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Definitions

• This invention relates to the treatment of chemokine mediated diseases using CXC chemokine receptor antagonists in combination (or association) with other pharmaceutical compounds.
• Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth.
• the class depends on whether the first two cysteines are separated by a single amino acid (CXC-chemokines) or are adjacent (CC-chemokines).
• the CXC-chemokines include interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1 ), neutrophil-activating protein-2 (NAP-2), GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, GCP-2, IP-10, MIG and PF4.
• CC chemokines include RANTES, MIP -1 ⁇ , MIP-2 ⁇ , monocyte chemotactic protein-1
• MCP-1 MCP-1
• MCP-2 MCP-2
• MCP-3 MCP-3
• eotaxin Individual members of the chemokine families are known to be bound by at least one chemokine receptor, with CXC-chemokines generally bound by members of the CXCR class of receptors, and CC-chemokines by members of the CCR class of receptors.
• IL-8 is bound by the CXCR-1 and CXCR-2 receptors.
• CXC-chemokines promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Fev. Immunol. 9, 617 (1991 ); Seitz et al., J. Clin. Invest. 87, 463 (1991 ); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341 , 643 (1993).
• the CXC-chemokine receptors represent promising targets for the development of novel anti-inflammatory agents.
• This invention provides a method of treating a CXC chemokine mediated disease comprising administering to a patient (i.e., a mammal, e.g. human) in need of such treatment, a therapeutically effective amount of: (a) One or more (e.g., one) compounds of the formula (I):
• the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more disease modifying antirheumatic drugs (DMARDs) such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like.
• DMARDs disease modifying antirheumatic drugs
• the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more nonsteroidal anti-inflammatory drugs (NSAIDs) such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like.
• NSAIDs nonsteroidal anti-inflammatory drugs
• the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of:
• a disease modifying antirheumatic drug such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like;
• a nonsteroidal anitinflammatory drug such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like;
• COX-2 selective inhibitors such as, for example, rofecoxib and celecoxib;
• COX-1 inhibitors such as, for example, piroxicam
• immunosuppressives such as, for example, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine; and
• steroids such as, for example, betamethasone, cortisone, prednisone or dexamethasone.
• the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of:
• a disease modifying antirheumatic drug such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like;
• a nonsteroidal anitinflammatory drug such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like;
• COX-2 selective inhibitors such as, for example, rofecoxib and celecoxib;
• COX-1 inhibitors such as, for example, piroxicam
• immunosuppressives such as, for example, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine
• steroids such as, for example, betamethasone, cortisone, prednisone or dexamethasone;
• a biological response modifier such as, for example, betamethasone, cortisone, prednisone or dexamethasone;
• the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I), in combination (or association) with an effective amount of one or more biological response modifiers (BRMs) such as, for example, anti-TNF antagonists including antibodies and/or receptors/receptor fragments, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like.
• BRMs biological response modifiers
• the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of: a) anti-inflammatory agents such as, for example, p38 kinase inhibitors, PDE4 inhibitors, and TACE inhibitors; b) chemokine receptor antagonists such as, for example, thalidomide; c) leukotriene inhibitors; and d) other small molecule inhibitors of pro-inflammatory cytokine production.
• a patient e.g., a human
• the invention provides a method of treating a chemokine mediated disease, said disease being a pulmonary disease (e.g., COPD, asthma, or cystic fibrosis) comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, ⁇ -2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors
• Agents that belong to these classes include, but are not limited to, beclomethasone, mometasone, ciclesonide, budesonide, fluticasone, albuterol, salmeterol, formoterol, loratadine, desloratadine, tiotropium bromide, MSI-ipratropium bromide, montelukast, theophilline, cilomilast, roflumilast, cromolyn, ZD-4407, talnetant, LTB-019, revatropate, pumafentrine, CP- 955, AR-C-89855, BAY-19-8004, GW-328267, QAB-149, DNK-333, YM-40461 and TH-9506 (or pharmaceutically acceptable formulations thereof).
• the invention provides a method of treating a chemokine mediated disease, said disease being multiple sclerosis comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of methotrexate, cyclosporin, leflunimide, sulfasalazine, ⁇ -methasone, ⁇ - interferon, glatiramer acetate, prednisone,etonercept, infliximab, and formulations thereof.
• one or more compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of methotrexate, cyclosporin, leflunimide, sulfasalazine, ⁇ -methasone, ⁇ - interferon, glatiramer acetate, prednisone,etonercept
• the invention provides a method of treating a chemokine mediated disease, said disease being rheumatoid arthritis comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IV inhibitor, an anti-TNF- ⁇ compound, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2- selective inhibiitors, other classes of compounds indicated for the treatment of rheumatoid arthritis, and formulations thereof.
• the invention provides a method of treating a chemokine mediated disease, said disease being rheumatoid arthritis comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IV inhibitor, an anti-TNF- ⁇ compound, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective inhibitors.
• the invention provides a method of treating a chemokine mediated disease, said disease being stroke and cardiac reperfusion injury comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpllb/llla antagonist, anticoagulants, other compounds indicated for the treatment of rheumatoid arthritis and formulations thereof.
• one or more compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpllb/llla antagonist, anticoagulants, other compounds indicated for the treatment of rheumatoid arthritis and formulations thereof.
• the invention provides a method of treating a chemokine mediated disease, said disease being stroke and cardiac reperfusion injury comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpllb/llla antagonist, and anticoagulants.
• one or more compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpllb/llla antagonist, and anticoagulants.
• the invention provides a method of treating a chemokine mediated disease, said disease being stroke and cardiac reperfusion injury comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of aneffective amount of one or more compounds selected from the group consisting of tenecteplase, TPA,reteplase, abciximab, eftiifbatide, heparin and formulations thereof.
