WO2011137587A1

WO2011137587A1 - Cytokine inhibitors

Info

Publication number: WO2011137587A1
Application number: PCT/CN2010/072479
Authority: WO
Inventors: Wei-Guo Su; Wei Deng; Yu Cai; Jifeng Duan
Original assignee: Hutchison Medipharma Limited
Priority date: 2010-05-06
Filing date: 2010-05-06
Publication date: 2011-11-10

Abstract

Provided is a compound of Formula (I): and/or at least one pharmaceutically acceptable salt thereof. Also provided are a method of inhibiting the activity of at least one protein chosen from TNFα, IL-1β, NF-κB, IL-10 and iNOS, a method of decreasing a level of a cytokine, and a method of treating a disorder mediated by overproduction of a cytokine, with at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof.

Description

CYTOKINE INHIBITORS

[001] Tumor necrosis factor alpha (TNFa), a mononuclear cytokine, is predominately produced by monocytes and macrophages. It possesses various biological activities, such as: (1) killing cancer cells or inhibiting growth of cancer cells, (2) enhancing the phagocytosis of neutrophilic

granulocytes, (3) up-regulating the production of peroxide, and (4) killing infection pathogens.

[002] Interleukin-1 beta (IL-Ι β), a cytokine secreted by cells such as monocyte macrophages and dendritic cells, mediates immune and inflammatory responses.

[003] Nuclear factor-kappa B (NF-κΒ) is a pro-inflammatory transcription factor. It upregulates cytokines, including TNFa and IL-Ι β, and thereby mediates inflammatory responses.

[004] Interleukin-10 (IL-10), also known as cytokine synthesis inhibitory factor (CSIF), is an antiinflammatory cytokine. IL-10 has pleiotropic effects on immunoregulation and inflammation. For instance, it down-regulates the expression of Thl cytokines, MHC class II antigens, and

costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. Moreover, IL-10 can block NF-κΒ activity, and may be involved in the regulation of the JAK-STAT signaling pathway.

[005] Inducible nitric oxide synthase (iNOS) is induced by endotoxins or cytokines (e.g., TNFa). It catalyzes the production of nitric oxide, a pleiotropic molecule, from L-aginine and oxygen.

[006] TNFa, IL-1 β, NF-κΒ, IL-10 and iNOS play roles in many physiological and pathological processes relating to a range of diseases, e.g., autoimmune diseases, inflammatory diseases, cancer, atherosclerosis, and diabetes. Therefore, modulating the expression or activity of TNFa, IL-1 β, NF- KB, IL-10 and/or iNOS can lead to treatment of these diseases.

[007] Provided is at least one compound of Formula I:

I,

and/or at least one pharmaceutically acceptable salt thereof wherein

A is chosen from optionally substituted heteroaryl and (CR'R")_n

wherein

n is 0, 1 , 2, 3, 4, or 5; for each occurrence, each of R' and R", independently, is H or optionally substituted Ci-io alkyl or R' and R", together with the carbon to which they are bound, form an optionally substituted 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl;

B is a bicyclic heteroaryl having 8 or 9 atoms of which 1 , 2, 3, or 4 of said 8 or 9 atoms are heteroatoms independently chosen from N, O and S;

X is chosen from (CR^a R^b')_m, SO, S0₂, CO, COO, CONR^c , NR^C', and NR^C CONR^d ; wherein m is 0, 1, 2, 3, 4, or 5;

each of R^a , R^b , R^c , and R^d , independently, is H or optionally substituted Ci-io alkyl; each of R¹ and R², independently, is hydrogen, halo, NR^clC(0)R^al, OR^bl, NR^clR^dl,

NR^clC(0)OR^bl, NR^clS(0)₂R^bl, or optionally substituted Ci-io alkyl, wherein each of R^al and R^bl, independently, is H, optionally substituted Ci-io alkyl, optionally substituted aryl, or optionally substituted heteroaryl, and each of R^cl and R^dl, independently, is H, optionally substituted C_1-10 alkyl, optionally substituted aryl, optionally substituted heteroaryl, or R^cl and R^dl together with the N atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocycloalkyl; and

R³ is H, halo, OC(0)R^a2, C(0)OR^b2, OR^b2, SR^b2, S0₂R^b2, C(0)NR^c2R^d2, NR^c2R^d2,

NR^c2C(0)R^a2, NR^c2C(0)C(0)OR^a2, NR^c2S(0)₂R^b2, Ci-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of Ci-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and

heterocycloalkylalkyl is optionally substituted, wherein

each of R^a2 and R^b2, independently, is H, Ci_-6 alkyl, Ci_-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, or heteroarylalkyl in which each of Ci- 6 alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, and heteroarylalkyl is optionally substituted;

each of R^c2 and R^d2, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of C_MO alkyl, d-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by one or more groups chosen from halo, NR^clC(0)R^al, OR^bl, NR^clR^dl, NR^clC(0)OR^bl, NR^clS(0)₂R^bl, and optionally substituted C_Mo alkyl;

or R^c2 and R^d2, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered optionally substituted heterocycloalkyl, provided that if A is (CR'R")_n where n is 0, then X is not (CR^a R^b )_m wherein m is 0, and further provided that -A-X-R³ is not methyl or CF₃.

[008] Also provided is a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt thereof descrbed herein and

at least one pharmaceutically acceptable carrier.

[009] Also provided is a method of inhibiting the activity of at least one protein chosen from TNFa, IL-1 β, NF-KB, IL-10 and iNOS, comprising contacting the at least one protein with an effective amount for inhibiting said activity of at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein.

[010] Also provided is a method of decreasing a level of a cytokine, comprising administering to a subject in need thereof an effective amount for decreasing said level of at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein.

[011] Also provided is a method of treating a disorder mediated by overproduction of a cytokine, comprising administering to a subject in need thereof an effective amount for treating said disorder of at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein.

[012] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout:

[013] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH₂ is attached through the carbon atom.

[014] The term "alkyl" herein refers to a straight or branched hydrocarbon, containing e.g. 1 -20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, ^-propyl, i- propyl, w-butyl, -butyl, and t-butyl. "Lower alkyl" refers to a straight or branched hydrocarbon, containing 1-4 carbon atoms. [015] By "alkoxy" is meant a straight or branched alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to 6 carbon atoms attached through the oxygen bridge. "Lower alkoxy" refers to a straight or branched alkoxy, wherein the alkyl portion contains 1-4 carbon atoms.

[016] The term "alkenyl" herein refers to a C_2-io straight or branched hydrocarbon, containing one or more C=C double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, 2- propenyl, and 2-butenyl.

[017] The term "alkynyl" herein refers to a C_2-io straight or branched hydrocarbon, containing one or more C≡C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2- propynyl, and 2-butynyl.

[018] The term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The ring may be saturated or have one or more double bonds (i.e. partially unsaturated).

[019] "Aryl" encompasses:

5- and 6-membered carbocyclic aromatic rings, for example, benzene;

bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and

tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[020] For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5 - to 7- membered heterocyclic ring containing one or more heteroatoms chosen from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein. Examples of aryl include phenyl (Ph), phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl.

[021] The term "heteroaryl" refers to

5- to 8-membered aromatic, monocyclic rings containing one or more, for example, from 1 to

4, or, in some embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon;

8- to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and

11 - to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

[022] For example, heteroaryl includes a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring.

[023] When the total number of S and O atoms in the heteroaryl group exceeds 1 , those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

[024] Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4- pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, indolyl, furylene, fluorenyl, pyrrolyl, imidazolyl, pyridizinyl, triazolyl, quinolinyl, isoquinolyl, quinazolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.

[025] Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.

[026] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-0^") substituents, such as pyridinyl N-oxides.

[027] The term "halo" includes fluoro, chloro, bromo, and iodo, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[028] The term "haloakyl" refers to an alkyl group having one or more halogen substituents.

Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCI3, CHC1₂, C₂Cl5, and the like.

[029] The term "arylalkyl" (or "heteroarylakyl") refers to alkyl substituted by aryl (or heteroaryl) and "cycloalkylalkyl" (or "heterocycloalkylalkyl") refers to alkyl substituted by cycloalkyl (or heterocycloalkyl). An example arylalkyl group is benzyl.

[030] The term "alkylamino" refers to an amino group substituted by an alkyl group. The term "dialkylamino" refers to an amino group substituted by two alkyl groups.

[031] By "heterocycloalkyl" is meant a single aliphatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1 -3 heteroatoms independently chosen from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. "Heterocycloalkyl" also refers to 5- to 7-membered heterocyclic ring containing one or more heteroatoms chosen from N, O, and S fused with 5- and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have one or more double bonds (i.e. partially unsaturated). The heterocycle can be substituted by oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring.

[032] By "optional" or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non- feasible and/or inherently unstable.

[033] The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. [034] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e., =0) then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.

[035] In some embodiments, "substituted with one or more groups" refers to two hydrogens on the designated atom or group being independently replaced with two selections from the indicated group of substituents. In some embodiments, "substituted with one or more groups" refers to three hydrogens on the designated atom or group being independently replaced with three selections from the indicated group of substituents. In some embodiments, "substituted with one or more groups" refers to four hydrogens on the designated atom or group being independently replaced with four selections from the indicated group of substituents.

[036] Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid

chromatography (HPLC) column. In addition, such compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound, such as keto-enol tautomers. Such compounds also include crystal forms including polymorphs and clathrates. Similarly, the term "salt" is intended to include all isomers, racemates, other mixtures, Z- and E-forms, tautomeric forms and crystal forms of the salt of the compound. [037] The compounds described herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[038] "Pharmaceutically acceptable salts" include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH₂)_n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[039] In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic

pharmaceutically acceptable addition salts.

[040] A "solvate," such as a "hydrate," is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates, including hydrates, of compounds. Similarly, "salts" includes solvates, such as hydrates, of salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi -hydrates.

[041] A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of compounds. Similarly, "salts" includes chelates of salts.

[042] A "non-covalent complex" is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound'.

[043] The term "hydrogen bond" refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry (G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp. 320-326 (1984)).

[044] "Hydrogen bond acceptor" refers to a group comprising an oxygen or nitrogen, such as an oxygen or nitrogen that is sp² -hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.

[045] The term "hydrogen bond donor" refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.

[046] As used herein the terms "group", "radical" or "fragment" are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.

[047] "Leaving group" refers to a charged or uncharged atom or group which departs during a substitution or displacement reaction. Exemplary leaving groups include halogen atoms such as a chlorine atom, a bromine atom and iodine atom and alkyl- or arylsulfonyloxy groups such as methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy and p-tolylsulfonyloxy.

[048] The term "active agent" is used to indicate a chemical substance which has biological activity. In some embodiments, an "active agent" is a chemical substance having pharmaceutical utility.

[049] "Treating" or "treatment" or "alleviation" refers to administering at least one compound and/or at least one pharmaceutically acceptable salt described herein to a subject that has a disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition toward the disease or disorder.

[050] The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of the activity of at least one protein chosen from TNFa, IL-1 β, NF-κΒ, IL-10 and iNOS" refers to a decrease in the activity of the at least one protein chosen from TNFa, IL-1 β, NF-KB, IL-10 and iNOS as a direct or indirect response to the presence of at least one compound and/or at least one pharmaceutically acceptable salt described herein, relative to the activity of the at least one protein in the absence of the at least one compound and/or the at least one pharmaceutically acceptable salt thereof. Without being bound by theory, it is pointed out that the decrease in activity may be due to the direct interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described herein with the at least one protein chosen from TNFa, IL-1 β, NF-KB, IL-10 and iNOS, or due to the interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described herein, with one or more other factors that in turn affect the activity of the at least one protein. For example, the presence of at least one compound and/or at least one pharmaceutically acceptable salt described herein, may decrease the activity of the the at least one protein by directly binding to the at least one protein chosen from TNFa, IL-1 β, NF-KB, IL-10 and iNOS, by causing (directly or indirectly) another factor to decrease activity of the at least one protein, or by (directly or indirectly) decreasing the amount of the at least one protein present in the cell or organism.

[051] "Decreasing a level of a cytokine" refers to a decrease in the level of a cytokine as a direct or indirect response to the presence of at least one at least one compound and/or at least one pharmaceutically acceptable salt described herein, relative to the level of the cytokine in the absence of the at least one compound and/or the at least one pharmaceutically acceptable salt thereof.

[052] The term "effective amount" refers to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein effective to "treat" a disease or disorder in a subject. The effective amount may cause any of the changes observable or measurable in a subject as described in the definition of "treating," "treatment" and "alleviation" above. For example, in the case of cancer, the effective amount can reduce the number of cancer or tumor cells; reduce the tumor size; inhibit or stop tumor cell infiltration into peripheral organs including, for example, the spread of tumor into soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer, reduce morbidity and mortality; improve quality of life; or a combination of such effects. An effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of the activity of at least one protein chosen from TNFa, IL-1 β, NF-κΒ, IL-10 and iNOS. For cancer therapy, efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and co-usage with other agents.

[053] The term "effective amount" may also refer to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein effective to inhibit the activity of at least one protein chosen from TNFa, IL-Ι β, NF-κΒ, IL-10 and iNOS. [054] The term "effective amount" may also refer to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described herein effective to decrease a level of a cytokine in a subject, as compared to the level of the cytokine prior to treatment of the subject with the at least one compound and/or the at least one pharmaceutically acceptable salt thereof.

