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WO2011137587A1 - Inhibiteurs de cytokines - Google Patents

Inhibiteurs de cytokines Download PDF

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Publication number
WO2011137587A1
WO2011137587A1 PCT/CN2010/072479 CN2010072479W WO2011137587A1 WO 2011137587 A1 WO2011137587 A1 WO 2011137587A1 CN 2010072479 W CN2010072479 W CN 2010072479W WO 2011137587 A1 WO2011137587 A1 WO 2011137587A1
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WIPO (PCT)
Prior art keywords
imidazo
pyridazin
phenyl
oxadiazol
methyl
Prior art date
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Ceased
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PCT/CN2010/072479
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English (en)
Inventor
Wei-Guo Su
Wei Deng
Yu Cai
Jifeng Duan
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Hutchmed Ltd
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Hutchison Medipharma Ltd
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Priority to PCT/CN2010/072479 priority Critical patent/WO2011137587A1/fr
Publication of WO2011137587A1 publication Critical patent/WO2011137587A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Tumor necrosis factor alpha a mononuclear cytokine
  • monocytes and macrophages a mononuclear cytokine
  • various biological activities such as: (1) killing cancer cells or inhibiting growth of cancer cells, (2) enhancing the phagocytosis of neutrophilic
  • Interleukin-1 beta IL- ⁇ ⁇
  • monocyte macrophages and dendritic cells mediates immune and inflammatory responses.
  • Nuclear factor-kappa B (NF- ⁇ ) is a pro-inflammatory transcription factor. It upregulates cytokines, including TNFa and IL- ⁇ ⁇ , and thereby mediates inflammatory responses.
  • Interleukin-10 also known as cytokine synthesis inhibitory factor (CSIF)
  • CCF cytokine synthesis inhibitory factor
  • IL-10 has pleiotropic effects on immunoregulation and inflammation. For instance, it down-regulates the expression of Thl cytokines, MHC class II antigens, and
  • IL-10 can block NF- ⁇ activity, and may be involved in the regulation of the JAK-STAT signaling pathway.
  • Inducible nitric oxide synthase is induced by endotoxins or cytokines (e.g., TNFa). It catalyzes the production of nitric oxide, a pleiotropic molecule, from L-aginine and oxygen.
  • cytokines e.g., TNFa
  • TNFa, IL-1 ⁇ , NF- ⁇ , 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 ⁇ , NF- KB, IL-10 and/or iNOS can lead to treatment of these diseases.
  • diseases e.g., autoimmune diseases, inflammatory diseases, cancer, atherosclerosis, and diabetes. Therefore, modulating the expression or activity of TNFa, IL-1 ⁇ , NF- KB, IL-10 and/or iNOS can lead to treatment of these diseases.
  • A is chosen from optionally substituted heteroaryl and (CR'R") n
  • n 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, S0 2 , 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 is H or optionally substituted Ci-io alkyl; each of R 1 and R 2 , independently, is hydrogen, halo, NR cl C(0)R al , OR bl , NR cl R dl ,
  • NR cl C(0)OR bl , NR cl S(0) 2 R 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
  • R 3 is H, halo, OC(0)R a2 , C(0)OR b2 , OR b2 , SR b2 , S0 2 R b2 , C(0)NR c2 R d2 , NR c2 R d2 ,
  • heterocycloalkylalkyl is optionally substituted, wherein
  • each of R a2 and R b2 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 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 cl C(0)R al , OR bl , NR cl R dl , NR cl C(0)OR bl , NR cl S(0) 2 R bl , and optionally substituted C M o alkyl;
  • 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-R 3 is not methyl or CF 3 .
  • composition comprising at least one compound and/or at least one pharmaceutically acceptable salt thereof descrbed herein and
  • At least one pharmaceutically acceptable carrier at least one pharmaceutically acceptable carrier.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • alkyl refers to a straight or branched hydrocarbon, containing e.g. 1 -20 carbon atoms.
  • 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.
  • 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.
  • alkenyl groups include, but are not limited to, vinyl, 2- propenyl, and 2-butenyl.
  • alkynyl herein refers to a C 2- io straight or branched hydrocarbon, containing one or more C ⁇ C triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, 2- propynyl, and 2-butynyl.
  • 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).
  • 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.
  • 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 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.
  • heteroaryl refers to aryl
  • 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.
  • heteroaryl includes a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • 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.
  • 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.
  • 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,
  • 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.
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-0 " ) substituents, such as pyridinyl N-oxides.
  • halo includes fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • haloakyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCI3, CHC1 2 , C 2 Cl5, and the like.
  • arylalkyl 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.
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • 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.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • 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.
  • 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.
  • 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.
  • Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers i.e., optically active forms
  • 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
  • Such compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds.