• This invention also provides novel compounds of formula (I), wherein said novel compounds are selected from the group consisting of:
• an effective amount means a therapeutically effective amount, e.g., an amount that provides a clinical response to the disease being treated.
• Examples of “one or more” include (a) 1 , 2 or 3, (b) 1 or 2, or (c) 1.
• Examples of "at least one" include (a) 1 , 2 or 3, (b) 1 or 2, or (c) 1.
• Alkyl means a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended. Preferred alkyl groups contain 1 to 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to 6 carbon atoms in the chain.
• Alkoxy means an alkyl-O group in which alkyl is as previously defined. Non- limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
• Alkenyl means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched. Where the number of carbon atoms is not specified, 2 to 20 carbons are intended. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 6 carbon atoms in the chain. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. Alkenylalkyl means that the alkenyl group is attached to the parent moiety through an alkyl group.
• Alkynyl means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched. Where the number of carbon atoms is not specified, 2 to 15 carbons are intended. Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. Alkynylalkyl means that the alkynyl group is attached to the parent moiety through an alkyl group.
• Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
• suitable aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and the like.
• Arylalkyl means an aryl-alkyl group in which the aryl and alkyl groups are as defined.
• suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to the parent moiety is through the alkyl group.
• Cycloalkyl means a non-aromatic ring system having 3 to 10 carbon atoms and one to three rings, preferably 5 to 10 carbon atoms. Preferred cycloalkyl rings contain 5 to 7 ring atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like.
• Cycloalkylalkyl means a cycloalkyl group attached to the parent moiety through an alkyl group. Non-limiting examples include cyclopropylmethyl, cyclohexylmethyl and the like.
• Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain 5 to 7 ring atoms.
• Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, norbornenyl and the like.
• Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
• Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
• Haloalkyl means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
• Heterocyclyl or “heterocyclic” means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Preferred heterocyclyls contain 5 to 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• heterocyclic acidic functional group is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like.
• Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
• Preferred heteroaryls contain 5 to 6 ring atoms.
• the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
• a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
• Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• chemokine mediated diseases include: psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs.
• anti-adhesion molecules examples include anti-CD11a (efalizumab), CD58- Fc (alefacept), anti-VLA (natalizumab), as well as small molecule antagonists of LFA-1 (such as IC-747), VLA-4 (such as GW559090), and LFA-3.
• leukotriene inhibitors include LTD4 receptor antagonists (e.g., Singulair), Zileuton, and inhibitors of 5-lipoxygenase.
• inhibitors of cytokine production examples include inhibitors of TNF- ⁇ such as thalidomide.
• TACE TNF- ⁇ converting enzyme
• methotrexate examples of other classes of compounds indicated for the treatment of rheumatoid arthritis.
• A is selected from the group consisting of: (1)
• B is selected from the group consisting of
• X is O, NH, or S; Z is 1 to 3;
• R 2 is selected from the group consisting of: hydrogen, OH, -C(O)OH, -SH, -SO 2 NR 13 R 14 , -NHC(O)R 13 , -NHSO 2 NR 13 R 14 , -NHSO 2 R 13 , -NR 13 R 14 , -C(O)NR 13 R 14 , -C(O)NHOR 13 , -C(O)NR 13 OH, - S(O 2 )OH, -OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups; each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, -OH, -CF 3 , -OCF 3 , -NO 2
• fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen
• R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R 9 is independently selected from the group consisting of: a) -R 1d , b) halogen, c) -CF 3 , d) -COR 13 , e) -OR 13 , f) -NR 13 R 14 , g) -NO2, h) -CN, i) -SO 2 R 13 , j) -SO 2 NR 13 R 14 , k) -NR 13 COR 14 ,
• each R 10 and R 11 is independently selected from the group consisting of R 13 , (e.g., hydrogen and alkyl (e.g., C-i to C 6 alkyl, such as methyl)), halogen, -CF 3 , -OCF 3 , -NR 13 R 14 , -NR 13 C(O)NR 13 R 14
• R 12 is selected from the group consisting of: hydrogen, -C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups; each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl
• -C(O)NR 13 R 14 and -SO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered heterocyclic ring), said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i.e., there is 1 to 3 substituents on the ring formed when the R 13 and R 14 groups are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, -C(O)OR 15 , -C(O)NR 15 R 16 , -SO
• each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
• R 17 is selected from the group consisting of: -SO 2 alkyl, -SO 2 aryl, -SO 2 cycloalkyl, and -SO 2 heteroaryl;
• R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, -C(O)R 19 ,
• each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;
• R 30 is selected from the group consisting of: alkyl, cycloalkyl, -CN, -NO 2 , or -SO 2 R 15 provided that R 15 is not H; each R 31 is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R 31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen and -CF 3 ; each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; g is 1 or 2; and t is O, 1 or 2.
• R 13 and R 14 are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl).
• Examples include, but are not limited to (1 ) -SO 2 NH 2 and (2) -SO 2 NR 13 R 14 wherein R 3 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example -SO2N(CH 3 ) 2 .
• R 3 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example -SO2N(CH 3 ) 2 .
• R 13 and R 14 are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). Examples include, but are not limited to -C(O)NR 13 R 14 wherein each R 13 and R 14 are the same or different alkyl group, e.g., the same alkyl group, such as, for example -C(O)N(CH 3 ) 2 .
• substituent A is preferably selected from the group consisting of:
• Substituent A in formula (I) is most preferably selected from the group consisting of:
• Substituent A in formula (I) is more preferably selected from the group consisting of:
• Substituent B in formula (I) is preferably selected from the group consisting of: wherein all substituents are as defined for formula (I).
• Substituent B in formula (I) is most preferably selected from the group consisting of:
• Substituent B in Formula (I) is more preferably selected from the group consisting of:
• Embodiment No. 1 is directed to the methods of this invention using compounds of formula (I) wherein B is: and all other substitutents are as defined for of formula (I).
