(3-fluoro-5- morpholinobenzamido)-2-

116 methylphenyl)-N-(2,2,2- trifluoroethyl)isoxazole-5- carboxamide

3-(5-(3-fluoro-5- morpholinobenzamido)-2-

117 methylphenyl)-N-(3 ,3,3- trifluoropropyl)isoxazole-5- carboxamide

3-(2-methyl-5-(5-

118 phenylnicotinamido)phenyl)-N- neopentylisoxazole-5-carboxamide

3-(2-methyl-5-(5-(piperidin-l -

1 19 yl)nicotinamido)phenyl)-N- neopentylisoxazole-5-carboxamide

3-(2-methyl-5-(5-(pyrrolidin-l-

120 yl)nicotinamido)phenyl)-N- neopentylisoxazole-5-carboxamide

No. Structure Compound Name

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

127 methylρhenyl)-N-(2,3 - dimethoxyb enzyl)-N- methylisoxazole-5-carboxamide

3-(5-(3-isopropylbenzamido)-2-

128 methylphenyl)-N- neopentyli soxazole-5 -carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

129 methylphenyl)-N-(2- methoxybenzyl)-N- methylisoxazole-5-carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

130 methylphenyl)-N-(3- methoxybenzyl)-N- methylisoxazole-5-carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

131 methylphenyl)-N-(3 ,5- dimethoxybenzyl)-N- methylisoxazole-5-carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

132 methylphenyl)-N-(( 1 - ethylpyrrolidin-2- yl)methyl)isoxazole-5-carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

133 methylphenyl)-N -

((tetrahydrofuran-2-

yl)methyl)isoxazole-5~carboxamide

o. Structure Compound Name

N-(3,5-dimethoxybenzyl)-3-(5-(3- fluoro-5-morpholinobenzamido)-2-

140 methylphenyl)isoxazole-5- carboxamide

N-(benzo[d][l,3]dioxol-5- ylmethyl)-3-(5-(3-fluoro-5-

141 morpholinobenzamido)-2- methylphenyl)isoxazole-5- carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

142 methylphenyl)-N-(2,3 - dimethoxybenzyl)isoxazole-5- carboxamide

3-(5-(3-(2-hydroxypropan-2-

143 yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide

3 -(5-(3 -acetylb enzamido)-2-

144 methylphenyl)-N- neopentylisoxazole-5-carboxamide

3-(5-(3-cyano-5- morpholinobenzamido)-2-

145 methylphenyl)-N-(3 - methoxybenzyl)isoxazole-5- carboxamide

No. Structure Compound Name

3-(5-(3-(2-methoxypropan-2-

146 yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide

3-(5-(3-tert-butyl-5- cyanobenzamido)-2-

147 methylphenyl)-N-(( 1 - ethylpyττolidin-2- yl)methyl)isoxazole-5-carboxamide

3-(5-(3-cyano-5- morpholinobenzamido)-2-

148 methylphenyl)-N-(( 1 - ethylpyrrolidin-2- yl)methyl)isoxazole-5-carboxamide

N-((l-ethylpyrrolidin-2-yl)methyl)-

3-(2-methyl-5-(3-morpholino-5-

149 (trifluoromethyl)benzamido)phenyl

)isoxazole-5-carboxamide

3 -(5-(3 -(2-ethoxypropan-2-

150 yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide

3-(5-(5-tert-butyl-3-cyano-2- methoxybenzamido)-2-

151 methylphenyl)-N-(l - methylpiperidin-4-yl)isoxazole-5- carboxamide

-

-

No. Structure Compound Name

3-(5-(3-tert-butyl-5-((4- methylpiperazin- 1 -

229 yl)methyl)benzamido)-2- methylphenyl)-N-(pyridin-4- ylmethyl)isoxazole-5-carboxamide

3-(5-(3-tert-butyl-5-((4- methylpiperazin- 1 - yl)methyl)benzamido)-2-

230 methylphenyl)-N- cyclopentylisoxazole-5- carboxamide

[00546] 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 I₅ 2, 3, 4, or 5 atoms, and so forth.

[00547] 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. [00548] . 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, i ssued 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. For example, this application is related to U.S. Provisional Application No. 60/753,634, filed December 22, 2005, entitled "Heterocyclic Cytokine Inhibitors", U.S. Provisional Application No. 60/787,362, filed March 30, 2006, entitled "Heterocyclic Cytokine Inhibitors," and U.S. Provisional Application No. 60/842,051, filed September 1 , 2006, entitled "Heterocyclic Cytokine Inhibitors," of which the entire contents of each is herein incorporated by reference.

