3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands

FIELD OF THE INVENTION

[0002] The present invention relates to novel substituted cyclobutenedione compounds, pharmaceutical compositions containing the compounds, and the use of the compounds and formulations in treating CXC chemokine-mediated diseases.

BACKGROUND OF THE INVENTION

[0003] 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. There are two main classes of chemokines, the CXC-chemokines and the CC-chemokines. The class depends on whether the first two cystepnes 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), GROα, GROβ, GROγ, ENA-78, GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES, MIP-1α, MIP-2β, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and 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. For example, IL-8 is bound by the CXCR-1 and CXCR-2 receptors.

[0004] Since 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).

[0005] ELRCXC chemokines including IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 (Strieter et al. 1995 JBC 270 p. 27348-57) have also been implicated in the induction of tumor angiogenesis (new blood vessel growth). All of these chemokines are believed to exert their actions by binding to the 7 transmembrane G-protein coupled receptor CXCR2 (also known as IL-8RB), while IL-8 also binds CXCR1 (also known as IL-8RA). Thus, their angiogenic activity is due to their binding to and activation of CXCR2, and possible CXCR1 for IL-8, expressed on the surface of vascular endothelial cells (ECs) in surrounding vessels.

[0006] Many different types of tumors have been shown to produce ELRCXC chemokines and their production has been correlated with a more aggressive phenotype (Inoue et al. 2000 Clin Cancer Res 6 p. 2104-2119) and poor prognosis (Yoneda et. al. 1998 J Nat Cancer Inst 90 p.447-454). Chemokines are potent chemotactic factors and the ELRCXC chemokines have been shown to induce EC chemotaxis. Thus, these chemokines probably induce chemotaxis of endothelial cells toward their site of production in the tumor. This may be a critical step in the induction of angiogenesis by the tumor. Inhibitors of CXCR2 or dual inhibitors of CXCR2 and CXCR1 will inhibit the angiogenic activity of the ELRCXC chemokines and therefore block the growth of the tumor. This anti-tumor activity has been demonstrated for antibodies to IL-8 (Arenberg et al. 1996 J Clin Invest 97 p. 2792-2802), ENA-78 (Arenberg et al. 1998 J Clin Invest 102 p.465-72), and GROα (Haghnegahdar et al. J. Leukoc Biology 2000 67 p. 53-62).

[0007] Many tumor cells have also been shown to express CXCR2 and thus tumor cells may also stimulate their own growth when they secrete ELRCXC chemokines. Thus, along with decreasing angiogenesis, inhibitors of CXCR2 may directly inhibit the growth of tumor cells.

[0008] Hence, the CXC-chemokine receptors represent promising targets for the development of novel anti-inflammatory and anti-tumor agents.

[0009] There remains a need for compounds that are capable of modulating activity at CXC-chemokine receptors. For example, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cell subsets into the inflammatory site and growth of tumors) would benefit by compounds that are inhibitors of IL-8 receptor binding.

SUMMARY OF THE INVENTION

[0010] This invention provides a method of treating a chemokine mediated disease in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of formula IA, as described below

[0011] This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of formula IA, as described below.

[0012] This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of formula IA, as described below, concurrently or sequentially with: (a) a microtubule affecting agent, or (b) an antineoplastic agent, or (c) an anti-angiogenesis agent, or (d) a VEGF receptor kinase inhibitor, or (e) antibodies against the VEGF receptor, or (f) interferon, and/or g) radiation.

[0013] This invention also provides a method of inhibiting angiogenesis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0014] This invention also provides a method of treating angiogenic ocular disease (e.g., ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization) in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0015] This invention also provides a method of treating a disease selected from the group consisting of: gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma associated virus and atherosclerosis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0016] This invention also provides a method of treating acute inflammatory pain, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0017] This invention also provides a method of treating chronic inflammatory pain, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0018] This invention also provides a method of treating acute neuropathic pain, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0019] This invention also provides a method of treating chronic neuropathic pain, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA, as described below.

[0020] This invention also provides a method of treating COPD, in a patient in need of such treatment, comprising administering to said patient and effective amount of at least one compound of formula IA as described below.

[0021] This invention also provides a method of treating acute inflammation, in a patient in need of such treatment, comprising administering to said patient and effective amount of at least one compound of formula IA as described below.

[0022] This invention also provides a method of treating chronic inflammation, in a patient in need of such treatment, comprising administering to said patient and effective amount of at least one compound of formula IA as described below.

[0023] This invention also provides a method of treating rheumatoid arthritis, in a patient in need of such treatment, comprising administering to said patient and effective amount of at least one compound of formula IA as described below.

[0024] This invention also provides novel compounds of formula IA, as described below.

[0025] This invention also provides a pharmaceutical composition comprising at least one (e.g., 1-3, usually 1) compound of formula IA, as described below, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0026] When any variable occurs more than one time in any moiety, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0027] Unless indicated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. For example, the definition of “alkyl” also applies to the “alkyl” portion of “alkoxy”.

[0028] “At least one” represents, for example, 1, or 1-2, or 1-3.

[0029] “Patient” includes both human and other mammals, preferably human.

[0030] “Mammal” includes a human being, and preferably means a human being.

[0031] “Alkyl” means a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.

[0032] “Alkoxy” means an alkyl-O-group wherein alkyl is as defined above. 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.

[0033] “Alkenyl” means a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon double bond, and 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include: ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

[0034] “Alkynyl” means a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon triple bond, and 2 to 15 carbon atoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

[0035] “Aryl” means an aromatic monocyclic or multicyclic ring system, wherein at least one ring is aromatic, comprising about 6 to about 14 carbon atoms, and preferably about 6 to about 10 carbon atoms. Non-limiting examples of suitable aryl groups include: phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

[0036] “Arylalkyl” means an aryl group, as defined above, bound to an alkyl group, as defined above, wherein the alkyl group is bound to the parent moiety. Non-limiting examples of suitable arylalkyl groups include benzyl, phenethyl and naphthleneylmethyl.

[0037] “Cycloalkyl” means saturated carbocyclic rings having 3 to 10 (e.g., 3 to 7) carbon atoms, preferably 5 to 10 carbon atoms, and more preferably 5 to 7 carbon atoms, and having one to three rings. Non-limiting examples of cycloalkyl groups include: cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0038] “Cycloalkylalkyl” means a cycloalkyl group bound to the parent moiety through an alkyl group. Non-limiting examples include: cyclopropylmethyl and cyclohexylmethyl.

[0039] “Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, and preferably 5 to 10 carbon atoms, and having at least one carbon-carbon double bond. Preferred cycloalkenyl rings have 5 to 7 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and norbornenyl.

[0040] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0041] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.

[0042] “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.

[0043] “Heterocyclyl” or “heterocyclic” or “heterocycloalkyl” means a non-aromatic saturated monocyclic or multicyclic ring system (i.e., a saturated carbocyclic ring or ring system) comprising 3 to 10 ring atoms (e.g., 3 to 7 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 have 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. Non-limiting examples of monocyclic heterocyclyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

[0044] The term heterocyclic acidic functional group is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like.

[0045] “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 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, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl.

[0046] “Heteroarylalkyl” means a heteroaryl group, as defined above, bound to an alkyl group, as defined above, where the bond to the parent moiety is through the alkyl group.

[0047] N-oxides can form on a tertiary nitrogen present in an R substituent, or on ═N— in a heteroaryl ring substituent and are included in the compounds of formula I.

[0048] 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.

[0049] As used herein, the term “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.

[0050] As used in the methods of this invention, “an effective amount” means a therapeutically acceptable amount (i.e., that amount which provides the desired therapeutic effective).

[0051] Also, as used herein, with reference to chemical structures or formulas, “Bn” represents benzyl, “Et” represents ethyl, “Me” represents methyl, and “Ph” represents phenyl.

[0052] Representative embodiments of this invention are described below. The embodiments have been numbered for purposes of reference thereto.

[0053] The methods of this invention use a compound of formula IA:

[0054] and the pharmaceutically acceptable salts (e.g., sodium or calcium salt) and solvates thereof, wherein:

[0055] A is selected from the group consisting of:

[0056] wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R9 groups;

[0057] wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R9 groups;

[0058] wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R9 groups; and

[0059] B is selected from the group consisting of

[0060] n is 0 to 6;

[0061] p is 1 to 5;

[0062] X is O, NH, or S;

[0063] Z is 1 to 3;

[0064] R2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO2NR13R14, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —NR13R14—C(O)NR13R14, —C(O)NHOR13, —C(O)NR13OH, —S(O2)OH, —OC(O)R13, 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: R9 groups;

[0065] each R3 and R4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —C(O)NR13R14, —SO(t)NR13R14, —SO(t)R13, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,

[0066] wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups;

[0067] each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NR13R14, —SO(t)NR13R14, —C(O)NR13OR14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups;

[0068] each R7 and R8 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, —CO2R13, —CONR13R14, alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more (e.g., 1 to 6) substituents on said substituted R7 and R8 groups, wherein each substitutent is independently selected from the group consisting of:

[0069] a) halogen,

[0070] b) —CF3,

[0071] c) —COR13,

[0072] d) —OR13,

[0073] e) —NR13R14

[0074] f) —NO2,

[0075] g) —CN,

[0076] h) —SO2OR13,

[0077] i) —Si(alkyl)3, wherein each alkyl is independently selected,

[0078] j) —Si(aryl)3, wherein each alkyl is independently selected,

[0079] k) —(R13)2R14Si, wherein each R13 is independently selected,

[0080] l) —CO2R13,

[0081] m) —C(O)NR13R14,

[0082] n) —SO2NR13R14,

[0083] o) —SO2R13,

[0084] p) —OC(O)R13,

[0085] q) —OC(O)NR13R14,

[0086] r) —NR13C(O)R14, and

[0087] s) —NR13CO2R14;

[0088] (fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen);

[0089] R8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;

[0090] each R9 is independently selected from the group consisting of:

[0091] a) —R13,

[0092] b) halogen,

[0093] c) —CF3,

[0094] d) —COR13,

[0095] e) —OR13,

[0096] f) —NR13R14

[0097] g) —NO2,

[0098] h) —CN,

[0099] i) —SO2R13,

[0100] j) —SO2NR13R14,

[0101] k) —NR13COR14,

[0102] l) —CONR13R14

[0103] m) —NR13CO2R14,

[0104] n) —CO2R13,

[0105] p) alkyl substituted with one or more (e.g., one) —OH groups (e.g., —(CH2)qOH, wherein q is 1-6, usually 1 to 2, and preferably 1),

[0106] q) alkyl substituted with one or more (e.g., one) —NR13R14 group (e.g., —(CH2)qNR13R14, wherein q is 1-6, usually 1 to 2, and preferably 1), and

[0107] r) —N(R13)SO2R14 (e.g., R13 is H and R14 is alkyl, such as methyl);

[0108] each R10 and R11 is independently selected from the group consisting of R13, hydrogen, alkyl (e.g., C1 to C6, such as methyl), halogen, —CF3, —OCF3, —NR13R14, —NR13C(O)NR13R14, —OH, —C(O)OR13, —SH, —SO(t)NR13R14, —SO2R13, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —C(O)NR13R14, —C(O)NR13OR14, —OC(O)R13 and cyano;

[0109] R12 is selected from the group consisting of: hydrogen, —C(O)OR13, 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 R12 groups and each substituent is independently selected from the group consisting of: R9 groups;

[0110] each R13 and R14 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, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF3, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R40)2, —C(O)OR15, —C(O)NR15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16; or

[0111] R13 and R14 taken together with the nitrogen they are attached to in the groups —C(O)NR13R14 and —SO2NR13R14 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 NR18; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., there is 1 to 3 substituents on the ring formed when the R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16, —NHC(O)OR15, halogen, and a heterocycloalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g.,

[0112] each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0113] R17 is selected from the group consisting of: —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;

[0114] R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;

[0115] each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;

[0116] R30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO2, or —SO2R15 provided that R15 is not H;

[0117] each R31 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 R31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF3;

[0118] each R40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and

[0119] t is 0, 1 or 2.

[0120] An embodiment of the present invention is directed to a method of treating a chemokine mediated disease in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0121] Examples of chemokine mediated diseases include: acute inflammation, chronic inflammation, rheumatoid arthritis, acute inflammatory pain, chronic inflammatory pain, acute neuropathic pain, chronic neuropathic pain, 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. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, bum therapy, periodontitis, transplant reperfusion injury and early transplantation rejection.

[0122] An embodiment of the present invention is directed to a method of treating cancer in a patient (e.g., a mammal, such as a human being) in need of such treatment, comprising administering to said patient, concurrently or sequentially, a therapeutically effective amount of (a) at least one (e.g., 1-3, and usually one) compound of formula IA, and (b) a microtubule affecting agent or antineoplastic agent or anti-angiogenesis agent or VEGF receptor kinase inhibitor or antibodies against the VEGF receptor or interferon, and/or c) radiation.

[0123] In further embodiments directed to the treatment of cancer, at least one (e.g., 1-3, and usually one) compound of formula IA is administered in combination with antineoplastic agents (e.g., one or more, such as one, or such as one or two), selected from the group consisting of: gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, taxotere and Vincristine.

[0124] In another embodiment the present invention provides a method of treating cancer in a patient (e.g., a mammal, such as a human being) in need of such treatment, comprising administering, concurrently or sequentially, an effective amount of (a) a compound of formula IA, and (b) a microtubule affecting agent (e.g., paclitaxel).

[0125] Another embodiment of the present invention is directed to a method of treating acute inflammatory pain, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0126] Another embodiment of the present invention is directed to a method of treating chronic inflammatory pain, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0127] Another embodiment of the present invention is directed to a method of treating acute neuropathic pain, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0128] Another embodiment of the present invention is directed to a method of treating chronic neuropathic pain, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0129] Another embodiment of the present invention is directed to a method of treating COPD, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0130] Another embodiment of the present invention is directed to a method of treating acute inflammation, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0131] Another embodiment of the present invention is directed to a method of treating chronic inflammation, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0132] Another embodiment of the present invention is directed to a method of treating rheumatoid arthritis, in a patient in need of such treatment (e.g., a mammal, preferably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof.

[0133] In another embodiment of the methods of this invention B is selected from the group consisting of:

[0134] wherein all substituents are as defined for formula IA.

[0135] In another embodiment of the methods of this invention B is:

[0136] wherein:

[0137] R2, R4, R5 and R6 are as defined for formula IA; and

[0138] R3 is selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —SO(t)NR13R14, —SO(t)R13, —C(O)NR13OR4, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups.

[0139] In the methods of this invention:

[0140] (1) substituent A in formula IA is preferably selected from the group consisting of:

[0141] wherein the above rings are unsubstituted or substituted, as described for formula IA: and

[0142] wherein in (a) and (b) above: each R7 and R8 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, —CO2R13, —CONR13R14, fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R7 and R8 substituted groups are selected from the group consisting of: a) cyano, b) —CO2R13, c) —C(O)NR13R14, d) —SO2NR13R14, e) —NO2, f) —CF3, g) —OR13, h) —NR 13R14, i) —OC(O)R13, j) —OC(O)NR13R14, and k) halogen; and R8a and R9 are as defined in formula IA; and

[0143] (2) substituent B in formula IA is preferably selected from the group consisting of:

[0144] wherein R2 to R6 and R10 to R14 are as defined above.

[0145] In the methods of this invention:

[0146] (1) substituent A in formula IA is more preferably selected from the group consisting of:

[0147] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; each R7 and R8 is independently selected is from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; and

[0148] wherein each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R8a is as defined in formula IA, and wherein R9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0149] (2) substituent B in formula IA is more preferably selected from the group consisting of:

[0150] wherein

[0151] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 or and —NHSO2R13;

[0152] R3 is selected from the group consisting of: —SO2NR13R14, —NO2, cyano, —C(O)NR13R14, —SO2R13; and —C(O)OR13;

[0153] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3, halogen, and —CF3;

[0154] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano;

[0155] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0156] each R10 and R11 is independently selected from the group consisting of: hydrogen, halogen, —CF3, —NR13R14, —NR13C(O)NR13R14, —C(O)OR13, —SH, —SO(t)NR13R14, —SO2R13, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —C(O)NR13R14, —C(O)NR13OR14, —OC(O)R13, —COR13, —OR13, and cyano;

[0157] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0158] R13 and R14 when taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR13R14—SO2NR13R14, —OC(O)NR13R14, —CONR13R14, —NR13C(O)NR13R14, —SOtNR13R14, —NHSO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR18; wherein R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20; wherein each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., the substituents on the ring formed when R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16 and halogen; and wherein each R15 and R16 is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

[0159] In the methods of this invention:

[0160] (1) substituent A in formula IA is even more preferably selected from the group consisting of:

[0161] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R8 is selected form the group consisting of: H, alkyl, —CF2CH3 and —CF3; and R9 is selected from the group consisting of: H, F, Cl, Br, alkyl or —CF3; and

[0162] wherein R7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R8 is selected form the group consisting of: H, alkyl, —CF2CH3 and —CF3; and R8a is as defined for formula IA.

[0163] In the methods of this invention:

[0164] (1) substituent A in formula IA is still even more preferably selected from the group consisting of:

[0165] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and

[0166] wherein R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined for formula IA.

[0167] (2) substituent B in formula IA is preferably selected from the group consisting of:

[0168] wherein:

[0169] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0170] R3 is selected from the group consisting of: —C(O)NR13R14, —SO2NR13R14, —NO2, cyano, —SO2R13; and —C(O)OR13;

[0171] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0172] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0173] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0174] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0175] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0176] R13 and R14 when taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR13R14, —SO2NR13R14, —OC(O)NR13R14, —CONR13R14, —NR13C(O)NR13R14, —SOtNR13R14, —NHSO2NR13R14 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 NR18 wherein R18 is selected from H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20, wherein each R19 and R20 is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., on the ring formed when R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16 and halogen; and wherein each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

[0177] In the methods of this invention:

[0178] (1) substituent A in formula IA is yet even still more preferably selected from the group consisting of:

[0179] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and

[0180] wherein R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined for formula IA.

[0181] (2) substituent B in formula IA is preferably selected from the group consisting of:

[0182] wherein:

[0183] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0184] R3 is selected from the group consisting of: —C(O)NR13R14—SO2NR13R14, —NO2, cyano, and —SO2R13;

[0185] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0186] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0187] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0188] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0189] each R13 and R14 is independently selected from the group consisting of: methyl and ethyl.

[0190] In the methods of this invention:

[0191] (1) substituent A in formula IA is most preferably selected from the group consisting of:

[0192] (2) substituent B in formula IA is preferably selected from the group consisting of:

[0193] wherein:

[0194] R2 is—OH;

[0195] R3 is selected from the group consisting of: —SO2NR13R14 and —CONR13R14;

[0196] R4 is selected form the group consisting of: H, —CH3 and —CF3;

[0197] R5 is selected from the group consisting of: H and cyano;

[0198] R6 is selected from the group consisting of: H, —CH3 and —CF3;

[0199] R11 is H; and

[0200] R13 and R14 are methyl.

[0201] The novel compounds of this invention are compounds of formula IA:

[0202] and their pharmaceutically acceptable salts (e.g., sodium or calcium salt) and solvates thereof, wherein:

[0203] A is selected from the group consisting of:

[0204] wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R9 groups;

[0205] wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R9 groups;

[0206] wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R9 groups; and

[0207] B is selected from the group consisting of:

[0208] provided that R3 for this group is selected from the group consisting of: —C(O)NR13R14,

[0209] n is 0 to 6;

[0210] p is 1 to 5;

[0211] X is O, NH, or S;

[0212] Z is 1 to 3;

[0213] R2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO2NR13R14, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —NR13R14, —C(O)NR13R14, —C(O)NHOR13, —C(O)NR13OH, —S(O2)OH, —OC(O)R13, 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: R9 groups;

[0214] each R3 and R4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —C(O)NR13R14, —SO(t)NR13R14, —SO(t)R13, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,

[0215] wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups;

[0216] each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NR 13R14, —SO(t)NR13R14, —C(O)NR13R14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups;

[0217] each R7 and R8 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, —CO2R13, —CONR13R14, alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more (e.g., 1 to 6) substituents on said substituted R7 and R8 groups, wherein each substituent is independently selected from the group consisting of:

[0218] a) halogen,

[0219] b) —CF3,

[0220] c) —COR13,

[0221] d) —OR13,

[0222] e) —NR13R14

[0223] f) —NO2,

[0224] g) —CN,

[0225] h) —SO2R13,

[0226] i) —Si(alkyl)3, wherein each alkyl is independently selected,

[0227] j) —Si(aryl)3, wherein each alkyl is independently selected,

[0228] k) —(R13)2R14Si, wherein each R13 is independently selected,

[0229] l) —CO2R13,

[0230] m) —C(O)NR13R14,

[0231] n) —SO2NR13R14,

[0232] o) —SO2R13,

[0233] p) —OC(O)R13,

[0234] q) —OC(O)NR13R14

[0235] r) —NR13C(O)R14, and

[0236] s) —NR13CO2R14;

[0237] (fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen);

[0238] R8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;

[0239] each R9 is independently selected from the group consisting of:

[0240] a) —R13,

[0241] b) halogen,

[0242] c) —CF3,

[0243] d) —COR13,

[0244] e) —OR13,

[0245] f) —NR13R14

[0246] g) —NO2,

[0247] h) —CN,

[0248] i) —SO2R13,

[0249] j) —SO2NR13R14,

[0250] k) —NR13COR14

[0251] l) —CONR13R14

[0252] m) —NR13CO2R14,

[0253] n) —CO2R13,

[0254] p) alkyl substituted with one or more (e.g., one) —OH groups (e.g., —(CH2)qOH, wherein q is 1-6, usually 1 to 2, and preferably 1),

[0255] q) alkyl substituted with one or more (e.g., one) —NR13R14 group (e.g., —(CH2)qNR13R14, wherein q is 1-6, usually 1 to 2, and preferably 1), and

[0256] r) —N(R13)SO2R14 (e.g., R13 is H and R14 is alkyl, such as methyl);

[0257] each R10 and R11 is independently selected from the group consisting of R13, hydrogen, alkyl (e.g., C1 to C6, such as methyl), halogen, —CF3, —OCF3, —NR13R14, —NR13C(O)NR13R14, —OH, —C(O)OR13, —SH, —SO(t)NR13R14, —SO2R13, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —C(O)NR13R14, —C(O)NR13OR14, —OC(O)R13 and cyano;

[0258] R12 is selected from the group consisting of: hydrogen, —C(O)OR13, 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 R12 groups and each substituent is independently selected from the group consisting of: R9 groups;

[0259] each R13 and R14 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, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF3, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R40)2, —C(O)OR15, —C(O)NR15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16; or

[0260] R13 and R14 taken together with the nitrogen they are attached to in the groups —C(O)NR13R14 and —SO2NR13R14 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 NR18; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., there is 1 to 3 substituents on the ring formed when the R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16, —NHC(O)OR15, halogen, and a heterocylcoalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g.,

[0261] each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0262] R17 is selected from the group consisting of: —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;

[0263] R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;

[0264] each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;

[0265] R30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO2, or —SO2R15 provided that R15 is not H;

[0266] each R31 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 R31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen, and —CF3;

[0267] each R40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and

[0268] t is 0, 1 or 2.