• Embodiment No. 2 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 3 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 4 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 5 is directed to the methods of this invention using compounds of formula (I) wherein B is: and all other substitutents are as defined for of formula (I).
• Embodiment No. 6 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 7 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 8 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 9 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 10 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 11 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 12 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 13 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 14 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 15 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 16 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 17 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 18 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 19 is directed to the methods of this invention using compounds of formula (I) wherein B is selected from the group consisting of:
• R for this B group is selected from the group consisting of: -C(O)NR 1 13S R DD 1144
• Embodiment No. 20 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 21 is directed to the methods of this invention using compounds of formula (I) wherein B is
• R 13 and R 14 are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents are as defined in formula (I).
• Embodiment No. 22 is directed to the methods of this invention using compounds of formula (I) wherein B is wherein:
• R 2 is -OH and all other substituents are as defined in formula (I), or
• R 2 is-OH
• R 13 and R 14 are independently selected from the group, consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), or
• R 2 is-OH
• R 13 and R 14 are the same or different and alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), for example the same alkyl group, for example methyl, and
• Embodiment No. 23 is directed to the methods of this invention using compounds of formula (I) wherein B is
• R is selected from the group consisting of:
• Embodiment No. 24 is directed to the methods of this invention using compounds of formula (I) wherein B is
• R 3 is selected from the group consisting of:
• R is -OH, and all other substituents are as defined in formula (I).
• Embodiment No. 25 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 26 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH, and all other substituents are as defined in formula (I).
• Embodiment No. 27 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is as defined for compounds of formula (I)
• R 13 and R 14 are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents areas defined for compounds of formula (I).
• R 13 and R 14 are the same or different alkyl group.
• R 13 and R 14 are the same alkyl group.
• R 13 and R 14 are methyl.
• Embodiment No. 28 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 13 and R 14 are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents areas defined for compounds of formula (I).
• R 3 and R 14 are the same or different alkyl group.
• R 13 and R 14 are the same alkyl group.
• R 13 and R 14 are methyl.
• Embodiment No. 29 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in Embodiment No. 23, R 4 is H, R 5 is H, R 6 is H, and all other substituents are as defined for compounds of formula (I).
• Embodiment No. 30 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in Embodiment No. 24, R 4 is H, R 5 is H, R 6 is H, and all other substituents areas defined for compounds of formula (I).
• Embodiment No. 31 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in Embodiments Nos. 21 , 22, 25 and 26, except that R 13 and R 14 are each methyl, and all other substituents are as defined in formula (I).
• Embodiment No. 32 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 11 is H, and all other substituents are as defined in formula (I).
• Embodiment No. 33 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH, and all other substituents are as defined in formula (I).
• Embodiment No. 34 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 3 is -C(O)NR 13 R 14 , and all other substituents are as defined in formula (I).
• Embodiment No. 35 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 3 is -S(O) t NR 3 R 14 (e.g., t is 2), and all other substituents are as defined in formula
• Embodiment No. 36 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 37 of this invention is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula (I).
• Embodiment No. 38 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -C(O)NR 13 R 14
• R 11 is H
• all other substituents are as defined in formula (I).
• Embodiment No. 39 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -S(O) t NR 13 R 14 (e.g., t is 2)
• R 11 is H
• all other substituents are as defined in formula (I).
• Embodiment No. 40 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -C(O)NR 13 R 14
• R 11 is H
• R 13 and R 14 are independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula (I).
• R 13 or R 14 is alkyl (e.g., methyl).
• An example of a substituted heteroaryl group is
• Embodiment No. 41 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -S(0) t NR 3 R 14 (e.g., t is 2)
• R 11 is H
• R 13 and R 14 are independently selected from the group consisting of:H and alkyl (e.g., methyl, ethyl, isopropyl, and t-butyl), and all other substituents are as defined in formula (I).
• R 3 is (1) -SO 2 NH 2 and (2) -SO 2 NR 13 R 14 wherein R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example -SO 2 N(CH 3 ) 2 .
• R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example -SO 2 N(CH 3 ) 2 .
• Embodiment No. 42 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 11 is H, and all other substituents are as defined in formula (I).
• Embodiment No. 43 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R is -OH, and all other substituents are as defined in formula(l).
• Embodiment No. 44 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 3 is -C(O)NR 13 R 14 , and all other substituents are as defined in formula (I).
• Embodiment No. 45 is directed to the methods of this invention using compounds of formula (I) wherein B is: R 3 is -S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula
• Embodiment No. 46 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• Embodiment No. 47 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula (I).
• Embodiment No. 48 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -C(O)NR 13 R 14
• R 11 is H
• all other substituents are as defined in formula (I).
• Embodiment No. 49 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -S(O) t NR 13 R 14 (e.g., t is 2)
• R 11 is H
• all other substituents are as defined in formula (I).
• Embodiment No. 50 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -C(O)NR 13 R 14
• R 11 is H
• R 13 and R 14 are independently selected from the group consisting of: alkyl, unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula (I).
• one of R 13 or R 14 is alkyl (e.g., methyl).
• An example of a substituted heteroaryl group is
• Embodiment No. 51 is directed to the methods of this invention using compounds of formula (I) wherein B is:
• R 2 is -OH
• R 3 is -S(O) t NR 13 R 14 (e.g., t is 2)
• R 11 is H
• R 13 and R 14 are independently selected from the group consisting of:H and alkyl (e.g., methyl, ethyl, isopropyl, and t- butyl), and all other substituents are as defined in formula (I).
• R 3 is
• Embodiment No. 52 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of: wherein R 2 to R 6 and R 10 to R 14 are as defined above for the compounds of formula (I).