[055] Provided is at least one compound of Formula I:

I,

and/or at least one pharmaceutically acceptable salt thereof wherein

A is chosen from optionally substituted heteroaryl and (CR'R")_n

wherein

n is 0, 1 , 2, 3, 4, or 5;

for each occurrence, each of R' and R", independently, is H or optionally substituted

Ci-io alkyl or R' and R", together with the carbon to which they are bound, form an optionally substituted 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl;

each of R^a , R^b , R^c , and R^d , independently, is H or optionally substituted C_1-10 alkyl; each of R¹ and R², independently, is hydrogen, halo, NR^clC(0)R^al, OR^bl, NR^clR^dl,

NR^clC(0)OR^bl, NR^clS(0)₂R^bl, or optionally substituted Ci-io alkyl, wherein each of R^al and R^bl, independently, is H, optionally substituted C_1-lo alkyl, optionally substituted aryl, or optionally substituted heteroaryl, and each of R^cl and R^dl, independently, is H, optionally substituted Ci-io alkyl, optionally substituted aryl, optionally substituted heteroaryl, or R^cl and R^dl together with the N atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocycloalkyl; and R³ is H, halo, OC(0)R^a2, C(0)OR^b2, OR^b2, SR^b2, S0₂R^b2, C(0)NR^c2R^d2, NR^c2R^d2,

NR^c2C(0)R^a2, NR^c2C(0)C(0)OR^a2, NR^c2S(0)₂R^b2, d-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of Ci-i₀ alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and

heterocycloalkylalkyl is optionally substituted, wherein

or R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered optionally substituted heterocycloalkyl,

provided that if A is (CR'R")_n where n is 0, then X is not (CR^a R^b )_m wherein m is 0, and further provided that -A-X-R³ is not methyl or CF₃.

In some embodiments, A is chosen from

each of which is optionally substituted and wherein

R is H or Ci-io alkyl, in which d-io alkyl is optionally substituted by one or more groups chosen from halo, C(0)R^a, OR^b, SR^b, S(0)₂R^b, NR^cR^d, and C(0)NR^cNR^d, in which each of R^a and R^b, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, or

heteroaryl, and

each of R^c and R^d, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, or heteroaryl, or R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl.

[057] In some embodiments, A i

[058] In some embodiments, B i

[059] In some embodiments, B i

[060] In some embodiments, X is (CR^a R^b')_m, CO, COO, NR^C', CONR^c , or NR^C CONR^d . In some embodiments, X is CH₂, NH, CO, COO, CONH, or NHCONH.

[061] In some embodiments, R¹ is H, OR^bl, NR^clC(0)R^al, NR^clR^dl, NR^clC(0)OR^bl, or

NR^clS(0)₂R^bl. In some embodiments, R¹ is H.

[062] In some embodiments, R² is H, OR^bl, NR^clC(0)R^al, NR^clR^dl, NR^clC(0)OR^bl, or

NR^clS(0)₂R^bl. In some embodiments, R² is H.

[063] In some embodiments, R³ is H, halo, C(0)NR^c2R^d2, NR^c2R^d2, NR^c2C(0)R^a2,

NR^c2C(0)C(0)OR^a2, NR^c2S(0)₂R^b2, heteroaryl, or heterocycloalkyl, in which each of heteroaryl and heterocycloalkyl is optionally substituted, wherein

each of R^c2 and R^d2, independently, is H, Ci-io alkyl, C_MO haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of Ci-io alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by one or more groups chosen from halo, NR^clC(0)R^al, OR^bl, NR^clR^dl, NR^clC(0)OR^bl, NR^clS(0)₂R^bl, and optionally substituted C _O alkyl;

or R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered optionally substituted heterocycloalkyl.

[064] In some embodiments, R³ is C(0)NR^c2R^d2 or NR^c2R^d2,

each of R^c2 and R^d2, independently, is H, C_1-10 alkyl, C_MO haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of C_MO alkyl, C_MO haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by one or more groups chosen from halo, NR^clC(0)R^al, OR^bl, NR^clR^dl, NR^clC(0)OR^bl, NR^clS(0)₂R^bl, and optionally substituted C _O alkyl; or R^c and R together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered optionally substituted heterocycloalkyl.

] Also provided is at least one compound chosen from

2-(3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

1 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)benzyl)-3 -(2-morpholinoethyl)urea;

1 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)benzyl)-3 -(2-methoxyethyl)urea;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)-2- methoxyethanamine;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)-2- morpholinoethanamine;

2-(3-(5-(mo holinomethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine;

(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)-N,N- dimethylmethanamine;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)methyl)aminoethanol;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)ethanamine;

2-(3-(5-((4-fluorophenoxy)methyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2- b]pyridazine;

2-(3-(5-(ethoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

2-(3-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

2-(3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

(3 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl acetate;

2-(3-(5-isopropyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)methanol;

2-(3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

2-(3-(5-(fluoromethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

2-(3-(5-ethyl-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

N-methyl-2-(3 -(5 -(trifluoromethyl)- 1 ,2,4-oxadiazol-3 -yl)phenyl)imidazo [1,2- b]pyridazin-6-amine;

ethyl 3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5-carboxylate;

ethyl 2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)acetate; 3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5-carboxylic acid;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5-carboxamide;

2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)acetic acid;

2-(3 -(5 -(methylthio methyl)- l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

2-(3-(5-(methylsulfonylmethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine; (3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine;

2-(3-(2-methoxyethoxy)-5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine;

2-(3 -(2-methoxyethoxy)-5 -(5 -methyl- 1 ,2,4-oxadiazol-3 -yl)phenyl)imidazo [ 1 ,2- b]pyridazine;

2-(3-(5-(fluoromethyl)-l,2,4-oxadiazol-3-yl)-5-(2-methoxyethoxy)phenyl)imidazo[l,2- b]pyridazine;

2-(3-(2-methoxyethoxy)-5-(5-(methoxymethyl)-l ,2,4-oxadiazol-3- yl)phenyl)imidazo[l,2-b]pyridazine;

2- (3-(5-(ethoxymethyl)-l,2,4-oxadiazol-3-yl)-5-(2-methoxyethoxy)phenyl)imidazo[l,2- b]pyridazine;

(3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4-oxadiazol-5- yl)methanol;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4-oxadiazole-5- carboxylic acid;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4-oxadiazole-5- carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin-2-yl)-l ,2,4- oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2,2,2- trifluoroethyl)-l,2,4-oxadiazole-5-carboxamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)acetamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2,2,2- trifluoroacetamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-chloroacetamide; N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-chlorobenzamide; N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- nitrobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-cyanobenzamide;

N-(3 -(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3 -bromobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- fluorobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- chlorobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- methylbenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2- fluorobenzenesulfonamide;

N-(2-(diethylamino)ethyl)-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5 -yl)acetamide;

N-butyl-2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)acetamide;

2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)-N-(((S )- tetrahydrofuran-2-yl)methyl)acetamide;

N-cyclopentyl-2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 - yl)acetamide;

2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)-N-(2- methoxyethyl)acetamide ;

2- (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)- 1 -morpholinoethan-

1-one;

N-cyclopropyl-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)acetamide;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-N-(2-mo holinoethyl)-l,2,4-oxadiazole-5- carboxamide;

N-ethyl-3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazole-5-carboxamide; N-cyclopentyl-3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5- carboxamide; (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 - yl)(morpholino)methanone;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-N-(2-methoxyethyl)-l ,2,4-oxadiazole-5- carboxamide;

N-(2-(dimethylamino)ethyl)-3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1,2,4- oxadiazole-5-carboxamide;

(4-ethylpiperazin-l -yl)(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)methanone;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-N-(thiophen-2-ylmethyl)-l,2,4-oxadiazole-5- carboxamide;

N-(2 -hydroxy ethyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5- carboxamide;

3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-N,N-dimethyl-l,2,4-oxadiazole-5- carboxamide;

(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)(pyrrolidin-l - yl)methanone;

3 -(3 -(imidazo [l,2-b]pyridazin-2-yl)phenyl)-N-methyl-l,2,4-oxadiazole-5 -carboxamide; 2-(3 -(imidazo [l,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

(2-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenylamino)pyridin-3 -yl)(pyrrolidin- 1 - yl)methanone;

N-(2 -hydroxy ethyl)-2-(3 -(imidazo [l ,2-b]pyridazin-2-yl)phenylamino)nicotinamide; ethyl 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)nicotinate;

N-cyclopropyl-2-(3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

(2-(3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)pyridin-3-yl)(morpholino)methanone;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(5-(morpholinomethyl)-l ,2,4-oxadiazol-3- yl)phenyl)methanesulfonamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)-5 -(5 -(piperidin- 1 -ylmethyl)- 1 ,2,4-oxadiazol-3 - yl)phenyl)methanesulfonamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)-5 -(5 -((2-methoxyethylamino)methyl)- 1 ,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide; N-(3-(5-((2-(dimethylamino)ethylamino)methyl)-l,2,4-oxadiazol-3-yl)-5-(imidazo[l ,2- b]pyridazin-2-yl)phenyl)methanesulfonamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)-5 -(5 -(piperazin- 1 -ylmethyl)- 1 ,2,4-oxadiazol-3 - yl)phenyl)methanesulfonamide;

N-(3-(5-(aminomethyl)-l,2,4-oxadiazol-3-yl)-5-(imidazo[l,2-b]pyridazin-2- yl)phenyl)methanesulfonamide;

2- (3-(5-(piperazin-l-ylmethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine; Nl -((3 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl)ethane-

1,2-diamine;

Nl -((3 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl)-N2,N2- dimethylethane-1 ,2-diamine;

2,2,2-trifluoro-N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)methyl)acetamide;

ethyl 2-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl) phenyl)-l,2,4-oxadiazol-5-yl)methyl- amino)-2-oxoacetate;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)- phenyl)-l ,2,4-oxadiazol-5-yl)methyl)-2- methoxyacetamide;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)-phenyl)-l,2,4-oxadiazol-5- yl)methyl)cyclopentanecarboxamide;

ethyl 3-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl) phenyl)-l,2,4-oxadiazol-5-yl)methyl- amino)-3-oxopropanoate;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)-phenyl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4- oxadiazol-5- yl)methyl)isobutyramide;

3- ((3-(imidazo[l,2-b]pyridazin-2-yl)benzylamino)methyl)benzonitrile;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-4-chlorobenzamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)benzyl)-2-methoxyacetamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)benzyl)-3 -cyanobenzenesulfonamide;

1 -(3 -(imidazo [l,2-b]pyridazin-2-yl)benzyl)-3-(thiophen-2-ylmethyl)urea;

3-bromo-N-((3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)methyl)benzamide; 4-chloro-N-((3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)methyl)benzamide;

N-((3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)methyl)butyramide;

N-((3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)methyl)cyclopropanecarboxamide;

N-((3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)(4- (methylsulfonyl)phenyl)methanamine;

2-methoxy-N-((3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)ethanamine;

N-((3-(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl)-2- methoxyacetamide;

ethyl 2-(3-(imidazo[l ,2-a]pyridin-2-yl)benzylamino)nicotinate;

l-(3-(imidazo[l,2-a]pyridin-2-yl)benzyl)-3-(2-chloro-4-fluorophenyl)urea;

1- (3-(imidazo[l,2-a]pyridin-2-yl)benzyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea; N-(2-(dimethylamino)ethyl)-2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5 -yl)acetamide;

2- (3-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)-imidazo[l,2-a]pyridine;

6-(3 -(5-(methoxymethyl)-l ,2,4-oxadiazol-3 -yl)phenyl)-2-methylimidazo[2, 1 -b]thiazole;

2-methyl-6-(3-(5-methyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[2,l -b]thiazole;

2-(3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-imidazo[l,2-a]pyridine;

2-methyl-6-(3 -(5-(trifluoromethyl)-l ,2,4-oxadiazol-3 -yl)phenyl)imidazo[2, 1 -b]thiazole;

(3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl acetate;

2- (3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)-imidazo[l,2-a]pyridine;

(3-(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methanol;

(3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l,2,4-oxadiazol-5-yl)methanol;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)propionamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)ethanesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-3-fluorobenzenesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-3-nitrobenzamide;

N-(3 -(2-methylimidazo [2, 1 -b]thiazol-6-yl)benzyl)-2-methoxyacetamide;

3- ((3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzylamino)methyl)benzonitrile;

l-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-(3-chloro-4-fluorophenyl)urea;

3-cyano-N-((3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)methyl)benzenesulfonamide; ethyl 4-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)ureido)piperidine-l-carboxylate; N-(3 -(2-methylimidazo [2, 1 -b]thiazol-6-yl)benzyl)-4-methoxybenzenesulfonamide; N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-4-cyanobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-4-methoxybenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-bromobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-chlorobenzenesulfonamide;

N-(3 -(2-methylimidazo [2, l-b]thiazol-6-yl)benzyl)-4-fluorobenzenesulfonamide;

(3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4-oxadiazol-5- yl)methyl acetate;

2-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4-oxadiazol-5- yl)methyl)aminoethanol;

methyl 3-(imidazo[l ,2-b]pyridazin-2-yl)benzylcarbamate;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-2-chlorobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-2-methylbenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-2-fluorobenzenesulfonamide;

N-(3 -(2-methylimidazo [2, l-b]thiazol-6-yl)benzyl)-2-chlorobenzenesulfonamide;