[0269] Representative embodiments of the novel compounds of this invention are described below. The embodiments have been numbered for purposes of reference thereto.

[0270] Embodiment No. 1 is directed to the novel compounds of formula IA wherein B is selected from the group consisting of:

[0271] provided that R3 for this group is selected from the group consisting of: —C(O)NR13R14,

[0272] wherein all substituents are as defined for the novel compounds of formula IA.

[0273] Embodiment No. 2 is directed to the novel compounds of formula IA wherein B is:

[0274] wherein R3 is selected from the group consisting of: —C(O)NR13R14,

[0275] and all other substituents are as defined in formula IA.

[0276] Embodiment No. 3 is directed to the novel compounds of formula IA wherein B is:

[0277] and all other substituents are as defined in formula IA.

[0278] Embodiment No. 4 is directed to the novel compounds of formula IA wherein B is

[0279] R13 and R14 are each the same or different alkyl group, and all other substituents are as defined in formula IA .

[0280] Embodiment No. 5 is directed to the novel compounds of formula IA wherein B is

[0281] and (1) R2 is —OH, and all other substituents are as defined in formula IA, or (2) R2 is —OH, and R13 and R14 are each the same or different alkyl group, and all other substituents are as defined in formula IA.

[0282] Embodiment No. 6 is directed to the novel compounds of formula IA wherein B is

[0283] R3 is selected from the group consisting of:

[0284] and all other substituents are as defined in formula IA.

[0285] Embodiment No. 7 is directed to the novel compounds of formula IA wherein B is

[0286] R3 is selected from the group consisting of:

[0287] R2 is —OH, and all other substituents are as defined in formula IA.

[0288] Embodiment No. 8 is directed to compounds of formula IA wherein B is:

[0289] R2, R13, and R14 are as defined for compounds of formula IA, and all other substituents are as defined in formula IA.

[0290] Embodiment No. 9 is directed to the novel compounds of formula IA wherein B is:

[0291] R2 is —OH, R13 and R14 are as defined for compounds of formula and all other substituents are as defined in formula IA.

[0292] Embodiment No. 10 is directed to the novel compounds of formula IA wherein B is:

[0293] R2 is as defined for compounds of formula IA, R13 and R14 are the same or different alkyl group, and all other substituents areas defined for compounds of formula IA.

[0294] Embodiment No. 11 is directed to the novel compounds of formula IA wherein B is:

[0295] R2 is —OH, R13 and R14 are the same or different alkyl group, and all other substituents areas defined for compounds of formula IA.

[0296] Embodiment No. 12 is directed to novel compounds of formula IA wherein B is as described in Embodiment No. 6, R4 is H, R5 is H, R6 is H, and all other substituents areas defined for compounds of formula IA.

[0297] Embodiment No. 13 is directed to novel compounds of formula IA wherein B is as described in Embodiment No. 7, R4 is H, R5 is H, R6 is H, and all other substituents areas defined for compounds of formula IA.

[0298] Embodiment No. 14 is directed to novel compounds of formula IA wherein B is as described in Embodiments Nos. 4, 5, 8 and 9, except that R13 and R14 are each methyl, and all other substituents are as defined in formula IA.

[0299] Embodiment No. 15 is directed to novel compounds of formula IA wherein B is selected from the group consisting of:

[0300] wherein all substituents are as defined for formula IA.

[0301] Embodiment No. 16 is directed to compounds of formula IA wherein B is:

[0302] wherein all substituents are as defined for formula IA.

[0303] Embodiment No. 17 is directed to compounds of formula IA wherein B is:

[0304] R11 is H, and all other substituents are as defined in formula IA.

[0305] Embodiment No. 18 is directed to compounds of formula IA wherein B is:

[0306] R2 is —OH, and all other substituents are as defined in formula IA.

[0307] Embodiment No. 19 is directed to compounds of formula IA wherein B is:

[0308] R3 is —C(O)NR13R14, and all other substituents are as defined in formula IA.

[0309] Embodiment No. 20 is directed to compounds of formula IA wherein B is:

[0310] R3 is —S(O)tNR13R14 (e.g., t is 2), and all other substituents are as defined in formula IA.

[0311] Embodiment No. 21 is directed to compounds of formula IA wherein B is:

[0312] R2 is —OH, R3 is —C(O)NR13R14, and all other substituents are as defined in formula IA.

[0313] Embodiment No. 22 of this invention is directed to compounds of formula IA wherein B is:

[0314] R2 is —OH, and R3 is —S(O)tNR13R14 (e.g., t is 2), and all other substituents are as defined in formula IA.

[0315] Embodiment No. 23 is directed to compounds of formula IA wherein B is:

[0316] R2 is —OH, R3 is —C(O)NR13R14, R11 is H, and all other substituents are as defined in formula IA.

[0317] Embodiment No. 24 is directed to compounds of formula IA wherein B is:

[0318] R3 is —S(OtNR13R14 (e.g., t is 2), each R13 and R14 are the same or different and are selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In this embodiment, each R13 and R14 are generally selected from the group consisting of: H and ethyl, and preferably R13 and R14 are ethyl.and all other substituents are as defined in formula IA.

[0319] Embodiment No. 25 is directed to compounds of formula IA wherein B is:

[0320] R3 is —S(O)tNR13R14 (e.g., t is 2), R11 is H, and each R13 and R14 are the same or different and are selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In this embodiment, each R13 and R14 are generally selected from the group consisting of: H and ethyl, and preferably R13 and R14 are ethyl.and all other substituents are as defined in formula IA.

[0321] Embodiment No. 26 is directed to compounds of formula IA wherein B is:

[0322] R2 is —OH, R3 is —S(O)tNR13R14 (e.g., t is 2), R11 is H, and all other substituents are as defined in formula IA.

[0323] Embodiment No. 27 is directed to compounds of formula LA wherein B is:

[0324] R2 is —OH, R3 is —C(O)NR13R14, R11 is H, and R13 and R14 are independently selected from the group consisting of: alkyl, unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula IA. In general, one of R13 or R14 is alkyl (e.g., methyl). An example of a substituted heteroaryl group is

[0325] Embodiment No. 28 is directed to compounds of formula IA wherein B is:

[0326] R2 is —OH, R3 is —S(O)tNR13R14 (e.g., t is 2), R11 is H, and each R13 and R14 are the same or different and are 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 IA. In this embodiment, each R13 and R14 are generally selected from the group consisting of: H and ethyl, and preferably R13 and R14 are ethyl.

[0327] Embodiment No. 29 is directed to compounds of formula IA wherein B is:

[0328] and all substituents are as defined in formula IA.

[0329] Embodiment No. 30 is directed to compounds of formula IA wherein B is:

[0330] and all substituents are as defined in formula IA.

[0331] Embodiment No. 31 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is as defined in any of the above preferred descriptions describing A for the compounds of formula IA used in the methods of treatment.

[0332] Embodiment No. 32 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is:

[0333] wherein the furan ring is unsubstituted or substituted as described in the definition of A for formula IA, and all other substituents are as defined for formula IA.

[0334] Embodiment No. 33 is directed to novel compounds of formula IA wherein B is described in any one of the Embodiment Nos. 1 to 30, and A is

[0335] wherein the furan ring is substituted and all other substituents are as defined for formula IA.

[0336] Embodiment No. 34 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is

[0337] wherein the furan ring is substituted with at least one (e.g., 1 to 3, or 1 to 2) alkyl group and all other substituents are as defined for formula IA.

[0338] Embodiment No. 35 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, A is

[0339] wherein the furan ring is substituted with one alkyl group and all other substituents are as defined for formula IA.

[0340] Embodiment No. 36 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is

[0341] wherein the furan ring is substituted with one C, to C3 alkyl group (e.g., methyl or isopropyl), and all other substituents are as defined for formula IA.

[0342] Embodiment No. 37 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is

[0343] as defined in any one of the Embodiment Nos. 32 to 36, except that R7 and R8 are the same or different and each is selected from the group consisting of: H and alkyl.

[0344] Embodiment No. 38 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is

[0345] as defined in any one of the Embodiment Nos. 32 to 36, except that R7 is H, and R8 is alkyl (e.g., ethyl or t-butyl).

[0346] Embodiment No. 39 is directed to the novel compounds of formula IA wherein:

[0347] (1) substituent A in formula IA is preferably selected from the group consisting of:

[0348] wherein the above rings are unsubstituted or substituted, as described for formula IA: and

[0349] and wherein in (a) and (b) above: each R7 and R8 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, —CO2R13, —CONR13R14, fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R7 and R8 substituted groups are selected from the group consisting of: a) cyano, b) —CO2R13, c) —C(O)NR13R14, d) —SO2NR13R14, e) —NO2, f —CF3, g) —OR13, h) —NR13R14, i) —OC(O)R13, j) —OC(O)NR13R14, and k) halogen; and R8a and R9 are as defined in formula IA; and

[0350] (2) substituent B in formula IA is preferably selected from the group consisting of:

[0351] wherein R2 to R6 and R10 to R14 are as defined above for the novel compounds of formula IA.

[0352] Embodiment No. 40 is directed to the novel compounds of formula IA wherein:

[0353] (1) substituent A in formula IA is more preferably selected from the group consisting of:

[0354] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; and

[0355] wherein each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R8a is as defined in formula IA, and wherein R9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF3, cyano, is —OCH3, and —NO2; each R17and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0356] (2) substituent B in formula IA is more preferably selected from the group consisting of:

100

[0357] wherein

[0358] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0359] R3 is selected from the group consisting of: —SO2NR13R14, —NO2, cyano, —C(O)NR13R14, —SO2R13; and —C(O)OR13;

[0360] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3, halogen, and —CF3;

[0361] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano;

[0362] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0363] each R10 and R11 is independently selected from the group consisting of: R13, hydrogen, halogen, —CF3, —NR13R14, —NR13C(O)NR13R14, —C(O)OR13, —SH, —SO(t)NR13R 14, —SO2R13, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —C(O)NR13R14, —C(O)NR13OR14, —OC(O)R13, —COR13, —OR13, and cyano;

[0364] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0365] R13 and R14 when taken together with the nitrogen they are attached to in the groups —C(O)NR13R14 and —SO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR18; wherein R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20; wherein each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., the substituents on the ring formed when R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16 and halogen; and wherein each R15 and R16 is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

[0366] Embodiment No. 41 is directed to the novel compounds of formula IA wherein:

[0367] substituent A in formula IA is even more preferably selected from the group consisting of:

101

[0368] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R8 is selected form the group consisting of: H, alkyl, —CF2CH3 and —CF3; and R9 is selected from the group consisting of: H, F, Cl, Br, alkyl or —CF3; and

102

[0369] wherein R7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R8 is selected form the group consisting of: H, alkyl, —CF2CH3 and —CF3; and R8a is as defined for formula IA.

[0370] Embodiment No. 42 is directed to the novel compounds of formula IA wherein:

[0371] (1) substituent A in formula IA is still even more preferably selected from the group consisting of:

103

[0372] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and

104

[0373] wherein R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined for formula IA.

[0374] (2) substituent B in formula IA is preferably selected from the group consisting of:

105

[0375] wherein:

[0376] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R 13;

[0377] R3 is selected from the group consisting of: —C(O)NR13R14, —SO2NR13R14, —NO2, cyano, —SO2R13; and —C(O)OR13;

[0378] R4is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0379] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0380] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0381] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0382] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0383] R13 and R14 when taken together with the nitrogen they are attached to in the groups —C(O)NR13R14 and —SO2NR13R14 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 NR18 wherein R18 is selected from H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20, wherein each R19 and R20 is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., on the ring formed when R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16—C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16 and halogen; and wherein each R15 and R16 is independently selected from the group consisting of: H. alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

[0384] Embodiment No. 43 is directed to the novel compounds of formula IA wherein:

[0385] (1) substituent A in formula IA is yet even still more preferably selected from the group consisting of:

106

[0386] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and

107

[0387] wherein R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined for formula IA;

[0388] (2) substituent B in formula IA is yet even still more preferably selected from the group consisting of:

108

[0389] wherein:

[0390] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0391] R3 is selected from the group consisting of: —C(O)NR13R14—SO2NR13R14, —NO2, cyano, and —SO2R13;

[0392] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0393] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0394] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0395] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0396] each R13 and R14 is independently selected from the group consisting of: methyl and ethyl.

[0397] Embodiment No. 44 is directed to the novel compounds of formula IA wherein:

[0398] (1) substituent A in formula IA is most preferably selected from the group consisting of:

109

110

[0399] (2) substituent B in formula IA is most preferably selected from the group consisting of:

111

[0400] wherein:

[0401] R2is —OH;

[0402] R3 is selected from the group consisting of: —SO2NR13R14 and —CONR13R14;

[0403] R4 is selected form the group consisting of: H, —CH3 and —CF3;

[0404] R5 is selected from the group consisting of: H and cyano;

[0405] R6 is selected from the group consisting of: H, —CH3 and —CF3;

[0406] R11 is H; and

[0407] R13 and R14 are methyl.

[0408] Embodiment No. 45 is directed to the novel compounds of formula IA wherein:

[0409] (1) substituent A in formula IA is selected from the group consisting of:

112

[0410] wherein the above rings are unsubstituted or substituted, as described for formula IA: and

113

[0411] wherein in (a) and (b) above: each R7 and R8 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, —CO2R13, —CONR13R14, fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R7 and R8 substituted groups are selected from the group consisting of: a) cyano, b) —CO2R13, c) —C(O)NR13R14, d) —SO2NR13R14, e) —NO2, f) —CF3, g) —OR13, h) —NR13R14, i) —OC(O)R13, j) —OC(O)NR13R14, and k) halogen; and R8a and R9 are as defined in formula IA; and

[0412] (2) substituent B in formula IA is:

114

[0413] wherein R2, R3 and R11 are as defined above for the novel compounds of formula IA.

[0414] Embodiment No. 46 is directed to the novel compounds of formula IA wherein:

[0415] (1) substituent A in formula IA is selected from the group consisting of:

115

[0416] wherein the above rings are unsubstituted or substituted, as described for formula IA: and

116

[0417] and

[0418] wherein in (a) and (b) above: each R7 and R8 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, —CO2R13, —CONR13R14, fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R7 and R8 substituted groups are selected from the group consisting of: a) cyano, b) —CO2R13, c) —C(O)NR13R14, d) —SO2NR13R14, e) —NO2, f) —CF3, g) —OR13, h) —NR13R14, i) —OC(O)R13, j) —OC(O)NR13R14, and k) halogen; and R8a and R9 are as defined in formula IA; and

[0419] (2) substituent B in formula IA is:

117

[0420] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0421] R3 is selected from the group consisting of: —SO2NR13R14, —NO2, cyano, —C(O)NR13R14, —SO2R13; and —C(O)OR13;

[0422] R11 is selected from the group consisting of: R13, hydrogen, halogen, —CF3, —NR13R14, —NR13C(O)NR13R14, —C(O)OR13, —SH, —SO(t)NR13R14, —SO2R13, —NHC(O)R13 —NHSO2NR13R14, —NHSO2R13—C(O)NR13R14, —C(O)NR13R14, —OC(O)R13, —COR13, —OR13, and cyano;

[0423] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0424] R13 and R14 when taken together with the nitrogen they are attached to in the groups —C(O)NR13R14 and —SO2NR13R14, form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR18; wherein R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20; wherein each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., the substituents on the ring formed when R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16 and halogen; and wherein each R15 and R16 is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

[0425] Embodiment No. 47 is directed to the novel compounds of formula IA wherein:

[0426] (1) substituent A in formula IA is selected from the group consisting of:

118

[0427] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; and

119

[0428] wherein each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R8a is as defined in formula IA, and wherein R9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF3, cyano, —OCH3, and —NO2; each R7 and R8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF3 and —CF2CH3), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

[0429] (2) substituent B in formula IA is:

120

[0430] wherein

[0431] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 or and —NHSO2R13;

[0432] R3 is —SO2NR13R14;

[0433] R11 is selected from the group consisting of: R13, hydrogen, halogen, —CF3, —NR13R14, —NR13C(O)NR13R14, —C(O)OR13, —SH, —SO(t)NR13R14, —SO2R13, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —C(O)NR13R14, —C(O)NR13OR14, —OC(O)R13, —COR13, —OR13, and cyano;

[0434] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl; or

[0435] R13 and R14 when taken together with the nitrogen they are attached to in the group —SO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR18; wherein R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20; wherein each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups (i.e., the substituents on the ring formed when R13 and R14 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)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16 and halogen; and wherein each R15 and R16 is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.

[0436] Embodiment No. 48 is directed to the novel compounds of formula IA wherein:

[0437] (1) substituent A in formula IA is selected from the group consisting of:

121

[0438] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and

122

[0439] wherein R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined for formula IA.

[0440] (2) substituent B in formula IA is:

123

[0441] wherein:

[0442] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0443] R3 is selected from the group consisting of: —C(O)NR13R14, —SO2NR13R14, —NO2, cyano, —SO2R13; and —C(O)OR13;

[0444] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0445] each R13 and R14 is independently selected from the group consisting of: H, methyl, ethyl, isopropyl and t-butyl.

[0446] Embodiment No. 43 is directed to the novel compounds of formula IA wherein:

[0447] (1) substituent A in formula IA is selected from the group consisting of:

124

[0448] wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF3; R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and

125

[0449] wherein R7 is selected from the group consisting of: H, —CF3, —CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined for formula IA;

[0450] (2) substituent B in formula IA is:

126

[0451] wherein:

[0452] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13 (preferably —OH);

[0453] R3 is —SO2NR13R14;

[0454] R11 is selected from the group consisting of: H, halogen and alkyl (preferably H); and

[0455] each R13 and R14 is independently selected from the group consisting of: H and ethyl, preferably R13 and R14 are ethyl.

[0456] Embodiment No. 50 is directed to the novel compounds of formula IA wherein:

[0457] (1) substituent A in formula IA is selected from the group consisting of:

127

128

[0458] (2) substituent B in formula IA is:

129

[0459] wherein:

[0460] R2 is —OH;

[0461] R3 is: —SO2NR13R14;

[0462] R11 is H; and

[0463] R13 and R14 are ethyl.

[0464] Embodiment No. 51 is directed to compounds of formula IA wherein B is selected from the group consisting of:

130

[0465] provided that R3 for this group is selected from the group consisting of: —C(O)NR13R14,

131

132

[0466] wherein all other substituents are as defined for formula IA.

[0467] Embodiment No. 52 is directed to compounds of formula IA wherein B is selected from the group consisting of:

133

[0468] wherein all substituents are as defined for formula IA.

[0469] Embodiment No. 53 is directed to compounds of formula IA wherein B is:

134

[0470] wherein all substituents are as defined for formula IA.

[0471] Embodiment No. 54 is directed to compounds of formula IA wherein B is:

135

[0472] wherein all substituents are as defined for formula IA.

[0473] Embodiment No. 55 is directed to compounds of formula IA wherein B is:

136

[0474] wherein all substituents are as defined for formula IA.

[0475] Embodiment No. 56 is directed to compounds of formula IA wherein B is:

137

[0476] wherein all substituents are as defined for formula IA.

[0477] Embodiment No. 57 is directed to compounds of formula IA wherein B is:

138

[0478] wherein all substituents are as defined for formula IA.

[0479] Embodiment No. 58 is directed to compounds of formula IA wherein B is:

139

[0480] wherein all substituents are as defined for formula IA.

[0481] Embodiment No. 59 is directed to compounds of formula IA wherein B is:

140

[0482] wherein all substituents are as defined for formula IA.

[0483] Embodiment No. 60 is directed to compounds of formula IA wherein B is:

141

[0484] wherein all substituents are as defined for formula IA.

[0485] Embodiment No. 61 is directed to compounds of formula IA wherein B is:

142

[0486] wherein all substituents are as defined for formula IA.

[0487] Embodiment No. 62 is directed to compounds of formula IA wherein B is selected from the group consisting of:

143

[0488] wherein all substituents are as defined for formula IA.

[0489] Embodiment No. 63 is directed to compounds of formula IA wherein B is described in any of Embodiment Nos. 51 to 62 and A is as described in any of Embodiments Nos. 31-44.

[0490] Embodiment No. 64 is directed to any one of the Embodiment Nos. 1 to 63 wherein the novel compound of formula IA is a pharmaceutically acceptable salt.

[0491] Embodiment No. 65 is directed to any one of the Embodiment Nos. 1 to 63 wherein the novel compound of formula IA is a sodium salt.

[0492] Embodiment No. 66 is directed to any one of the Embodiment Nos. 1 to 63 wherein the novel compound of formula IA is a calcium salt.

[0493] Embodiment No. 67 is directed to a pharmaceutically acceptable salt of any one of the representative novel compounds described below.

[0494] Embodiment No. 68 is directed to a sodium salt of any one of the representative novel compounds described below.

[0495] Embodiment No. 69 is directed to a calcium salt of any one of the representative novel compounds described below.

[0496] Embodiment No. 70 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) novel compound of formula IA as described in any one of the Embodiment Nos. 1 to 69 in combination with a pharmaceutically acceptable carrier (or diluent).

[0497] Embodiment No. 71 is directed to a method of treating any one of the diseases described herein (e.g., the chemokine mediated diseases, and cancer) comprising administering to a patient in need of such treatment an effective amount (e.g., a therapeutically effective amount) of a novel compound of formula IA as described in any one of the Embodiment Nos. 1 to 69.

[0498] Embodiment No. 72 is directed to novel compounds of Examples 2006, 2010, 2015, 2029, 2034, 2035, 2038, 2039, 2047, 2050, 2074, 2079, and 2087.

[0499] Embodiment No. 73 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) novel compound of Embodiment No. 72 (or a pharmaceutically acceptable salt or solvate thereof, e.g., a calcium or sodium salt) in combination with a pharmaceutically acceptable carrier (or diluent).

[0500] Embodiment No. 74 is directed to a method of treating any one of the diseases described herein (e.g., the chemokine mediated diseases, and cancer) comprising administering to a patient in need of such treatment an effective amount (e.g., a therapeutically effective amount) of at least one (e.g., 1 to 3, usually 1) compound of

[0501] Embodiment No. 72 (or a pharmaceutically acceptable salt or solvate thereof, e.g., a calcium or sodium salt).

[0502] Representative compounds of the invention include but are not limited to:

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

[0503] Preferred compounds of the invention include:

165

166

167

168

169

170

171

172

173

174

175

[0504] A more preferred group of compounds includes:

176

177

178

179

180

[0505] A most preferred group of compounds includes:

181

182

183

[0506] Certain compounds of the invention 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.

[0507] 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.

[0508] Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, 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. Examples of 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. 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.

[0509] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0510] Compounds of formula IA can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of this invention.

[0511] In a preferred embodiment of the treatment of cancer, a compound of formula IA is administered in combination with one of the following antineoplastic agents: gemcitabine, paclitaxel (Taxol®), 5-Fluorourcil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, or Vincristine.