• Embodiment No. 53 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
• R 2 is selected from the group consisting of: H, OH, -NHC(O)R 13 or and -NHSO 2 R 13 ;
• R 3 is selected from the group consisting of: -SO 2 NR 13 R 14 , -NO 2 , cyano, -C(O)NR 13 R 14 , -SO 2 R 13 ; and -C(O)OR 13 ;
• R 4 is selected from the group consisting of: H, -NO 2 , cyano, -CH 3 , halogen, and -CF 3 ;
• R 5 is selected from the group consisting of: H, -CF 3 , -NO 2 , halogen and cyano
• R 6 is selected from the group consisting of: H, alkyl and -CF 3
• each R 10 and R 11 is independently selected from the group consisting of: R 13 , hydrogen, halogen, -CF 3 , -NR 13 R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)OR 13 , -SH, -SO ( t ) NR 13 R 14 ,-SO 2 R 13 , -NHC(O)R 13 , -NHSO 2 NR 13 R 14 , -NHSO 2 R 13 , -C(O)NR 13 R 14 , -C(O)NR 13 OR 14 , -OC(O)R 13 , -COR 13 , -OR 13 , and cyano; each R 13 and R 14 is independently selected from the group consisting of: H, methyl, e
• each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i.e., the substituents on the ring formed when R 13 and R 14 are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, -C(O)OR 15 , -C(O)NR 15 R 16 , -SO t NR 15 R 16 , -C(O)R 15 , -SO 2 R 15 provided that R 15
• Embodiment No. 54 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
• R 2 is selected from the group consisting of: H, OH, -NHC(O)R 13 and -NHSO 2 R 13 ;
• R 3 is selected from the group consisting of: -C(O)NR 13 R 14 , -SO 2 NR 13 R 14 , -NO 2 , cyano, -SO 2 R 13 ; and -C(O)OR 13 ;
• R 4 is selected from the group consisting of: H, -NO 2 , cyano, -CH 3 or -CF 3 ;
• R 5 is selected from the group consisting of: H, -CF 3 , -NO 2 , halogen and cyano;
• R 6 is selected from the group consisting of: H, alkyl and -CF 3 ;
• R 11 is selected from the group consisting of: H, halogen and alkyl; and each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or R 13 and R 14 when taken together with the nitrogen they are attached to in the groups -NR 13 R 14 , -C(O)NR 13 R 14 , -SO 2 NR 13 R 14 , -OC(O)NR 13 R 14 , -CONR 13 R 14 , -NR 13 C(O)NR 13 R 14 , -SO t NR 13 R 14 , -NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from O, S or NR 18 wherein R 18 is selected from H, alkyl, aryl, heteroaryl, -C(O)R 19 , -SO 2 R 19 and -C(O)NR 19
• R 2 is selected from the group consisting of: H, OH, -NHC(O)R 13 and -NHSO 2 R 13 ;
• R 3 is selected from the group consisting of: -C(O)NR 13 R 14 -SO 2 NR 13 R 14 , -NO 2 , cyano, and -SO 2 R 13 ;
• R 4 is selected from the group consisting of: H, -NO 2 , cyano, -CH 3 or -CF 3 ;
• R 5 is selected from the group consisting of: H, -CF3, -NO 2 , halogen and cyano;
• R 6 is selected from the group consisting of: H, alkyl and -CF 3 ;
• R 11 is selected from the group consisting of: H, halogen and alkyl; and each R 3 and R 14 is independently selected from the group consisting of: H, methyl and ethyl.
• Embodiment No. 56 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
• R 2 is -OH
• R 3 is selected from the group consisting of: -SO 2 NR 13 R 14 and -CONR 13 R 14 ;
• R 4 is selected form the group consisting of: H, -CH 3 and -CF 3 ;
• R 5 is selected from the group consisting of: H and cyano;
• R 6 is selected from the group consisting of: H, -CH 3 and -CF 3; R 11 is H; and
• R 13 and R 14 are independently selected from the group consisting of H and methyl (e.g., for -SO 2 NR 13 R 14 both R 13 and R 14 are H, or both R 13 and R 14 are methyl, also, for example, for -CONR 13 R 14 both R 13 and R 14 are methyl).
• Embodiment No. 57 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of: wherein all substituents are as defined for formula (I).
• Embodiment No. 58 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
• Embodiment No. 59 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
• Embodiment No. 60 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, -CO 2 R 13 , -CONR 13 R 14 , fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R 7 and R 8 substituted groups are selected from the group consisting of: a) cyano, b) -CO 2 R 13 , c) -C(O)NR 13 R 14 , d) -SO 2 NR 13 R 14 , e)
• Embodiment No. 61 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF 3 and -CF 2 CH 3 ), cycloalkyl (e.g.,cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, -CF 3 , cyano, -OCH 3 , and -NO 2 ; and
• each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF 3 and -CF 2 CH 3 ), cycloalkyl (e.g.,cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R 8a is as defined in formula (I), and wherein R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, -CF 3 , cyano, -OCH 3 , and -NO 2 ; each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -
• Embodiment No. 62 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• R 7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl
• R 8 is selected form the group consisting of: H, alkyl, -CF 2 CH 3 and -CF 3
• R 9 is selected from the group consisting of: H, F, Cl, Br, alkyl or -CF 3 ;
• V X 8a R' wherein R 7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R 8 is selected form the group consisting of: H, alkyl, -CF 2 CH 3 and -CF 3 ; and R 8a is as defined for formula (I).
• Embodiment No. 63 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• R 7 is selected from the group consisting of: H, -CF 3 , -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and (b)
• R 7 is selected from the group consisting of: H, -CF3, -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula (I).