Claims

CLAIMSWhat 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 of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with a target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with a target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein;

wherein the compound is a cytokine inhibitor.

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

3. The compound claim 1 , wherein the pocket-expanding moiety comprises a 6 membered aryl or heteroaryl moiety, substituted by a substituted or unsubstituted C_2-4 alkyl, C₃.g cycloalkyl, or heterocyclyl group.

4. The compound of claim 3, wherein the C_2-4 alkyl group is a substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl group.

5. The compound of claim 3, wherein the C₃..₉ cycloalkyl group is a substituted or unsubstituted cyclohexyl or norbornyl group.

6. The compound of claim 3, wherein the heterocyclyl group is a substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidyl, 8-oxa-3-aza- bicyclo[3.2.1]octan-3-yl, oxazepanyl, thiazolyl, or thiomorpholinyl group.

7. The compound of claim 1, wherein the orienting moiety comprises a phenyl, pyridyl, or pyridazinyl group, substituted by a halogen, methyl or trifluoromethyl group.

8. The compound of claim 1, wherein the linker moiety comprises an oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl group.

9. The compound of claim 1 , wherein the anchoring moiety comprises a substituted or unsubstituted amide, hydrazide or urethane group.

10. A compound of Formula I,

stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein

X and Y are each independently CH or N;

A is F, Cl, Br, I, NR₂, or a Cj_-3 alkyl or -0(Ci_-3 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated;

B, D and E are each independently N, NR, O, S or CR; wherein B₇ D, and E are selected such that the ring containing B, D₃ and E is aromatic;

G is an aryl or heteroaryl group, wherein G is substituted by one or more R¹,

R² or R³;

L¹ is -C(O)NH-;

-(CR'₂)_n-C(O)NR-(CR'₂)_p-, -(CR'₂)_n-C(O)NRNR-(CR'₂)p-, or -(CR'₂)_n-O-C(O)NR-(CR'₂)_p-; Q is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group; each R¹ is independently F, Cl₅ 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, -NO₂, a substituted or unsubstituted alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR'_2> -NR'_2> -NRC(O)R", -NR⁵C(O)OR", -NR⁵SO₂R", -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(Ci_-4 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted

alkyl 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; each m is independently O, 1 or 2; and n and p are each independently O, 1, 2 or 3.

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

Formula II.

12. The compound of claim 10, wherein the compound is

13. The compound of claim 10, wherein B is N.

14. The compound of claim 10, wherein D is NH, O or S.

15. The compound of claim 10, wherein E is CH or O.

16. The compound of claim 10, wherein A is F, -CH₃, or -CF₃.

17. The compound of claim 10, wherein G is a phenyl, pyrimidyl or pyridyl group.

18. The compound of claim 17, wherein G is

19. The compound of claim 10, wherein L² is -C(O)-(CR'2)p-, -(CH₂)_n-C(O)NR-(CH₂)_p- or -(CH₂)_n-C(O)NRNR-(CH₂)_p-.

20. The compound of claim 19, wherein L² is -C(O)-,-C(O)CH₂-, -C(O)CH₂CH₂-, -C(O)CH₂CH₂CH₂-, -C(O)NHNH-, -C(O)N(CH₃)NH-, -C(O)N(CH₃)NH-CH₂-, -C(O)N(CH₃)NH-CH₂CH₂-, -C(O)N(CH₃)NH-CH₂CH₂CH₂-, -C(O)NHNH-CH₂-, -C(O)NHNH-CH₂CH₂- Or -C(O)NHNH-CH₂CH₂CH₂-, -C(O)NH-, -C(O)N(CH₃)-, -C(O)N(CHs)-CH₂-, -C(O)N(CHa)-CH₂CH₂-, -C(O)N(CH₃)-CH₂CH₂CH₂-, -C(O)NH-CH₂-, -C(O)NH-CH₂CH₂- Or-C(O)NH-CH₂CH₂CH₂-.

21. The compound of claim 10, wherein the compound is

22. The compound of claim 10, wherein the compound is

Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group;

23. The compound of claim 10, wherein Q is H, or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, pyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidyl, or piperazinyl group.

24. The compound of claim 23, wherein Q is a substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or neopentyl group.

25. The compound of claim 10, wherein R¹ is F, -CN, -NR₂, or a substituted or unsubstituted Cj_-4 alkyl, C₃.₉ cycloalkyl, aryl, heterocyclyl or heterocyclyl alkyl group.