[0512] In another preferred embodiment, the present invention provides a method of treating cancer, comprising administering, concurrently or sequentially, and effective amount of a compound of formula IA and a microtubule affecting agent e.g., paclitaxel.

[0513] Another embodiment of the invention is directed to a method treating cancer, comprising administering to a patient in need thereof, concurrently or sequentially, a therapeutically effective amount of (a) a compound of formula IA, and (b) an antineoplastic agent, microtubule affecting agent or anti-angiogenesis agent.

[0514] For preparing pharmaceutical compositions from the compounds described by this invention, 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's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0515] 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.

[0516] 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.

[0517] 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.

[0518] The compounds of the invention 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.

[0519] Preferably the compound is administered orally.

[0520] Preferably, the pharmaceutical preparation is in a unit dosage form. In such 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.

[0521] 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.

[0522] 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. For convenience, the total dosage may be divided and administered in portions during the day as required.

[0523] The amount and frequency of administration of the compounds of the invention 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.

[0524] Classes of compounds that can be used as the chemotherapeutic agent (antineoplastic agent) include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below.

[0525] Alkylating agents (including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide.

[0526] Antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

[0527] Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is commercially available as Taxol® and is described in more detail below in the subsection entitled “Microtubule Affecting Agents”), Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.

[0528] Hormones and steroids (including synthetic analogs): 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.

[0529] Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

[0530] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians' Desk Reference” (PDR), e.g., 2002 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

[0531] As used herein, a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, microtubule stabilizing agents or agents that disrupt microtubule formation.

[0532] Microtubule affecting agents useful in the invention are well known to those of skill in the art and include, but are not limited to allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC 608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, and discodermolide (see Service, (1996) Science, 274:2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.

[0533] Particularly preferred agents are compounds with paclitaxel-like activity. These include, but are not limited to paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives are available commercially. In addition, methods of making paclitaxel and paclitaxel derivatives and analogues are well known to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506).

[0534] More specifically, the term “paclitaxel” as used herein refers to the drug commercially available as Taxol® (NSC number: 125973). Taxol® inhibits eukaryotic cell replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper structures for mitosis. Of the many available chemotherapeutic drugs, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Canc. Inst. 82:1247-1259).

[0535] Additional microtubule affecting agents can be assessed using one of many such assays known in the art, e.g., a semiautomated assay which measures the tubulin-polymerizing activity of paclitaxel analogs in combination with a cellular assay to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41:3747).

[0536] Generally, activity of a test compound is determined by contacting a cell with that compound and determining whether or not the cell cycle is disrupted, in particular, through the inhibition of a mitotic event. Such inhibition may be mediated by disruption of the mitotic apparatus, e.g., disruption of normal spindle formation. Cells in which mitosis is interrupted may be characterized by altered morphology (e.g., microtubule compaction, increased chromosome number, etc.).

[0537] Compounds with possible tubulin polymerization activity can be screened in vitro. In a preferred embodiment, the compounds are screened against cultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in particular for microtubule compaction. In vivo screening of positive-testing compounds can then be performed using nude mice bearing the WR21 tumor cells. Detailed protocols for this screening method are described by Porter (1995) Lab. Anim. Sci., 45(2):145-150.

[0538] Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically such assays involve assays for inhibition of microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U.S. Pat. No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity.

[0539] Methods for the safe and effective administration of the above-mentioned microtubule affecting agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians' Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

[0540] The amount and frequency of administration of the compounds of formula IA and the chemotherapeutic agents and/or radiation therapy will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated. A dosage regimen of the compound of formula IA can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses, to block tumor growth. Intermittant therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

[0541] The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

[0542] In the methods of this invention, a compound of formula IA is administered concurrently or sequentially with a chemotherapeutic agent and/or radiation. Thus, it is not necessary that, for example, the chemotherapeutic agent and the compound of formula IA, or the radiation and the compound of formula IA, should be administered simultaneously or essentially simultaneously. The advantage of a simultaneous or essentially simultaneous administration is well within the determination of the skilled clinician.

[0543] Also, in general, the compound of formula IA and the chemotherapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, the compound of formula IA may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician .

[0544] The particular choice of a compound of formula IA, and chemotherapeutic agent and/or radiation will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.

[0545] The compound of formula IA, and chemotherapeutic agent and/or radiation may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound of formula or IA.

[0546] If the compound of formula IA, and the chemotherapeutic agent and/or radiation are not administered simultaneously or essentially simultaneously, then the initial order of administration of the compound of formula IA, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compound of formula IA may be administered first, followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first, followed by the administration of the compound of formula IA. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

[0547] For example, the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compound of formula IA followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.

[0548] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a component (therapeutic agent—i.e., the compound of formula IA, chemotherapeutic agent or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.

[0549] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radio-logical studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

BIOLOGICAL EXAMPLES

[0550] The compounds of the present invention 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-α chemokine as demonstrated by the following in vitro assays.

[0551] Receptor Binding Assays:

[0552] CXCR1 SPA Assay

[0553] For each well of a 96 well plate, a reaction mixture of 10 μg hCXCR1-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in 100 μl was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCl2, 1 mM MgCl2, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1 assay buffer. 20× stock solutions of test compounds were prepared in DMSO (Sigma). A 6× stock solution of IL-8 (R&D) was prepared in CXCR2 assay buffer. The above solutions were added to a 96-well assay plate (PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assay buffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM). 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 IC50 values. Compounds of this invention had an IC50 of <20 μM. The most preferred compounds had a Ki within the range of 3 nM to 1120 nM.

[0554] CXCR2 SPA Assay

[0555] For each well of a 96 well plate, a reaction mixture of 4 μg hCXCR2-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in 100 μl was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2 mM CaCl2, 1 mM MgCl2). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN), was prepared in the CXCR2 assay buffer. 20× stock solutions of test compounds were prepared in DMSO (Sigma). A 6× stock solution of GRO-α (R&D) was prepared in CXCR2 assay buffer. The above solutions were added to a 96-well assay plate (PerkinElmer or Corning) as follows: 10 μl test compound or DMSO, 40 ul CXCR2 assay buffer or GRO-α stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM). When 40× stock solutions of test compounds in DMSO were prepared, then the above protocol was used except instead 5 μl test compound or DMSO and 45 μl CXCR2 assay buffer were used. The assay plates were shaken for 5 minutes on a plate shaker, then incubated for 2-8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of total binding minus non-specific binding (250 nM Gro-α or 50 μM antagonist) was determined and IC50 values calculated. Compounds of this invention had an IC50 of <5 μM. The most preferred compounds had a Ki within the range of 0.8 nM to 40 nM. The compound of Example 360.31 had a Ki of 3 nM. The compound of Example 360.106 had a Ki of 0.8 nM.

[0556] Calcium Fluorescence Assay (FLIPR)

[0557] HEK 293 cells stably transfected with hCXCR2 and Gαι/q were plated at 10,000 cells per well in a Poly-D-Lysine Black/Clear plate (Becton Dickinson) and incubated 48 hours at 5% CO2, 37° C. The cultures were then incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye Loading Buffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), 2.5 mM Probenicid (Sigma) for 1 hour. The cultures were washed with wash buffer (HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then 100 μl/well wash buffer was added.

[0558] During incubation, compounds were prepared as 4× stocks in 0.4% DMSO (Sigma) and wash buffer and added to their respective wells in the first addition plate. IL-8 or GRO-α (R&D Systems) concentrations were prepared 4× in wash buffer+0.1% BSA and added to their respective wells in second addition plate.

[0559] Culture plate and both addition plates were then placed in the FLIPR imaging system to determine change in calcium fluorescence upon addition of compound and then ligand. Briefly, 50 μl of compound solutions or DMSO solution was added to respective wells and change in calcium fluorescence measured by the FLIPR for 1 minute. After a 3 minute incubation within the instrument, 50 μl of ligand was then added and the change in calcium fluorescence measured by the FLIPR instrument for 1 minute. The area under each stimulation curve was determined and values used to determine % Stimulation by compound (agonist) and % Inhibition of Total Calcium response to ligand (0.3 nM IL-8 or GRO-α) for IC50 values of the test compounds.

[0560] Chemotaxis Assays for 293-CXCR2

[0561] A chemotaxis assay is setup using Fluorblok inserts (Falcon) for 293-CXCR2 cells (HEK-293 cells overexpressing human CXCR2). The standard protocol used at present is as follows:

[0562] 1. Inserts are coated with collagenIV (2 ug/ml) for 2 hrs at 37° C.

[0563] 2. The collagen is removed and inserts are allowed to air dry overnight.

[0564] 3. Cells are labeled with 10 uM calcein AM (Molecular Probes) for 2 hrs. Labeling is done in complete media with 2% FBS.

[0565] 4. Dilutions of compound are made in minimal media (0.1% BSA) and placed inside the insert which is positioned inside the well of a 24 well plate. Within the well is IL-8 at a concentration of 0.25 nM in minimal media. Cells are washed and resuspended in minimal media and placed inside the insert at a concentration of 50,000 cells per insert.

[0566] 5. Plate is incubated for 2 hrs and inserts are removed and placed in a new 24 well. Fluorescence is detected at excitation=485 nM and emission=530 nM.

[0567] Cytotoxicity Assays

[0568] A cytotoxicity assay for CXCR2 compounds is conducted on 293-CXCR2 cells. Concentrations of compounds are tested for toxicity at high concentrations to determine if they may be used for further evaluation in binding and cell based assays. The protocol is as follows:

[0569] 1. 293-CXCR2 cells are plated overnight at a concentration of 5000 cells per well in complete media.

[0570] 2. Dilutions of compound are made in minimal media w/0.1% BSA. Complete media is poured off and the dilutions of compound are added. Plates are incubated for 4, 24 and 48 hrs. Cells are labeled with 10 uM calcein AM for 15 minutes to determine cell viability. Detection method is the same as above.

[0571] Soft Agar Assay

[0572] 10,000 SKMEL-5 cells/well are placed in a mixture of 1.2% agar and complete media with various dilutions of compound. Final concentration of agar is 0.6%. After 21 days viable cell colonies are stained with a solution of MTT (1 mg/ml in PBS). Plates are then scanned to determine colony number and size. IC50 is determined by comparing total area vs. compound concentration.

[0573] Compounds of formula IA may be produced by processes known to those skilled in the art, in the following reaction schemes, and in the preparations and examples below.

[0574] A general procedure for the preparation of compounds of formula IA is as follows:

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185

[0575] Scheme 1

[0576] An amine is condensed (Step A) with a nitrosalicylic acid under standard coupling conditions and the resulting nitrobenzamide is reduced (Step B) under hydrogen atmosphere in the presence of a suitable catalyst. The remaining partner required for the synthesis of the final target is prepared by condensing an aryl amine with the commercially available diethylsquarate to give the aminoethoxysquarate product. Subsequent condensation of this intermediate with the aminobenzamide prepared earlier provides the desired chemokine antagonist (Scheme 1).

[0577] Scheme 2

[0578] Alternatively, 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.

186

187

[0579] Scheme 3

[0580] Benztriazole compounds of Formula (I) or IA 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.

[0581] Scheme 4

[0582] 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.

188

189

[0583] Scheme 5

[0584] Indazole structures of Formula (I) or IA 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).

[0585] Scheme 6

[0586] Indole structures of Formula (I) or IA 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).

[0587] The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art.

Preparative Example 1

[0588]

190

[0589] 3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min. (R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resulting suspension was stirred at room temperature overnight. The solid was filtered and the filtrate washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the residue by preparative plate chromatography (silica gel, 5% MeOH/CH2Cl2 saturated with AcOH) gave the product (338 mg, 46%, MH+=267).

Preparative Example 2

[0590]

191

[0591] Step A

[0592] 3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 23 g) and N,N-diisopropylethylamine (DIEA, 26 mL) in anhydrous CH2Cl2 (125 mL) were combined and stirred at 25° C. for 30 min. (R)-(+)-3-pyrrolidinol (8.7 g) in CH2Cl2 (25 mL) was added over 25 min and the resulting suspension was stirred at room temperature overnight. The mixture was extracted with 1M NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1M HCl (aq), extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (7 g) which was used without further purification.

[0593] Step B

[0594] The crude product from Step A above was stirred with 10% Pd/C (0.7 g) in MeOH (100 mL) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 10% MeOH/CH2Cl2 saturated with NH4OH) to give the product (2.5 g, 41%, MH+=223).

Preparative Example 2.1

[0595]

192

[0596] To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CH2Cl2 (10 mL) was added benzylisocyanate (3 mmol). After stirring for 2 hrs, amine scavenger resin (1.9 mmol) was added and the mixture was stirred overnight, filtered, the resin back-washed with CH2Cl2 and methanol, and the organics concentrated in vacuo. Stirring of the crude material in 4N HCl/dioxane (40 mL) for 2.5 hrs before concentrating in vacuo gave the title compound (41%, MH+=369).

Preparative Example 2.2-2.6

[0597] Following the procedures set forth in Preparative Example 2.1 but using the isocyanate (or chloroformate) indicated in the Table below, the amines were obtained and used without further purification.

1PrepEx.AmineIsocyanateAmine2.2

193

194

195

2.3

196

197

198

2.4

199

200

201

2.5

202

203

204

2.6

205

206

207

Preparative Example 2.7

[0598]

208

[0599] To N-BOC-3-(amino)piperidine (5 mmol) dissolved in CH2Cl2 (30 mL) was added trifluoromethanesulfonic anhydride (5 mmol) and the mixture was stirred overnight. The mixture was concentrated in vacuo, diluted with CH2Cl2 (10 mL) and treated with trifluoroacetic acid (10 mL). After stirring for 2 hr, the mixture was concentrated in vacuo to give the title compound (43%, MH+=233.1).

Preparative Example 2.8

[0600]

209

[0601] Step A

[0602] 3-Nitrosalicylic acid (5 mmol) and N-hydroxysuccinimide (5 mmol) were added to a solution of 2% DMF/CH2Cl2, followed by DCC (5 mmol). After stirring for 2 hr, the mixture was filtered and concentrated in vacuo and the residue used directly in Step B.

[0603] Step B

[0604] The product from Step A above was suspended in DMF and to this was added morpholino-2-carboxylic acid HCl (5 mmol) in CH2Cl2 (10 mL)/DMF (5 mL) and diisopropylethylamine (10 mmol). The mixture was stirred overnight, filtered, basified with 1N NaOH (50 mL), washed with CH2Cl2, acidified with 5N HCl and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the desired compound which was used directly in Step C (MH+=296).

[0605] Step C

[0606] Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step B above, the title compound was obtained (23%, MH+=267).

Preparative Example 2.9

[0607]

210

[0608] Step A

[0609] 2-Piperazinecarboxylic acid and 2-chloro-1,3-pyrimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+=209).

[0610] Step B

[0611] Following a similar procedure as Preparative Example 2.8, Step B except using the product from Preparative Example 2.9 Step A above, the desired compound was obtained (41%, MH+=374).

[0612] Step C

[0613] Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step B above, the desired compound was obtained (99%, MH+=344).

Preparative Example 2.10

[0614]

211

[0615] Step A

[0616] Following a similar procedure as Preparative Example 2.8, Step A except using 3-nitrobenzoic acid, the desired compound was obtained and used directly in Step B.

[0617] Step B

[0618] Following a similar procedure as Preparative Example 2.8, Step B except using the products from Preparative Example 2.9, Step A and Preparative Example 2.10, Step A, the desired compound was obtained (86%).

[0619] Step C

[0620] Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step B above, the desired compound was obtained (67%, MH+=331).

Preparative Example 2.11

[0621]

212

[0622] Step A

[0623] N-Benzylpiperidone (2 g, HCl salt, hydrate) was stirred with THF (20 mL), concentrated to dryness, and placed under high vac. The residue was diluted in THF (20 mL), and methyllithium was added (2.5 eq of 1.6N in Et2O) via syringe. After stirring for 3 hr, the mixture was concentrated in vacuo, diluted with water, extracted with CH2Cl2, and dried over Na2SO4. Filtration and concentrating in vacuo gave the desired product (50%, MH+=205).

[0624] Step B

[0625] Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the title compound was obtained (95%, MH+=116).

Preparative Example 2.12

[0626]

213

[0627] Step A

[0628] To N-benzyl-N-methylamine (20 mmol) dissolved in acetone (50 mL) was added concentrated HCl (20 mmol), paraformaldehyde (30 mmol) and 2-propanol (2 mL). After stirring at reflux overnight, the mixture was concentrated in vacuo, diluted with water, basified to pH 14 and extracted with ether. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (98%) which was used directly in Step B.

[0629] Step B

[0630] The product from Step A above (500 mg) was dissolved in MeOH (20 mL) and to this was added NaBH4 (50 mg). After stirring for 10 min, the solution was concentrated in vacuo to give the desired compound which was used directly in Step C without purification.

[0631] Step C

[0632] The product from Step B above was diluted with MeOH (20 mL) and to this was added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) and the mixture stirred under H2 atmosphere (balloon) overnight. The mixture was filtered, 4N HCl in dioxane (1 mL) was added, and the mixture was concentrated in vacuo to give the desired compound that was used directly without purification.

Preparative Example 2.13

[0633]

214

[0634] Step A

[0635] Following a similar procedure as Preparative Example 2, Step A except using methyl glycinate, the desired ester was obtained. The mixture was poured into 200 mL of 1N NaOH, then extracted with dichloromethane. The pH was adjusted to 1 and NaCl was added until saturation. After several hours, the resulting precipitate was filtered and washed with cold water to give the desired product (42%).

[0636] Step B

[0637] Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step A above, the title compound was obtained (95%).

Preparative Example 2.14

[0638]

215

[0639] Step A

[0640] Following a similar procedure as in Preparative Example 2.13, Step A except using methyl N-methylglycinate, the desired product was obtained (18%).

[0641] Step B

[0642] Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the title compound was obtained (95%, MH+=225).

Preparative Example 2.15

[0643]

216

[0644] The cyclobutenedione intermediate from Preparative Example 87 (200 mg), DIEA (100 ul), 3-aminosalicylic acid (120 mg) and EtOH (4 ml) were combined and heated to reflux overnight to give the title compound (90%, MH+=367).

Preparative Example 2.16

[0645]

217

[0646] The above n-oxide (2 g) was combined with H2NMe/H2O (15 cm3) and heated to 140° C. overnight. Potassium carbonate (1.3 g) added and the mixture concentrated in vacuo. Extraction with EtOH and concentration of the filtrate in vacuo gave 1.56 g of crude amine (MH+=125).

Preparative Example 3-10.50

[0647] Following the procedures set forth in Preparative Examples 1-2 but using the carboxylic acid, amine, and coupling agent [DCC (Prep. Ex. 1) or PyBrop (Prep. Ex. 2)] listed in the Table below, the indicated amide products were obtained and used without further purification.

21. Coupling AgentPrepCarboxylic2. % YieldEx.acidAmineProduct3. MH+ 3

218

219

220

1. PyBrop 2. 87%, 86% 3. 181 4

221

222

223

1. PyBroP 2. 49% 3. 209 5

224

NH3

225

1. PyBroP 2. 95% 3. 153 6

226

227

228

1. PyBroP 2. 83% 3. 167 7

229

230

231

1. PyBroP 2. 76% 3. 223 8

232

233

234

1. PyBroP 2. 65, 53 3. 209 9

235

236

237

1. PyBroP 2. 59, 69 3. 20710

238

239

240

1. PyBroP 2. 49, 86 3. 23710.1

241

242

243

1. PyBroP 2. 30, 88 3. 19310.2

244

245

246

1. PyBroP 2. 26, 87 3. 19510.3

247

248

249

1. PyBroP 2. 38 3. 20910.4

250

251

252

1. PyBroP 2. 29 3. 20910.5

253

254

255

1. PyBroP 2. 38 3. 22310.6

256

257

258

1. PyBroP 2. 32, 99 3. 367.910.7

259

260

261

1. PyBroP 2. 35, 99 3. 23710.8

262

263

264

1. DCC 2. 30, 99 3. 26910.9

265

266

267

1. PyBroP 2. 58, 95 3. 233.110.10

268

269

270

1. PyBroP 2. 42, 95 3. 238.910.13

271

272

273

1. PyBroP 2. 51, 95 3. 30710.14

274

275

276

1. PyBroP 2. 55 3. 34710.15

277

278

279

1. PyBroP 2. 41 3. 369.110.16

280

281

282

1. PyBroP 2. 56 3. 354.910.17

283

284

285

1. PyBroP 2. 56 3. 30810.18

286

287

288

1. PyBroP 2. 10, 95 3. 252.910.19

289

290

291

1. PyBroP 2. 42, 95 3. 24910.20

292

293

294

1. PyBroP 2. 15, 95 3. 264.910.21

295

296

297

1. PyBroP 2. 64, 95 3. 27310.22

298

299

300

1. PyBroP 2. 45, 95 3. 27310.23

301

302

303

1. PyBroP 2. 44, 95 3. 28110.24

304

305

306

1. PyBroP 2. 41, 95 3. 281.110.25

307

308

309

1. PyBroP 2. 48, 95 3. 25710.26

310

311

312

1. DCC 2. 15, 99 3. 23510.28

313

314

315

1. PyBroP 2. 52, 95 3. 237.110.29

316

317

318

1. PyBroP 2. 31, 95 3. 259.110.30

319

320

321

1. PyBroP 2. 54, 95 3. 250.910.31

322

323

324

1. PyBroP 2. 64, 95 3. 210.910.32

325

326

327

1. PyBroP 2. 47, 95 3. 19710.33

328

329

330

1. PyBroP 2. 47, 95 3. 27310.34

331

332

333

1. PyBroP 2. 51, 95 3. 237.110.35

334

335

336

1. PyBroP 2. 60, 90 3. 22410.36

337

338

339

1. PyBroP 2. 65, 99 3. 25210.37

340

341

342

1. PyBroP 2. 58, 99 3. 23910.38

343

344

345

1. PyBroP 2. 35, 99 3. 221.110.39

346

347

348

1. PyBroP 2. 42, 99 3. 235.210.40

349

350

351

1. DCC 2. 32, 99 3. 293.110.41

352

353

354

1. PyBroP 2. 45, 99 3. 223.110.42

355

356

357

1. PyBroP 2. 55, 81 3. 251.110.43

358

359

360

1. PyBroP 2. 68, 66 3. 224.910.44

361

362

363

1. PyBroP 2. 68, 66 3. 241.110.45

364

365

366

1. PyBroP 2. 44, 40 3. 29510.46

367

368

369

1. DCC 2. 37, 81 3. 26510.47

370

371

372

1. PyBroP 2. 71, 95 3. 293.110.48

373

374

375

1. PyBroP 2. 35, 99 3. 220.910.49

376

377

378

1. DCC 2. 16, 99 3. 209.010.50

379

380

381

1. DCC 2. 18, 99 3. 264.0

Preparative Example 10.55

Alternative Procedure for Preparative Example 3

[0648]

382

[0649] To the nitrosalicylic acid (3 g) dissolved dichloromethane (150 mL) at room temperature was added oxalyl chloride (4.3 mL) and DMF (0.01 eq.). After stirring for one day the mixture was concentrated in a vacuum to give a semi solid which was used directly in step B.