N-(3 -(2-methylimidazo [2, l-b]thiazol-6-yl)benzyl)-2-methylbenzenesulfonamide;

N-(3 -(2-methylimidazo [2, l-b]thiazol-6-yl)benzyl)-3-chlorobenzenesulfonamide;

N-(3 -(2-methylimidazo [2, l-b]thiazol-6-yl)benzyl)-2-fluorobenzenesulfonamide;

l-(3-(6-(methylamino)imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-(2-methoxyethyl)urea;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-4-fluorobenzenesulfonamide;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)(phenyl)methanamine;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-nitrobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-nitrobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-(3- methoxyphenyl)acetamide ;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-methoxyacetamide; l-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(2-methoxyphenyl)urea;

l-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(2-chloro-4-fluorophenyl)urea;

3 -(3 -(imidazo [1 ,2-a]pyridin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5-ol; 1 -((3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)methyl)-3 -(3 -methylpyridin-2-yl)urea;

l-(3-cyanophenyl)-3-((3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)methyl)urea;

1 -((3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)methyl)-3 -(phenylsulfonyl)urea;

l-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(4-fluorobenzyl)urea;

l-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(3-chlorophenyl)urea;

1- (3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(3-methoxyphenyl)urea;

2- (3 -(5 -methyl- 1 H- 1 ,2,4-triazol-3 -yl)phenyl)imidazo [ 1 ,2-b]pyridazine;

2-(3 -(5 -methyl- 1 H- 1 ,2,4-triazol-3 -yl)phenyl)-imidazo [ 1 ,2-a]pyridine;

ethyl 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenylamino)nicotinate; 2-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenylamino)nicotinamide; (3 -(3 -(imidazo[ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)(piperidin- 1 - yl)methanone;

2- (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)acetamide;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4-oxadiazole-5- carboxamide;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)methyl)methanesulfonamide;

N,N-diethyl-2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 - yl)acetamide;

2- (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)-N-methylacetamide;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2-(piperidin-l- yl)ethyl)-l,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2- morpholinoethyl)-l ,2,4-oxadiazole-5-carboxamide;

2- (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)- 1 -(piperazin-1 - yl)ethanone;

N-(3 -chlorobenzyl)-2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 - yl)acetamide;

3 - (3 -(imidazo [l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-methyl- 1,2,4- oxadiazole-5-carboxamide; N-(3-chlorobenzyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)- 1 ,2,4-oxadiazole-5-carboxamide;

2- (3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)-N-methylnicotinamide;

N-cyclopropyl-3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazole-5-carboxamide;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyrimidin-2-yl)- 1 ,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin-3- ylmethyl)-l ,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(5-methylthiazol-2- yl)-l ,2,4-oxadiazole-5-carboxamide; and

2-(3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)-N-(2-methoxyethyl)nicotinamide; and/or at least one pharmaceutically acceptable salt thereof.

[066] Also provided is a chemical process for preparing the compounds and pharmaceutically acceptable salts thereof described herein.

[067] In some embodiments, the process comprises coupling a compound of the following formula:

wherein B, R¹, and R² are as described herein with a compound of the formula

R³-(CR^aR^b)_n-C(0)-L

in which L is a leaving group and R³, R^a, R^b, and n are as described herein.

[068] In some embodiments, the process comprises coupling a compound of the following formula:

wherein A is -(CR^aR^b)_n and B, R¹, and R² are as described with a compound of the formula:

L-X^x-R³

wherein L is a leaving group, X¹ is chosen from (CR^a R^b )_m wherein m is 0, SO, S0₂, or CO, and R is NR^c2R^d2, Ci-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of Ci-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted wherein R^a , R^b , R^c2, and R^d2 are as described herein.

[069] In some embodiments, the process comprises coupling a compound of the following formula:

wherein L is a leaving group, A is optionally substituted heteroaryl, and B, R¹, and R² are as described herein with a compound of the following formula

H-R 3c

wherein R^3c is OC(0)R^a2, OR^b2, SR^b2, S0₂R^b2NR^c2R^d2, NR^c2C(0)R^a2, NR^c2C(0)C(0)OR^a2,

NR^c2S(0)₂R^b2, Ci-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of Ci-i₀ alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted wherein R^a2, R^b2, R^c2, and R^d2 are as described herein..

[070] After each coupling described above, in some embodiments, the process further comprises forming a pharmaceutically acceptable salt or solvate of the compound of Formula I obtained.

[071] The compounds thus obtained can be further modified at their peripheral positions to provide the desired compounds. Synthetic chemistry transformations are described, for example, in R.

Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons

(1994) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons

(1995) and subsequent editions thereof.

[072] In some embodiments, the at least one compound and/or at least one pharmaceutically acceptable salt described herein, are purified by column chromatography, high performance liquid chromatography, crystallization, or other suitable methods.

[073] Also provided is a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described herein, and at least one pharmaceutically acceptable carrier.

[074] A composition described herein, can be administered in various known manners, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. [075] An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added to tablets. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

[076] A sterile injectable composition (e.g., aqueous or oleaginous suspension) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.

[077] An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

[078] A topical composition can be formulated in form of oil, cream, lotion, ointment and the like. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers can be found in U.S. Patents 3,989,816 and 4,444,762. [079] Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. An example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. An example of such an ointment is one which includes about 30% by weight almond and about 70% by weight white soft paraffin.

[080] A pharmaceutically acceptable carrier refers to a carrier that is compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which form specific, more soluble complexes with the at least one compound and/or at least one pharmaceutically acceptable salt described herein), can be utilized as

pharmaceutical excipients for delivery of the active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, lactose, sodium lauryl sulfate, and pigments such as D&C Yellow # 10.

[081] Also provided is a method of inhibiting the activity of at least one protein chosen from TNFa, IL-1 β, NF-KB, IL-10 and iNOS. The method comprises contacting the at least one protein with an effective amount of at least one compound and/or at least one pharmaceutically acceptable salt thereof for inhibiting said activity of the of at least one protein chosen from TNFa, IL-1 β, NF-κΒ, IL-10 and iNOS.

[082] Also provided is a method of decreasing a level of a cytokine (e.g., TNFa, IL-1 β or IL-10), e.g., by inhibiting the production of the cytokine in a subject. The method comprises administering to a subject in need thereof an effective amount for decreasing said level of at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof. A subject refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[083] Also provided is a method of treating a disorder mediated by an overproduction of a cytokine (e.g., TNFa, IL-1 β or IL-10), such as, an inflammatory disease, an autoimmune disease, cancer, diabetes, allergy or atherosclerosis. Nonlimiting examples of disorders mediated by an

overproduction of a cytokine include inflammatory arthritis such as rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), bronchitis (including chronic bronchitis), liver inflammation, renal inflammation, airway inflammation, cystic fibrosis, asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), emphysema, rhinitis, septic shock, chronic heart failure, macular degeneration,

arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, systemic lupus

erythematosus, polymyositis/dermatomyositis, psoriasis, acute myelogenous leukemia, AIDS dementia complex, hematosepsis, rejection of a transplanted graft, graft-versus-host disease, uveitis, acute pancreatitis, allergy, atherosclerosis, Alzheimer's disease, inflammatory demyelinating disease such as multiple sclerosis, and periodontal disease. The method comprises administering to a subject in need thereof an effective amount for treating said disorder of at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof.

[084] The at least one compound and/or at least one pharmaceutically acceptable salt described herein can also be used to achieve a beneficial therapeutic effect, for example, in subjects with cancer. As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and bloodborne tumors. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary and metastatic cancers.

[085] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen- dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including e.g., malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid carcinoma.

[086] Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia;

myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.

[087] In some embodiments, the examples of the cancer to be treated include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, bone cancer, and leukemia.

[088] In some embodiments, the at least one compound and/or at least one pharmaceutically acceptable salt described herein, is administered in conjunction with another therapeutic agent. In some embodiments, the other therapeutic agent is one that is normally administered to patients with the disease or condition being treated. For example, the other therapeutic agent may be an antiinflammatory agents, an anti-diabetes drug, or an anti-cancer agent, depending on the disease or condition being treated. The at least one compound and/or at least one pharmaceutically acceptable salt described herein, may be administered with the other therapeutic agent in a single dosage form or as a separate dosage form. When administered as a separate dosage form, the other therapeutic agent may be administered prior to, at the same time as, or following administration of the at least one compound and/or at least one pharmaceutically acceptable salt described herein.

[089] Nonlimiting examples of anti-inflammatory agents include corticosteroids (e.g., fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide), disease-modifying agents (e.g., antimalarials, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, metronidazole, injectable and oral gold, or D-penicillamine), nonsteroidal antiinflammatory drugs (e.g., acetominophen, aspirin, sodium salicylate, sodium

cromoglycate, magnesium salicylate, choline magnesium salicylate, salicylsalicylic acid, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, fluriprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamate, meclofenamate sodium, mefenamic acid, nabumetone, oxaprozin, phenyl butyl nitrone (PBN), sulindac, or tolmetin), COX-2 inhibitors, inhibitors of cytokine synthesis/release (e.g., anti-cytokine antibodies, anti-cytokine receptor antibodies, and the like). [090] Nonlimiting examples of anti-diabetes agents include free pancreatic islets, encapsulated pancreatic islets, oral insulin, intravenous insulin, amylin hormone, dihydropyridine calcium channel blockers (e.g., nifedipine, nitrendipine, nisoldipine, and the like), acetohexamide, chlorpropamide, glyburide, glipizide, metformin, tolbutamide, tolazamide, and the like.

[091] Nonlimiting examples of anti-cancer agents include: radiotherapy; immunotherapy; DNA damaging chemotherapeutic agents; and chemotherapeutic agents that disrupt cell replication.

[092] Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

[093] Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-kappa B inhibitors, including inhibitors of I kappa B kinase;

antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.

[094] Suitable in vitro assays can be used to preliminarily evaluate the efficacy of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein, in inhibiting the activity of at least one protein chosen from TNFa, IL-1 β, NF-κΒ, IL-10 and iNOS, or decreasing the level of a cytokine (e.g., TNFa, IL-1 β or IL-10). Compounds that demonstrate activity in the preliminary screening can further be screened by in vivo assays. For example, a test compound can be administered to an animal (e.g., a mouse model) and its effects in inhibiting the activity of at least one protein chosen from TNFa, IL-Ι β, NF-κΒ, IL-10 and iNOS, or in decreasing the level of a cytokine, can be assessed. [095] The at least one compound and/or at least one pharmaceutically acceptable salt described herein, can further be examined by in vivo assays for efficacy in treating a disorder mediated by overproduction of at least one cytokine (e.g., TNFa, IL-1 β or IL-10). For example, the compounds described herein, and/or the pharmaceutically acceptable salts thereof, can be administered to an animal (e.g., a mouse model) having such an disorder and its therapeutic effects can be accessed. Based on the results, an appropriate dosage range and administration route for animals, such as humans, can also be determined.

EXAMPLES

[096] Shown below are exemplary compounds, compounds 1-180.

31

32

Com ound 84 Compound 85 Compound 86 Compound 87

ompoun Compound 89 ompoun Compound 91

Compound 92 Compound 93 Compound 94

Compound 95 Compound 96 Compound 97

Compound 104 Compound 105 Compound 106

Compound 117 Compound 118

Compound 120 Compound 121

Compound 122

Compound 129

Compound 131 Compound 132 Compound 133

Compound 134 Compound 135 Compound 136

Compound 137 Compound 138 Compound 139

Compound 140 Compound 141

Compound 143 Compound 144

Compound 148

Compound 151

Compound 154

Compound 155 Compound 156 Compound 157

Compound 158 Compound 159

Compound 162 Compound 163

Compound 167 Compound 168 Compound 169

[097] Examples 1 -180 below provide detailed descriptions of how compounds 1 -180 were prepared.

[098] Compounds and pharmaceutically acceptable salts thereof described herein can be made according to the following examples. It will be understood by those skilled in the art that the following examples do not limit the invention. For example, it may be possible to alter exact solvents, conditions and reagents and quantities. The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data were determined using an Agilent 6120 or Agilent 1100. All reagents, except intermediates, are commercially available.

Example 1

[099] Compound 1 : 2-(3-(5-methyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine was prepared as outlined and described below.

[0100] 1 mmol 3-(2-bromoacetyl)benzonitrile and 1 mmol 6-chloropyridazin-3 -amine in EtOH were heated to reflux for 10 h, then cooled to room temperature. The orange-red precipitate was collected by filtration, washed with cold EtOH, and air-dried to give 3-(6-chloroimidazo[l,2-b]pyridazin-2- yl)benzonitrile.

[0101] 10% Pd/C was added to the solution of 3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)benzonitrile (50 mg, 0.2 mmol) in THF/MeOH. The reaction mixture was stirred vigorously at room temperature for 5 h under hydrogen and the Pd-C was then removed. The filtrate was concentrated in vacuo to give 3-(imidazo[l,2-b]pyridazin-2-yl)benzonitrile as a yellow-white solid.

[0102] A mixture of 0.5 mmol 3-(imidazo[l,2-b]pyridazin-2-yl)benzonitrile, 1 mmol NH₂OH.HCl and 1 mmol EtsN in EtOH was stirred at reflux for 4 h then cooled. Excess solvent was removed in vacuo to afford the crude product. Acetic anhydride (2 mmol) was added to the mixture solution of the crude product, THF, and DMAP (cat.) at room temperature and then the mixture was heated to and stirred at 100 C for 24 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give 2-(3-(5-methyl-l ,2,4-oxadiazol-3- yl)phenyl)imidazo[l,2-b]pyridazine. MS (m/e): 278.4 (M+l).