• Embodiment No. 64 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• R 7 is selected from the group consisting of: H, -CF 3 , -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
• R 7 is selected from the group consisting of: H, -CF 3 , -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula IA;
• Embodiment No. 65 is directed compounds of formula (I) wherein substituent A is selected from the group consisting of:
• Embodiment No. 66 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• Embodiment No. 67 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• Embodiment No. 68 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
• Embodiment No. 69 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is as defined in any one of the Embodiment Nos. 60 to 68.
• Embodiment No. 70 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
• Embodiment No. 71 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
• Embodiment No. 72 is directed to the methods of this invention using compounds of formula (1) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
• Embodiment No. 73 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
• furan ring is unsubstituted or substituted as described in the definition of A for formula (1), and all other substituents are as defined for formula (I).
• Embodiment No. 74 is directed to the methods of this invention using compounds of formula (I) wherein B is described in any one of the Embodiment Nos. 1 to 59, and A is
• Embodiment No. 75 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is
• Embodiment No. 76 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, A is
• furan ring is substituted with one alkyl group and all other substituents are as defined for formula (I).
• Embodiment No. 77 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is
• furan ring is substituted with one C ⁇ to C 3 alkyl group (e.g., methyl or isopropyl), and all other substituents are as defined for formula (I).
• C ⁇ to C 3 alkyl group e.g., methyl or isopropyl
• Embodiment No. 78 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is as defined in any one of the Embodiment Nos. 73 to 77, except that R 7 and R 8 are the same or different and each is selected from the group consisting of: H and alkyl.
• Embodiment No. 79 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is as defined in any one of the Embodiment Nos. 73 to 77, except that R 7 is H, and R 8 is alkyl (e.g., ethyl or t-butyl).
• Embodiment No. 80 is directed to the methods of this invention using compounds of formula (I) wherein:
• each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, -CO 2 R 13 , -CONR 13 R 14 , fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R 7 and R 8 substituted groups are selected from the group consisting of: a) cyano, b) -CO 2 R 13 , c) -C(O)NR 13 R 14 , d) -SO 2 NR 13 R 14 , e)
• R 2 to R 6 and R 10 to R 14 are as defined above for the compounds of formula (I).
• Embodiment No. 81 is directed to the methods of this invention using compounds of formula (I) wherein:
• each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF 3 and -CF 2 CH 3 ), cycloalkyl (e.g..cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, -CF 3 , cyano, -OCH 3) and -NO 2 ; and (b)
• each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF 3 and -CF 2 CH 3 ), cycloalkyl (e.g..cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R 8a is as defined in formula (I), and wherein R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, -CF3, cyano, -OCH 3 , and -NO 2 ; each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF),
• R 2 is selected from the group consisting of: H, OH, -NHC(O)R 13 or and -NHSO2R 13 ;
• R 3 is selected from the group consisting of: -SO 2 NR 13 R 14 , -NO 2 , cyano,
• R 4 is selected from the group consisting of: H, -NO2, cyano, -CH3, halogen, and -CF 3 ;
• R 5 is selected from the group consisting of: H, -CF3, -NO 2 , halogen and cyano
• R 6 is selected from the group consisting of: H, alkyl and -CF3
• each R 10 and R 11 is independently selected from the group consisting of: R 13 , hydrogen, halogen, -CF 3 , -NR 13 R 14 , -NR 13 C(O)NR 13 R 14 , -C(O)OR 13 , -SH, -SO (t )NR 13 R 4 ,-SO 2 R 13 , -NHC(O)R 13 , -NHSO 2 NR 13 R 14 , -NHSO 2 R 13 , -C(O)NR 13 R 14 , -C(O)NR 13 OR 14 , -OC(O)R 13 , -COR 13 , -OR 13 , and cyano; each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl and
• Embodiment No. 82 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is even more preferably selected from the group consisting of:
• R 7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl
• R 8 is selected form the group consisting of: H, alkyl, -CF 2 CH 3 and -CF 3
• R 9 is selected from the group consisting of: H, F, Cl, Br, alkyl or -CF 3 ;
• R 7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl
• R 8 is selected form the group consisting of: H, alkyl, -CF 2 CH 3 and -CF
• R 8a is as defined for formula (I).
• Embodiment No. 83 is directed to the methods of this invention using compounds of formula (I) wherein:
• substituent A is selected from the group consisting of: (a)
• R 7 is selected from the group consisting of: H, -CF 3 , -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
• R 7 is selected from the group consisting of: H, -CF 3 , -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula (I); and
• R 2 is selected from the group consisting of: H, OH, -NHC(O)R 13 and -NHSO 2 R 13 ;
• R 3 is selected from the group consisting of: -C(O)NR 13 R 14 , -SO 2 NR 13 R 14 , -NO 2 , cyano, -SO 2 R 13 ; and -C(O)OR 13 ;
• R 4 is selected from the group consisting of: H, -NO 2 , cyano, -CH 3 or -CF 3 ;
• R is selected from the group consisting of: H, -CF 3 , -NO 2 , halogen and cyano;
• R 6 is selected from the group consisting of: H, alkyl and -CF 3 ;
• R 11 is selected from the group consisting of: H, halogen and alkyl; and each R 13 and R is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or
• R 13 and R 14 when taken together with the nitrogen they are attached to in the groups -NR 13 R 14 , -C(O)NR 13 R 14 , -SO 2 NR 13 R 14 , -OC(O)NR 13 R 14 , -CONR 13 R 14 , -NR 13 C(O)NR 13 R 1 ⁇ -SO t NR 13 R 14 , -NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from O, S or NR 18 wherein R 18 is selected from H, alkyl, aryl, heteroaryl, -C(0)R 19 , -SO 2 R 19 and -C(O)NR 19 R 20 , wherein each R 19 and R 20 is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i.e., on
• Embodiment No. 84 is directed to the methods of this invention using compounds of formula (I) wherein: (1 ) substituent A is selected from the group consisting of:
• R 7 is selected from the group consisting of: H, -CF 3 , -CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
• R 7 is selected from the group consisting of: H, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula (I); (2) substituent B is selected from the group consisting of:
• R 2 is selected from the group consisting of: H, OH, -NHC(O)R 13 and
• R 3 is selected from the group consisting of: -C(O)NR 13 R 14 -SO 2 NR 13 R 14 , -NO 2 , cyano, and -SO 2 R 13 ;
• R 4 is selected from the group consisting of: H, -NO , cyano, -CH 3 or -CF 3 ;
• R 5 is selected from the group consisting of: H, -CF 3 , -NO 2 , halogen and cyano;
• R 6 is selected from the group consisting of: H, alkyl and -CF 3 ;
• R 11 is selected from the group consisting of: H, halogen and alkyl; and each R 13 and R 14 is independently selected from the group consisting of: H, methyl and ethyl.