  • 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.
  • 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.
  • 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.
  • “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-(CH 2 ) n -COOH where n is 0-4, and like salts.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • 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.
  • 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.
  • “salts” includes solvates, such as hydrates, of salts.
  • Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi -hydrates.
  • 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.
  • salts includes chelates of salts.
  • 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.
  • 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'.
  • 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)).
  • Hydrogen bond acceptor refers to a group comprising an oxygen or nitrogen, such as an oxygen or nitrogen that is sp 2 -hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.
  • 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.
  • group 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.
  • 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.
  • active agent is used to indicate a chemical substance which has biological activity.
  • an “active agent” is a chemical substance having pharmaceutical utility.
  • 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.
  • inhibitortion 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 ⁇ , NF- ⁇ , IL-10 and iNOS” refers to a decrease in the activity of the at least one protein chosen from TNFa, IL-1 ⁇ , 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.
  • 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 ⁇ , 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.
  • 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 ⁇ , 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.
  • 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.
  • 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.
  • 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 ⁇ , NF- ⁇ , IL-10 and iNOS.
  • 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.
  • 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- ⁇ ⁇ , NF- ⁇ , IL-10 and iNOS.
  • 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.
  • A is chosen from optionally substituted heteroaryl and (CR'R") n
  • n 0, 1 , 2, 3, 4, or 5;
  • 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, S0 2 , 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 C 1-10 alkyl; each of R 1 and R 2 , independently, is hydrogen, halo, NR cl C(0)R al , OR bl , NR cl R dl ,
  • NR cl C(0)OR bl , NR cl S(0) 2 R 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 R 3 is H, halo, OC(0)R a2 , C(0)OR b2 , OR b2 , SR b2 , S0 2 R b2 , C(0)NR c2 R d2 , NR c2 R d2 ,
  • heterocycloalkylalkyl is optionally substituted, wherein
  • each of R a2 and R b2 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 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 cl C(0)R al , OR bl , NR cl R dl , NR cl C(0)OR bl , NR cl S(0) 2 R bl , and optionally substituted C M o alkyl;
  • 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
  • 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-R 3 is not methyl or CF 3 .
  • A is chosen from
  • 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) 2 R b , NR c R d , and C(0)NR c NR d , in which each of R a and R b , independently, is H, Ci-io alkyl, Ci-io haloalkyl, aryl, or
  • each of R c and R d 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.
  • X is (CR a R b' ) m , CO, COO, NR C' , CONR c , or NR C CONR d .
  • X is CH 2 , NH, CO, COO, CONH, or NHCONH.
  • R 1 is H, OR bl , NR cl C(0)R al , NR cl R dl , NR cl C(0)OR bl , or
  • R 1 is H.
  • R 2 is H, OR bl , NR cl C(0)R al , NR cl R dl , NR cl C(0)OR bl , or
  • R 2 is H.
  • R 3 is H, halo, C(0)NR c2 R d2 , NR c2 R d2 , NR c2 C(0)R a2 ,
  • NR c2 C(0)C(0)OR a2 NR c2 S(0) 2 R b2 , heteroaryl, or heterocycloalkyl, in which each of heteroaryl and heterocycloalkyl is optionally substituted, wherein
  • each of R a2 and R b2 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 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 cl C(0)R al , OR bl , NR cl R dl , NR cl C(0)OR bl , NR cl S(0) 2 R bl , and optionally substituted C O alkyl;
  • 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.
  • R 3 is C(0)NR c2 R d2 or NR c2 R d2 ,
  • each of R c2 and R d2 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 cl C(0)R al , OR bl , NR cl R dl , NR cl C(0)OR bl , NR cl S(0) 2 R bl , and optionally substituted C O alkyl; or R c and R together with the
  • the process comprises coupling a compound of the following formula:
  • L is a leaving group and R 3 , R a , R b , and n are as described herein.
  • the process comprises coupling a compound of the following formula:
  • A is -(CR a R b ) n and B, R 1 , and R 2 are as described with a compound of the formula:
  • L is a leaving group
  • X 1 is chosen from (CR a R b ) m wherein m is 0, SO, S0 2 , or CO, and R is NR c2 R 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.
  • the process comprises coupling a compound of the following formula:
  • L is a leaving group
  • A is optionally substituted heteroaryl
  • B, R 1 , and R 2 are as described herein with a compound of the following formula
  • R 3c is OC(0)R a2 , OR b2 , SR b2 , S0 2 R b2 NR c2 R d2 , NR c2 C(0)R a2 , NR c2 C(0)C(0)OR a2 ,
  • the process further comprises forming a pharmaceutically acceptable salt or solvate of the compound of Formula I obtained.
  • 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.
  • composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described herein, and at least one pharmaceutically acceptable carrier.