383

[0650] To the material from step A diluted in dichloromethane (50 mL) and cooled to 0° C. was added dimethyl amine in THF (2N solution, 24.6 mL) and triethylamine (4 eq.). After stirring for 24 hours at room temperature the mixture was concentrated in vacuo, diluted with 1M sodium hydroxide (30 mL) and after a half hour was washed with dichloromethane. The aqueous phase was acidified with 6M HCl (aq), extracted with dichloromethane and the organic phase was washed with water, dried over Na2SO4 and concentrated to give the title compound (3.2 g, 93%).

384

[0651] A mixture of the product from step B above (6 g), 10% Pd/C (0.6 g), and EtOH (80 mL) was stirred in a parr shaker under hydrogen (40 psi) at room temperature for 2 days. Filtration through celite and concentration in vacuo afforded the title product (5.1 g, 99%, MH+=181).

Preparative Example 11

[0652]

385

[0653] Step A

[0654] Following a similar procedure as in Preparative Example 1 except using dimethylamine (2M in THF, 33 mL) and 5-methylsalicylic acid (5 g), the desired product was prepared (6.5 g).

[0655] Step B

[0656] Nitric acid (0.8 mL) in H2SO4 was added to a cooled (−20° C.) suspension of the product from Step A above (3 g) in H2SO4 (25 mL). The mixture was treated with 50% NaOH (aq) dropwise, extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a crude solid (2.1 g, 44%, MH+=225).

[0657] Step C

[0658] The product was prepared in the same manner as described in Step B of Preparative Example 2 (0.7 g, 99%, MH+=195).

Preparative Example 11.1

[0659]

386

[0660] Step A

[0661] The above amine was reacted with the acid using the procedure set forth in Preparative Example 2, Step A to yield the desired amide (54%).

[0662] Step B

[0663] Na2S2O4 (1.22 g) was dissolved in water (4 ml) followed by the addition of NH3/H2O (300 ul). The solution ws then added to the product from Step A (200 mg) in dioxane (4 ml) and stirred for 30 min. The crude material was purified via flash column chromatography (CH2Cl2/MeOH, 20:1) to give 100mg of product (56%, MH+=251).

Preparative Example 11.2

[0664]

387

[0665] Following the procedures set forth in Preparative Example 11.1, Steps A and B, but using N-methylmethoxylamine, the title compound was obtained (86%, MH+=181).

Preparative Example 11.10

[0666]

388

[0667] Step A

[0668] Following the procedure set forth in Preparative Example 1, but using N-hydroxysuccinimide and 2% DMF in CH2Cl2, the desired amide was obtained (33%, MH+=297).

[0669] Step B

[0670] Following the procedure set forth in Preparative Example 2, Step B, the amine was prepared (99%, MH+=267).

Preparative Example 11.11-11.18

[0671] Following the procedures set forth in Preparative Examples 11.11 but using the carboxylic acid, amine, and coupling agent DCC indicated, the indicated amide products were obtained and used without further purification.

3PrepCarboxylic1. % YieldEx.acidAmineProduct2. MH+11.11

389

390

391

1. 45, 92 2. 310.011.12

392

393

394

1. 45, 95 2. 247.211.13

395

396

397

1. 85, 85 2. 251.111.14

398

399

400

1. 99, 92 2. 211.111.15

401

402

403

1. 48, 84 2. 26511.16

404

405

406

1. 78, 91 2. 238.111.17

407

408

409

1. 67, 90 2. 265.111.18

410

411

412

1. 28, 99 2. 2.267

Preparative Example 12

[0672]

413

[0673] Step A

[0674] Following a similar procedure as described in Preparative Example 2 Step A except using dimethylamine in place of R-(+)-3-pyrrolidinol, the desired product was prepared.

[0675] Step B

[0676] The product from step A above (8 g) was combined with iodine (9.7 g), silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirred overnight. Filtration, concentration of the filtrate, re-dissolution in CH2Cl2 and washing with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the product (7.3 g, 57%, MH+=337).

[0677] Step C

[0678] The product from Step B above (3.1 g) was combined with DMF(50 mL) and MeI (0.6 mL). NaH (60% in mineral oil, 0.4 g) was added portionwise and the mixture was stirred overnight. Concentration in vacuo afforded a residue which was diluted with CH2Cl2, washed with 1M NaOH (aq), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification through a silica gel column (EtOAc/Hex, 1:1) gave the desired compound (1.3 g, 41%, MH+=351).

[0679] Step D

[0680] The product from Step D above (200 mg), Zn(CN)2 (132 mg), Pd(PPh3)4 (130 mg) and DMF (5 mL) were heated at 80° C. for 48 hrs, then cooled to room temperature and diluted with EtOAc and 2M NH4OH. After shaking well, the organic extract was dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by preparative plate chromatography (Silica, EtOAc/Hex, 1:1) to give the desired compound (62 mg, 44%, MH+=250).

[0681] Step E

[0682] BBr3 (1.3 mL, 1M in CH2Cl2) was added to a CH2Cl2 solution (5 mL) of the product from step D above (160 mg) and stirred for 30 min. The mixture was diluted with water, extracted with CH2Cl2, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the desired compound (158 mg, MH+=236).

[0683] Step F

[0684] A mixture of the product from step E above (160 mg), platinum oxide (83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25-40 psi) for 1.5 hr. Filtration through celite and concentration in vacuo afforded the product (165 mg, MH+=206).

Preparative Example 12.1

[0685]

414

[0686] Step A

[0687] Following a similar procedure as in Preparative Example 2, Step A except using 3-(methylaminomethyl)pyridine and 3-nitrosalicylic acid, the desired compound was prepared (41%).

[0688] Step B

[0689] The compound from Step A above ( 0.3 g) was diluted with chloroform (15 mL) and stirred with mCPBA (0.4 g) for 2 hr. Purification by column chromatography (silica, 10% MeOH/CH2Cl2) gave the pyridyl N-oxide (0.32 g, 100%, MH+=303.9).

[0690] Step C

[0691] Following a similar procedure as in Preparative Example 11.1, Step B, but using the product from Step B above, the desired compound was obtained (15%, MH+=274).

Preparative Example 12.2

[0692]

415

[0693] Step A

[0694] 3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and concentrated H2SO4 (1 mL) were stirred at reflux overnight, concentrated in vacuo, diluted with CH2Cl2, and dried over Na2SO4. Purification by column chromatography (silica, 5% MeOH/CH2Cl2) gave the methyl ester (2.8 g, 65%).

[0695] Step B

[0696] Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the desired compound was obtained (95%, MH+=1 67.9).

Preparative Example 12.3

[0697]

416

[0698] To morpholine-2-carboxilic acid (200 mg) in EtOH (40 mL) at 0° C. was added acetyl chloride (3 mL) and the mixture was stirred at reflux overnight. Concentration in vacuo, dilution with CH2Cl2 and washing with NaHCO3 (aq) gave the title compound (99%, MH+=160.1).

Preparative Example 12.4

[0699]

417

[0700] To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0° C. was added a solution of borane. THF complex (1N, 10.38 ml) and the mixture was stirred for 30 min at 0° C., and for 2 hr at room temperature. Water (200 ml) was added to the reaction and the mixture extracted with CH2Cl2, dried with Na2SO4, and concentrated in vacuo to give 490 mg of product (26%). The product was then stirred in 4N HCl/dioxane to give the amine salt.

Preparative Example 13

[0701]

418

[0702] Step A

[0703] Following a similar procedure as in Preparative Example 1 except using dimethylamine (2M in THF, 50 mL) and 4-methylsalicylic acid (15 g), the desired compound was prepared (6.3 g, 35%).

[0704] Step B

[0705] The product from step A above (1.5 g) was combined with iodine (2.1 g), NaHCO3 (1.1 g), EtOH (40 mL) and water (10 mL) and stirred overnight. Filtration, concentration of the filtrate, re-dissolution in CH2Cl2 and washing with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0.5-0.7% MeOH/CH2Cl2) gave the product (0.5 g, 20%, MH+=306).

[0706] Step C

[0707] Nitric acid (3.8 mL) in AcOH (10 mL) was added to the product from Step B above (0.8 g) and the mixture was stirred for 40 min. The mixture was diluted with water and extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as an orange solid (0.8 g, 92%, MH+=351).

[0708] Step D

[0709] A mixture of the product from step C above (800 mg), 10% Pd/C (100 mg), and EtOH/MeOH (40 mL) was stirred in a parr shaker under hydrogen (45 psi) for 1.5 hr. Filtration through celite and concentration in vacuo afforded the title product after purification by preparative plate chromatography (Silica, 10% MeOH/CH2Cl2, saturated with NH4OH) to give the product (92 mg, 22%, MH+=195).

Preparative Example 13.1

[0710]

419

[0711] Step A

[0712] Following a similar procedure as in Preparative Example 2, Step A except using dimethylamine (2M in THF, 23 ml) and 5-bromosalicylic acid (5 g), the desired compound was prepared (4.2 g, 75%, MH+=244).

[0713] Step B

[0714] Nitric acid (10 ml) in AcOH (100 ml) was added to the product from Step A above (2 g) and the mixture was stirred for 20 min. The mixture was diluted with water and extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a yellow solid (1.9 g, 80%, MH+=289).

[0715] Step C

[0716] The product from Step B above (1.9 g) was partially dissolved in EtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl2.2H2O (5.74 g) was added and stirred at room temperature overnight. The crude reaction was concentrated in vacuo, diluted with CH2Cl2 and washed with NaHCO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a solid (185 mg, 9%, MH+=259).

Preparative Example 13.2

[0717]

420

[0718] Step A

[0719] Following a similar procedure as in Preparative Example 2, Step A, except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylic acid (5 g), the desired compound was prepared (4.5 g, 78%, MH+=200).

[0720] Step B

[0721] Nitric acid (10 ml) in AcOH (100 ml) was added to the product from Step A above (2 g) and the mixture was stirred for 20 min. The mixture was diluted with water and extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a solid (2.2 g, 88%, MH+=245).

[0722] Step C

[0723] The product from Step B above (2.2 g) was partially dissolved in EtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl2.2H2O (7.01 g) was added and stirred at room temperature overnight. The crude reaction was concentrated in vacuo, diluted with CH2Cl2 and neutralized with NaOH. The entire emulsion was filtered though celite, the layers were separated and the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a solid (540 mg, 22%, MH+=215).

Preparative Example 13.3

[0724]

421

[0725] Step A

[0726] 3-Nitrosalicylic acid (10 g), PyBroP (20.52 g), and DIEA (28 ml) in anhydrous CH2Cl2 (200 ml) were combined and stirred at room temperature for 10 min. Dimethylamine (2M in THF, 55 ml) was added and let the reaction stir over the weekend. The mixture was extracted with 1N NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1N HCl (aq), extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The oil was taken up in ether and a solid crashed out, triterated in ether to give 4.45 g of a solid (39%, MH+=211).

[0727] Step B

[0728] The product from Step A (2.99 g), K2CO3 (9.82 g), and iodomethane (8.84 ml) were combined in acetone and heated to reflux overnight. The reaction was filtered and concentrated in vacuo. The oil was taken up in CH2Cl2 and washed with 1N NaOH, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 3.3 g of an oil (99%, MH+=225).

[0729] Step C

[0730] The crude product from Step B (3.3 g) was stirred with 10% Pd/C (350 mg) in EtOH (50 ml) under a hydrogen gas atmosphere at 20 psi overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 2.34 g of a solid (85%, MH+=195).

[0731] Step D

[0732] The product from Step C (469 mg) was dissolved in AcOH (6 ml). 1.95M Br2 in AcOH (1.23 ml) was added dropwise to the reaction and the mixture was stirred at room temperature for 1 hour. 50% NaOH was added to the reaction at 0° C. and the mixture was extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by preparative plate chromatography (Silica, 5% MeOH/CH2Cl2) to give the desired product (298 mg, 23%, MH+=273).

[0733] Step E

[0734] BBr3 (2.14 ml, 1M in CH2Cl2) was added to a CH2Cl2 solution (8 ml) of the product from Step D above (290 mg) and stirred overnight. A solid formed and was filtered, taken up in MeOH/CH2Cl2 and purified by preparative plate chromatography (Silica, 5% MeOH/CH2Cl2) to give the desired product (137 mg, 49%, MH+=259).

Preparative Example 13.4

[0735]

422

[0736] Step A

[0737] To the product from Preparative Example 13.3 Step D (200 mg) was added phenylboronic acid (98 mg), PdCl2(PPh3)2 (51 mg), and Na2CO3 (155 mg) in THF/H2O (4 ml/1 ml). The solution was heated at 80° C. overnight. EtOAc was added to reaction and washed with 1N NaOH. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by preparative plate chromatography (5% MeOH/CH2Cl2) to give 128 mg of an oil (65%, MH+=271).

[0738] Step B

[0739] Following a similar procedure as in Preparative Example 13.3 Step E and using the product from Step A above, the desired compound was prepared (0.1 g, 69%, MH+=257.1).

Preparative Example 13.5-13.7

[0740] Following the procedures set forth in Preparative Example 13.4 but using the boronic acid from the Preparative Example indicated in the Table below, the amine products were obtained.

41. Yield (%)Prep Ex.Boronic AcidProduct2. MH+13.5

423

424

1. 15% 2. 25813.6

425

426

1. 32% 2. 32513.7

427

428

1. 18% 2. 325

Preparative Example 13.8

[0741]

429

[0742] Step A

[0743] 2-Cyanophenol (500 mg), sodium azide (819 mg), and triethylamine hydrochloride (1.73 g) were combined in anhydrous toluene and heated to 99° C. overnight. After the reaction cooled down, product was extracted with H2O. Aqueous layer was acidified with conc. HCl dropwise giving a precipitate, which was filtered to give the product (597 mg, 87%, MH+=163).

[0744] Step B

[0745] Nitric acid (0.034 ml) in AcOH (5 ml) was added to the product from Step A above (100 mg) in AcOH and the mixture was allowed to stir for 1 hr. CH2Cl2 and H2O were added to reaction. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil. Trituration in ether gave the product as a solid (12 mg, 9%, MH+=208).

[0746] Step C

[0747] The product from step C (56 mg) was stirred with 10% Pd/C (20 mg) in EtOH/MeOH (15 ml) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo to give 29 mg is of a solid (62%, MH+=178).

Preparative Example 13.9

[0748]

430

[0749] The amine was prepared following the procedure disclosed in WO Patent Application 01/68570.

Preparative Example 13.10

[0750]

431

[0751] The amine was prepared following the procedure disclosed in WO Patent Application 01/68570.

Preparative Example 13.11

[0752]

432

[0753] Step A

[0754] Following the procedure described in Preparative Example 88.2, Step A, the ketone was prepared (6.4 g, 36%).

[0755] Step B

[0756] To a solution of ketone (1 g) and 2-R-methylbenzylamine (0.73 ml) in anhydrous toluene (20 ml) was added 1N TiCl4 in toluene (3 ml) at room temperature for 1.5 hrs. The precipitate was filtered and the filtrate was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 18/1) to give 800 mg of product (71%).

[0757] Step C

[0758] The imine from above (760 mg) and DBU (800 ul) were stirred without solvent for 4 hr. The crude reaction was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 8/1) to give 600 mg of product (79%).

[0759] Step D

[0760] The imine from Step C (560 mg) was dissolved in ether (8 ml). 3N HCl (5 ml) added and let stir at room temperature overnight. The ether layer was separated and concentrated in vacuo to give 400 mg of the amine hydrochloride product (93%).

Preparative Example 13.12

[0761]

433

[0762] The title compound was prepared similarly as in Preparative Example 13.11, but using the 2-S-methylbenzylamine instead of 2-R-methylbenzylamine (69%).

Preparative Example 13.13

[0763]

434

[0764] Step A

[0765] At room temperature, CsF (60 mg) was added to a mixture of furfuraldehyde (1.3 ml) and TMS-CF3 (2.5 g) and stirred at room temperature (24 h) and refluxed for another 12h. 3N HCl (40 ml) was added and after 4 hr, the mixture was extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the product (2.6 g, 100%).

[0766] Step B

[0767] To a solution of alcohol from above (2.6 g) in CH2Cl2 at room temperature was added Dess-Martin reagent (10 g) portionwise and 1 drop of water. After stirring for 3 hr at room temperature, 10% Na2S2O3 (60 ml) was added and after stirring overnight, the solid was filtered off and the filtrate was extracted with CH2Cl2. The organic layer was washed with saturated sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. Ether/hexane (1:2; 30 ml) was added to the residue, filtered, and filtrate concentrated in vacuo to give the product (2 g, 78%).

[0768] Step C

[0769] Following the procedures described in Preparative Example 13.11, Steps B, C and D, the amine salt was prepared.

Preparative Examples 13.15-13.17B

[0770] Following the procedure set forth in Preparative Example 13.13, but using the prepared or commercially available aldehydes, the optically pure amine products in the Table below were obtained.

5PrepEx.AldehydeAmineProductYield (%)13.15

435

436

437

20%13.16

438

439

440

31%13.17

441

442

443

66%13.17A

444

445

446

38%13.17B

447

448

449

31%

Preparative Example 13.18

[0771]

450

[0772] The title compound was prepared from trifluorophenylketone according to the procedures described in Preparative Example 13.11, Steps B, C, and D (68%).

Preparative Example 13.19

[0773]

451

[0774] Step A

[0775] Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (˜200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0).

[0776] Step B

[0777] Methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (13.7 g), available from step A, was dissolved in 75 mL of THF, and added with a 1.0 M sodium hydroxide aqueous solution (65 mL, 65.0 mmol). The mixture was stirred at room temperature for 24 h. A 1.0 M hydrogen chloride aqueous solution was added dropwise to the mixture until pH was approximately 2. The acidic mixture was extracted with CH2Cl2 (100 mL×2, 50 mL). The combined organic extracts were washed with brine (40 mL), dried with Na2SO4, and concentrated under reduced pressure to a solid, 10.0 g (100%, over two steps) of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (MH+=237.0).

[0778] Step C

[0779] To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (6.5 g, 27.4 mmol) in 140 mL of CH2Cl2, obtained from step B, was added bromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH2Cl2, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL×3) and brine (30 mL). The organic solution was dried with Na2SO4, filtered, and concentrated to an oil. This crude oil product was purified by flash column chromatography, eluting with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded a solid, further dried on high vacuum, yielding 6.76 g (93%) of N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH+=265.0, M+2=266.1).

[0780] Step D

[0781] An oven dried three-neck round bottom flask was equipped with a refluxing condenser, charged sequentially with palladium acetate (95 mg, 0.42 mmol), (R)-BINAP (353 mg, 0.57 mmol), cesium carbonate (9.2 g, 28.33 mmol), and N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (3.74 g, 14.2 mmol, from step C). The solid mixture was flushed with nitrogen. Toluene (95 mL) was added to the solid mixture followed by benzophenone imine (3.6 mL, 21.5 mmol). The mixture was heated to reflux and continued for 10 h. A second batch of palladium acetate (95 mg, 0.42 mmol) and (R)-BINAP (353 mg, 0.57 mmol) in 5 mL of toluene was added. Refluxing was continued for 14 h. The third batch of palladium acetate (30 mg, 0.13 mmol) and (R)-BINAP (88 mg, 0.14 mmol) was added, and reaction continued at 110° C. for 24 h. The mixture was cooled to room temperature, diluted with ether (50 mL), filtered through a layer of Celite, rinsing with ether. The filtrate and rinsing were concentrated under reduced pressure to an oil, which was purified twice by flash column chromatography using CH2Cl2 and CH2Cl2-MeOH (200:1) as eluents. Removal of solvents afforded 4.1 g (79%) of the amido-thiophene diphenylimine product as a solid (MH+=365.1).

[0782] Step E

[0783] To a stirred solution of thiophene imine (5.09 g, 13.97 mmol), obtained from step D, in 140 mL of CH2Cl2 at −78° C. was added dropwise a 1.0 M solution of boron tribromide in CH2Cl2. The mixture was stirred for 3 h while the temperature of the cooling bath was increased slowly from −78° C. to −15° C. 100 mL of H2O was added, the mixture was stirred at room temperature for 30 min, then the two layers were separated. The organic layer ( as A) was extracted with H2O (30 mL×2). The aqueous layer and aqueous extracts were combined, washed with CH2Cl2 (30 mL), and adjusted to pH ˜8 using a saturated NaHCO3 aqueous solution. The neutralized aqueous solution was extracted with CH2Cl2 (100 mL×3), the extracts were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to a light yellow solid, 1.49 g of N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide (first crop). The previous separated organic layer A and organic washing were combined, stirred with 30 mL of a 1.0 M HCl aqueous solution for 1 h. The two layers were separated, the aqueous layer was washed with CH2Cl2 (30 mL) and adjusted to pH ˜8 using a saturated NaHCO3 aqueous solution, and the separated organic layer and organic washing were combined as organic layer B. The neutralized aqueous solution was extracted with CH2Cl2 (30 mL×4), the extracts were washed with brine, dried by Na2SO4, and concentrated under reduced pressure to give 0.48g of a solid as the second crop of the titled product. Organic layer B from above was washed with brine, and concentrated to an oil, which was separated by preparative TLC (CH2Cl2-MeOH=50:1) to afford 0.45 g of a solid as the third crop of the titled product. The overall yield of the product, N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide, is 2.32 g (89%) (MH+=187.0).

Preparative Example 13.20

[0784]

452

[0785] Step A

[0786] To the product from Preparative Example 13.19 Step D (1.56 g) in CH2Cl2 (55 ml) was added potassium carbonate (1.8 g) followed by dropwise addition of bromine (0.45 ml). After 5 hr of mixing, water (100 ml) was added to the reaction and the layers were separated. The aqueous layer was extracted with CH2Cl2, which was then washed with brine, saturated sodium bicarbonate, and brine again. The organic layer was dried with Na2SO4, and concentrated in vacuo. The residue was purified via flash column chromatography (CH2Cl2) to yield 1.6 g of product (83%).

[0787] Step B

[0788] The product from above was reacted in the procedure set forth in Preparative Example 13.19 Step C to give the amine.

Preparative Example 13.21

[0789]

453

[0790] Step A

[0791] To the product from Preparative Example 13.20, Step A (300 mg) in THF (7 ml) at −78° C. was added a solution of n-BuLi (1.6M in hexanes, 0.54 ml). After 1 hr, iodomethane (0.42 ml) was added dropwise. After 3 hrs of stirring at −78° C., the reaction was warmed to room temperature overnight. Saturated ammonium chloride and water were added to the reaction and extracted with CH2Cl2. The organic layer was washed with saturated sodium bicarbonate and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative plate chromatography (CH2Cl2-MeOH=70:1 to 50:1) to afford the product (111 mg, 43%).

[0792] Step B

[0793] The product from above was reacted in the procedure set forth in Preparative Example 13.19, Step E to give the amine.