Example 2 [0103] Compound 2: l-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(2-morpholinoethyl)urea was prepared as outlined and described below.

[0104] Raney-Ni (cat.) and NH₃.H₂0 (4-5 drops) were added to the solution of 3-(imidazo[l,2- b]pyridazin-2-yl)benzonitrile (25 mg) in MeOH. The mixture was stirred vigorously at room temperature for 1 h under hydrogen and the Raney-Ni was then removed. The filtrate was concentrated in vacuo to give (3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)methanamine.

[0105] 0.2 mmol (3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)methanamine and 1 mmol K2CO3 in dry Toluene were stirred for 30 min at 30 C, added with CDI (0.2 mmol), and stirred again for 2 h. Then 0.2 mmol

and DMAP (cat.) were added and the solution was heated to 60 C with stirring for 2 h. The reaction was concentrated in vacuo and the residue was purified by column chromatography on silica gel to give l-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-(2- morpholinoethyl)urea. MS (m/e): 381.4 (M+l).

Example 3

[0106] Compound 3: l-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(2-methoxyethyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 326.3 (M+l).

Example 4

[0107] Compound 4: N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl)- 2-methoxyethanamine was prepared as outlined and described below.

[0108] A mixture of 0.5 mmol 3-(imidazo[l,2-b]pyridazin-2-yl)benzonitrile, 1 mmol NH2OH.HCI and 1 mmol Et₃N in EtOH were stirred at reflux for 4 h then cooled. Excess solvent was removed in vacuo to afford the crude product. 2-chloroacetyl chloride (2 mmol) was added to the mixture solution of the crude product in Toluene at room temperature and then the mixture was heated to reflux for 24 h. The solution was washed with NH4C1 solution, dried (MgS04), filtered, and concentrated to give the intermediate. Then the intermediate was added to Toluene and the mixture was heated to reflux for 2h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give 2-(3 -(5 -(chloro methyl)- l,2,4-oxadiazol-3- yl)phenyl)imidazo[l,2-b]pyridazine.

[0109] A mixture of 2-(3-(5-(chloromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2- b]pyridazine(1.5mmol), sodium iodide(cat) and 2-methoxyethanamine(3mmol) in EtOH were stirred under reflux for 2h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give N-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl)phen l)-l,2,4-oxadiazol-5-yl)methyl)-2-methoxyethanamine. MS (m/e): 351.4 (M+l).

Example 5

[0110] Compound 5: N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl)- 2-morpholinoethanamine was prepared in a manner similar to that described in Example 4. MS (m/e): 406.4 (M+l).

Example 6

[0111] Compound 6: 2-(3-(5-(mo holinomethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 363.4 (M+l).

Example 7

[0112] Compound 7: (3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)-N,N- dimethylmethanamine was prepared in a manner similar to that described in Example 4. [0113] MS (m/e): 321.3 (M+1).

Example 8

[0114] Compound 8: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)aminoethanol was prepared in a manner similar to that described in Example 4. MS (m/e): 337.3 (M+1 ).

Example 9

[0115] Compound 9: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)ethanamine was prepared in a manner similar to that described in Example 4. MS (m/e): 321.3 (M+1 ).

Example 10

[0116] Compound 10: 2-(3-(5-((4-fluorophenoxy)methyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 388.3 (M+1).

Example 11

[0117] Compound 11 : 2-(3-(5-(ethoxymethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 322.3 (M+1).

Example 12

[0118] Compound 12 2-(3-(5-(methoxymethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 308.4 (M+1).

Example 13

[0119] Compound 13 2-(3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 1. MS (m/e): 332.2 (M+1).

Example 14

[0120] Compound 14: (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl acetate was prepared in a manner similar to that described in Example 4. MS (m/e): 336.3 (M+1). Example 15 [0121] Compound 15 : 2-(3-(5-isopropyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1. MS (m/e): 306.3 (M+l).

Example 16

[0122] Compound 16: (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methanol was prepared in a manner similar to that described in Example 4. MS (m/e): 294.2 (M+l ).

Example 17

[0123] Compound 17: 2-(3-(5-cyclopropyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1. MS (m/e): 304.3 (M+l ).

Example 18

[0124] Compound 18: 2-(3-(5-(fluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 296.2 (M+l).

Example 19

[0125] Compound 19: 2-(3-(5-ethyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1. MS (m/e): 292.3 (M+l).

Example 20

[0126] Compound 20: N-methyl-2-(3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3- yl)phen l)imidazo[l ,2-b]pyridazin-6-amine was prepared as outlined and described below.

[0127] A mixture of 3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)benzonitrile (0.25mmol) and l OmL methylamine methanol solution was heated at 125°C in microwave synthesizer for 30min, and then purified to provide 3-(6-(methylamino)imidazo[l ,2-b]pyridazin-2-yl)benzonitrile. [0128] A mixture of 0.2mmol 3-(6-(methylamino)imidazo[l,2-b]pyridazin-2-yl)benzonitrile, 0.8 mmol NH₂OH.HCl and EtsN in EtOH was stirred at reflux for 4 h then cooled. Excess solvent was removed in vacuo to afford the crude product. Trifluoroacetic anhydride (2 mmol) was added to the mixture solution of the crude product, THF, and DMAP (cat.) at room temperature and then the mixture was heated to reflux for 12 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give 2,2,2-trifluoro-N-methyl-N-(2-(3-(5- (trifluoromethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazin-6-yl)acetamide.

[0129] A mixture of 2,2,2-trifluoro-N-methyl-N-(2-(3-(5-(trifluoromethyl)-l,2,4-oxadiazol-3- yl)phenyl)imidazo[l,2-b]pyridazin-6-yl)acetamide (0.15mmol) and K2CO3 (0.3mmol) in 20mL methanol -water(4:l) was heated at 60°C for lh. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give N-methyl-2-(3-(5- (trifluoromethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazin-6-amine. MS (m/e): 360.92 (M+1).

Example 21

[0130] Compound 21 : ethyl 3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazole-5- carboxylate was prepared in a manner similar to that described in Example 1. MS (m/e): 336.0 (M+1).

Example 22

[0131] Compound 22: ethyl 2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)acetate was prepared in a manner similar to that described in Example 1. MS (m/e): 350.0 (M+1). Example 23

[0132] Compound 23 : 3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazole-5-carboxylic acid was prepared in a manner similar to that described in Example 1. MS (m/e): 307.8 (M+1). Example 24

[0133] Compound 24 3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 307.0 (M+1).

Example 25

[0134] Compound 25: 2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)acetic acid was prepared in a manner similar to that described in Example 1. MS (m/e): 321.8 (M+1). Example 26 [0135] Compound 26: 2-(3-(5-(methylthiomethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 323.8 (M+l).

Example 27

[0136] Compound 27: 2-(3-(5-(methylsulfonylmethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e): 355.9 (M+l).

Example 28

[0137] Compound 28: (3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine was prepared as outlined and described below.

[0138] l -bromo-2-methoxyethane(5.0 mmol), dimethyl 5-hydroxyisophthalate(0.49 ml), and K₂CO₃ (2.5 mmol) in DMF(10 mL) were stirred for 12h at 60 C, then the solution was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (MgSC>4), filtered, and concentrated to give dimethyl 5-(2-methoxyethoxy)isophthalate.

[0139] NaOH(5.46 mmol) was added to the solution of dimethyl 5-(2-methoxyethoxy)isophthalate (4.55 mmol) in 20 ml MeOH and 5.5 ml H₂0 and stirred for 4h at 40 C. Excess solvent was removed in vacuo and the residue was treated with IN HC1 (aqueous) and extracted with EtOAc. The organic phase was washed with brine, dried (MgS0₄), filtered, and concentrated to afford 3- (methoxycarbonyl)-5 -(2-methoxyethoxy)benzoic acid.

[0140] 3-(methoxycarbonyl)-5-(2-methoxyethoxy)benzoic acid (4.36 mmol) in 12.5 mL SOCl₂ was stirred at reflux for 4h. Excess SOCl₂ was removed in vacuo and the residue was dissolved in THF. Ammonia hydrate solution was added and the mixture was stirred at room temperature for 2h. The solution was poured to the water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO^, filtered, and concentrated to provide methyl 3-carbamoyl-5-(2- methoxyethoxy)b enzoate .

[0141] POCI3 (1.42 mmol) was added to the solution of methyl 3-carbamoyl-5-(2- methoxyethoxy)b enzoate (1.38 mmol) in 14 ml 1 ,2-dichloroethane and stirred for 5h at reflux. Then the solution was cooled to room temperature, poured into ice-water and extracted with EtOAc. The combined organic phases were dried (MgS0₄), filtered, and concentrated to yield methyl 3-cyano-5- (2-methoxyethoxy)benzoate.

[0142] A solution of AlMe3 in hexane (2.05 mmol) was dropped into the solution of DMEDA (2.59 mmol) in 20 ml dry toluene slowly at 0 C under N₂. The solution continued to be stirred at room temperature for another lh and then was added methyl 3-cyano-5-(2-methoxyethoxy)benzoate (1.87 mmol) and stirred at reflux for 8 h. The mixture was poured into water and extracted with EtOAc. The combined organic phases were dried (MgS0₄), filtered, and concentrated to give 3-acetyl-5-(2- methoxyethoxy)benzonitrile.

[0143] Br₂ (18.5 mmol) was dropped into the solution of 3-acetyl-5-(2-methoxyethoxy)benzonitrile (17.6 mmol) in 150 ml ether at 0 C, and stirred at room temperature for 5 h. The solution was washed with brine, dried (MgS04), filtered, and concentrated to afford 3-(2-bromoacetyl)-5-(2- methoxyethoxy)benzonitrile.

[0144] 3-(2-bromoacetyl)-5-(2-methoxyethoxy)benzonitrile (4.36 mmol) and 6-chloropyridazin-3- amine (5.14 mmol) in 40 ml EtOH were stirred at reflux for 5h, then cooled, and filtered. The filter cake was 3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile. [0145] 3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile (2.17 mmol) in 20 ml MeOH was added Pd/C and stirred at room temperature for 4h. Pd-C was removed and the filtrate was concentrated to provide 3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)benzonitrile.

[0146] 3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile (0.61 mmol) in 40ml MeOH was added Raney-Ni and 2 ml ammonia hydrate solution and stirred at room temperature for 3 h under hydrogen. Raney-Ni was removed and the filtrate was concentrated to yield (3- (imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine. MS (m/e): 299.7 (M+l ). Example 29

[0147] Compound 29: 2-(3-(2-methoxyethoxy)-5-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3- yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 406.2 (M+l).

Example 30

[0148] Compound 30: 2-(3-(2-methoxyethoxy)-5-(5-methyl-l ,2,4-oxadiazol-3- yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 352.2 (M+l).

Example 31

[0149] Compound 31 : 2-(3-(5-(fluoromethyl)-l ,2,4-oxadiazol-3-yl)-5-(2- methoxyethoxy)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 370.9 (M+l ).

Example 32

[0150] Compound 32: 2-(3-(2-methoxyethoxy)-5-(5-(methoxymethyl)-l ,2,4-oxadiazol-3- yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 382.2 (M+l).

Example 33

[0151] Compound 33 : 2-(3-(5-(ethoxymethyl)-l ,2,4-oxadiazol-3-yl)-5-(2- methoxyethoxy)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 396.4 (M+l ).

Example 34 [0152] Compound 34: (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazol-5-yl)methanol was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 368.3 (M+l).

Example 35

[0153] Compound 35 : 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazole-5-carboxylic acid was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 382.3 (M+l).

Example 36

Compound 36: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4-oxadiazole- 5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 381.3 (M+l).

Example 37

Compound 37: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin-2-yl)- l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 458.4 (M+l).

Example 38

Compound 38: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2,2,2- trifluoroethyl)-l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 463.2 (M+l).

Example 39

Compound 39: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)acetamide was prepared in a manner similar to that described in Example 28. MS (m/e): 341.4 (M+l ).

Example 40

[0154] Compound 40: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2,2,2- trifluoroacetamide was prepared in a manner similar to that described in Example 28. MS (m/e): 395.3 (M+l ).

Example 41

[0155] Compound 41 : N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2- chloroacetamide was prepared in a manner similar to that described in Example 28. MS (m/e): 375.2 (M+l).

Example 42 [0156] Compound 42: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- chlorobenzamide was prepared in a manner similar to that described in Example 28. MS (m/e):

438.2 (M+l ).

Example 43

[0157] Compound 43 : N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- nitrobenzenesulfonamide was prepared in a manner similar to that described in Example 28. MS (m/e): 484.3 (M+l).

Example 44

[0158] Compound 44: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- cyanobenzamide was prepared in a manner similar to that described in Example 28. MS (m/e) : 428.4 (M+l ).

Example 45

[0159] Compound 45 : N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- bromobenzamide was prepared in a manner similar to that described in Example 28. MS (m/e):

482.3 (M+l ).

Example 46

[0160] Compound 46: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 28. MS (m/e): 457.3 (M+l).

Example 47

[0161] Compound 47: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- chlorobenzenesulfonamide was prepared in a manner similar to that described in Example 28. MS (m/e): 473.9 (M+l).