• Embodiment No. 85 is directed to the methods of this invention using compounds of formula (I) wherein:
• R 2 is -OH
• R 3 is selected from the group consisting of: -SO 2 NR 13 R 14 and -CONFER" * ;
• R 4 is selected form the group consisting of: H, -CH3 and -CF 3 ;
• R 5 is selected from the group consisting of: H and cyano;
• R 6 is selected from the group consisting of: H, -CH3 and -CF 3;
• R 11 is H
• R 13 and R 14 are independently selected from the group consisting of H and methyl (e.g., for -SO 2 NR 13 R 14 both R 13 and R 14 are H, or both R 13 and R 14 are methyl, also, for example, for -CONR 13 R 14 both R 13 and R 14 are methyl).
• Embodiment No. 86 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 65 and substituent B is as defined in Embodiment No. 57.
• Embodiment No. 87 is directed to the methods of this invention using compounds of formula (1) wherein substituent A is as defined in Embodiment No. 65 and substituent B is as defined in Embodiment No. 58.
• Embodiment No. 88 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 65 and substituent B is as defined in Embodiment No. 59.
• Embodiment No. 89 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 66 and substituent B is as defined in Embodiment No. 57.
• Embodiment No. 90 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 66 and substituent B is as defined in Embodiment No. 58.
• Embodiment No. 91 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 66 and substituent B is as defined in Embodiment No. 59.
• Embodiment No. 92 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 67 and substituent B is as defined in Embodiment No. 57.
• Embodiment No. 93 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 67 and substituent B is as defined in Embodiment No. 58.
• Embodiment No. 94 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 67 and substituent B is as defined in Embodiment No. 59.
• Embodiment No. 95 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 68 and substituent B is as defined in Embodiment No. 57.
• Embodiment No. 96 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 68 and substituent B is as defined in Embodiment No. 58.
• Embodiment No. 97 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 68 and substituent B is as defined in Embodiment No. 59.
• Embodiment No. 98 is directed to the methods of this invention using compounds of formula (I) as defined in any one of the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is a pharmaceutically acceptable salt.
• Embodiment No. 99 is directed to the methods of this invention using compounds of formula (I) as defined in any one of the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is a sodium salt.
• Embodiment No. 100 is directed to the methods of this invention using compounds of formula (I) as defined in any one of the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is a calcium salt.
• Embodiment No. 101 is directed to the methods of this invention using a pharmaceutically acceptable salt of any one of the representative compounds of formula (I) described below.
• Embodiment No. 102 is directed to the methods of this invention using a sodium salt of any one of the representative compounds of formula (I) described below.
• Embodiment No. 103 is directed to the methods of this invention using a calcium salt of any one of the representative compounds of formula (I) described below.
• Embodiment No. 104 is directed to the methods of this invention using a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1 ) compound of formula (I) as described in any one of the Embodiment Nos. 1 to 103 in combination with a pharmaceutically acceptable carrier (or diluent).
• Embodiment No. 105 is directed to a pharmaceutically acceptable salt of a novel compound of formula (I), wherein said compound is selected from the group consisting of:
• Embodiment No. 106 is directed to a calcium salt of any one of the novel compounds of formula (I) described in Embodiment No. 105.
• Embodiment No. 107 is directed to a sodium salt of any one of the novel compounds of formula (I) described in Embodiment No. 105.
• Embodiment No. 108 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) novel compound of formula (I) as described in
• Embodiment No. 105 in combination with a pharmaceutically acceptable carrier (or diluent).
• Representative compounds of formula (I) useful in the methods of this invention include but are not limited to:
• Preferred compounds of formula (I) useful in the methods of this invention include:
• a more preferred group of compounds of formula (I) useful in the methods of this invention include:
• a most preferred group of compounds of formula (I) useful in the methods of this invention include:
• Certain compounds of formula (I) may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers).
• the invention contemplates all such stereoisomers both in pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional methods.
• Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
• Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts.
• the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids.
• suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
• the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
• the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
• This invention also includes Prodrugs of the novel compounds of this invention, and of the compounds of formula (I) useful in the methods of this invention.
• the term "prodrug,” as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20 th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD..
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
• the compounds of formula (I) may also be deliverable transdermally.
• the transdermal composition can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compound of formula (I) is administered orally.
• the pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art.
• the total dosage may be divided and administered in portions during the day as required.
• the amount and frequency of administration of the compounds of formula (I) and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
• a typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.
• the compounds used in combination with the compounds of formula (I) can be administered in their normally prescribed amounts as know by the skilled clinician (see, for example, the Physicians' Desk Reference, 56 th edition, 2002, published by Medical Economics company, Inc. at Montvale, NJ 07645-1742, the disclosure of which is incorporated herein by reference thereto).
• the amount and frequency of administration of the compounds used in combination with the compounds of formula (I) will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
• BIOLOGICAL ASSAYS The compounds of formula (I) are useful in the treatment of CXC-chemokine mediated conditions and diseases. This utility is manifested in their ability to inhibit IL- 8 and GRO- ⁇ chemokine as demonstrated by the following in vitro assays.