Preparative Example 13.22

[0794]

454

[0795] Step A

[0796] To the product from Preparative Example 13.19 (400 mg), Step D in CH2Cl2-pyridine (14 ml) was added N-chlorosuccinimide (220 mg). The mixture was stirred for 5 hr and then diluted with CH2Cl2 and washed with water, saturated sodium bicarbonate and brine, and concentrated in vacuo. The crude product was purified via preparative plate chromatography (CH2Cl2-MeOH=50:1) to give 180 mg of product (64%).

[0797] Step B

[0798] The product from above (274 mg) was reacted in the procedure set forth in Preparative Example 13.19, Step E to give the amine (89 mg, 58%).

Preparative Example 13.23

[0799]

455

[0800] Step A

[0801] To a stirred solution of acid (630 mg) from Preparative Example 13.19, Step B in CH2Cl2 (25 ml) was added oxalyl chloride (235 ul) followed by a catalytic amount of DMF (10 ul). The mixture was stirred for 1 hr, then potassium carbonate (1.8 g) was added followed by 3-amino-5-methylisoxazole (443 mg). The reaction stirred overnight and was quenched with water (25 ml). Layers were separated and the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative plate chromatography (CH2Cl2) to afford the product (580 mg, 78%, MH+=317,319).

[0802] Step B

[0803] The acid from the above (750 mg) step was reacted following the procedure set forth in Preparative Example 13.3, Step B to yield 625 mg of product (80%, MH+=331).

[0804] Step C

[0805] The product from above was reacted following the procedure set forth in Preparative Example 13.19, Step D to yield 365 mg of product (53%)

[0806] Step D

[0807] The product from above was reacted following the procedure set forth in Preparative Example 13.19, Step E to give the amine product (MH+=254).

Preparative Example 13.25

[0808]

456

[0809] Step A

[0810] To a solution of 2-methylfuran (1 g) in ether (30 ml) was added n-BuLi (5.32 ml) at −78° C. The reaction was warmed to room temperature and then refluxed at 38° C. for 1 hr. The reaction was cooled back down to −78° C. where the furyl lithium was quenched with trifluorobutyraldehyde and let stir at room temperature overnight. Saturated ammonium chloride added and extracted with ether. Purified via flash column chromatography to yield pure product (2 g, 80%)

[0811] Step B

[0812] The azide was prepared using the procedure from Preparative Example 75.75, Step B and the alcohol (1 g) from above and carried on crude to Step C below.

[0813] Step C

[0814] The amine was prepared using the procedure from Preparative Example 75.75, Step C to yield 400 mg of an oil (53%).

Preparative Example 13.26

[0815]

457

[0816] Step A

[0817] Perfluoroiodide (3.6 ml) was condensed at −78° C. Ether (125 ml) was added followed by the methyllithium.lithiumbromide complex (1.5M in ether, 18.4 ml). After 15 min, a solution of 5-methylfuraldehyde (2.5 ml) in ether was added dropwise. The reaction was warmed to 45° C. and let stir for 2 hr. Saturated ammonium chloride (30 ml) and water (30 ml) were added and let stir at room temperature for 1 hr. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give 5.86 g of product (100%).

[0818] Step B

[0819] The alcohol from above was reacted to form the azide using the procedure set forth in Preparative Example 75.75 Step B.

[0820] Step C

[0821] The azide from above was reacted to form the racemic amine using the procedure set forth in Preparative Example 75.75 Step C.

Preparative Example 13.27

[0822]

458

[0823] Step A

[0824] Following the procedure set forth in Preparative Example 13.26, Step A, the alcohol was prepared (100%).

[0825] Step B

[0826] To a solution of the alcohol (500 mg) from step A above in CH2Cl2 (20 ml) was added N-methyl-morpholine monohydrate (575 mg) and a catalytic amount of tetrapropyl ammonium perruthenate (76 mg). After 3 hr, the mixture was diluted with hexane (10 ml) and filtered through a silica pad, rinsing with hexane: CH2Cl2 (200 ml). The filtrate was concentrated in vacuo to give 350 mg of product (70.7%)

[0827] Step C

[0828] The ketone (1.19 g) from Step B was dissolved in THF (9.5 ml) and cooled to 0° C. A solution of S-methyl oxazoborolidine (1M in toluene, 1 ml) followed by a solution of borane complexed with dimethylsulfide (9.5 ml, 2M in THF) was added to the solution. The mixture was stirred at 0° C. for 30 min and continued at room temperature for 5 hr. The mixture was cooled back down to 0° C. and methanol (15 ml) was added dropwise to the mixture. After 30 min, the mixture was concentrated in vacuo to give an oily residue.

[0829] The residue was dissolved in CH2Cl2 and washed with 1N HCl, water, and brine. Dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified via flash column chromatography (Hex/CH2Cl2, 1:1) to afford 1.14 g of an oil (67%).

[0830] Step D

[0831] The alcohol (1.14 g) from above was reacted to form the azide using the procedure set forth in Preparative Example 75.75 Step B.

[0832] Step E

[0833] The azide (1.11 g) from above was stirred with 10% Pd/C (280 mg) in EtOH (40 ml) under a hydrogen gas atmosphere overnight. The reaction was filtered through celite, the filtrate was concentrated in vacuo to give 700 mg of product (70%).

Preparative Example 13.28

[0834]

459

[0835] Step A

[0836] To a stirred solution of 1-(2-thienyl)-1-propanone (3 g) in acetic anhydride (6 ml) at 0° C. was added dropwise a solution of fuming nitric acid in acetic acid (2 ml in 10 ml). After 30 min, the reaction was warmed to room temperature and let stir for 5 hrs where a solid precipitated out. Ice was added to the reaction and the solid was filtered. The solid was purified by flash column chromatography (Hex/CH2Cl2, 3:1 and 2:1) to yield 800 mg of desired product (20%).

[0837] Step B

[0838] The above nitro-thiophene compound (278 mg) was reduced using the procedure set forth in Preparative Example 2, Step B to give 54 mg of product (23%).

[0839] Step C

[0840] The above amine (395 mg), TEA (1 ml) and methanesulfonylchloride (0.5 ml) were combined in CH2Cl2 (35 ml) and stirred at room temperature for 1 hr. The reaction was quenched with saturated sodium bicarbonate (15 ml). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford product (854 mg, 100%).

[0841] Step D

[0842] To the above product (854 mg) in THF (25 ml) was added dropwise a solution of tetrabutylammonium fluoride (1M in THF, 2.8 ml). The mixture was stirred overnight, then diluted with CH2Cl2 (30 ml), washed with ammonium chloride and brine, dried over over Na2SO4, filtered and concentrated in vacuo to afford product (2.36 g, >100%).

[0843] Step E

[0844] The ketone (2.36 g) above was reacted via the procedure set forth in Preparative Example 88.2, Step B to yield 547 mg of product (86.6%).

[0845] Step F

[0846] To the product from step E (310 mg) in dimethoxyethane (12 ml) was added dropwise a solution of LAH (1M in ether, 3.8 ml). The mixture was heated to reflux overnight. The reaction was cooled to room temperature, SiO2 was added as well as water (1 ml) dropwise and let stir for 15 min. The mixture was filtered and the filtrate was concentratred in vacuo. The crude product was purified by preparative plate chromatography (MeOH/CH2Cl2, 15:1) to give the amine product (40 mg, 14%).

Preparative Example 13.29

[0847]

460

[0848] Step A

[0849] To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture was stirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, the mixture was poured carefully into crushed ice, and extracted with dichloromethane. The extracts were washed with brine, dried over magnesium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.2 g).

[0850] Step B

[0851] 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).

[0852] Step C

[0853] The product from Step B above (4.3 g) was dissolved in dichloromethane (125 mL) and cooled in a −78° C. bath. A solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirred for 4 h while the temperature was increased slowly from −78° C. to 10° C. H2O was added, the two layers were separated, and the aqueous layer was extracted with dichloro-methane. The combined organic layer and extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.96 g of the desired hydroxy-compound.

[0854] Step D

[0855] 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 H2O. The aqueous mixture was adjusted to pH˜5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with a 10% Na2S2O3 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.

[0856] Step E

[0857] 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.

[0858] Step F

[0859] The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D.

[0860] Step G

[0861] 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. H2O (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. The residue was dissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) and hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. The mixture was poured into an aqueous mixture of sodium hydroxide (1.0 M aq, 50 mL) and ether (100 mL). The two layers were separated. The aqueous layer was washed with ether three times. The combined ether washings were re-extracted with H2O once. The aqueous layers were combined, washed once with dichloromethane, adjusted to pH˜6 using 3.0 M and 0.5 M hydrogen chloride aqueous solutions, and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 1.2 g of desired amine compound.

Preparative Examples 13.30-13.32

[0862] Following the procedures set forth in Preparative Example 13.29, but using commercially available amines, hydroxy-amino-thiophene products in the Table below were obtained.

6Yield (%)Prep Ex.AmineProductMH+13.30Bn2NH

461

10% 375.113.31MeBnNH

462

14% 299.013.32EtBnNH

463

22%13.32A(Et)2NH

464

25%

Preparative Example 13.33

[0863]

465

[0864] Step A

[0865] 2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), the product from step A of Preparative Example 13.29, was converted to 3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%, MH+=312.1) by using ethylbenzyl-amine, following the procedure set forth in Preparative Example 13.29, Step B.

[0866] Step B

[0867] The product from step A above (5.5 g, 17.70 mmol) was demethylated following the procedure set forth in Preparative Example 13.29, Step C. The alcohol product was obtained in 4.55 g (87%, MH+=298.0).

[0868] Step C

[0869] The product from Step B above (4.55 g, 15.30 mmol) was brominated using the procedure set forth in Preparative Example 13.29, Step D. The corresponding bromide was obtained in 4.85 g (84%).

[0870] Step D

[0871] The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) was methylated using the procedure set forth in Preparative Example 13.29, Step E. The product was obtained in 4.82 g (96%).

[0872] Step E

[0873] The product from Step D above (4.82 g, 12.36 mmol) was stirred with concentrated sulfuric acid (5 mL) at room temperature for 3 h. Ice water (30 mL) was added to the mixture followed by CH2Cl2 (50 mL). The aqueous mixture was adjusted to pH˜6 using a 1.0 M NaOH aqueous solution. The layers were separated. The aqueous layer was extracted with CH2Cl2 (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to a dark brown oil, which was purified by flash column chromatography, eluting with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded 3.03 g (82%) of the debenzylated product (M+=300.0, M+2=302.0).

[0874] Step F

[0875] 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. The desired product was obtained in 1.36 g (97%, M+=314.1, M+2 =316.0).

[0876] Step G

[0877] The product from Step F (1.36 g, 4.33 mmol) was converted to imine product (1.06 g, 55%, MH+=415.1) using the procedure set forth in Preparative Example 13.29, Step F.

[0878] Step H

[0879] The imine product from Step G (1.06 g, 2.56 mmol) was converted to the desired hydroxy-amino thiophene compound (0.26 g, 43%) using the procedure set forth in Preparative Example 13.29, Step G.

Preparative Example 13.34

[0880]

466

[0881] Step A

[0882] 2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol), the product from step A of Preparative Example 13.29, was dissolved in 100 mL of CH2Cl2 and 20 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5 g, 35.68 mmol) was added. The mixture was stirred for 20 h at room temperature, diluted with 100 mL of CH2Cl2, and washed with a 0.5 N HCl aqueous solution (50 mL×2), H2O (50 mL), and brine (50 mL). The organic solution was dried with Na2SO4, and concentrated in vacuo to a brown oil. This oil was dissolved in 100 mL of CH2Cl2, washed again with a 0.5 M HCl aqueous solution (30 mL×3) and brine. After dried over Na2SO4, the organic solution was concentrated in vacuo to a yellow solid, 4.48 g (91%, MH+=275.0) of the desired product.

[0883] Step B

[0884] The product from Step A above (4.48 g, 16.33 mmol) was dissolved in acetone (100 mL), added with potassium carbonate (5.63 g, 40.80 mmol) and iodomethane (10.1 mL, 163.84 mmol). The mixture was stirred at room temperature for 1.5 h, diluted with 100 mL of hexanes and 50 mL of CH2Cl2, and filtered through a 1-in silica gel pad, rinsing with CH2Cl2. The filtrate was concentrated under reduced pressure to give 4.23 g (90%, MH+=289.0) of the desired product as a light yellow solid.

[0885] Step C

[0886] To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol) in 8 mL of N,N′-dimethylforamide at room temperature was added ethanethiol (0.45 mL, 6.0 mmol) dropwise. After 5 min, the mixture became a clear solution, and was added to a stirred solution of the product obtained from Step B above (0.45 g, 1.56 mmol) in 2 mL of N,N′-dimethylforamide in a round bottom flask. The flask was sealed with a ground glass stopper, and the mixture was heated at 90-95° C. for 4 h. After cooled to room temperature, the mixture was poured into 20 mL of a 1.0 M NaOH aqueous solution, further rinsed with 20 mL of H2O. The aqueous mixture was washed with diethyl ether (30 mL×2), adjusted to PH˜5 using a 0.5 M HCl aqueous solution, and extracted with CH2Cl2 (50 mL×4). The combined extracts were washed with brine, dried (Na2SO4), and concentrated to a dark yellow solution. This was dissolved in 50 mL of ethyl acetate, washed with H2O (30 mL×2) and brine (30 mL), dried over Na2SO4. Evaporation of solvent gave 0.422 g of the alcohol product (99%, MH+=275.0).

[0887] Step D

[0888] The alcohol obtained from Step C above (0.467 g, 1.70 mmol) was brominated using the procedure set forth in Preparative Example 13.29, Step D, to afford the corresponding bromide in 0.607 g (100%).

[0889] Step E

[0890] The bromide obtained from Step D above (0.607 g, 1.72 mmol) was methylated using the procedure set forth in Preparative Example 13.29, Step E, to give the desired product in 0.408 g (65%, M+=367, M+2=369.1).

[0891] Step F

[0892] The product (0.405 g, 1.103 mmol) from Step E above was converted to the imine compound (0.29 g, 56%) using the procedure set forth in Preparative Example 13.29,Step F.

[0893] Step G

[0894] 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 H2O was used as rinsing and combined to the aqueous layer. The aqueous mixture was washed with diethyl ether (40 mL×3), adjusted to pH˜6 using a 1.0 M HCl aqueous solution, and extracted with ethyl acetate (40 mL×3). The organic extracts were washed with H2O (20 mL×2), brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give 0.112 g of the desired hydroxy-amino thiophene sulfonamide (64%, MH+=290).

Preparative Example 13.35

[0895]

467

[0896] Step A

[0897] To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38 mL) at −78° C. and stirred at room temperature for half an hour. The reaction mixture again cooled to −78° C. and quenched with cyclopropyl amide 1 and stirred for two hours at −78° C. and slowly warmed to room temperature. The reaction mixture stirred for three hours at room temperature and quenched with the addition of saturated ammonium chloride solution. The mixture was taken to a separatory funnel, washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using column chromatography to afford the ketone 3.0 g (87%) as a pale yellow oil.

[0898] Step B

[0899] To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. was added R-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwise followed by addition of a solution of borane complexed with dimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30 minutes 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. The residue was extracted with ether, washed with water, 1M HCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and removal of solvent afforded the crude alcohol which was purified by silica gel chromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 13.36

[0900]

468

[0901] Step A

[0902] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) was mixed with SnCl4 (0.05 mL) and heated at 100° C. for 3 hours. After cooling the reaction mixture, water (10 mL) 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 0.9 g (43%) as a yellow oil.

[0903] Step B

[0904] The step B alcohol was obtained following a similar procedure set forth in the preparative example 13.35 Step B.

Preparative Example 13.37

[0905]

469

[0906] Step A:

[0907] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and 3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indium powder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture was stirred over night, diluted with water and extracted with ether. The ether layer was washed with water, brine and purified by silicagel chromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 13.38-13.45

[0908] Following a similar procedure set forth in Preparative Examples 13.25 and 13.35, and using the indicated Furan and Electrophile, the following Alcohols in the Table below were prepared.

7Prep.exFuranElectrophileAlcoholYield13.38

470

471

472

86%13.39

473

474

475

69%13.40

476

477

478

84%13.41

479

480

481

82%13.42

482

483

484

60%13.43

485

486

487

65%13.44

488

489

490

82%13.45

491

492

493

89%

Preparative Examples 13.50-13.61

[0909] Following a similar procedure set forth in Preparative Examples 13.25, and using the indicated Alcohol, the following Amines in the Table below were prepared.

8PREP. EX.ALCOHOLAMINE% YIELD13.5013.45

494

28%13.5113.38

495

58%13.5213.36

496

69%13.5313.35

497

81%13.5413.37

498

82%13.5513.39

499

45%13.5613.41

500

57%13.5713.40

501

58%13.5813.44

502

54%13.5913.42

503

53%13.6013.43

504

50%13.6113.37

505

82%

Preparative Example 13.70

[0910]

506

[0911] Step A

[0912] The imine was prepared following the procedure set forth in the preparative example 13.19 from the known bromoester (1.0 g) as a yellow solid, Step A to yield 1.1 g (79%).

[0913] Step B

[0914] The Step A product (0.6 g) was reacted following the procedure set forth in the preparative example 13.19 to give the amine product 0.19 g (64%).

[0915] Step C

[0916] The Step B product (1.0 g) was reacted following the procedure set forth in the preparative example 13.19 to give the acid as yellow solid 0.9 g (94%)

[0917] Step D

[0918] The Step C product (0.35 g) was reacted following the procedure set forth in the preparative example 13.19 to give the amino acid as yellow solid 0.167 g (93%).

Preparative Example 14

[0919]

507

[0920] Step A

[0921] 3-Nitro-1,2-phenylenediamine (10 g), sodium nitrite (5.4 g) and acetic acid (20 mL) were heated at 60° C. overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B.

[0922] Step B

[0923] The product from Step A above (2.8 g) was stirred with 10% Pd/C (0.3 g) in MeOH (75 mL) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo, to give the product (2.2 g, MH+=135).

Preparative Example 15

[0924]

508

[0925] Step A

[0926] N-methyl-4-bromopyrazole-3-carboxylic acid was prepared according to known methods, see: Yu. A. M.; Andreeva, M. A.; Perevalov, V. P.; Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. 1. in Zh. Obs. Khim. (Journal of General Chemistry of the USSR) 1982, 52, 2592, and refs cited therein.

[0927] Step B

[0928] To a solution of N-methyl-4-bromopyrazole-3-carboxylic acid (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25° C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mL×4). The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH2Cl2-MeOH (20:1), to give 1.09 g of the amide product (48%, MH+=232.0).

[0929] Step C

[0930] To a solution of the amide (0.67 g), obtained from step B, in 8 mL of concentrated sulfuric acid at 0° C. was added potassium nitrate (1.16 g) in small portions. The cooling bath was removed and the mixture was heated at 110° C. for 6 h. After cooling to 25° C., the mixture was poured into 80 mL of H2O, and an additional 20 mL of H2O was used as a rinse. The aqueous mixture was extracted with CH2Cl2 (100 mL×4). The combined extracts were washed with brine (50 mL), sat. NaHCO3 aqueous solution (50 mL), brine (50 mL), and dried with Na2SO4. Evaporation of solvent gave an oil, which solidified on standing. The crude product was purified by flash column chromatography, eluting with CH2Cl2-MeOH (1:0, 50:1 and 40:1). Removal of solvents afforded 0.521 g (65%) of the product as a solid (MH+=277.1)

[0931] Step D

[0932] The product (61 mg) obtained from step C was dissolved in 3 mL of THF. To this solution at −78° C. was added dropwise along the inside wall of the flask a 1.6 M solution of n-butyl lithium in hexane. After 45 min, a solution of methyl borate (0.1 mL) in THF (1.0 mL) was added. After 1.5 h, a solution of acetic acid in THF (0.25 mL, 1:10 v/v) was added to the cold mixture. Stirring was continued for 10 min, and a 30 wt % aqueous hydrogen peroxide solution (0.1 mL) was added. An additional portion of hydrogen peroxide aqueous solution (0.05 mL) was added 20 min later. The cooling bath was removed, and the mixture was stirred at 25° C. for 36 h. The mixture was poured into 30 mL of H2O, and the aqueous mixture was extracted with ethyl acetate (30 mL×4). The extracts were combined, washed with brine (10 mL), 5% NaHCO3 aqueous solution (10 mL) and brine (10 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure to a residue, which was then purified by preparative thin layer chromatography eluting with CH2Cl2-MeOH (20:1) to give the hydroxylated product (5 mg, 10%, MH+=215.3).

[0933] Step E

[0934] By treating the hydroxylated product of Step E with H2 under the conditions of 10% palladium on carbon in ethanol, one would obtain the desired hydroxyl-amino compound.

Preparative Example 16

[0935]

509

[0936] Step A

[0937] Following a similar procedure used in Preparative Example 13, Step C except using the known compound, 4-methyl-pyrimidin-5-ol, the product can be prepared.

[0938] Step B

[0939] Following a similar oxidation procedure used in Preparative Example 15, Step A except using the compound from Step A above, the product can be prepared.

[0940] Step C

[0941] Following a similar procedure used in Preparative Example 11, Step A except using the compound from Step B above, the product can be prepared.

[0942] Step D

[0943] Following a similar procedure used in Preparative Example 12, Step F except using the compound from Step C above, the product can be prepared.

Preparative Example 17

[0944]

510

[0945] Step A

[0946] Following a similar procedure used in Preparative Example 11, Step A except using the known 4-hydroxynicotinic acid, the product can be prepared.

[0947] Step B

[0948] Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared.

[0949] Step C

[0950] Following a similar procedure used in Preparative Example 12, Step F except using the compound from Step C above, the product can be prepared.

Preparative Example 18

[0951]

511

[0952] Step A

[0953] Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared.

[0954] Step B

[0955] Stirring the compound from Step A above, a suitable Pt or Pd catalyst and EtOH under hydrogen atmosphere (1-4 atm) the product can be prepared.

Preparative Example 19

[0956]

512

[0957] The product from Preparative Example 3 (14.6 g) dissolved in absolute EtOH (100 mL) was added dropwise over 4 hours to a stirred ethanolic (100 mL) solution of diethylsquarate (19 mL, 128 mmol). After 5 days, the reaction mixture was concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 0-5% MeOH/CH2Cl2) gave the product (65%, MH+=305, mp=178.6° C.).

Preparative Example 19.1

[0958]

513

[0959] The amine from Prepartive Example 3 (5 g) and dimethylsquarate (3.95 g) in MeOH were stirred overnight. The precipitated product was filtered to give 6.32 g of solid (78%, MH+=291.1)

Preparative Example 19.2

[0960]

514

[0961] The hydroxy thiophene amine from Preparative Example 13.34 (108 mg, 0.37 mmol) was dissolved in 5 mL of ethanol and stirred with diethoxysquarate (0.14 mL, 0.95 mmoL) and potassium carbonate (52 mg, 0.38 mmol) at room temperature overnight. The mixture was diluted with H2O (25 mL), adjusted to pH˜6 using a 1.0 M HCl aqueous solution, and extracted with ethyl acetate (40 mL×3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to an oil, which was purified by flash column chromatography, eluting with CH2Cl2-MeOH (100:1, v/v). Removal of solvents afforded 83.5 mg of the titled product (MH+=414).