Example 48

[0162] Compound 48: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- methylbenzenesulfonamide was prepared in a manner similar to that described in Example 28. MS (m/e): 453.4 (M+l).

Example 49

[0163] Compound 49: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2- fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 28. MS (m/e): 457.4 (M+l). Example 50

[0164] Compound 50: N-(2-(diethylamino)ethyl)-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)- l ,2,4-oxadiazol-5-yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 420.3 (M+l).

Example 51

[0165] Compound 51 : N-butyl-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 377.3 (M+l).

Example 52

[0166] Compound 52: 2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)-N-(((S)- tetrahydrofuran-2-yl)methyl)acetamide was prepared in a manner similar to that described in

Example 1. MS (m/e): 350.2 (M+l).

Example 53

[0167] Compound 53 : N-cyclopentyl-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5-yl)acetamide was prepared in a manner similar to that described in Example 1.

[0168] MS (m/e): 389.3 (M+l).

Example 54

[0169] Compound 54: 2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)-N-(2- methoxyethyl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 379.2 (M+l ).

Example 55

[0170] Compound 55 : 2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)-l - morpholinoethan-1 -one was prepared in a manner similar to that described in Example 1. MS (m/e): 391.4 (M+l ).

Example 56

[0171] Compound 56: N-cyclopropyl-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5-yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 361.2 (M+l).

Example 57 [0172] Compound 57: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-N-(2-morpholinoethyl)-l ,2,4- oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 420 (M+l).

Example 58

[0173] Compound 58: N-ethyl-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5- carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 335.3 (M+l).

Example 59

[0174] Compound 59: N-cyclopentyl-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole- 5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 375.4 (M+l).

Example 60

[0175] Compound 60: (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)(morpholino)methanone was prepared in a manner similar to that described in Example 1. MS (m/e): 377.3 (M+l).

Example 61

[0176] Compound 61 : 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-N-(2-methoxyethyl)-l ,2,4- oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 365.3 (M+l).

Example 62

[0177] Compound 62: N-(2-(dimethylamino)ethyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 378.4 (M+l).

Example 63

[0178] Compound 63 : (4-ethylpiperazin-l -yl)(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5-yl)methanone was prepared in a manner similar to that described in Example 1. MS (m/e): 404.4 (M+l).

Example 64

[0179] Compound 64: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-N-(thiophen-2-ylmethyl)-l ,2,4- oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 403.4 (M+l). Example 65

[0180] Compound 65 : N-(2-hydroxyethyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 351.3 (M+l).

Example 66

[0181] Compound 66: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-N,N-dimethyl-l ,2,4-oxadiazole- 5-carboxamide can be prepared in a manner similar to that described in Example 1. MS (m/e): 335.3 (M+l).

Example 67

[0182] Compound 67: (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)(pyrrolidin-l -yl)methanone was prepared in a manner similar to that described in Example 1. MS (m/e): 361.1 (M+l).

Example 68

[0183] Compound 68: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-N-methyl-l ,2,4-oxadiazole-5- carboxamide was prepared in a manner similar to that described in Example 1. MS (m/e): 321.3 (M+l).

Example 69

[0184] Compound 69: 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)nicotinamide was prepared as outlined and described below.

[0185] Br₂ (l ml) was dropwise added to a solution of 3-acetylbenzonitrile (2.9 g) in Et₂0 (100 ml) at 0 ^°C , and then the mixture was stirred at room temparature for 4 h. Water was added, and then the mixture was extracted with EtOAc. The organic layer was dried over Na₂S0₄, and concentrated to give an oil, i.e., 3-(2-bromoacetyl)benzonitrile, which was directly used for the next step without purification.

[0186] A solution of 3-(2-bromoacetyl)benzonitrile and 6-chloropyridazin-3 -amine (2.6 g) in 100 ml

EtOH was heated to reflux overnight. Then the mixture was cooled to room temperature, and the precipitate was filtered to give 3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)benzonitrile.

[0187] A mixture of 3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)benzonitrile (1 g) and Pd/C (500 mg) in THF (200 ml) was stirred at room temparature for 6 h equipped with a H₂ balloon. Then the solvent was removed under reduced pressure and 3-(imidazo[l ,2-b]pyridazin-2-yl)benzonitrile was obtained.

[0188] A solution of 3-(imidazo[l ,2-b]pyridazin-2-yl)benzonitrile (3.16 g) and 6M NaOH

(20 ml) in 40 ml EtOH was heated to reflux for 2 h. Then the mixture was diluted with water and acidified with HCl. The precipitate was filtered to give 3-(imidazo[l ,2-b]pyridazin-2-yl)benzoic acid.

[0189] A solution of 3-(imidazo[l ,2-b]pyridazin-2-yl)benzoic acid (180 mg), DPPA (195 μ 1) and Et₃N (125 μ 1) in 20 ml toluene was heated to reflux for 4 h. Then t-BuOH (0.5 ml) was added and reflux was continued overnight. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with diluted HCl, brine and NaHC0₃ (aq), and was concentrated to give a solid. After purification by chromatography, tert-butyl 3-(imidazo[l ,2-b]pyridazin-2- yl)phenylcarbamate was obtained.

[0190] A solution of tert-butyl 3-(imidazo[l ,2-b]pyridazin-2-yl)phenylcarbamate (90 mg) and TFA (50 μ 1) in CH₂C1₂ (20 ml) was stirred at 35 ^°C overnight. Then NaOH solution was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give 3-(imidazo[l ,2- b]pyridazin-2-yl)aniline.

[0191] TsOH (9 mg) was added to a solution of 3-(imidazo[l ,2-b]pyridazin-2-yl)aniline (10 mg) and 2-chloronicotinamide (9 mg) in 3 ml C4H9OH. The mixture was stirred at 160 °C for 20

hours. Then water was added, and the reaction solution was extracted with EtOAc. The organic layer was washed with brine and solvent was removed. 2-(3-(imidazo[l ,2-b]pyridazin-2- yl)phenylamino)nicotinamide was purified by TLC. MS (m/e): 331.3 (M+l ). Example 70

[0192] Compound 70: (2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)pyridin-3-yl)(pyrrolidin-l - yl)methanone was prepared in a manner similar to that described in Example 69. MS (m/e): 385.4 (M+l).

Example 71

[0193] Compound 71 : N-(2-hydroxyethyl)-2-(3-(imidazo[l ,2-b]pyridazin-2- yl)phenylamino)nicotinamide was prepared in a manner similar to that described in Example 69. MS (m/e): 375.4 (M+l).

Example 72

[0194] Compound 72: ethyl 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)nicotinate was prepared in a manner similar to that described in Example 69. MS (m/e): 360.3 (M+l).

Example 73

[0195] Compound 73 : N-cyclopropyl-2-(3-(imidazo[l ,2-b]pyridazin-2- yl)phenylamino)nicotinamide was prepared in a manner similar to that described in Example 69. MS (m/e): 371.4 (M+l).

Example 74

[0196] Compound 74: (2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)pyridin-3- yl)(morpholino)methanone was prepared in a manner similar to that described in Example 69. MS (m/e): 401.4 (M+l).

Example 75

[0197] Compound 75 : N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(5-(mo holinomethyl)-l ,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide was prepared as outlined and described below.

[0198] A mixture of 3-methoxycarbonyl-5-nitrobenzoic acid (44.4 mmol), SOCl₂ (40 mL) and DMF (1 mL) was heated to reflux for 2 hours. Then the excessive SOCl₂ was removed under reduced pressure. The residue was dissolved in DCM (80 mL), and after cooling by ice-water, NH3.H20 (15 mL) was added dropwise. After addition, it continued to be stirred for 5 min. The resulting mixture was filtrated to give methyl-3-carbamoyl-5-nitrobenzoate.

[0199] POCI3 (27 mmol) was added to the solution of methyl-3-carbamoyl-5-nitrobenzoate (27 mmol) in 1 ,2-dichloroethane (80 mL). Then the solution was heated to reflux for 3 hours. After cooling, it was poured into water. The organic layer was washed with saturated NaHCC solution and brine sequentially, dried over anhydrous Na₂S04, and concentrated to give methyl-3-cyano-5- nitrobenoate.

[0200] 10 Pd/C (0.293 g) was added to the solution of methyl-3-cyano-5-nitrobenoate (9.4 mmol) in MeOH (150 mL) and THF (50 mL). Then the solution was stirred at room temperature for 3 hours. After filtration, it was concentrated to give methyl-3-amine-5- cyanobenoate.

[0201] CH₃S0₂C1 (36.8 mmol) was added to the solution of methyl-3-amine-5-cyanobenoate (9.2 mmol), pryridine (46 mmol) and DMAP (1.36 mmol) in DCM (150 mL). The solution was then heated to reflux for 1.5 hours. After cooling, diluted hydrochloric acid was poured into the solution. The organic layer was washed with water and brine sequentially, dried over anhydrous Na₂SC>4, and concentrated. The crude product was purified by column chromatography to afford methyl-3-cyano- 5 -(methylsulfonamido)benoate.

[0202] A1(CH₃)₃ (9.8 mmol) was added dropwise under nitrogen to a solution of DMEDA (2.16 mmol) in dry toluene (40 mL) which was cooled with ice-water. Stirring was continued for 2 hours at room temperature. Then, methyl-3-cyano-5-(methylsulfonamido)benzoate (1. 96 mmol) was added, and the reaction mixture was heated to reflux overnight. After cooling, it was poured into diluted hydrochloric acid, and the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine sequentially, dried over anhydrous Na₂SC>4, and concentrated to afford N-(3-acetyl-5-cyanophenyl)methanesulfonamide.

[0203] Br₂ (0.6 mmol) was added dropwise to the solution of N-(3-acetyl-5- cyanophenyl)methanesulfonamide (0.5 mmol) in Et₂0 (50 mL). After addition, it continued to be stirred for 1.5 hours. Then the reaction mixture was washed with water and brine sequentially, dried over anhydrous Na₂S0₄, and concentrated to afford N-(3-(2-bromoacetyl)-5- cyanopheny l)methanesulfonamide .

[0204] A mixture of N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide (0.53 mmol) and 6- chloropyridazin-3-amine (0.53 mmol) in EtOH (7 mL) was refluxed for 3.5 hours. After cooling, the resulting mixture was filtrated to give N-(3-(6-chloroimidazo[l,2-b]pyridazin-2-yl)-5- cyanopheny l)methanesulfonamide .

[0205] 10% Pd/C (9 mg) was added to the solution of N-(3-(6-chloroimidazo[l ,2-b]pyridazin-2-yl)- 5-cyanophenyl)methanesulfonamide (0.15 mmol) in THF (20 mL). Then the mixture was stirred at room temperature for 6 hours. After filtration, it was concentrated to give N-(3-cyano-5- (imidazo[l,2-b]pyridazin-2-yl)phenyl)methanesulfonamide.

[0206] A mixture of N-(3-cyano-5-(imidazo[l,2-b]pyridazin-2-yl)phenyl)methanesulfonamide (0.24 mmol), hydroxylamine hydrochloride (0.72 mmol), and triethylamine (0.96 mmol) in EtOH (12 mL) was refluxed for 4 hours. After removal of the solvent in vacuo, the residue was dissolved in THF (12 mL). (C1CH₂C0)₂0 (0.72 mmol) and triethylamine (0.96 mmol) were added to the solution. The mixture was stirred at room temperature for 1 hours, and then heated to reflux for 8 hours. After removal of the solvent in vacuo and addition of water, the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine sequentially, dried over anhydrous Na₂SC>4 and concentrated. The resulting residue was purified by column chromatography to give N-(3-(5- (chloromethyl)- 1 ,2,4-oxadiazol-3 -yl)-5 -(imidazo[ 1 ,2-b]pyridazin-2-yl)phenyl)methanesulfonamide. [0207] A mixture of N-(3-(5-(chloromethyl)-l ,2,4-oxadiazol-3-yl)-5-(imidazo[l ,2-b]pyridazin-2- yl)phenyl)methanesulfonamide (0.086 mmol), morpholine (0.346 mmol) and K2CO3 (0.173 mmol) in DMF (4 mL) was stirred at 80°C for 1.5 hours. After cooling, it was poured into water and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated. The resulting residue was purified by column chromatography to give the title product. MS (m/e): 456.3 (M+l).

Example 76

[0208] Compound 76: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(5-(piperidin-l -ylmethyl)-l ,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide was prepared in a manner similar to that described in Example 75. MS (m/e): 454.3 (M+l).

Example 77

[0209] Compound 77: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(5-((2-methoxyethylamino)methyl)- l ,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide was prepared in a manner similar to that described in Example 75. MS (m/e): 444.3 (M+l).

Example 78

[0210] Compound 78: N-(3-(5-((2-(dimethylamino)ethylamino)methyl)-l ,2,4-oxadiazol-3-yl)-5- (imidazo[l ,2-b]pyridazin-2-yl)phenyl)methanesulfonamide was prepared in a manner similar to that described in Example 75. MS (m/e): 457.3 (M+l ).

Example 79

[0211] Compound 79: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(5-(piperazin-l -ylmethyl)-l ,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide was prepared in a manner similar to that described in Example 75. MS (m/e): 455.3 (M+l).