26. The compound of claim 25, wherein R¹ is F, -CN, or -N(Ci_-3 alkyl)₂ wherein each C|.₃ alkyl group is independently substituted or unsubstituted, or R¹ is a substituted or unsubstituted isopropyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, phenyl, 8- oxa-3-aza-bicyclo[3.2.1]octan-3-yl, thiazolyl, CHb-thiazolyl, CH^CHa-thiazolyl, pyrrolidinyl, CH₂-pyrrolidinyl, CH₂CH₂-pyrrolidinyl, piperidyl, CH₂-piperidyl, CH₂CH₂-piperidyl, morpholinyl, CH₂-morpholinyl, CH₂CH₂-morpholinyl, thiomorpholinyl, CH₂-thiomorpholinyl, CH₂CH₂-thiomorpholinyl, piperazinyl, CH₂-piperazinyl, CH₂CH₂-piperazinyl, oxazepanyl, CH₂-oxazepanyl, or CH₂CH₂-oxazepanyl group.

27. The compound of claim 10, wherein R² is a substituted or unsubstituted Ci_-4 alkyl or heterocyclylalkyl group, F, Cl, -CN, -NO₂, OR', -C(O)OR', -C(O)NR'₂, -NRC(O)R", -NRC(O)OR", -NR'SO₂R", -NR^* C(0)NR'₂, or -SO₂NR'₂.

28. The compound of claim 27, wherein the alkyl group is substituted with NRR.

29. The compound of claim 27, wherein the heterocyclylalkyl group is a substituted or unsubstituted -(Cj.₃ alkyl)-pyrrolidinyl, -(Ci-₃ alkyl)-piperidyl,

-(Ci-₃ alkyl)-piρerazinyl, or -(Ci-₃ alkyl)-morpholinyl group.

_*

30. The compound of claim 27, wherein R² is F, CF₃, -CN, -NO₂, -O(C_1-6 alkyl), -C(O)O(C_-6 alkyl), -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(C_1-6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO₂(C_L6 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(Ci_-6 alkyl), -SO₂NH(aryl), or -Sθ₂NH(aralkyl), wherein each Ci-₆ alkyl, aryl, or aralkyl group is substituted or unsubstituted.

31. The compound of claim 10, wherein R³ is a substituted or unsubstituted Ci_-4 alkyl or -0(Ci_-4 alkyl) group, or is a partially or fully halogenated -0(Ci_-2 alkyl) group.

32. The compound of claims 10, 11 or 12, wherein G is phenyl and R¹ is F, Cl, -CN, -N(C]_₃ alkyl)₂ wherein each C_L3 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted morpholinyl, thiomorpholinyl, 8-oxa-3-aza- bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, isopropyl, tert-butyl, iso-butyl, sec-butyl, or cyclohexyl group.

33. The compound of claim 32, wherein R¹ is F, Cl, a substituted or unsubstituted morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, tert-butyl, or cyclohexyl group.

34. The compound of claim 32, wherein R² is a substituted or unsubstituted Ci_-4 alkyl or heterocyclylalkyl group, F, -CN, -NO₂, -0(C_1-6 alkyl), -C(O)O(Ci- 6 alkyl), -C(O)NH₂, -C(O)NH(C)_-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(C_L6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO₂(Ci_-6 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(C_L6 alkyl), -SO₂NH(aryl) or -SO₂NH(aralkyl), wherein each Ci_-6 alkyl, aryl, or aralkyl group is substituted or unsubstituted.

35. The compound of claim 34, wherein the alkyl group is substituted with NRR.

36. The compound of claim 34, wherein the heterocyclylalkyl group is a substituted or unsubstituted -(Ci_₃ alkyl)-pyrrolidinyl, -(Ci-₃ alkyl)-piperidyl,

-(Ci-₃ alkyl)-piperazinyl, or -(Ci-₃ alkyl)-morpholinyl group.

37. The compound of claim 34, wherein R² is F, CF₃, -CN, -C(O)NH₂, -C(O)NH(Ci_-6 alkyl), -NHSO₂(C_1-6 alkyl), or -SO₂NH(C ,_₆ alkyl), wherein each C_1-6 alkyl group is substituted or unsubstituted.

38. The compound of claim 34, wherein R³ is a substituted or unsubstituted C1-₄ alkyl or -0(C_M alkyl) group, or is a partially or fully halogenated -0(Ci_-2 alkyl) group.

39. The compound of claim 10, 11 or 12, wherein I/ '-Q is

40. The compound of claim 39, wherein G is a phenyl or a pyridyl group.

41. The compound of claim 10, wherein the compound is

42. The compound of claim 10 wherein the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.

43. A composition comprising a compound of claim 10, 11 or 12 and a pharmaceutically acceptable carrier.

44. 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 10.

45. The method of claim 44, 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, iπsulinitis, 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.

46. The method of claim 45, wherein the cancer is breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, osteosarcoma, or follicular lymphoma.