Preparative Example 20-23.14B

[0962] Following the procedures set forth in Preparative Example 19 but using the amine from the Preparative Example indicated in the Table below, the cyclobutenedione intermediates were obtained.

9Amine from1. Yield (%)Prep Ex.Prep Ex.Product2. MH+204

515

1. 85% 2. 3332111

516

1. 44% 2. 31921.16

517

1. 9% 2. 291222

518

1. 38% 2. 3472314

519

1. 51% 2. 25923.110.1

520

1. 62% 2. 31723.210.2

521

1. 61% 2. 31923.312

522

1. 40% 2. 33023.410.3

523

1. 42% 2. 33323.510.4

524

1. 40% 2. 33323.610.5

525

1. 37% 2. 34723.713.2

526

1. 39% 2. 33923.813.1

527

1. 42% 2. 383/38523.913.19

528

1. 51% 2. 31123.1013.20

529

1. 67% 2. 389.1, 39023.1113.3

530

1. 52% 2. 383/38523.1213.21

531

1. 76% 2. 325.123.1313.22

532

1. 54%23.1413.23

533

1. 62% 2. 37823.14A13.70 Step B

534

1. 60% 2. 13823.14B13.70 Step D

535

1. 65%

Preparative Example 23.15A-23.15F

[0963] Following the procedures set forth in Preparative Example 19.2 but using the amines from the Preparative Example indicated in the Table below, the corresponding cyclobutenedione intermediates were prepared.

10Amine from1. Yield (%)Prep Ex.Prep Ex.Product2. MH+23.15A13.29

536

1. 66% 2. 34723.15B13.30

537

1. 21% 2. 49923.15C13.31

538

1. 41% 2. 42323.15D13.32

539

1. 26% 2. 43723.15E13.33

540

1. 48% 2. 361.123.15F 13.32A

541

1. 68% 2. 375.1

Preparative Example 23.16-23.26

[0964] Following the procedures set forth in Preparative Example 19 but using the amine from the Preparative Example indicated in the Table below, the cyclobutenedione intermediate products were obtained.

11PrepAmine fromYieldEx.Prep Ex.Product(%)23.1613.11

542

91%23.1713.12

543

81%23.1813.17

544

47%23.1913.27

545

21%23.2013.26

546

10%23.2113.25

547

49%23.2213.13

548

80%23.2313.15

549

63%23.2413.16

550

64%23.2513.17A

551

48%23.2613.17B

552

66%

Preparative Example 24

[0965]

553

[0966] Step A

[0967] To a solution of N-protected amino acid (1.5 g, 6.9 mmol) in CH2Cl2 (25 mL) at room temperature was added DIPEA (3.6 mL, 20.7 mmol), and PyBrop (3.4 g, 6.9 mmol) followed by MeNH2 (6.9 mL, 13.8 mmol, 2.0 M in CH2Cl2). The resulting solution was stirred for 18 h at room temperature (until TLC analysis deemed the reaction to be complete). The resulting mixture was washed sequentially with 10% citric acid (3×20 mL), sat. aq. NaHCO3 (3×20 mL), and brine (3×20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with CH2Cl2/MeOH (40:1) to afford 1.0 g (63% yield) of a solid.

[0968] Step B

[0969] To a round bottom charged with the N-protected amide (1.0 g, 4.35 mmol) (from Step A) was added 4N HCl/dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with Et2O (20 mL) and concentrated under reduced pressure. The crude product was treated with Et2O (2×20 mL) and concentrated under reduced pressure to afford 0.72 g (˜100% yield) of crude product as the HCl salt. This material was taken on without further purification or characterization.

Preparative Examples 25-33.1

[0970] Following the procedure set forth in Preparative Example 24 but using the commercially available N-protected amino acids and amines in the Table below, the amine hydrochloride products were obtained.

12PrepEx.Amino acidAmineProduct1. Yield (%)25

554

NH3

555

1. 70%26

556

557

558

1. 71%27

559

560

561

1. 66%28

562

563

564

1. 65%29

565

566

567

1. 90%30

568

569

570

1. 68%31

571

572

573

1. 68%32

574

575

576

1. 97%33

577

578

579

1. 97%33.1

580

581

582

1. 20%

Preparative Example 33.2

[0971]

583

[0972] Step A

[0973] BOC-valine (45 mg) and PS-carbodiimide (200 mg) were suspended in CH2Cl2 (4 ml). After addition of the CH2Cl2-amine solution (0.138N, 1 ml), the mixture was shaken overnight. The solution was filtered and the resin was washed with more CH2Cl2, and the filtrate was concentrated in vacuo to yield the product, which was carried on directly in Step B.

[0974] Step B

[0975] The crude material from Step A was dissolved in 4N HCl/dioxane (2.5 ml) and stirred for 2 h. The reaction was concentrated in vacuo to yield the desired amine hydrochloride, which was used directly in the next step.

Preparative Examples 33.3-33.47

[0976] Following the procedure set forth in Example 33.2 but using the commercially available N-protected amino acids in the Table below, the amine hydrochloride products were obtained.

13PrepEx.Amino acidAmineProduct33.3

584

585

586

33.4

587

588

589

33.5

590

591

592

33.6

593

594

595

33.7

596

597

598

33.8

599

600

601

33.9

602

603

604

33.10

605

606

607

33.11

608

609

610

33.12

611

612

613

33.13

614

615

616

33.14

617

618

619

33.15

620

621

622

33.16

623

624

625

33.17

626

627

628

33.18

629

630

631

33.19

632

633

634

33.20

635

636

637

33.21

638

639

640

33.22

641

642

643

33.23

644

645

646

33.24

647

648

649

33.25

650

651

652

33.26

653

654

655

33.27

656

657

658

33.28

659

660

661

33.29

662

663

664

33.30

665

666

667

33.31

668

669

670

33.32

671

672

673

33.33

674

675

676

33.34

677

678

679

33.35

680

681

682

33.36

683

684

685

33.37

686

687

688

33.38

689

690

691

33.39

692

693

694

33.40

695

696

697

33.41

698

699

700

33.42

701

702

703

33.43

704

705

706

33.44

707

708

709

33.45

710

711

712

33.46

713

714

715

33.47

716

717

718

Preparative Example 34

[0977]

719

[0978] To a solution of 3-chlorobenzaldehyde (2.0 g, 14.2 mmol) in THF (5 mL) at 0° C. was added LiN(TMS)2 (17.0 ml, 1.0 M in THF) dropwise and the resulting solution was stirred for 20 min. EtMgBr (6.0 mL, 3.0 M in Et2O) was added dropwise and the mixture was refluxed for 24 h. The mixture was cooled to room temperature, poured into saturated aqueous NH4Cl (50 mL), and then extracted with CH2Cl2 (3×50 volumes). The organic layers were combined, concentrated under reduced pressure. The crude residue was stirred with 3 M HCl (25 mL) for 30 min and the aqueous layer was extracted with CH2Cl2 (3×15 mL) and the organic layers were discarded. The aqueous layer was cooled to 0° C. and treated with solid NaOH pellets until pH=10 was attained. The aqueous layer was extracted with CH2Cl2 (3×15 mL) and the organic layers were combined. The organic layer was washed with brine (1×25 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 1.6 g (66% yield) of the crude amine as an oil (MH+ 170). This material was determined to be>90% pure and was used without further purification.

Preparative Example 34.1

[0979]

720

[0980] The aldehyde (3.5 g) and conc. HCl (20 ml) were combined and stirred overnight at 40° C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1.76 g of product (55%)

Preparative Example 34.2

[0981]

721

[0982] Chlorine was bubbled into 100 ml of CH2Cl2 at 10° C. The aldehyde (3.73 ml) was charged with 50 ml of CHCl3 and then cooled to 0° C. AlCl3 was added portionwise, followed by the chlorine solution and let stir at room temperature overnight. The reaction was poured into 150 ml of ice and 50 ml of 3N HCl and stirred for 30 min. Organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The crude product was purified via flash column chromatography (Hex/EtOAc 40/1) to yield 1.5 g of pure product.

Preparative Example 34.3

[0983]

722

[0984] Step A

[0985] The ketone (3.25 g) was reacted following the procedure set forth in Preparative Example 88.2, Step B to give the oxime (3.5 g, 99%).

[0986] Step B

[0987] The product from step A (1.2 g) was stirred with AcOH (3 ml) and Pd/C (10%, 300 mg) in EtOH (40 ml) under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude material dissolved in ether and washed with 2N NaOH, organic washed with brine, dried with Na2SO4, and concentrated in vacuo to give product (960 mg, 86%).

Preparative Example 34.4

[0988]

723

[0989] Step A

[0990] To a suspension of NaH (1.45 g) in DMF (25 ml) under a nitrogen atmosphere was added p-bromophenol (5 g) at 0° C. After stirring for 20 min, BrCH2CH(OEt)2 (5.3 ml) was added and the reaction was heated to reflux overnight. The solution was cooled and poured into ice water (80 ml) and extracted with ether. The ether layer was washed with 1N NaOH and brine, dried with MgSO4, filtered and concentrated in vacuo to give 8.4 g of crude product (100%)

[0991] Step B

[0992] To a solution of the product from Step A (8.4 g) in benzene (50 ml) was added polyphosphoric acid (10 g). The mixture was heated at reflux for 4 hrs. The reaction was cooled to 0° C. and poured into ice water (80 ml) and extracted with ether. The ether layer was washed with saturated sodium bicarbonate and brine, dried with MgSO4, filtered and concentrated in vacuo to give 4.9 g of crude product (85%)

[0993] Step C

[0994] To a solution of the product from Step B (2 g) in ether (20 ml) at −78° C. was added t-BuLi dropwise. After stirring for 20 min, DMF (950 mg) was added dropwise and the mixture was stirred at −25° C. for 3 hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 980 mg of crude product (67%).

[0995] Step D

[0996] To a solution of aldehyde (400 g) in ether (10 ml) was added LiN(TMS)2 (1M in THF, 3.3 ml) at 0° C. dropwise. The solution was stirred at 0° C. for 30 min and EtMgBr (3M in THF, 1.83 ml) was added dropwise. The reaction was refluxed overnight, cooed to 0° C., quenched with saturated ammonium chloride and extracted with ether. The ether was stirred with 3N HCl (20 ml), then the aqueous layer was basified with NaOH pellets and extracted with ether. The ether layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 220 mg of product (46%).

Preparative Example 34.5

[0997]

724

[0998] Following the procedures set forth in Preparative Example 34.4 Steps A through D, but using m-bromophenol (8 g), both amines were formed and separated by preparative plate chromatography (63-65%, MH+=175).

Preparative Example 34.6

[0999]

725

[1000] To a solution of 3-methyl-thiophene (5 g) in ether (50 ml) was added dropwise a solution of n-BuLi (1.6M in hexane, 32 ml). The mixture was stirred for 1.5 hr at room temperature. DMF (5.1 ml) was then added and let stir overnight. The mixture was poured into saturated ammonium chloride and extracted with ether. The ether layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The crude product was purified via flash column chromatography (EtOAc/Hex 20:1) to afford 5.27 g of an oil (84%).

Preparative Example 34.7

[1001]

726

[1002] Step A

[1003] To a solution of 4-bromo-2-furaldehyde (4 g) in MeOH (75 ml) was added trimethyl-orthoformate (3.8 ml). A catalytic amount of p-toluene sulfonic acid (195 mg) and the mixture was heated to reflux for 3.5 hr. The reaction was cooled down and potassium carbonate was added. The mixture was filtered through a silica gel pad. The filtrate was concentrated in vacuo, dissolved in CH2Cl2 and filtered. The filtrate was again concentrated in vacuo to give 4.03 g of product (80%).

[1004] Step B

[1005] To a solution of the product from Step A (2.02 g) in THF (80 ml) at −78° C. was added dropwise a solution of n-BuLi (2.5M in hexanes, 4.4 ml) and stirred for 1.5 hr. A solution of iodomethane (1.7 ml) was added and let stir for 2.5 hrs at −60° C. The cooling bath was removed and saturated ammonium chloride was added and let stir for 10 min. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo to afford 1.34 g of crude product.

[1006] Step C

[1007] The product from Step B (1.43 g) was dissolved in acetone (50 ml) and treated with a catalytic amount of p-toluene sulfonic acid (80 mg). The mixture was heated to reflux for 2 hr. The reaction was cooled down and solid potassium carbonate was added. The mixture was filtered through a silica gel pad and the filtrate was concentrated in vacuo to give 1.246 g of crude product.

Preparative Example 34.8

[1008]

727

[1009] Step A

[1010] To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20 ml) was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution of methyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixture and stirred for 16 hr. Water was added and the aqueous mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 g of product (90%).

[1011] Step B

[1012] To a solution of the product from Step A (3.6 g) in toluene (16 ml) was added tributyltin hydride (5.4 ml) followed by AIBN (555 mg). The mixture was heated to 85° C. for 3.5 hr. After cooling, the mixture was separated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06 g of product (73%).

[1013] Step C

[1014] To a solution of product from Step B (2.05 g) in THF (60 ml) at 0° C. was added a solution of LAH (1M in ether, 12.8 ml). The reaction was stirred at room temperature for 30 min. Water and 1M NaOH was added until a precipitate formed, diluted with EtOAc, stirred for 30 min and then filtered through a celite pad. The organic filtrate was concentrated in vacuo to give 1.56 g of product (93%).

[1015] Step D

[1016] To a solution of product from Step C (2.15 g) in CH2Cl2 (100 ml) was added Dess-Martin oxidant (7.26 g) in CH2Cl2 (45 ml) and stirred for 30 min. The mixture was diluted with ether (200 ml). The organic layer was washed with 1N NaOH, water and brine, dried with MgSO4, filtered and concentrated in vacuo to give oil and solid. The material was extracted with ether and filtered. Some solid crystallized out from the filtrate, filtered again, and the filtrate was concentrated in vacuo to give 2.19 g of product.

Preparative Example 34.9

[1017]

728

[1018] Step A

[1019] To a solution of carboxylic acid (5 g) in CH2Cl2 (400 ml) at 0° C. was added N(OCH3)CH3.HCl (11.5 g), DEC (15.1 g), HOBt (5.3 g) and NMM (43 ml) and stirred for 14 hr. The mixture was diluted with CH2Cl2 (100 ml) and the organic layer was washed with 10% HCl, saturated sodium bicarbonate and brine, dried with Na2SO4, and concentrated in vacuo to afford 5.74 g of crude product (85%).

[1020] Step B

[1021] To a solution of iodoethane (0.56 ml) in ether (5 ml) at −78° C. was added a solution of t-BuLi (1.7M in pentane, 8.3 ml) dropwise. The mixture was warmed to room temperature for 1 hr and transferred to a 100 ml round bottom charged with the product from Step A (1 g) in THF (12 ml) at −78° C. The mixture was stirred at −78° C. for 1 hr and at 0° C. for an additional 2 hr. 1M HCl was added dropwise followed by CH2Cl2. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo to afford 620 mg of product (76%).

[1022] Step C

[1023] To a solution of the product from Step B (620 mg) in THF/MeOH (10:1) at 0° C. was added NaBH4 (250 mg) in one portion. The mixture was stirred overnight at 0° C., concentrated in vacuo and the crude material was dissolved in CH2Cl2 and washed with 1N NaOH and brine, dried with Na2SO4, and concentrated in vacuo to afford 510 mg of product.

[1024] Step D

[1025] The above material was reacted in the procedures set forth in Preparative Example 75.75 Steps B and C to yield 170 mg of amine product (28%).

Preparative Example 34.10

[1026]

729

[1027] The above amine was made analogous to the procedures set forth in Patent WO96/22997 p.56, but using ethylglycine instead of benzylglycine in the DCC coupling.

Preparative Example 34.11

[1028]

730

[1029] Step A

[1030] To the nitro compound (3.14 g) and cyclohexylmethanol (1.14 g) in THF (50 ml) was added PPH3 (4.72 g) and cooled to 0° C. Diisopropylazadicarboxylate (3.15 ml) was added dropwise and let stir overnight. The reaction was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 30:1) to give product (3.3 g), which was carried on directly to the next step.

[1031] Step B

[1032] To the product from step A (3.3 g) in EtOH (50 ml) was added 10% Pd/C (1.7 g) under a hydrogen atmosphere at 55 psi and let stir overnight. The reaction was filtered through celite and concentrated in vacuo to give 3.2 g of product.

Preparative Example 34.12

[1033]

731

[1034] Step A

[1035] A solution of acid (2 g) in ether (20 ml) was added dropwise to a suspension of LiAlH4 (350 mg) in ether (15 ml) at 0° C. The solution was refluxed for 3 hr and stirred at room temperature ovenright. 5% KOH was added and reaction was filtered, extracted with ether, dried with MgSO4, filtered and concentrated in vacuo to give the product (1.46 g, 79%, MH+=166).

[1036] Step B

[1037] To a solution of alcohol from above (1.46 g) in CH2Cl2 at room temperature was added Dess-Martin reagent (5.6 g) portionwise and one drop of water and let stir over the weekend at room temperature. 10% Na2S2O3 was added and stirred for 20 min, extracted with CH2Cl2, washed with saturated sodium bicarbonate, dried with Na2SO4, and concentrated in vacuo to afford 1.1 g of product (76%).

Preparative Example 34.13

[1038]

732

[1039] The above compound was prepared according to the procedure set forth in EP 0 555 153 A1.

Preparative Example 34.14

[1040]

733

[1041] The aldehyde (500 mg) from above was reacted following the procedure set forth in the Preparative Example 13.4, Step A to yield 372 mg of product (76%).

Preparative Example 34.15-34.16

[1042] Following the procedures set forth in Preparative Example 34.8 but using the nitroalkanes indicated in the table below, the aldehydes were prepared.

14Prep.Ex.NitroalkaneAldehydeYield34.15

734

735

17%34.16

736

737

21%

Preparative Example 34.17

[1043]

738

[1044] Step A

[1045] To a stirred suspension of 5-bromo-2-furoic acid (15.0 g, 78.54 mmol) in 225 mL of CH2Cl2 at room temperature was added oxalyl chloride followed by a catalytic amount of N,N′-dimethylforamide. After 1 h, ethanol (20 mL) was added followed by triethylamine (22 mL). Reaction was continued for 15 h. The mixture was concentrated under reduced pressure to a residue, which was extracted with excess volume of hexanes, and hexanes-CH2Cl2 (3:1, v/v). The extracts were filtered, the filtrated was concentrated to a yellow oil, dried on high vacuum, yielding 17.2 g (93%) of the desired ester.

[1046] Step B

[1047] The ester product obtained from Step A above (17.2 g, 73.18 mmol) was converted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g, 37%) using the literature procedure: J. Am. Chem. Soc., 1939, 61, 473-478.

[1048] Step C

[1049] The ester product obtained from Step B above (7.9 g, 27.13 mol) was reduced to the alcohol (6.32 g) using the procedure set forth in Preparative Example 34.8, Step C.

[1050] Step D

[1051] The product obtained from Step C above (6.32 g) was dissolved in 140 mL of THF and cooled in a −78° C. bath. A 2.5 M solution of n-butyllithium in hexanes (22 mL, 55.0 mmol) was added dropwise along the side wall of the flask. After 15 min, H2O (˜70 mL) was added. Cooling bath was removed, the mixture was stirred for an additional 1 h. Brine (50 mL) and CH2Cl2 (300 mL) were added, the two layers were separated, the aqueous layer was extracted with CH2Cl2 (100 mL), and the combined organic layers ere dried by Na2SO4. Evaporation of solvents afforded 5.33 g (crude) of the debrominated product as a reddish brown oil.

[1052] Step E

[1053] The alcohol product obtained from Step D above (5.33 g) was oxidized to the corresponding aldehyde (3.06 g, 74% over three steps) using the procedure set forth in Preparative Example 34.8, Step D.

Preparative Example 34.18

[1054]

739

[1055] Step A

[1056] To a stirred solution of cyclopropyl bromide (4.0 mL, 50 mmol) in 120 mL of ether at −78° C. was added dropwise a 1.7M solution of t-butyllithium in pentane (44.5 mL, 75.7 mmol). After 10 min, cooling bath was removed, stirring was continued for 1.5 h. The mixture was cooled again in a −78° C. bath, and 3-furaldehyde (3.5 mL, 41.9 mmol) was added. Reaction was continued for 1 h, and quenched with a saturated NH4Cl aqueous solution. The aqueous mixture was extracted with CH2Cl2 (100 mL×3). The organic extracts were washed with brine, dried by Na2SO4, filtered, and concentrated in vacuo to give 5.3 g (91%) of the alcohol product as a yellow oil.

[1057] Step B

[1058] Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added dropwise to a vigorously stirred suspension of sodium iodide (32 g, 213.5 mmol) in 100 mL of acetonitrile. After 5 min, a solution of the alcohol obtained from Step A above (4.93 g, 35.68 mmol) in 100 mL of acetonitrile was added dropwise. Stirring was continued for 5 min. H2O (100 mL) was added, the layers were separated, and the aqueous layer was extracted with ether (100 mL×2). The organic layers were combined, washed with a 10% Na2S2O3 aqueous solution and brine, and dried over Na2SO4. Evaporation of solvents gave a dark brown oil, which was filtered through a 5-in silica gel column, eluting with CH2Cl2-hexanes (1:3.5, v/v). Removal of solvents afforded 4.22 g (47%) of the iodo product as a light yellow oil.

[1059] Step C

[1060] The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was added dropwise. After 20 min, cooling bath was removed. Reaction was continued for 2.5 h, and quenched with H2O (20 mL). The aqueous mixture was stirred overnight and separated. The aqueous layer was extracted with ether (30 mL). The combined organic layers were washed with brine, dried by Na2SO4, and filtered through a Celite pad. Removal of solvent gave 1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.

[1061] Step D

[1062] 3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above, was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (6.0 mL, 10.2 mmol) was added dropwise along the side wall of the flask. The mixture was stirred for 3 h from −78° C. to 0° C., and continued for 1 h at room temperature. A solution of N,N′-dimethylforamide (1.1 mL, 14.23 mmol) was added. Reaction was continued overnight, and quenched with a saturated NH4Cl aqueous solution. The two layers were separated, the aqueous layer was extracted with CH2Cl2 (30 mL×2). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated to an oil, which was purified by preparative TLC (CH2Cl2-hexanes=1:1.5, v/v) to give 0.48 g (36%) of the aldehyde (contaminated by some 3-butyl-2-furaldehyde).

Preparative Example 34.19

[1063]

740

[1064] Step A

[1065] 3-Ethylfuran was prepared from 3-hydroxymethylfuran according to literature procedure: J. Org. Chem., 1983, 48,1106-1107.

[1066] Step B

[1067] 3-Ethylfuran obtained from Step A above was converted to 4-ethyl-2-furaldehyde using the procedure set forth in Preparative Example 34.32, Step D.

Preparative Examples 35-51.20

[1068] Following the procedure set forth in Preparative Example 34 but using the commercially available aldehydes and Grignard reagents listed in the Table below, the amine products below were obtained.