Example 80

[0212] Compound 80: N-(3-(5-(aminomethyl)-l ,2,4-oxadiazol-3-yl)-5-(imidazo[l ,2-b]pyridazin-2- yl)phenyl)methanesulfonamide was prepared in a manner similar to that described in Example 75. MS (m/e): 386.3 (M+l).

Example 81

[0213] Compound 81 : 2-(3-(5-(piperazin-l -ylmethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine was prepared in a manner similar to that described in Example 4. MS (m/e):

361.9(M+1)

Example 82 [0214] Compound 82: Nl -((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)ethane-l ,2-diamine was prepared in a manner similar to that described in Example 4. MS (m/e): 336.2 (M+l).

Example 83

[0215] Compound 83 : Nl -((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)-N2,N2-dimethylethane-l ,2-diamine was prepared in a manner similar to that described in Example 4. MS (m/e): 364.2 (M+l).

Example 84

[0216] Compound 84: 2-(3-(5-(morpholinomethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine hydrochloride was prepared in a manner similar to that described in Example 4. MS (m/e): 363.2 (M+l).

Example 85

[0217] Compound 85 : 2,2,2-trifluoro-N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5-yl)methyl)acetamide was prepared in a manner similar to that described in Example 4. MS (m/e): 389.2 (M+l).

Example 86

[0218] Compound 86: ethyl 2-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl) phenyl)-l ,2,4-oxadiazol-5- yl)methyl- amino)-2-oxoacetate was prepared in a manner similar to that described in Example 4. MS (m/e): 393.2 (M+l).

Example 87

[0219] Compound 87: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)- phenyl)-l ,2,4-oxadiazol-5- yl)methyl)-2-methoxyacetamide was prepared in a manner similar to that described in Example 4. MS (m/e): 365.2 (M+l).

Example 88

[0220] Compound 88: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-phenyl)-l ,2,4-oxadiazol-5- yl)methyl)cyclopentanecarboxamide was prepared in a manner similar to that described in Example 4. MS (m/e): 389.2 (M+l).

Example 89

[0221] Comopound 89: ethyl 3-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl) phenyl)- l ,2,4-oxadiazol-5 - yl)methyl- amino)-3-oxopropanoate was prepared in a manner similar to that described in Example 4. MS (m/e): 407.2 (M+l). Example 90

[0222] Compound 90: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-phenyl)-l ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide was prepared in a manner similar to that described in Example 4. MS (ro/e):361.2 (M+l).

Example 91

[0223] Compound 91 : N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5- yl)methyl)isobutyramide was prepared in a manner similar to that described in Example 4. MS (m/e): 363.2 (M+l ).

Example 92

[0224] Compound 92: 3-((3-(imidazo[l ,2-b]pyridazin-2-yl)benzylamino)methyl)benzonitrile was prepared in a manner similar to that described in Example 2. MS (m/e): 340 (M+l).

Example 93

[0225] Compound 93 : N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-4-chlorobenzamide was prepared in a manner similar to that described in Example 2. MS (m/e): 363 (M+l).

Example 94

[0226] Compound 94: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-2-methoxyacetamide was prepared in a manner similar to that described in Example 2. MS (m/e): 297 (M+l).

Example 95

[0227] Compound 95 : N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-cyanobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 390 (M+l ).

Example 96

[0228] Compound 96: l -(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(thiophen-2-ylmethyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 364 (M+l).

Example 97

[0229] Compound 97: 3-bromo-N-((3-(2-methylimidazo[2,l -b]thiazol-6- yl)phenyl)methyl)benzamide was prepared in a manner similar to that described in Example 2. MS (m/e): 427 (M+l).

Example 98

[0230] Compound 98: 4-chloro-N-((3-(2-methylimidazo[2,l -b]thiazol-6- yl)phenyl)methyl)benzamide was prepared in a manner similar to that described in Example 2. MS (m/e): 383 (M+l). Example 99

[0231] Compound 99: N-((3-(2-methylimidazo[2,l -b]thiazol-6-yl)phenyl)methyl)butyramide was prepared in a manner similar to that described in Example 2. MS (m/e): 314 (M+l).

Example 100

[0232] Compound 100: N-((3-(2-methylimidazo[2,l -b]thiazol-6- yl)phenyl)methyl)cyclopropanecarboxamide was prepared in a manner similar to that described in Example 2. MS (m/e): 312 (M+l).

Example 101

[0233] Compound 101 : N-((3-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)(4-(methylsulfonyl)phenyl)methanamine was prepared in a manner similar to that described in Example 4. MS (m/e): 480 (M+l ).

Example 102

[0234] Compound 102: 2-methoxy-N-((3-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)phenyl)-l ,2,4- oxadiazol-5-yl)methyl)ethanamine was prepared in a manner similar to that described in Example 4. MS (m/e): 370 (M+l).

Example 103

[0235] Compound 103 : N-((3-(3-(imidazo[l ,2-a]pyridin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methyl)- 2-methoxyacetamide was prepared in a manner similar to that described in Example 2. MS (m/e): 296.3 (M+l ).

Example 104

[0236] Compound 104: ethyl 2-(3-(imidazo[l ,2-a]pyridin-2-yl)benzylamino)nicotinate was prepared in a manner similar to that described in Example 2. MS (m/e): 373.4 (M+l).

Example 105

[0237] Compound 105: l -(3-(imidazo[l ,2-a]pyridin-2-yl)benzyl)-3-(2-chloro-4-fluorophenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 395.8 (M+l ).

Example 106

[0238] Compound 106: l -(3-(imidazo[l ,2-a]pyridin-2-yl)benzyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 445.8 (M+l).

Example 107 [0239] Compound 107: N-(2-(dimethylamino)ethyl)-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)- l ,2,4-oxadiazol-5-yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 391.3 (M+1).

Example 108

[0240] Compound 108: 2-(3-(5-(methoxymethyl)-l ,2,4-oxadiazol-3-yl)phenyl)-imidazo[l ,2- a] pyridine was prepared in a manner similar to that described in Example 1. MS (m/e): 307 (M+1). Example 109

[0241] Compound 109 : 6-(3-(5-(methoxymethyl)-l ,2,4-oxadiazol-3-yl)phenyl)-2- methylimidazo[2,l -b]thiazole was prepared in a manner similar to that described in Example 1. MS (m/e): 327.3 (M+1).

Example 110

[0242] Compound 110: 2-methyl-6-(3-(5-methyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[2,l - b] thiazole was prepared in a manner similar to that described in Example 1. MS (m/e): 397.3 (M+1). Example 11 1

[0243] Compound 11 1 : 2-(3-(5-methyl-l ,2,4-oxadiazol-3-yl)phenyl)-imidazo[l ,2-a]pyridine was prepared in a manner similar to that described in Example 1. MS (m/e): 277 (M+1).

Example 112

[0244] Compound 112: 2-methyl-6-(3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3- yl)phenyl)imidazo[2,l -b]thiazole was prepared in a manner similar to that described in Example 1. MS (m/e): 351.3 (M+1).

Example 113

[0245] Compound 113 : (3-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl acetate was prepared in a manner similar to that described in Example 1. MS (m/e): 355.3 (M+1).

Example 114

[0246] Compound 114: 2-(3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)-imidazo[l ,2- a]pyridine was prepared in a manner similar to that described in Example 1. MS (m/e): 331.2 (M+1 ). Example 115

[0247] Compound 115: (3-(3-(imidazo[l ,2-a]pyridin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methanol was prepared in a manner similar to that described in Example 1.

Example 116 [0248] Compound 116: (3-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methanol was prepared in a manner similar to that described in Example 1. MS (m/e): 313.2 (M+l).

Example 117

[0249] Compound 117: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)propionamide was prepared in a manner similar to that described in Example 2. MS (m/e): 300.2 (M+l).

Example 118

[0250] Compound 118: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)ethanesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 336.2 (M+l).

Example 119

[0251] Compound 119: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3- fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 402.3 (M+l).

Example 120

[0252] Compound 120: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-nitrobenzamide was prepared in a manner similar to that described in Example 2. MS (m/e): 393.3 (M+l).

Example 121

[0253] Compound 121 : N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-2-methoxyacetamide was prepared in a manner similar to that described in Example 2. MS (m/e): 316 (M+l).

Example 122

[0254] Compound 122: 3-((3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzylamino)methyl)benzonitrile was prepared in a manner similar to that described in Example 2. MS (m/e): 359.3 (M+l ).

Example 123

[0255] Compound 123 : l -(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(3-chloro-4-fluorophenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 396.5 (M+l ).

Example 124

[0256] Compound 124: 3-cyano-N-((3-(2-methylimidazo[2,l -b]thiazol-6- yl)phenyl)methyl)benzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 409 (M+l).

Example 125 [0257] Compound 125: ethyl 4-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)ureido)piperidine-l - carboxylate was prepared in a manner similar to that described in Example 2. MS (m/e): 423.3 (M+l).

Example 126

[0258] Compound 126: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-4- methoxybenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 414.3 (M+l).

Example 127

[0259] Compound 127: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-4-cyanobenzamide was prepared in a manner similar to that described in Example 2. MS (m/e): 373.2 (M+l).

Example 128

[0260] Compound 128: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-4-methoxybenzamide was prepared in a manner similar to that described in Example 2. MS (m/e): 359.2 (M+l).

Example 129

[0261] Compound 129: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-bromobenzamide was prepared in a manner similar to that described in Example 2.

Example 130

[0262] Compound 130: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-chlorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 399.3 (M+l ).

Example 131

[0263] Compound 131 : (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methanamine hydrochloride was prepared in a manner similar to that described in Example 4. MS (ro/e):293.2 (M+l).

Example 132

[0264] Compound 132: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-4- fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 402.2 (M+l).

Example 133

[0265] Compound 133 : (3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazol-5-yl)methyl acetate was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 410.1 (M+l). Example 134

[0266] Compound 134: 2-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazol-5-yl)methyl)aminoethanol was prepared in a manner similar to that described in Example 4 and Example 28. MS (m/e): 411.2 (M+l).

Example 135

[0267] Compound 135: methyl 3-(imidazo[l ,2-b]pyridazin-2-yl)benzylcarbamate was prepared in a manner similar to that described in Example 2. MS (m/e):2&3.2 (M+l ).

Example 136

[0268] Compound 136: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-2-chlorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 399.4 (M+l ).

Example 137

[0269] Compound 137: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-2 -methylbenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 379.3 (M+l ).

Example 138

[0270] Compound 138: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-2-fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 383.3 (M+l ).

Example 139

[0271] Compound 139: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-2- chlorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 418.4 (M+l).

Example 140

[0272] Compound 140: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-2- methylbenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 398.3 (M+l).

Example 141

[0273] Compound 141 : N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3- chlorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 418.4 (M+l).

Example 142 [0274] Compound 142: N-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-2- fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 2. MS (m/e): 402.4 (M+l).

Example 143

[0275] Compound 143 : l -(3-(6-(methylamino)imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(2- methoxyethyl)urea was prepared in a manner similar to that described in Example 2 and Example 20. MS (m/e): 355.1 (M+l).

Example 144

[0276] Compound 144: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-4-fluorobenzenesulfonamide was prepared in a manner similar to that described in Example 2.

Example 145

[0277] Compound 145: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazol-5-yl)methyl)(phenyl)methanamine was prepared in a manner similar to that described in Example 4 and Example 26. MS (m/e): 457.1 (M+l).

Example 146

[0278] Compound 146: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-nitrobenzenesulfonamide was prepared in a manner similar to that described in Example 2.

Example 147

[0279] Compound 147: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-nitrobenzamide was prepared in a manner similar to that described in Example 2.

Example 148

[0280] Compound 148: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-(3- methoxyphenyl)acetamide was prepared in a manner similar to that described in Example 28. MS (m/e): 447.1 (M+l).

Example 149

[0281] Compound 149: N-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2- methoxyacetamide was prepared in a manner similar to that described in Example 28. MS (m/e) : 370.9 (M+l ).

Example 150 [0282] Compound 150: l -(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(2-methoxyphenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 392.9 (M+1 ).

Example 151

[0283] Compound 151 : l -(3-(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-3-(2-chloro-4-fluorophenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 396.0 (M+1).

Example 152

[0284] Compound 152: 3-(3-(imidazo[l ,2-a]pyridin-2-yl)phenyl)-l ,2,4-oxadiazol-5-ol was prepared in a manner similar to that described in Example 1. MS (m/e): 279.0 (M+1).

Example 153

[0285] Compound 153 : l -((3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)methyl)-3-(3-methylpyridin-2- yl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 358.9 (M+1). Example 154

[0286] Compound 154: l -(3-cyanophenyl)-3-((3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)methyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 368.0 (M+1).

Example 155

[0287] Compound 155: l -((3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)methyl)-3-(phenylsulfonyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 407.9 (M+1).

Example 156

[0288] Compound 156: l -(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(4-fluorobenzyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 394.9 (M+1).

Example 157

[0289] Compound 157: l -(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(3-chlorophenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 397.1 (M+1).

Example 158

[0290] Compound 158: l -(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(3-methoxyphenyl)urea was prepared in a manner similar to that described in Example 2. MS (m/e): 393 (M+1).

Example 159

[0291] Compound 159: 2-(3-(5-methyl-lH-l ,2,4-triazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine was prepared in a manner similar to that described in Example 1. MS (m/e): 276.8 (M+1).