• a reaction mixture of 10 ⁇ g hCXCR1-CHO overexpressing membranes (Biosignal) and 200 ⁇ g/well WGA-SPA beads (Amersham) in 100 ⁇ l was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCI 2 , 1mM MgCI 2 , 125 mM NaCI, 0.1% BSA) (Sigma).
• CXCR1 assay buffer 25 mM HEPES, pH 7.8, 2 mM CaCI 2 , 1mM MgCI 2 , 125 mM NaCI, 0.1% BSA
• a 0.4 nM stock of ligand, [125l]-IL-8 (NEN) was prepared in the CXCR1 assay buffer.
• 20X stock solutions of test compounds were prepared in DMSO (Sigma).
• a 6 X stock solution of IL-8 (R&D) was prepared in CXCR2 assay buffer.
• the assay plates were shaken for 5 minutes on plate shaker, then incubated for 8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of Total binding-NSB (250 nM IL-8) was determined for IC 0 values.
• a working stock of 0.25 ⁇ g/ ⁇ l hCXCR1-CHO over- expressing membranes with a specific activity of 0.05 pmol/mg (Biosignal Packard) and 25 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 0.1 mM CaCI 2 , 1 mM MgCI 2 , 100 mM NaCI) (Sigma). This mixture was incubated on ice for 30 minutes and then centrifuged at 2500 rpm for 5 minutes. The beads and membranes were resuspended in CXCR1 assay buffer to the same concentrations as in the original mixture.
• a working stock of 0.025 ⁇ g/ ⁇ l hCXCR1-CHO over- expressing membranes with a specific activity of 3.47 pmol/mg (Euroscreen) and 5 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2.0 mM CaCI 2 , 1mM MgCI 2 , 125 mM NaCI) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.125 nM stock of ligand, [ 125 I]-IL- 8 (Perkin Elmer Life Sciences), was prepared in the CXCR1 assay buffer.
• a reaction mixture of 4 ⁇ g hCXCR2-CHO overexpressing membranes (Biosignal) and 200 ⁇ g/well WGA-SPA beads (Amersham) in 100 ⁇ l was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, % mM CaCI 2 , 1mM MgCI 2 ).
• a 0.4 nM stock of ligand, [125l]-IL-8 (NEN) was prepared in the CXCR2 assay buffer.
• 20X stock solutions of test compounds were prepared in DMSO (Sigma).
• a 6 X stock solution of GRO- ⁇ (R&D) was prepared in CXCR2 assay buffer.
• a working stock of 0.031 ⁇ g/ ⁇ l hCXCR2-CHO over- expressing membranes with a specific activity of 0.4 pmol/mg (Biosignal Packard) and 2.5 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCI 2 , 1 mM MgCI 2 ) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.50 nM stock of ligand, [ 125 l]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR2 assay buffer.
• Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 13.3-fold in CXCR2 assay buffer.
• the assay plates were incubated for 2 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). TC- 50 values were quantified using nonlinear regression analysis in GraphPad Prism.
• a working stock of 0.02 ⁇ g/ ⁇ l hCXCR2-CHO over- expressing membranes with a specific activity of 0.6 pmol/mg (Biosignal Packard) and 2 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCI 2 , 1 mM MgCI 2 ) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.40 nM stock of ligand, [ 25 l]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR2 assay buffer.
• Carrageenan (0.05 ml of an I % solution in saline) was injected into one hindpaw of male Sprague-Dawley rats. Paw volumes (ml) were measured by a water displacement plethysmometer prior to and 3 h after the injection of carrageenan. The increase in paw volume that occurred between the two timepoints was determined for each group. Rats received Compound A:
• a neutralizing rat anti- mouse TNF ⁇ antibody or matched rat IgG isotype control was administered intraperitoneally two hours prior to SCW injection and Compound A or methylcellulose vehicle was orally administered one hour prior to SCW injection.
• Knee swelling measurements were performed 2 hours after SCW injection using a dial-gauge caliper (Starret, Athol, MA) by measuring the difference in swelling between the right and left knee joints.
• Patellar organ cultures for assessment of synovial cytokine and chemokine and prostaglandin levels were prepared at 2 hours after SCW injection and established as described (Lubberts et al, 1998), using ELISA kits obtained from R&D Systems (Minneapolis, MN).
• the aminobenzamide of Scheme 1 is first condensed with commercially available diethylsquarate to give an alternate monoethoxy intermediate. Condensation of this intermediate with an amine gives the desired chemokine antagonist.
• Benztriazole compounds of Formula (I) are prepared by stirring nitrophenylenediamines with sodium nitrite in acetic acid at 60°C to afford the nitrobenzotriazole intermediate (Scheme 3). Reduction of the nitro group in the presence of palladium catalyst and hydrogen atmosphere provides the amine compound. Subsequent condensation of this intermediate with the aminooethoxysquarate prepared earlier (Scheme 1 ) provides the desired chemokine antagonist.
• Scheme 4 Condensation of nitrophenylenediamines with anhydrides or activated acids at reflux (Scheme 4) affords benzimidazole intermediates which after reduction with hydrogen gas and palladium catalyst and condensation with the aminoethoxysquarate previously prepared (Scheme 1 ) affords benzimidazole chemokine antagonists.
• Indazole structures of Formula (I) can be prepared according to Scheme 5 by reduction of nitroindazole A (J. Am. Chem Soc. 1943, 65, 1804-1805) to give aminoindazole B and subsequent condensation with the aminoethoxysquarate prepared earlier (Scheme 1 ).
• Indole structures of Formula (I) can be prepared according to Scheme 6 by reduction of nitroindole A (J. Med. Chem. 1995, 38, 1942-1954) to give aminoindole B and subsequent condensation with the aminoethoxysquarate prepared earlier (Scheme 1 ).