15PrepGrignard1. Yield (%)Ex.AldehydeReagentAmine2. MH+35

741

EtMgBr

742

1. 65% 2. 15436

743

EtMgBr

744

1. 75% 2. 18037

745

EtMgBr

746

1. 78% 2. 17038

747

EtMgBr

748

1. 34% 2. 20439

749

EtMgBr

750

1. 68% 2. 15040

751

EtMgBr

752

1. 40% 2. 22041

753

EtMgBr

754

1. 73% 2. 15442

755

EtMgBr

756

1. 52% 2. 22043

757

EtMgBr

758

1. 55% 2. 18044

759

EtMgBr

760

1. 20% 2. 20445

761

EtMgBr

762

1. 80% 2. 16646

763

EtMgBr

764

1. 35% 2. 22047

765

i-PrMgBr

766

1. 20% 2. 15048

767

EtMgBr

768

1. 77% 2. [M—NH2]+ = 149 49

769

EtMgBr

770

1. 77% 2. 17250

771

EtMgBr

772

1. 78% 2. [M—NH2]+ = 14751

773

EtLi

774

1. 10% 2. 11651.2

775

EtMgBr

776

1. 37% 2. 16151.3

777

EtMgBr

778

1. 63% 2. 21651.4

779

EtMgBr

780

1. 71% 2. 22851.5

781

EtMgBr

782

1. 89% 2. 16851.6

783

EtMgBr

784

1. 20% 2. 22851.8

785

EtMgBr

786

1. 36% 2. 22251.10

787

788

789

1. 95% 2. 152.151.11

790

EtMgBr

791

1. 61% 2. 138.1 MH+—H2O51.12

792

EtMgBr

793

1. 70% 2. 184.151.18

794

EtMgBr

795

1. 42% 2. 147 [M—NH2]+51.19

796

EtMgBr

797

1. 67% 2. 20451.20

798

EtMgBr

799

1. 33% 2. 188

Preparative Examples 51.25-51.31

[1069] Following the procedure set forth in Example 34 but using the commercially available aldehydes and Grignard reagents listed in the Table below, the amine products were obtained.

16PrepGrignardYieldEx.AldehydeReagentAmine(%)51.25

800

EtMgBr

801

20%51.26

802

803

804

77%51.27

805

EtMgBr

806

51%51.28

807

808

809

56%51.29

810

811

812

54%51.30

813

EtMgBr

814

80%51.31

815

816

817

10%

Preparative Example 52

[1070]

818

[1071] Step A

[1072] A mixture of 2-(trifluoroacetyl)thiophene (2 mL, 15.6 mmol), hydroxylamine hydrochloride (2.2 g, 2 eq), diisopropylethylamine (5.5 mL, 2 eq) and MeOH (50 mL) was stirred at reflux for 48-72 hrs, then concentrated in vacuo. The residue was diluted with EtOAc, washed with 10% KH2PO4 and dried over Na2SO4 (anhydrous). Filtration and concentration afforded the desired oxime (2.9 g, 96%) which was used directly in Step B without further purification.

[1073] Step B

[1074] To a mixture of the product from Step A above in TFA (20 mL) was added Zn powder (3 g, 3 eq) portionwise over 30 min and stirred at room temperature overnight. The solid was filtered and the mixture reduced in vacuo. Aqueous NaOH (2 M) was added and the mixture was extracted several times with CH2Cl2. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the desired product (1.4 g, 50%).

Preparative Examples 53-61

[1075] Following the procedure set forth in Preparative Example 52 but using the commercially available ketones listed in the Table below, the following amines were obtained.

17Prep1. Yield (%)ExampleKetoneAmine2. MH+53

819

820

1. 11% 2. 12854

821

822

1. 33% 2. 14255

823

824

1. 49% 2. 15656

825

826

1. 5% 2. 15457

827

828

1. 47% 2. 17458

829

830

1. 71% 2. 19059

831

832

1. 78% 2. 19160

833

834

1. 80% 2. 19061

835

836

1. 9% 2. 156

Preparative Example 62

[1076]

837

[1077] To a cooled (0-5° C.) suspension of L-α-(2-thienyl)glycine (0.5 g) and LiBH4 (2M in THF, 3.8 mL) in anhydrous THF (10 mL) was slowly added a THF (5 mL) solution of iodine (0.8 g). After stirring at room temperature for 15 min, the mixture was stirred at relux overnight. After cooling to room temperature, MeOH was added dropwise until gas evolution ceased and after 30 min, the mixture was evaporated. The oily residue was stirred in 20 mL KOH for 4 hrs, diluted with brine and extracted with EtOAc.

[1078] The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (50% EtOAc/CH2Cl2, silica) afforded the product (0.3 g, 63%, MH+=144).

Preparative Example 63

[1079]

838

[1080] CeCl3—7H2O was dried at 140-150° C. for 22 hr. To this solid was added THF (80 mL, anhydrous) and after stirring for 2 hr, the suspension was cooled to −78° C. and to it was added methyl lithium over 30 min. After stirring for an additional 30 min 2-thiophenecarbonitrile dissolved in anhydrous THF (4.5 mL) was added and the resulting mixture stirred for an additional 4.5 hr at −78° C. Concentrated aqueous NH3 (25 mL) was added and the mixture was warmed to room temperature and filtered through celite. The filtrate was extracted with dichloromethane, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (5% MeOH, CH2Cl2, silica) afforded the desired product (1.2 g, 62%).

Preparative Example 64

[1081]

839

[1082] Step A

[1083] To a solution of (D)-valinol (4.16 g, 40.3 mmol) in CH2Cl2 (60 mL) at 0° C. was added MgSO4 (20 g) followed by dropwise addition of 3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution was stirred at 0° C. for 2 h and was allowed to warm to room temperature and stir overnight (14 h). The mixture was filtered and the drying agent was washed with CH2Cl2 (2×10 mL). The filtrate was concentrated under reduced pressure to afford 8.4 g (100%) of an oil which was taken onto the next step without further purification.

[1084] Step B

[1085] To a solution of the imine (8.4 g, 40.2 mmol) from Step A in CH2Cl2 (60 mL) at room temperature was added Et3N (6.2 mL, 44.5 mmol) followed by dropwise addition of TMSCI (5.7 mL, 44.5 mmol). The mixture was stirred for 6 h at room temperature whereupon the ppt that had formed was filtered off and washed with CH2Cl2 (2×10 mL). The combined filtrate was concentrated under reduced pressure and was taken up in Et2O/hexane (1:1/150 mL). The precipitate was filtered off and the filtrate was concentrated under reduced pressure to afford 10.1 g (89%) of the protected imine as an oil. This material was taken onto the next step without further purification.

[1086] Step C

[1087] To a solution of Etl (4.0 g, 25.6 mmol) in Et2O (40 mL) at −78° C. was added t-BuLi (30.1 mL, 51.2 mmol, 1.7 M in pentane) and the mixture was stirred for 10 min. The mixture was warmed to room temperature, stirred for 1 h, and was recooled to −40° C. A solution of the imine (6.0 g, 21.4 mmol) from Step B in Et2O (30 mL) was added dropwise via addition funnel to afford a bright orange mixture. The reaction mixture was stirred for 1.5 h at −40° C. then 3M HCl (50 mL) was added and the mixture was allowed to warm to room temperature. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with Et2O (2×30 mL) and the organic layers were combined and discarded. The aqueous layer was cooled to 0° C. and carefully treated with solid NaOH pellets until pH=12 was attained. The aqueous layer was extracted with Et2O (3×30 mL) and the combined layers were washed with brine (1×30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 4.8 g (94% yield) of the amine as an oil. This material was taken on crude to the next step without further purification.

[1088] Step D

[1089] To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80 mL) at room temperature was added MeNH2 (25 mL, 40% in water) followed by addition of a solution of H5IO6 (14.0 g, 61.4 mmol) in H2O (25 mL). The heterogenous mixture was stirred for 1.5 h (until the reaction was complete by TLC) and the precipitate was filtered off. The resulting filtrate was diluted with water (50 mL) and the mixture was extracted with Et2O (4×60 mL). The combined organic layers were concentrated to a volume of ˜30 mL whereupon 3M HCl (75 mL) was added. The mixture was stirred overnight (12 h at room temperature) after which the mixture was concentrated to remove the volatiles. The aqueous layer was extracted with Et2O (3×40 mL) and the organic layers were discarded. The aqueous layer was cooled to 0° C. and was carefully treated with solid NaOH pellets until pH˜12 was reached. The aqueous layer was extracted with Et2O (3×60 mL) and the combined organic layers were dried (MgSO4). The organic layer was concentrated under reduced pressure to afford 2.8 g (97% yield) of the desired amine as an oil [MH+ 154]. This compound was proven to be>85% pure by 1H NMR and was used crude in the subsequent coupling step.

Preparative Examples 65-75.10J

[1090] Following the procedure set forth in Preparative Example 64 but using the commercially available aldehydes, amino alcohols, and organolithium reagents in the Table below, the optically pure amine products in the Table below were obtained.

18PrepAminoOrgano1. Yield (%)Ex.AldehydeAlcohollithiumProduct2. MH+65

840

841

EtLi

842

1. 62% 2. 15466

843

844

EtLi

845

1. 70% 2. 15467

846

847

848

849

1. 54% 2. 16668

850

851

852

853

1. 67% 2. 16669

854

855

EtLi

856

1. 67 2. 15470

857

858

EtLi

859

1. 42% 2. 14271

860

861

EtLi

862

1. 36% 2. 14272

863

864

865

866

1. 62% 2. 14873

867

868

t-BuLi

869

1. 27% 2. 25674

870

871

t-BuLi

872

1. 15% 2. 16475

873

874

875

876

1. 7% 2. 20475.1

877

878

EtLi

879

1. 65% 2. 123 [M—NH2]+75.2

880

881

EtLi

882

1. 62% 2. 123 [M—NH2]+75.3

883

884

EtLi

885

1. 93% 2. 139 [M—NH2]+75.4

886

887

tBuLi

888

1. 50% 2. 167 [M—NH2]+75.5

889

890

tBuLi

891

1. 48% 2. 167 [M—NH2]+75.6

892

893

EtLi

894

1. 97% 2. 139 [M—NH2]+75.7

895

896

iPrLi

897

1. 87 2. 153 [M—NH2]+75.8

898

899

900

901

1. 94% 2. 151 [M—NH2]+75.9

902

903

EtLi

904

1. 75% 2. 151 [M—NH2]+75.10

905

906

tBuLi

907

1. 30% 2. 179 [M—NH2]+75.10A

908

909

910

911

1. 61% 2. 135 [M—NH2]+75.10B

912

913

EtLi

914

1. 24 2. 15475.10C

915

916

EtLi

917

1. 32% 2. 165 [M—NH2]+75.10D

918

919

MeLi

920

1. 47% 2. 137 [M—NH2]+75.10E

921

922

iPrLi

923

1. 30% 2. 165 [M—NH2]+75.10F

924

925

926

927

1. 67% 2. 163.0 [M—NH2]+75.10G

928

929

EtLi

930

1. 24% 2. 165 [M—NH2]+75.10H

931

932

EtLi

933

1. 70% 2. 19475.10J

934

935

EtLi

936

1. 54% 2. 208

Preparative Examples 75.11-75.59

[1091] Following the procedure set forth in Preparative Example 64 but using the prepared or commercially available aldehydes, amino alcohols, and organolithium reagents in the Table below and carrying the amine on crude, the optically pure amine products in the Table below were obtained.

19PrepAminoOrganoYieldEx.AldehydeAlcohollithiumProduct(%)75.11

937

938

939

940

52%75.12

941

942

943

944

50%75.13

945

946

iPrLi

947

57%75.14

948

949

iPrLi

950

54%75.15

951

952

iPrLi

953

58%75.16

954

955

956

957

61%75.17

958

959

EtLi

960

72%75.18

961

962

963

964

68%75.19

965

966

iPrLi

967

77%75.20

968

969

t-BuLi

970

15%75.21

971

972

MeLi

973

50%75.22

974

975

EtLi

976

23%75.24

977

978

EtLi

979

20%75.27

980

981

EtLi

982

65%75.28

983

984

iPrLi

985

61%75.29

986

987

EtLi

988

90%75.30

989

990

iPrLi

991

62%75.31

992

993

iPrLi

994

43%75.32

995

996

997

998

50%75.33

999

1000

1001

1002

50%75.34

1003

1004

tBuLi

1005

51%75.35

1006

1007

MeLi

1008

51%75.36

1009

1010

tBuLi

1011

57%75.37

1012

1013

tBuLi

1014

60%75.38

1015

1016

EtLi

1017

73%75.39

1018

1019

MeLi

1020

48%75.41

1021

1022

1023

1024

52%75.42

1025

1026

EtLi

1027

40%75.43

1028

1029

tBuLi

1030

20%75.44

1031

1032

t-BuLi

1033

79%75.45

1034

1035

iPrLi

1036

55%75.46

1037

1038

tBuLi

1039

39%75.47

1040

1041

iPrLi

1042

55%75.48

1043

1044

1045

1046

34%75.49

1047

1048

EtLi

1049

61%75.50

1050

1051

tBuLi

1052

25%75.51

1053

1054

iPrLi

1055

33%75.52

1056

1057

tBuLi

1058

30%75.53

1059

1060

EtLi

1061

39%75.54

1062

1063

1064

1065

38%75.55

1066

1067

EtLi

1068

64%75.56

1069

1070

EtLi

1071

46%75.57

1072

1073

EtLi

1074

62%75.58

1075

1076

iPrLi

1077

24%75.59

1078

1079

EtLi

1080

70%

Preparative Example 75.75

[1092]

1081

[1093] Step A

[1094] To a solution of aldehyde (2.5 g) in ether (50 ml) at 0° C. was added EtMgBr (4.56 ml) dropwise. The heterogenous mixture was stirred for 2 hr at 0° C. and then poured into a beaker of saturated ammonium chloride (25 ml), ice and CH2Cl2 (30 ml). After the biphasic mixture stirred for 10 min, the organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the product (2.41 g, 95%)

[1095] Step B

[1096] To a solution of alcohol from Step A above (1 g) in toluene at room temperature was added DPPA. The mixture was cooled to 0° C. and DBU was added and let stir for 12 hr at room temperature. The layers were separated and the organic layer was washed with water, 1N HCl and dried over Na2SO4, filtered, and concentrated in vacuo. Purified by preparative plate chromatography (hexane/EtOAc 20/1) to give the product (840 mg, 75%).

[1097] Step C

[1098] To a solution of azide (730 mg) from Step B above in THF (7 ml) was added PPh3 (1 g). The heterogenous solution was stirred for 12 hr, whereupon water (1.5 ml) was added. The mixture was refluxed overnight, cooled to room temperature and concentrated in vacuo. Ether and 1N HCl were added to the residue. The aqueous layer was cooled to 0° C., basified with NaOH pellets and extracted with ether. The ether layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product (405 mg, 62%).

[1099] Step D

[1100] To a solution of azide in THF at −10° C. was added LiAIH4 portionwise. The heterogenous solution was stirred at room temperature for 1 hr and then refluxed for 4 hr. The solution was cooled to 0° C. and water, 2M NaOH and ether were added to the reaction. The mixture was filtered through a celite pad. The filtrate was treated with 3N HCl. The aqueous layer was cooled to 0° C., basified with NaOH pellots and extracted with ether. The ether layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product.

Preparative Example 75.76-75.90

[1101] Following a similar procedure set forth in Preparative Example 75.75, and using the reduction procedure indicated, the following amines were obtained.

20PrepReducingEx.AldehydeStepProduct% Yield75.76

1082

1083

43%75.77

1084

1085

36%75.78

1086

1087

32%75.79

1088

1089

42%75.80

1090

1091

56%75.81

1092

1093

35%75.82

1094

1095

13%75.83

1096

1097

42%75.84

1098

1099

39%75.85

1100

1101

26%75.86

1102

1103

25%75.87

1104

1105

14%75.88(34.14)

1106

1107

49%75.89(34.13)

1108

1109

34%75.90

1110

1111

44%

Preparative Example 76

[1102]

1112

[1103] The desired compound was prepared according to methods previously described in J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 76.1

[1104]

1113

[1105] Step A

[1106] To a solution of amine from Preparative Example 75.90 (2.22 g) in CH2Cl2 (50 ml) at 0° C. was added TEA (3.03 ml) followed by BOC2O (2.85 g). The heterogenous mixture was allowed to stir at room temperature overnight. 10% Citric acid was added to the reaction and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, brine and dried with Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc 10:1) to afford 2.7 g of an oil (81%).

[1107] Step B

[1108] Following the procedure from Preparative Example 13.4, Step A, but using the product from Step A above (450 mg) and 3-thiophene boronic acid (284 mg), the product was prepared (325 mg, 71%).

[1109] Step C

[1110] To the product from Step B (325 g) was added 4M HCl in dioxane (1.31 ml) and let stir for 1 hr. The reaction was concentrated in vacuo and taken up in CH2Cl2 and concentrated in vacuo again. This procedure was repeated 5 times to afford a semisolid (89%).

Preparative Example 76.2-76.3

[1111] Following the procedures set forth in Preparative Example 76.1, but using the commercially available boronic acids, the indicated amines were prepared.

21Prep Ex.Boronic AcidProductYield (%)76.2

1114

1115

70%76.3

1116

1117

35%

Preparative Example 76.10

[1112]

1118

[1113] Step A

[1114] The product from Preparative Example 75.75, Step A (2.5 g) was reacted via the Preparative Example 13.11, Step B to give the ketone (1.93 g, 78%).

[1115] Step B

[1116] To a solution of ketone from Step A above (500 mg) in THF (5 ml) at 0° C. was added S-2-methyl-CBS-oxazaborolidine (0.98 ml) dropwise followed by BH3.Me2S (1.48 ml). The mixture was stirred at 0° C. for 2 hr and was allowed to warm to room temperature and stir overnight. The mixture was cooled to 0° C. and treated with is MeOH (10 ml). After stirring for 20 min, the reaction was concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with 1M HCl, saturated sodium bicarbonate, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by preparative plate chromatography (Hex/EtOAc 4:1) to afford 650 mg of an oil (89%).

[1117] Step C

[1118] The chiral alcohol from Step B above was reacted via the Preparative Example 75.75 Step B to give the azide.

[1119] Step D

[1120] The azide from Step C above was reacted via the Preparative Example 75.75 Step C to give the amine product.

Preparative Example 76.11

[1121]

1119

[1122] The desired compound was prepared as in Preparative Example 76.10, but using the R-2-methyl-CBS-oxazaborolidine in step B.

Preparative Example 77

[1123]

1120

[1124] The desired compound was prepared according to methods previously described in J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 78

[1125]

1121

[1126] The desired compound was prepared according to methods previously described in Chem. Pharm. Bull. 1991, 39,181-183.

Preparative Example 78.1

[1127]

1122

[1128] The desired compound was prepared according to methods previously described in J. Organometallic Chem. 1998, 567, 31-37.

Preparative Example 79

[1129]

1123

[1130] The desired compound was prepared according to methods previously described in Chem. Pharm. Bull. 1991, 39, 181-183.

Preparative Example 80

[1131]

1124

[1132] The desired compound was prepared according to methods previously described in a) Synthesis 1987, 998-1001, b) Synthesis 1996, 641-646 and c) J. Med. Chem. 1991, 34, 2176-2186.

Preparative Example 81

[1133]

1125

[1134] The desired compound was prepared according to methods previously described in a) Synthesis 1987, 998-1001, b) Synthesis 1996, 641-646 and c) J. Med. Chem. 1991, 34, 2176-2186.

Preparative Example 82

[1135]

1126

[1136] The desired compound was prepared according to methods previously described in J. Med. Chem. 1988, 31, 2176-2186.

Preparative Example 83

[1137]

1127

[1138] To a solution of carboxylic acid (1.5 g, 7.89 mmol) in H2O/acetone (1:10/12 mL total) at 0° C. was added Et3N (1.43 mL, 10.3 mmol) followed by addition of ethyl chloroformate (0.83 mL, 8.68 mmol). The resulting mixture was stirred for 30 min after which a solution of NaN3 (0.77 g, 11.8 mmol) in H2O (2 mL) was added dropwise. The resultant heterogenous mixture was stirred for 1 h at 0° C., then cold water (5 mL) and Et2O (10 mL) were added. The layers were separated and the aqueous layer was extracted with Et2O (2×10 mL). The organic layers were combined, toluene (20 mL) was added, and the organic layers were dried (MgSO4) and concentrated under reduced pressure to a volume of 20 mL. t-BuOH (5 mL) was added and the mixture was refluxed for 12 h. The mixture was concentrated under reduced pressure and the crude residue was taken up in 3M HCl (30 mL) and was heated at reflux for 12 h. The mixture was cooled to room temperature and extracted with Et2O (3×15 mL). The aqueous layer was cooled to 0° C. and solid NaOH pellets were added until pH˜12 was reached. The aqueous layer was extracted with Et2O (3×30 mL) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford 0.78 g (61% yield) of an oil [MH+ 162]. This material was used without further purification.

Preparative Example 84

[1139]

1128

[1140] The corresponding cyclopropyl analog was prepared according to the procedure outlined in Preparative Example 83.

Preparative Example 85

[1141]

1129

[1142] The corresponding cyclohexyl analog was prepared according to the procedure outlined in Preparative Example 83.

Preparative Example 86

[1143]

1130

[1144] The desired compound was prepared according to methods previously described in J. Org. Chem. 1978, 43, 892-898.

Preparative Example 87

[1145]

1131

[1146] A mixture of (R)-(+)phenylpropanolamine (8.2 g), 3,4-diethoxy-3-cyclobutene-1,2-dione (10 g) and absolute EtOH (75 mL) was stirred at 0-25° C. for 12 hrs. Filtration and concentration of the filtrate gave a syrup which was chilled in the freezer to give a solid. Trituration of the solid with diethyl ether gave the desired product (10.5 g, 71%, MH+=260).

Preparative Example 87.1

[1147]

1132

[1148] (R)-1-phenyl propylamine (4.82 ml) and 3,4-dimethoxy-3-cylclobutene-1,2-dione (5.03 g) were combined in MeOH (40 ml) and stirred overnight. Reaction concentrated in vacuo and purified via flash column chromatography (MeOH/CH2Cl2, 1:40) to yield 2.75 g of product (31%, MH+=246).

Preparative Example 88

[1149]

1133

[1150] A mixture of (S)-(+)-3-methyl-2-butylamine (3.0 g), 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g) and absolute EtOH (100 mL) was stirred at 0-25° C. for 12 hrs. Filtration and concentration of the filtrate gave a syrup which solidified upon dilution with Et2O. Trituration of the solid with diethyl ether gave the desired product as a solid (4.4 g, 72%, MH+=212).

Preparative Example 88.1

[1151]

1134

[1152] A mixture of amine from Preparative Example 75.1 (370 mg), 3,4-diethoxy-3-cyclobutene-1,2-dione (0.39 ml) and absolute EtOH (5 ml) was stirred at room temperature overnight. Purification by preparative plate chromatography (3% EtOH/CH2Cl2) afforded the desired product (263 mg, 37%).