Example 160 [0292] Compound 160: 2-(3-(5-methyl-lH-l ,2,4-triazol-3-yl)phenyl)-imidazo[l ,2-a]pyridine was prepared in a manner similar to that described in Example 1. MS (m/e): 275.9 (M+l).

Example 161

[0293] Compound 161 : ethyl 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenylamino)nicotinate was prepared in a manner similar to that described in Example 28 and Example 69. MS (m/e): 433.7 (M+l ).

Example 162

[0294] Compound 162: 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenylamino)nicotinamide was prepared in a manner similar to that described in Example 28 and Example 69. MS (m/e): 404.9 (M+l).

Example 163

[0295] Compound 163 : (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)(piperidin- 1 -yl)methanone was prepared in a manner similar to that described in Example 1. MS (m/e): 375 (M+l).

Example 164

[0296] Compound 164: 2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 320.9 (M+l).

Example 165

[0297] Compound 165: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 26. MS (m/e): 381.2 (M+l).

Example 166

[0298] Compound 166: N-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)methanesulfonamide was prepared in a manner similar to that described in Example 4. MS (m/e): 371.0 (M+l).

Example 167

[0299] Compound 167: N,N-diethyl-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol- 5-yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 377.3 (M+l).

Example 168 [0300] Compound 168: 2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)-N- methylacetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 335.2 (M+l).

Example 169

[0301] Compound 169: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2- (piperidin-l -yl)ethyl)-l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28.

Example 170

[0302] Compound 170: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2- morpholinoethyl)-l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 494.3 (M+l).

Example 171

[0303] Compound 171 : 2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)-l - (piperazin-1 -yl)ethanone was prepared in a manner similar to that described in Example 1. MS (m/e): 390.2 (M+l ).

Example 172

[0304] Compound 172: N-(3-chlorobenzyl)-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4- oxadiazol-5-yl)acetamide was prepared in a manner similar to that described in Example 1. MS (m/e): 445.3 (M+l).

Example 173

[0305] Compound 173 : 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-methyl- l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 395.2 (M+l).

Example 174

[0306] Compound 174: N-(3-chlorobenzyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenyl)-l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 505.3 (M+l).

Example 175

[0307] Compound 175: 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)-N-methylnicotinamide was prepared in a manner similar to that described in Example 69. MS (m/e): 345.2 (M+l).

Example 176 [0308] Compound 176: N-cyclopropyl-3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenyl)-l,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28.

Example 177

[0309] Compound 177: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N- (pyrimidin-2-yl)-l,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 459.2 (M+l).

Example 178

[0310] Compound 178: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N- (pyridin-3-ylmethyl)-l,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 472 (M+l).

Example 179

[0311] Compound 179: 3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(5- methylthiazol-2-yl)-l ,2,4-oxadiazole-5-carboxamide was prepared in a manner similar to that described in Example 1 and Example 28. MS (m/e): 478.2 (M+l).

Example 180

[0312] Compound 180: 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)-N-(2- methoxyethyl)nicotinamide was prepared in a manner similar to that described in Example 69. MS (m/e): 389.2 (M+l).

Example 181 : In vivo assays

[0313] Balb/c mice (female, body weight 18 g-20 g) were used. For each test compound, a test compound suspension in 0.25% Tween80 and 1% carboxymethyl cellulose (CMC) was administered orally or parenterally. The negative control group was administered with the vehicle alone, while the positive control group was administered with Prednisone (10 mg/kg). Half an hour later, all mice were injected intraperitoneally with lipopolysaccharide (LPS) (15 mg/kg, lOmL/kg). Two hours after LPS injection, the mice were bled for serum. Concentrations of TNF-a and IL-1 β in the serum, which was stored at -20 °C overnight, were determined by ELISA. Tested compounds from this invention demonstrated inhibition of TNFoc and IL-Ιβ production at a dose ranging from 1 to 1000 mg/kg.

Example 182: In vitro study of LPS induced IL-10 mRNA production in RAW264.7 macrophages

[0314] 1. Reagents and Materials: RAW264.7 cells, Cell Bank of the Chinese Academy of Science (Shanghai, China), TCM13;

Fetal bovine serum, Gibco, 16000-044;

96 well plate, FALCON, 353072;

RNeasy 96 Kit, QIAGEN, 74182;

High-Capacity cDNA Archive kit, Applied Biosystems, 4368813;

SYBR Green I, Dingguo, DH392-2;

ABsolute QPCR ROX 2X Master Mix kit, Thermo Fisher Scientific, AB-1139;

Thermo-Fast 96 PCR Plate Non-skirted, low profile, Abgene, AB-0700;

qPCR stip tubes, Corbett, 3001-002;

Compound stock solution 10 mM, solublized in DMSO;

LPS, Sigma, Cat: L4391 ;

RG-3000A real time PCR system equipped with Rotor-Gene 6.1 software, Corbett.

[0315] 2. Procedures:

[0316] (1) Cell seeding: RAW264.7 cells were seeded at 2 l0⁴ cells/well in lOOul DMEM/10%FB S in 96 well plates. Cells were grown overnight.

[0317] (2) Compound treatment: Cells were pretreated with 3, 10, 30 μΜ testing compounds, or 0.1%DMSO for 30 mins, followed by treatment with 5 ng/ml LPS or vehicle control for 2 hrs.

[0318] (3) RNA extraction and reverse transcription: total cell RNA was extracted with RNeasy 96 Kit according to the manufacture's instructions and the final elution volume was 80 μΐ. The RNA samples were then reverse transcribed with a High-Capacity cDNA Archive kit with a reduced reaction volume of 10 μΐ, including 5 μΐ RNA.

[0319] (4) Quantitative PCR: The above cDNA templates were diluted at 4 folds with RNase free water. SYBR Green I based qPCR reactions were carried out to quantify IL-10 mRNA level (SYBR Green I was used as fluorescence probe). The mouse IL-10 and β -actin primer sequences were as follows:

IL-10: Upstream, 5'-GACCAGCTGGACAACATACTGCTAA-3';

Downstream, 5'-GATAAGGCTTGGCAACCCAAGTAA-3'.

β -actin: Upstream, 5'- ATTGCCGACAGGATGCAGA-3';

Downstream, 5'-GAGTACTTGCGCTCAGGAGGA-3 '.

[0320] qPCR reaction system: 2^χ qPCR ROX Mix 10 μΐ

Upstream primer (lOpmol) 1 μΐ

Downstream primer (lOpmol) 1 μΐ

cDNA template 5 μ1

SYBR Green I (1 :800) 1 μΐ

H20 2 1

Total volume 20 μΐ

[0321] The reactions were heated to 95 °C for 15 min before being cycled 40 times between 95 °C for 20 s and 56 °C for 20 s, 72 °C for 20 s.

[0322] (5) Data analysis: The relative fold-change of IL-10 expression level was quantified using the 2^Λ (- δ 6 Ct) method.

δ δ Ct= δ Ct LPS or LPS/oompound- $ Ct_veh, ^ Ct= Ct IL-10-Ctaotin

[0323] The effect of the tested compound was expressed as LPS%. All samples were run in duplicate and were repeated twice. Test results were expressed as Mean ± SD from two independent experiments.

[0324] 3. Results:

[0325] Pretreatment with the tested compounds enhanced LPS induced IL-10 mRNA production in RAW264.7 cells.

[0326] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0327] From the above description, one skilled in the art can easily ascertain the essential

characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

WHAT IS CLAIMED IS:

1. At least one compound of Formula I

I,

and/or at least one pharmaceutically acceptable salt thereof wherein

A is chosen from optionally substituted heteroaryl and (CR'R")_n

wherein

n is 0, 1 , 2, 3, 4, or 5;

for each occurrence, each of R' and R", independently, is H or optionally substituted C_MO alkyl or R' and R", together with the carbon to which they are bound, form an optionally substituted 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl;

X is chosen from (CR^a R^b')_m, SO, S0₂, CO, COO, CONR^c , NR^C', and

NR^C CONR^d ; wherein

m is 0, 1, 2, 3, 4, or 5;

each of R^a , R^b , R^c , and R^d , independently, is H or optionally substituted Ci-io alkyl;

each of R¹ and R², independently, is hydrogen, halo, NR^clC(0)R^al, OR^bl, NR^clR^dl, NR^clC(0)OR^bl, NR^clS(0)₂R^bl, or optionally substituted Ci-io alkyl, wherein

each of R^al and R^bl, independently, is H, optionally substituted C_1-10 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, and each of R^cl and R^dl, independently, is H, optionally substituted Ci-io alkyl, optionally substituted aryl, optionally substituted heteroaryl, or R^cl and R^dl together with the N atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocycloalkyl; and

R³ is H, halo, OC(0)R^a2, C(0)OR^b2, OR^b2, SR^b2, S0₂R^b2, C(0)NR^c2R^d2, NR^c2R^d2, NR^c2C(0)R^a2, NR^c2C(0)C(0)OR^a2, NR^c2S(0)₂R^b2, d-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of Ci-io alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted, wherein

each of R^a2 and R^b2, independently, is H, Ci_-6 alkyl, Ci_-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, or heteroarylalkyl in which each of Ci-₆ alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, and heteroarylalkyl is optionally substituted;

each of R^c2 and R^d2, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of C_MO alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and

heterocycloalkylalkyl is optionally substituted by one or more groups chosen from halo, NR^clC(0)R^al, OR^bl, NR^clR^dl,

NR^clC(0)OR^bl, NR^clS(0)₂R^bl, and optionally substituted Ci-io alkyl;

or R^c2 and R^d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered optionally substituted heterocycloalkyl, provided that if A is (CR'R")_n where n is 0, then X is not (CR^a R^b )_m wherein m is 0, and

further provided that -A-X-R³ is not methyl or CF₃. At least one compound of claim 1, and/or at least one pharmaceutically acceptable salt thereof wherein A is chosen from

each of which is optionally substituted and wherein

R is H or Ci-io alkyl, in which Ci-io alkyl is optionally substituted by one or more groups chosen from halo, C(0)R^a, OR^b, SR^b, S(0)₂R^b, NR^cR^d, and C(0)NR^cNR^d,

in which each of R^a and R^b, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, or heteroaryl, and

each of R^c and R^d, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, or

heteroaryl, or R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl. The at least one compound of claim 2, and/or at least one pharmaceutically acceptable salt thereof, wherein A is

The at least one compound of any one of claims 1 to 3, and/or at least one harmaceutically acceptable salt thereof, wherein B is

_or

The at least one compound of claim 4, and/or at least one pharmaceutically acceptable salt thereof, wherein B is

The at least one compound of any one of claims 1 to 5, and/or at least one pharmaceutically acceptable salt thereof, wherein X is (CR^a R^b )_m, CO, COO, NR^C , CONR^c , or NR^C CONR^d .

The at least one compound of claim 6, and/or at least one pharmaceutically acceptable salt thereof, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

The at least one compound of any one of claims 1 to 7, and/or at least one pharmaceutically acceptable salt thereof, wherein R¹ is H, OR^bl, NR^clC(0)R^al, NR^clR^dl, NR^clC(0)OR^bl, or NR^clS(0)₂R^bl.

9. The at least one compound of claim 8, and/or at least one pharmaceutically

acceptable salt thereof, wherein R¹ is H.

10. The at least one compound of any one of claims 1 to 9, and/or at least one pharmaceutically acceptable salt thereof, wherein R² is H, OR^bl, NR^clC(0)R^al, NR^clR^dl, NR^clC(0)OR^bl, or NR^clS(0)₂R^bl.

11. The at least one compound of claim 10, and/or at least one pharmaceutically

acceptable salt thereof, wherein R² is H.