  • a composition described herein can be administered in various known manners, such as orally, parenterally, by inhalation spray, or via an implanted reservoir.
  • 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.
  • useful diluents include lactose and dried corn starch.
  • 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.
  • a sterile injectable composition e.g., aqueous or oleaginous suspension
  • a sterile injectable composition 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.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • 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.
  • a non-toxic parenterally acceptable diluent or solvent for example, as a solution in 1 ,3-butanediol.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • compositions for delivery of the active ingredients include colloidal silicon dioxide, magnesium stearate, cellulose, lactose, sodium lauryl sulfate, and pigments such as D&C Yellow # 10.
  • 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 ⁇ , NF- ⁇ , IL-10 and iNOS.
  • a method of decreasing a level of a cytokine e.g., TNFa, IL-1 ⁇ or IL-10
  • 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.
  • a method of treating a disorder mediated by an overproduction of a cytokine e.g., TNFa, IL-1 ⁇ or IL-10
  • a cytokine e.g., TNFa, IL-1 ⁇ or IL-10
  • an inflammatory disease e.g., an autoimmune disease, cancer, diabetes, allergy or atherosclerosis.
  • an autoimmune disease e.g., IL-1 ⁇ or IL-10
  • cytokine 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,
  • 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
  • diabetes mellitus systemic lupus
  • 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.
  • 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.
  • 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.
  • cancer includes, but is not limited to, solid tumors and bloodborne tumors.
  • cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
  • the term “cancer” further encompasses primary and metastatic cancers.
  • 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
  • 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;
  • AML acute myeloid leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL non-Hodgkin's lymphoma
  • B-cell lymphoma including follicular lymphoma and mantle
  • MDS myelodysplastic syndromes
  • RA refractory anemia
  • RARS refractory anemia with ringed siderblasts
  • RAEB refractory anemia with excess blasts
  • RAEB-T myelodysplastic syndromes
  • 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.
  • the at least one compound and/or at least one pharmaceutically acceptable salt described herein is administered in conjunction with another therapeutic agent.
  • the other therapeutic agent is one that is normally administered to patients with the disease or condition being treated.
  • 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.
  • 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).
  • cytokine synthesis/release e.g., anti-cytokine antibodies, anti-cytokine receptor antibodies, and the like.
  • 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.
  • Nonlimiting examples of anti-cancer agents include: radiotherapy; immunotherapy; DNA damaging chemotherapeutic agents; and chemotherapeutic agents that disrupt cell replication.
  • 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, capec
  • 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
  • other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication e.g., trastuzumab, rituximab, cetuximab, and bevacizumab
  • 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 ⁇ , NF- ⁇ , IL-10 and iNOS, or decreasing the level of a cytokine (e.g., TNFa, IL-1 ⁇ or IL-10).
  • a cytokine e.g., TNFa, IL-1 ⁇ or IL-10.
  • Compounds that demonstrate activity in the preliminary screening can further be screened by in vivo assays.
  • 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- ⁇ ⁇ , NF- ⁇ , IL-10 and iNOS, or in decreasing the level of a cytokine, can be assessed.
  • 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 ⁇ or IL-10).
  • 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 1 -180 below provide detailed descriptions of how compounds 1 -180 were prepared.
  • 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 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 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).
  • 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).
  • 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).
  • 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).
  • A1(CH 3 ) 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 Na 2 SC>4, and concentrated to afford N-(3-acetyl-5-cyanophenyl)methanesulfonamide.
  • Example 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 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 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 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 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 150 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 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).
  • 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 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).
  • 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 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.
  • 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
  • mice Female, body weight 18 g-20 g were used.
  • 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).
  • Prednisone 10 mg/kg.
  • 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 ⁇ 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- ⁇ 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
  • Fetal bovine serum Gibco, 16000-044;
  • 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 ⁇ . The RNA samples were then reverse transcribed with a High-Capacity cDNA Archive kit with a reduced reaction volume of 10 ⁇ , including 5 ⁇ RNA.
  • IL-10 Upstream, 5'-GACCAGCTGGACAACATACTGCTAA-3';
  • ⁇ -actin Upstream, 5'- ATTGCCGACAGGATGCAGA-3';

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Abstract

L'invention concerne un composé de formule (I) et/ou au moins un sel pharmaceutiquement acceptable dudit composé. Elle concerne aussi une méthode pour inhiber l'activité d'au moins une protéine choisie parmi TNFα, IL-1β, NF-κB, IL-10 et iNOS, une méthode pour diminuer le niveau d'une cytokine, et une méthode pour traiter un trouble lié à une surproduction d'une cytokine, avec au moins un composé de formule I et/ou au moins un sel pharmaceutiquement acceptable dudit composé.
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