• Step B The product from Step A above (4.5 g) was dissolved in dichloromethane (140 mL) and added with triethylamine (8.8 mL) followed by diethyl amine in THF (2M, 21 mL). The resulting mixture was stirred at room temperature overnight. The mixture was washed with brine and saturated bicarbonate (aq) and brine again, dried over sodium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.4 g).
• step C above The product from step C above (3.96 g) was dissolved in 125 mL of dichloromethane, and added with potassium carbonate (6.6 g) followed by bromine (2 mL). The mixture was stirred for 5 h at room temperature, quenched with 100 mL of H 2 O. The aqueous mixture was addjusted to pH ⁇ 5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with a 10 % Na 2 S 2 O 3 aqueous solution and brine, dried over sodium sulfate, and filtered through a celite pad. The filtrate was concentrated in vacuo to afford 4.2 g of the desired bromo-compound. Ste E
• Step D The product from Step D (4.2 g) was dissolved in 100 mL of acetone and added with potassium carbonate (10 g) followed by iodomethane (9 mL). The mixture was heated to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatography eluting with dichloromethane-hexanes (1 :1 , v/v) to give 2.7 g of the desired product.
• step E The product from step E (2.7 g) was converted to the desired imine compound
• the imine product from step F (3 g) was dissolved in 80 mL of dichloromethane and cooled in a -78°C bath. A solution of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. The mixture was stirred for 4.25 h from -78°C to 5°C. H 2 O (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed with brine, and concentrated to an oily residue.
• Step E The product from Step E (1.34 g, 4.45 mmol) was methylated using the procedure set forth in Preparative Example 13.29, Step E.
• Step C To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol) in
• the imine product obtained from Step F above (0.29 g, 0.61 mmol) was demethylated using the procedure set forth in Step C above to give the corresponding alcohol as a dark yellow oil, which was dissolved in 5 mL methanol and added with sodium acetate (0.12 g, 1.46 mmol) and hydroxyamine hydrochloride (0.075 g, 1.08 mmol). The resulting mixture was stirred at room temperature for 3 h, and poured into 10 mL of 1.0 M NaOH aqueous solution. 30 mL of H 2 O was used as rinsing and combined to the aqueous layer.
• step B alcohol was obtained following a similar procedure set forth in the preparative example 13.35 Step B.
• the imine was prepared following the procedure set forth in WO 02/083624
• Step A product (0.6g) was reacted following the procedure set forth in the preparative example 13.19 to give the amine product 0.19g (64%).
• Step B product (1.0g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 to give the acid as yellow solid 0.9g (94%).
• Step C product (0.35g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 to give the amino acid as yellow solid 0.167g (93%).
• Step C If one were to use a similar procedure to that used in WO 02/083624 Preparative Example 13.19 Step B, except using the product from Step A above, one would obtain the desired compound. Step C
• Step B If one were to treat the product from Step C of WO 02/083624 Example 1125 with BuLi (2.2 eq.) in THF followed by quenching of the reaction mixture with N,N,- dimethylsulfamoyl chloride (1.1 eq.) then one would obtain the title compound. Step B
• step C above The product from step C above (3.96 g) was dissolved in 125 mL of dichloromethane, and added with potassium carbonate (6.6 g) followed by bromine (2 mL). The mixture was stirred for 5 h at room temperature, quenched with 100 mL of H 2 O. The aqueous mixture was addjusted to pH ⁇ 5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with brine, dried over sodium sulfate, and filtered through a celite pad. The filtrate was concentrated in vacuo to afford 4.2 g of the desired bromo-compound.
• Step E The product from Step D (4.2 g) was dissolved in 100 mL of acetone and added with potassium carbonate (10 g) followed by iodomethane (9 mL). The mixture was heated to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatography eluting with dichloromethane-hexanes (1 :1 , v/v) to give 2.7 g of the desired product.
• Step F The product from Step D (4.2 g) was dissolved in 100 mL of acetone and added with potassium carbonate (10 g) followed by iodomethane (9 mL). The mixture was heated to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatography
• step E The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of WO 02/083624 Preparative Example 13.19 step D.
• the imine product from step F (3 g) was dissolved in 80 mL of dichloromethane and cooled in a -78°C bath. A solution of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. The mixture was stirred for 4.25 h from -78°C to 5°C. H 2 O (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed with brine, and concentrated to an oily residue.
• Step D the imine was prepared from the known bromoester (1.0g) to yield 1.1g (79%) as a yellow solid.
• Step A The product of Step A (0.6g) was reacted following the procedure set forth in
• Step B The product of Step B (1.0g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 Step B to give the acid as yellow solid 0.9g (94%).
• Step C The product of Step C (0.35g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 Step E to give the amino acid as yellow solid 0.167g (93%).
• Step B To a solution of ketone (1.0g) from Step A above in THF (5.0mL) at 0°C was added f?-methyl oxazoborolidine (1.2mL, 1M in toluene) dropwise followed by addition of a solution of borane complexed with dimethyl sulfide (1.85mL, 2M in THF). The reaction mixture was stirred for 30minut.es at 0°C and than at room temperature for one hour. The reaction mixture was cooled to 0°C and MeOH was added carefully. The mixture was stirred for 20 minutes and was concentrated under reduced pressure.
• Step A An equimolar mixture of 2-methylfuran (1.0g) and anhydride (2.6g) was mixed with SnCI 4 (0.05mL) and heated at 100°C for 3 hours. After cooling the reaction mixture, water (10mL) was added, followed by saturated sodium carbonate solution until it becomes alkaline. The reaction mixture was extracted with ether several times and the combined ether layer was washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using silica gel chromatography to afford the ketone 0.9g (43%) as a yellow oil.
• Step B The title alcohol was obtained following a similar procedure set forth in

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