12. The at least one compound of any one of claims 1 to 11 , and/or at least one

pharmaceutically acceptable salt thereof, wherein R³ is H, halo, C(0)NR^c2R^d2, NR^c2R^d2, NR^c2C(0)R^a2, NR^c2C(0)C(0)OR^a2, NR^c2S(0)₂R^b2, heteroaryl, or heterocycloalkyl, in which each of heteroaryl and heterocycloalkyl is optionally substituted, wherein

each of R^a2 and R^b2, independently, is H, Ci_-6 alkyl, Ci_-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, or

heteroarylalkyl in which each of Ci-₆ alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, and heteroarylalkyl is optionally substituted;

each of R^c2 and R^d2, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of C_MO alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by one or more groups chosen from halo, NR^clC(0)R^al, OR^bl, NR^clR^dl, NR^clC(0)OR^bl, NR^clS(0)₂R^bl, and optionally substituted Ci-io alkyl;

13. The at least one compound of claim 12, and/or at least one pharmaceutically

acceptable salt thereof, wherein R³ is C(0)NR^c2R^d2 or NR^c2R^d2, each of R^c2 and R^d2, independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, in which each of C_MO alkyl, d-io haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by one or more groups chosen from halo, NR^clC(0)R^al, OR^bl, NR^clR^dl,

NR^clC(0)OR^bl, NR^clS(0)₂R^bl, and optionally substituted Ci-io alkyl;

14. At least one compound chosen from:

2-(3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

1 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)benzyl)-3 -(2-morpholinoethyl)urea;

1 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)benzyl)-3 -(2-methoxyethyl)urea;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)- 2-methoxyethanamine;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)- 2-morpholinoethanamine;

2-(3-(5-(mo holinomethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)methyl)ethanamine;

2-(3-(5-((4-fluorophenoxy)methyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2- b]pyridazine; 2-(3-(5-(ethoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine; 2-(3 -(5-(methoxymethyl)-l ,2,4-oxadiazol-3 -yl)phenyl)imidazo[l ,2- b]pyridazine;

2-(3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2- b]pyridazine;

(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)methyl acetate;

2-(3-(5-isopropyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine; (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)methanol; 2-(3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine; 2-(3-(5-(fluoromethyl)-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2-b]pyridazine;

2- (3-(5-ethyl-l,2,4-oxadiazol-3-yl)phenyl)imidazo[l,2-b]pyridazine;

ethyl 3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5- carboxylate;

ethyl 2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 - yl)acetate;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5-carboxylic acid;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole-5-carboxamide; 2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)acetic acid;

2-(3 -(5 -(methylthio methyl)- l,2,4-oxadiazol-3-yl)phenyl)imidazo[ 1,2- b]pyridazine;

2-(3 -(5 -(methylsulfonylmethyl)- 1 ,2,4-oxadiazol-3 -yl)phenyl)imidazo [ 1 ,2- b]pyridazine;

(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine; 2-(3-(2-methoxyethoxy)-5-(5-(trifluoromethyl)-l,2,4-oxadiazol-3- yl)phenyl)imidazo[l,2-b]pyridazine; 2-(3-(2-methoxyethoxy)-5-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl)imidazo[l,2-b]pyridazine;

2-(3-(5-(fluoromethyl)-l,2,4-oxadiazol-3-yl)-5-(2- methoxyethoxy)phenyl)imidazo [1 ,2 -b ]pyridazine ;

2- (3-(5-(ethoxymethyl)-l,2,4-oxadiazol-3-yl)-5-(2- methoxyethoxy)phenyl)imidazo [1 ,2 -b ]pyridazine ;

(3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4- oxadiazol-5 -yl)methanol;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4- oxadiazole-5-carboxylic acid;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4- oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin- 2-yl)-l,2,4-oxadiazole-5-carboxamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)acetamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2- chloroacetamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- chlorobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- nitrobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4- cyanobenzamide; N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3- bromobenzamide ;

N-(2-(diethylamino)ethyl)-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)acetamide;

N-butyl-2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)acetamide;

N-cyclopentyl-2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4- oxadiazol-5 -yl)acetamide;

2- (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)- 1 - morpholinoethan-1 -one;

N-cyclopropyl-2-(3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l,2,4- oxadiazol-5 -yl)acetamide;

3 - (3 -(imidazo [l,2-b]pyridazin-2-yl)phenyl)-N-(2-mo holinoethyl)- 1,2,4- oxadiazole-5-carboxamide;

N-ethyl-3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazole-5 - carboxamide;

N-cyclopentyl-3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazole- 5 -carboxamide; (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 - yl)(morpholino)methanone;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-N-(2-methoxyethyl)-l ,2,4- oxadiazole-5-carboxamide;

N-(2-(dimethylamino)ethyl)-3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazole-5-carboxamide;

(4-ethylpiperazin-l -yl)(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4- oxadiazol-5 -yl)methanone;

3 -(3 -(imidazo [l,2-b]pyridazin-2-yl)phenyl)-N-(thiophen-2-ylmethyl)- 1,2,4- oxadiazole-5-carboxamide;

N-(2 -hydroxy ethyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l , 2,4- oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-N,N-dimethyl-l,2,4-oxadiazole-5- carboxamide;

(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)(pyrrolidin- l-yl)methanone;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-N-methyl-l,2,4-oxadiazole-5- carboxamide;

2-(3 -(imidazo [l,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

N-(2 -hydroxy ethyl)-2-(3 -(imidazo [1 , 2-b]pyridazin-2- yl)phenylamino)nicotinamide;

ethyl 2-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenylamino)nicotinate;

N-cyclopropyl-2-(3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

(2-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenylamino)pyridin-3 - yl)(morpholino)methanone;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(5-(morpholinomethyl)-l ,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide; N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)-5 -(5 -(piperidin-1 -ylmethyl)-l ,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)-5 -(5 -((2-methoxyethylamino)methyl)- 1 ,2,4-oxadiazol-3 -yl)phenyl)methanesulfonamide;

N-(3-(5-((2-(dimethylamino)ethylamino)methyl)-l,2,4-oxadiazol-3-yl)-5- (imidazo[l,2-b]pyridazin-2-yl)phenyl)methanesulfonamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)-5 -(5 -(piperazin- 1 -ylmethyl)- 1,2,4- oxadiazol-3-yl)phenyl)methanesulfonamide;

2-(3-(5-(piperazin-l-ylmethyl)-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[l ,2- b]pyridazine;

Nl-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)ethane-l ,2-diamine;

Nl-((3-(3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)-l ,2,4-oxadiazol-5- yl)methyl)-N2,N2-dimethylethane-l , 2 -diamine;

2,2,2-trifluoro-N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4- oxadiazol-5 -yl)methyl)acetamide;

ethyl 2-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl) phenyl)-l,2,4-oxadiazol-5- yl)methyl- amino)-2-oxoacetate;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)- phenyl)-l ,2,4-oxadiazol-5- yl)methyl)-2-methoxyacetamide;

ethyl 3-((3-(3-(imidazo[l ,2-b]pyridazin-2- yl) phenyl)-l,2,4-oxadiazol-5- yl)methyl- amino)-3 -oxopropanoate;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)-l,2,4- oxadiazol-5- yl)methyl)isobutyramide; 3-((3-(imidazo[l,2-b]pyridazin-2-yl)benzylamino)methyl)benzonitrile;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-4-chlorobenzamide;

N-(3 -(imidazo[l ,2-b]pyridazin-2-yl)benzyl)-2-methoxyacetamide;

N-(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)benzyl)-3 -cyanobenzenesulfonamide;

1- (3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-(thiophen-2-ylmethyl)urea;

3- bromo-N-((3-(2-methylimidazo[2,l-b]thiazol-6- yl)phenyl)methyl)b enzamide ;

4- chloro-N-((3-(2-methylimidazo[2,l-b]thiazol-6- yl)phenyl)methyl)b enzamide ;

N-((3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)methyl)butyramide;

N-((3-(2-methylimidazo[2,l-b]thiazol-6- yl)phenyl)methyl)cyclopropanecarboxamide;

N-((3 -(3 -(2-methylimidazo [2, 1 -b]thiazol-6-yl)phenyl)- 1 ,2,4-oxadiazol-5- yl)methyl)(4-(methylsulfonyl)phenyl)methanamine;

2- methoxy-N-((3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l ,2,4- oxadiazol-5-yl)methyl)ethanamine;

ethyl 2-(3 -(imidazo [1 ,2-a]pyridin-2-yl)benzylamino)nicotinate;

1 -(3 -(imidazo [l,2-a]pyridin-2-yl)benzyl)-3-(2-chloro-4-fluorophenyl)urea;

1 - (3 -(imidazo [l,2-a]pyridin-2 -yl)benzyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea;

N-(2-(dimethylamino)ethyl)-2-(3-(3-(imidazo[l,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)acetamide;

2- (3-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)phenyl)-imidazo[l,2- a] pyridine;

6-(3 -(5-(methoxymethyl)-l ,2,4-oxadiazol-3 -yl)phenyl)-2-methylimidazo[2, 1 - b] thiazole;

2-methyl-6-(3-(5-methyl-l ,2,4-oxadiazol-3-yl)phenyl)imidazo[2,l -b]thiazole; 2-(3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-imidazo[l,2-a]pyridine; 2-methyl-6-(3 -(5-(trifluoromethyl)-l ,2,4-oxadiazol-3 -yl)phenyl)imidazo[2, 1 - b]thiazole;

(3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l,2,4-oxadiazol-5- yl)methyl acetate;

2- (3-(5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl)phenyl)-imidazo[l,2-a]pyridine; (3-(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)-l ,2,4-oxadiazol-5-yl)methanol; (3-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)phenyl)-l,2,4-oxadiazol-5- yl)methanol;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)propionamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)ethanesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-3- fluorobenzenesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-3-nitrobenzamide;

N-(3 -(2-methylimidazo [2, 1 -b]thiazol-6-yl)benzyl)-2-methoxyacetamide;

3- ((3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzylamino)methyl)benzonitrile; l-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-(3-chloro-4-fluorophenyl)urea; 3-cyano-N-((3-(2-methylimidazo[2,l-b]thiazol-6- yl)phenyl)methyl)benzenesulfonamide;

ethyl 4-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)benzyl)ureido)piperidine- 1 - carboxylate;

N-(3 -(2-methylimidazo [2,1 -b]thiazol-6-yl)benzyl)-4- methoxybenzenesulfonamide;

N-(3 -(2-methylimidazo [2, l-b]thiazol-6-yl)benzyl)-4-cyanobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-4-methoxybenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-bromobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-chlorobenzenesulfonamide;

N-(3 -(2-methylimidazo [2,1 -b]thiazol-6-yl)benzyl)-4- fluorobenzenesulfonamide;

(3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l,2,4- oxadiazol-5-yl)methyl acetate; 2-((3 -(3 -(imidazo [1 ,2-b]pyridazin-2-yl)-5 -(2-methoxyethoxy)phenyl)- 1,2,4- oxadiazol-5-yl)methyl)aminoethanol;

methyl 3-(imidazo[l ,2-b]pyridazin-2-yl)benzylcarbamate;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-2-chlorobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-2-methylbenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-2-fluorobenzenesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-2- chlorobenzenesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-2- methylbenzenesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-3- chlorobenzenesulfonamide;

N-(3-(2-methylimidazo[2,l-b]thiazol-6-yl)benzyl)-2- fluorobenzenesulfonamide;

1 -(3 -(6-(methylamino)imidazo [1 ,2-b]pyridazin-2-yl)benzyl)-3 -(2- methoxyethyl)urea;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-4-fluorobenzenesulfonamide;

N-((3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-l ,2,4- oxadiazol-5-yl)methyl)(phenyl)methanamine;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-nitrobenzenesulfonamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)benzyl)-3-nitrobenzamide;

N-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2- methoxyacetamide;

l-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(2-methoxyphenyl)urea;

1 -(3 -(imidazo [l,2-b]pyridazin-2-yl)benzyl)-3-(2-chloro-4-fluorophenyl)urea;

3 -(3 -(imidazo [1 ,2-a]pyridin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5-ol;

1 -((3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)methyl)-3 -(3 -methylpyridin-2- yl)urea; l-(3-cyanophenyl)-3-((3-(imidazo[l ,2-b]pyridazin-2-yl)phenyl)methyl)urea; 1 -((3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)methyl)-3 -(phenylsulfonyl)urea; l-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(4-fluorobenzyl)urea; l-(3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(3-chlorophenyl)urea;

1- (3-(2-methylimidazo[2,l -b]thiazol-6-yl)benzyl)-3-(3-methoxyphenyl)urea;

2-(3 -(5 -methyl- 1 H- 1 ,2,4-triazol-3 -yl)phenyl)-imidazo [ 1 ,2-a]pyridine;

ethyl 2-(3 -(imidazo [1 ,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenylamino)nicotinate;

2-(3 -(imidazo [l,2-b]pyridazin-2-yl)-5 -(2- methoxyethoxy)phenylamino)nicotinamide;

(3 -(3 -(imidazo[ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)(piperidin- l-yl)methanone;

3 - (3 -(imidazo [l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)- 1,2,4- oxadiazole-5-carboxamide;

2- (3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)-N- methylacetamide;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2- (piperidin-1 -yl)ethyl)-l ,2,4-oxadiazole-5-carboxamide;

2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)- 1 - (piperazin-1 -yl)ethanone;

N-(3 -chlorobenzyl)-2-(3 -(3 -(imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)- 1,2,4- oxadiazol-5 -yl)acetamide; 3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-methyl- 1 ,2,4-oxadiazole-5-carboxamide;

N-(3-chlorobenzyl)-3-(3-(imidazo[l ,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenyl)- 1 ,2,4-oxadiazole-5 -carboxamide;

2- (3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)-N-methylnicotinamide; N-cyclopropyl-3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2- methoxyethoxy)phenyl)- 1 ,2,4-oxadiazole-5 -carboxamide;

3- (3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N- (pyrimidin-2-yl)-l,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin- 3-ylmethyl)-l ,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[l,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(5- methylthiazol-2-yl)-l ,2,4-oxadiazole-5-carboxamide; and

2-(3-(imidazo[l,2-b]pyridazin-2-yl)phenylamino)-N-(2- methoxyethyl)nicotinamide;

and/or at least one pharmaceutically acceptable salt thereof.

15. A composition comprising at least one compound and/or at least one

pharmaceutically acceptable salt thereof of any one of claims 1 to 14 and at least one pharmaceutically acceptable carrier.

16. A method of inhibiting the activity of at least one protein chosen from TNFa, IL- 1β, NF-KB, IL-10 and iNOS, comprising contacting the at least one protein with an effective amount for inhibiting said activity of at least one compound and/or at least one pharmaceutically acceptable salt thereof of any one of claims 1 to 14.

17. A method of decreasing a level of a cytokine, comprising administering to a subject in need thereof an effective amount for decreasing said level of at least one compound and/or at least one pharmaceutically acceptable salt thereof of any one of claims 1 to 14.

18. A method of treating a disorder mediated by overproduction of a cytokine, comprising administering to a subject in need thereof an effective amount for treating said disorder of at least one compound and/or at least one pharmaceutically acceptable salt thereof of any one of claims 1 to 14.