47. The method of claim 45, wherein the non-articular inflammatory condition is intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis, or fϊbromyalgic syndrome.

48. The method of claim 45, wherein the cardiac failure is heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass.

49. The method of claim 45, wherein the disorder related to fibrinolysis is acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation, 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, leukopenia or thrombocytopenia.

50. The method of claim 45, wherein the acute or chronic pain is or is associated with neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension headache, 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, herniated intervertebral disc-induced sciatica, post-surgery pain, cancer-related pain, vascular pain, visceral pain, childbirth, or HIV-related pain.

51. The method of claim 44, 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, psoriasis, 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, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain.

52. The method of claim 44, wherein the cytokine-mediated disorder is 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, or atherosclerosis.

53. The method of claim 44, wherein the cytokine-mediated disorder is allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, or surgery or trauma-induced proliferative vitreoretinopathy.

54. The method of claim 44, wherein the cytokine-mediated disorder is allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, obliterative bronchiolitis, emphysema, asthma, bronchitis, mucus hypersecretion, SARS infection, silicosis or respiratory tract inflammation.

55. The method of claim 44, wherein the cytokine-mediated disorder is psoriasis, pemphigus, eczema, atopic dermatitis, contact dermatitis, or acne.

56. The method of claim 44, wherein the cytokine-mediated disorder is 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, or epilepsy.

57. The method of claim 44, wherein the cytokine-mediated disorder is a bone resorption disease, osteopetrosis, osteoporosis, or osteoarthritis.

58. The method of claim 44, wherein the cytokine-mediated disorder is diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia or bulimia nervosa.

59. The method of claim 44, wherein the cytokine-mediated disorder is sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, or drug resistance.

60. The method of claim 44, 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.

61. The method of claim 44, wherein the cytokine mediated disorder is a neutrophil-mediated disorder.

62. The method of claim 61 , 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.

63. The method of claim 44, 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.

64. The method of claim 63, wherein the cytokine is TNFa or IL-I .

65. The method of claim 44, wherein the disorder is 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, 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, degenerative joint disease, dermatitis, diarrhea, dry eye, dyslipidemia, dyspnea, dyslipidemia, edema, end- stage renal disease, epstein-barr virus infections, fever, 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, peripheral nerve disorders, peripheral neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis.

66. 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 10.

67. The method of claim 66, 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.

68. 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 proinflammatory 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 10.

69. 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 10.

70. 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 10.

71. 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 10.

72. A method comprising administering to a subject an amount of a cytokine inhibitor effective to increase the HDL-I evel of the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

73. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the triglyceride-level of the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

74. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

75. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the HbAIc value in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

76. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the insulin-level in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

77. A method comprising administering to a subject an amount of a cytokine inhibitor effective to decrease the HOMA Insulin Resistance Index in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

78. A method comprising administering to a subject an amount of a cytokine inhibitor effective to increase the indirect bilirubin-level in the subject relative to the level prior to the administration of the cytokine inhibitor, wherein the cytokine inhibitor is a compound of claim 10.

79. A method of preparing a compound of claim 10, 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; under conditions suitable to provide a compound of Formula I; wherein A, B, D, E, X, Y, L², Q and G are as defined in Formula I, and Z is an activating moiety.

80. A method of preparing a compound of Formula IV

Formula IV the method comprising contacting a compound of Formula V

Formula V with H-C ≡C-L', under conditions suitable to provide a compound of

Formula IV;

wherein L' is -L²-Q, -(CH₂)_n-C(O)OPco_> or -(CH₂)pNR-P_N, wherein P_Co is a carboxy protecting group, P_N is an amine protecting group, and A, X, Y, L², n, p and Q are as defined in claim 10.

81. A compound of Formula VI,

Formula VI wherein

V is an alkyl or cycloalkyl group, optionally partially or fully halogenated;

T is -CN, -SO₂NR'₂, -C(O)NR'₂, or -NR' SO₂R";

U is-O(Ci_-6 alkyl); 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.

82. A compound of Formula VII₃

Formula VII wherein

K is a C_2-G alkyl or a cycloalkyl group, optionally partially or fully halogenated;

J is -CN, -SO₂NR'₂, or-NR'SOaR"; 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 R_p is H or a substituted on unsubstituted alkyl, aralkyl or heterocyclalkyl group.

83. A compound of Formula VIII

Formula VIII wherein

R_m is hydrogen or a substituted or unsubstituted Ci .₆ alkyl group; and m is 0, 1 or 2.

84. The compound of claim 82, wherein R_n, is H.

85. The compound of claim. 10, wherein the compound is selected from

List 1.