Preparative Example 88.2

[1153]

1135

[1154] Step A

[1155] 2-Methylthiophene (3 g) was dissolved in THF and cooled to 40° C. N-butyllithium (2.5M in hexane, 12.24 ml) added dropwise and let stir at −40° C. for 30 min. CuBr.(CH3)2S (6.29 g) added and let warm to −25° C. where the trifluoroaceticanhydride (4.32 ml) was added. The reaction was stirred at −15° C. over the weekend. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 4.59 g of an oil (78%).

[1156] Step B

[1157] The product from Step A (4.58 g), hydroxylamine hydrochloride (3 g), sodium acetate (4.4 g), EtOH (75 ml) and H2O (7.5 ml) were combined and heated to 75° C. overnight. The reaction was concentrated in vacuo , taken up 1N HCl, extracted with ether, dried with MgSO4, filtered and concentrated in vacuo to give 4.58 g of the product (93%, MH+=210).

[1158] Step C

[1159] The product from Step B above (4.5 g) was dissolved in TFA (40 ml) and cooled to 0° C. Zn powder (4.2 g) was added portionwise and let reaction warm to room temperature and stir overnight. The reaction was concentrated in vacuo, taken up in 1N NaOH, extracted with ether, dried with MgSO4, filtered and concentrated in vacuo to give 3.43 g of the product (80%).

[1160] Step D

[1161] The product from Step C (526 mg), 3,4-diethoxy-3-cyclobutene-1,2-dione (0.4 ml) and absolute EtOH (10 ml) was stirred at room temperature overnight. Purification by preparative plate chromatography (10% EtOAc/Hex) to give 178 mg of product (21%, MH+=320).

Preparative Example 88.3

[1162]

1136

[1163] Following a similar procedure as described in Preparative Example 88.2, but instead using 2-methylfuran, the above cyclobutenedione intermediate was prepared.

Preparative Example 88.4

[1164]

1137

[1165] The amine from Preparative Example 75.1 (973 mg) and the dimethoxysquarate (870 mg) were dissolved in MeOH (20 ml) and stirred for 3 days. The reaction was concentrated in vacuo and purified via flash column chromatography (MeOH/CH2Cl2, 1%) to yield 325 mg of product (19%, MH+=249.8).

Preparative Example 88.5

[1166]

1138

[1167] The amine from Preparative Example 75.9 (323 mg) and the dimethoxysquarate (426 mg) were dissolved in MeOH (10 ml) and stirred over the weekend. The reaction was concentrated in vacuo and purified via flash column chromatography (MeOH/CH2Cl2, 1:20) to yield 407 mg of product (57%, MH+=235.8).

Preparative Example 89

[1168]

1139

[1169] To a solution of KH (0.45 g, 11.3 mmol) in THF (15 mL) at room temperature was added amine hydrochloride (0.85 g, 5.1 mmol) portionwise to afford a heterogenous reaction mixture. The mixture was allowed to stand overnight (12 h) and MeI (0.32 mL, 5.1 mmol) was added dropwise. The mixture was stirred for 6 h after which the mixture was carefully poured into cold brine (125 mL). The mixture was extracted with Et2O (3×25 mL) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the crude product as an oil. This material was carried on crude to the coupling step without further purification or characterization.

Preparative Example 89.1

[1170]

1140

[1171] To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added (R)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture. The mixture was allowed to stand overnight (18 hr) and then MeI (1.59 ml) was added dropwise. The mixture was stirred for 4 hr after which brine was added. Extracted with ether, dried with K2CO3, filtered and concentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 89.2

[1172]

1141

[1173] To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added (S)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture. The mixture was allowed to stand overnight (18 hr) and then MeI (1.59 ml) was added dropwise. The mixture was stirred for 4 hr after which brine was added. Extracted with ether, dried with K2CO3, filtered and concentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 90

[1174]

1142

[1175] The corresponding cis analog was prepared in an analogous fashion utilizing the procedure described in Preparative Example 89. This material was also used without further purification.

Preparative Example 91

[1176]

1143

[1177] The desired compound was prepared according to methods previously described in J. Org. Chem. 1987, 52, 4437-4444.

Preparative Example 92

[1178]

1144

[1179] The desired compound was prepared according to methods previously described in Bull. Chem. Soc. Jpn. 1962, 35, 11-16.

Preparative Example 93

[1180]

1145

[1181] The desired amine was prepared from the corresponding ketone according to standard methods previously described in a) Synthesis 1987, 998-1001, b) Synthesis 1996, 641-646 and c) J. Med. Chem. 1991, 34, 2176-2186.

Preparative Example 94

[1182]

1146

[1183] The desired amine was prepared from the corresponding ketone according to standard methods previously described in a) Synthesis 1987, 998-1001, b) Synthesis 1996, 641-646 and c) J. Med. Chem. 1991, 34, 2176-2186.

Preparative Example 95

[1184]

1147

[1185] Step A

[1186] Lithium hexamethyldisilylazide (34 mL, 1M in THF) was added dropwise to a −78° C. THF (20 mL) solution of isobutyronitrile (2.8 mL). After 40 min, cyclopropylmethylbromide (5 g) was added and the mixture warmed to and stirred at 25° C. overnight. After cooling to 0° C., 1M HCl (aq) was added and the mixture was extracted with diethyl ether, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at 0° C. to give the desired product (4.5 g).

[1187] Step B

[1188] Methyl Lithium (17 mL, 1.4 M in Et2O) was added to the product from Step A above (1.5 g) in Et2O (anhydrous) at 0° C. The mixture was stirred at 0-25° C. overnight, then diluted with 3M HCl (aq), extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered, concentrated in vacuo at 0° C. and used directly in Step C.

[1189] Step C

[1190] The product from Step B above was added to a slurry of NaBH4 (1.4 g) in isopropanol (50 mL) at 0° C., then the mixture was stirred at reflux for 8 hr and at room temperature for 48 hrs. Water was added and the mixture was stirred for 30 min, then extracted with diethyl ether, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was diluted with CH2Cl2 and extracted with 3M HCl. The organic phase was discarded and the aqueous phase was basified with NaOH (aq) and extracted with CH2Cl2. Drying over anhydrous Na2SO4, filtering, and concentration in vacuo gave the desired compound (0.5 g).

Preparative Example 96

[1191]

1148

[1192] Step A

[1193] 2-Thiophenecarbonyl chloride (2.0 mL, 18.7 mmol) was dissolved in 100 mL dichloromethane. After addition of diisopropylethylamine (4.1 mL, 23.4 mmol) and Boc-piperazine (3.66 g, 19.7 mmol), the mixture was stirred for 4 h at room temperature. The resulting mixture was put into water (500 mL) and acidified with 3N HCl to pH˜1. Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in the next step without any further purification. 1H NMR (300 MHz, d6-DMSO) 1.60 (s, 9H), 3.29 (dd, 4H), 3.69 (dd, 4H), 7.23 (dd, 1H), 7.49 (d, 1 H), 7.79 (d, 1H).

[1194] Step B

[1195] The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 2 h, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. 1H NMR (300 MHz, d6-DMSO) 2.81 (dd, 4H), 3.63 (dd, 4H), 7.21 (dd, 1H), 7.46 (d, 1H), 7.82 (d, 1H).

[1196] Step C

[1197] The crude material (3.50 g, 17.8 mmol) from Step B was dissolved in dichloromethane (100 mL). After addition of diisopropylethylamine (18.7 mL, 107 mmol), 3-nitrosalicylic acid (3.3 g, 18.0 mmol), and PyBrOP (10.4 g, 22.3 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (200 mL). Extraction with dichloromethane (2×200 mL) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCl and subsequently extracted with dichloromethane (3×100 mL). The combined organic phases of the acidic extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (2.31 g, 34% over 3 steps). 1H NMR (300 MHz, d6-DMSO) 3.30-3.90 (m, 8H), 7.10-8.20 (m, double signals due to E/Z-isomers, 6H), 10.82 (s, 1H).

[1198] Step D

[1199] The nitro-compound (2.3 g, 6.4 mmol) from Step C was dissolved in methanol (50 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (1.78 g, 84%). 1H NMR (300 MHz, d6-DMSO) 3.30-3.90 (m, 8H), 7.22 (m, 2H), 7.55 (d, 1H), 7.71 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 10.85 (bs, 1H).

Preparative Example 97

[1200]

1149

[1201] Step A

[1202] Picolinic acid (3.0 g, 24.3 mmol) was suspended in SOCl2 (15 mL). After addition of dimethylformamide (5 drops), the reaction mixture was stirred for 4 hours. Evaporation of the solvent yielded the corresponding acid chloride as HCl-salt. Without any further purification, the solid was suspended in 120 mL dichloromethane. After addition of diisopropylethylamine (12.7 mL, 73 mmol) and Boc-piparazine (4.8 g, 25.5 mmol), the reaction was stirred over night at room temperature. The resulting mixture was put into water (500 mL) and extracted with dichloromethane (2×100 mL). Drying over sodium sulfate resulted in sufficiently pure product that was used in Step B without any further purification. 1H NMR (300 MHz, d6-DMSO) 1.63 (s, 9H), 3.21 (dd, 4H), 3.61 (dd, 4H), 7.57 (dd, 1H), 7.63 (d, 1H), 7.98 (dd, 1H), 8.70 (d, 1H).

[1203] Step B

[1204] The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 2 days, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2>100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. 1H NMR (300 MHz, d6-DMSO) 2.77 (dd, 2H), 2.83 (dd, 1H), 3.38 (dd, 2H), 3.64 (dd, 1H), 7.58 (dd, 1H), 7.62 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H).

[1205] Step C

[1206] The crude material (1.35 g, 7.06 mmol) from Step B was dissolved in dichloromethane (50 mL). After addition of diisopropylethylamine (3.7 mL, 21.2 mmol), 3-nitrosalicylic acid (1.36 g, 7.41 mmol), and PyBrOP (3.62 g, 7.77 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (300 mL). Extraction with dichloromethane (2×100 mL) removed any PyBrOP products. The aqueous phase was acidified with 3N HCl. Adjustment of the pH with saturated sodium carbonate solution to almost neutral crushed the desired compound out of solution. The aqueous phase was subsequently extracted with dichloromethane (3×100 mL). The combined organic layers of the neutral extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol=20/1) to yield the desired product (1.35 g, 16% over 3 steps). 1H NMR (300 MHz, d6-DMSO) 3.30-3.95 (m, 8H), 7.22 (m, 1H), 7.61 (m, 1H), 7.73 (d, 2H), 8.03 (m, 1H), 8.17 (m, 1H), 8.69 (m, 1H), 10.82 (s, 1H).

[1207] Step D

[1208] The nitro-compound (1.35 g, 3.79 mmol) from Step C was dissolved in methanol (60 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=20/1) to yield the desired product (1.10 g, 89%). 1H NMR (300 MHz, d6-DMSO) 3.50-3.85 (m, 8H), 6.47 (dd 1H), 6.74 (m, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H).

Preparative Example 98

[1209]

1150

[1210] Step A

[1211] 1-Methyl-2-pyrrolecarboxylic acid (2.5 g, 20.0 mmol) was dissolved in dichloromethane (50 mL). After addition of PyBrOP (16.3g. 35.0 mmol), diisopropylethylamine (14.0 mL, 73.0 mmol) and Boc-piparazine (5.5 g, 30.0 mmol), the reaction was stirred over night at room temperature before being put into 1N sodium hydroxide (200 mL). Extraction with dichloromethane (2×100 ml ) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCl. Adjustment of the pH with saturated sodium carbonate solution to almost neutral precipitated the desired compound. The aqueous phase was subsequently extracted with dichloromethane (3×100 mL). The combined organic phases of the neutral extraction were dried over sodium sulfate. Removal of the solvent resulted in sufficiently pure product that was used in Step B without any further purification. 1H NMR (300 MHz, d6-DMSO) 1.59 (s, 9H) 3.21 (dd, 4H), 3.61 (dd, 4H), 3.74 (s, 3H), 6.11 (dd, 1H), 6.33 (d, 1H), 7.01 (d, 1H).

[1212] Step B

[1213] The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 3 h, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (3×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. 1H NMR (300 MHz, d6-DMSO) 2.79 (dd, 4H), 3.62 (dd, 4H), 3.76 (s, 3H), 6.11 (dd, 1H), 6.37 (d, 1H), 6.96 (d, 1H).

[1214] Step C

[1215] The crude material (3.15 g, 16.3 mmol) from Step B was dissolved in dichloromethane (100 mL). After addition of diisopropylethylamine (8.5 mL, 49.0 mmol), 3-nitrosalicylic acid (3.13 g, 17.1 mmol), and PyBrOP (9.11 g, 19.6 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) removed all PyBrOP products. The aqueous phase was then carefully acidified with 3N HCl until the color of the solution changes from orange to yellow and the desired compound crashed out of solution. The aqueous phase was subsequently extracted with dichloromethane (3×100 ml). The combined organic layers of the acidic extraction were dried over sodium sulfate and concentrated in vacuo to yield the desired product. 1H NMR (300 MHz, d6-DMSO) 3.35-3.85 (m, 8H), 3.79 (s, 3H), 6.13 (dd, 1H), 6.45 (d, 1H), 7.01 (s, 1H), 7.22 (dd, 1H), 7.70 (d, 1H), 8.16 (d, 1H), 10.83 (s, 2H).

[1216] Step D

[1217] The crude nitro-compound from Step C was suspended in methanol (60 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. The filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (2.61 g, 40% for 4 steps). 1H NMR (300 MHz, d6-DMSO) 3.45-4.80 (m, 8H), 3.79 (s, 3H), 6.17 (dd, 1H), 6.45 (m, 2H), 6.78 (m, 2H), 7.01 (d, 1H).

Preparative Example 99

[1218]

1151

[1219] Step A

[1220] 2-Bromopyridine N-oxide hydrochloride (1.13 g, 5.37 mmol) and Boc-piperazine (1.50 g, 8.06 mmol) were heated to 80° C. in pyridine (10 mL) over night. The reaction mixture was put into water (300 mL) and then extracted with dichloromethane (2×100 mL). The combined organic phases were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (500 mg, 33%). 1H NMR (300 MHz, d-CDCl3) 1.60 (s, 9H), 3.46 (dd, 4H), 3.78 (dd, 4H), 6.99 (m, 2H), 7.37 (dd, 1H), 8.33 (d, 1H).

[1221] Step B

[1222] The purified product (500 mg, 1.79 mmol) was stirred for 30 min with 4N HCl/dioxane (15 mL). Evaporation of the solvent yielded the crude amine (465 mg) as multiple HCl-salt which was used in Step C without any further purification. 1H NMR (300 MHz, d6-DMSO) 3.38 (m, 4H), 4.81 (m, 4H), 7.34 (dd, 1H), 7.55 (d, 1H), 7.86 (dd, 1H), 8.55 (d, 1H).

[1223] Step C

[1224] The crude material (370 mg, 1.48 mmol) from Step B was suspended in dichloromethane (20 mL). After addition of diisopropylethylamine (2.6 mL, 14.8 mmol), 3-nitrosalicylic acid (406 mg, 2.22 mmol), and PyBrOP (1.21 g, 2.59 mmol), the mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (50 mL). Extraction with dichloromethane (2×50 mL) removed all PyBrOP products. The aqueous phase was then carefully acidified (pH˜4-5) with 3N HCl and extracted with dichloromethane (3×50 mL). The combined organic layers of the acidic extraction were dried over sodium sulfate, concentrated in vacuo and purified by column chromatography (dichloromethane/methanol=10/1) to yield the desired product (330 mg, 65%).

[1225] LCMS calculated: 344.1, found: (M+1)+ 345.1

[1226] Step D

[1227] Sodium hydrosulfite (1.05 g) was dissolved in water (3.0 mL) to yield a 1.5N solution. Addition of dioxane (3.0 mL) was followed by injection of conc. ammonium hydroxide (0.60 mL, yields a 1.0N concentration). After addition of the nitro-compound (100 mg, 0.29 mmol), the reaction mixture was stirred for 0.5 h. Subsequently, the solvent was removed and the residue suspended in dichloromethane/methanol (10/1). Filtration through Celite removed most of the salts. Final purification by column chromatography (dichloromethane/methanol=5/1) yielded the desired product (68 mg, 75%).

[1228] LCMS calculated: 314.14, found: (M+1)+ 315.1

Preparative Example 100

[1229]

1152

[1230] Step A

[1231] 4-Bromopyridine hydrochloride (3.0 g, 15.4 mmol) was dissolved in water (15 mL). After addition of N-benzylpiperazine (14.8 mL, 85.0 mmol) and 500 mg copper sulfate, the reaction mixture was heated overnight to 140° C. The resulting product was extracted with ether (5×75 mL), dried over sodium sulfate and concentrated. Final purification by column chromatography (dichloromethane/methanol/NH4OH=10/1/0.1) yielded the desired product (2.16 g, 55%). 1H NMR (300 MHz, d-CDCl3) 2.68 (dd, 4H), 3.45 (dd, 4H), 6.76 (d, 2H), 7.40 (m, 5H), 8.38 (d, 2H).

[1232] Step B

[1233] The benzylamine (2.16 g, 8.54 mmol) from Step A, ammonium formate (2.71 g, 43.0 mmol) and Pd(C) (10%, 1.0 g) was suspended in methanol (50 mL) and refluxed for 3 h. The palladium was filtered off and the filtrate was concentrated. The sufficiently pure product was used in Step C without any further purification. 1H NMR (300 MHz, d-CDCl3) 2.48 (bs, 1H), 3.13 (dd, 4H), 3.41 (dd, 4H), 7.78 (d, 2H), 8.39 (d, 2H).

[1234] Step C

[1235] The crude material (1.15 g, 7.06 mmol) from Step B was dissolved in dichloromethane (50 mL). After addition of diisopropylethylamine (4.7 mL, 42.4 mmol), 3-nitrosalicylic acid (1.94 g, 10.6 mmol), and PyBrOP (5.78 g, 12.3 mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (300 mL). Extraction with dichloromethane (2×100 mL) removed all PyBrOP products. The aqueous phase was carefully acidified to pH˜5-6 with 3N HCl and extracted with dichloromethane (3×100 mL). The combined organic layers of the neutral extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol/NH4OH=10/1/0.1) to yield the desired product (850 mg, 37% for 2 steps).

[1236] Step D

[1237] The nitro-compound (850 mg, 2.59 mmol) from Step C was dissolved in methanol (40 mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol/NH4OH=10/1/0.1) to yield the desired product (650 g, 84%). 1H NMR (300 MHz, d6-DMSO) 3.40-3.75 (bm, 8H), 6.49 (dd, 1H), 6.76 (m, 2H), 6.93 (d, 2H), 8.28 (d, 2H).

Preparative Example 101

[1238]

1153

[1239] Step 1

[1240] N,N′-Dibenzyl-ethane-1,2-diamine (20 mL, 0.0813 mol), triethylamine (22.66 mL, 0.1626 mol) and benzene (100 mL) were combined in a round bottom flask. A solution of 2,3-dibromo-propionic acid ethyl ester (11.82 mL, 0.0813 mol) in benzene (50 mL) was added dropwise. The solution was refluxed over night and monitored by TLC (20% ethyl acetate/hexane). The reaction was cooled to room temperature, then filtered and washed with benzene. The filtrate was concentrated then purified by column chromatography (15% ethyl acetate/hexane). The product was isolated as an oil (25.42 g, 0.0752 mol, 92%). MS: calculated: 338.20, found: 339.2

[1241]

1
H NMR (300 MHz, CDCl3) 1.23 (t, 3H), 2.48 (m, 3H), 2.62 (m, 1H), 2.73 (m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.42 (d, 1H), 3.56 (m, 2H), 3.91 (d, 1H), 4.17 (m, 2H), 7.27 (m, 10H).

[1242] Step 2

[1243] In a Parr shaker vessel, the ester (25.43 g, 0.075 mol) and methanol (125 mL) were combined. The vessel was purged with argon and palladium catalyst (5% on carbon, 2.5 g) was added. The system was shaken under an atmosphere of hydrogen overnight. TLC (20% ethyl acetate/hexane) indicated that reaction was complete. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated and the product isolated as a solid (11.7 g, 0.074 mol, 98%).

[1244] MS: calculated: 158.11 , found:159.2 1H NMR (300 MHz, CDCl3) 1.27 (t, 3H), 2.70 (m, 4H), 2.96 (m, 1H), 3.13 (dd, 1H), 3.43 (dd, 1H), 4.18 (m, 2H).

Preparative Example 102

[1245]

1154

[1246] Piperazine-2-carboxylic acid ethyl ester (3.11 g, 0.0197 mol), diisopropylethylamine (5.15 mL, 0.0296 mol) and methylene chloride (200 mL) were combined in a round bottom flask. While stirring at room temperature, a solution of N,N-dimethylcarbamoyl chloride (1.81 mL, 0.0197 mol) in methylene chloride (20 mL) was added dropwise. The reaction was stirred for one hour. After this time the reaction was concentrated and carried on to the next step without further purification. (99% yield).

[1247] MS: calculated: 229.14, found: 230.1

[1248]

1
H NMR (300 MHz, CDCl3) 1.30 (t, 3H), 2.85 (s, 6H), 3.10 (m, 3H), 3.31 (m, 2H), 3.60 (m, 2H), 4.21 (q, 2H).

Preparative Example 103-104

[1249] Following the procedure described for Example 102, the Products listed in the table below were prepared using the commercially available chloride shown and piperazine-2-carboxylic acid ethyl ester from Preparative Example 101.

221. Yield (%)ExampleChlorideProduct2. (M + 1)+103

1155

1156

1. 99% 2. 237.1104

1157

1158

1. 62% 2. 253.1

Preparative Example 105

[1250]

1159

[1251] Step 1

[1252] 3-Nitrosalicylic acid (3.61 g, 0.0197 g), DCC (2.03 g, 0.0099 mol) and ethyl acetate (130 mL) were combined in a round bottom flask and stirred for 15 min. 4-Dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (4.51 g, 0.0197 g) was added, and the reaction was stirred for 72 hours. The reaction mixture was concentrated then dissolved in dichloromethane. The organic phase was washed once with 0.1N sodium hydroxide. The aqueous phase was back extracted once with dichloromethane. The aqueous phase was acidified and wash three times with ethyl acetate. The aqueous phase was concentrated and purified by column chromatography (5% methanol/DCM).

[1253] MS: calculated: 394.15, found: 395.0

[1254]

1
H NMR (300 MHz, CDCl3) 1.32 (t, 3H), 2.86 (m, 7H), 3.15 (m, 1H), 3.51 (m, 4H), 4.24 (m, 3H), 7.15 (m, 1H), 7.66 (m, 1H), 8.20 (m, 1H), 10.86 (bs, 1H).

[1255] Step 2

[1256] 4-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxylic acid ethyl ester (0.80 g, 0.002 mol) and methanol (50 mL) were combined in a round bottom flask. The system was purged with argon. To the solution was added 5% palladium on carbon (˜100 mg). The flask was purged with hydrogen and stirred overnight. The reaction was filtered through a pad of celite and washed with methanol. The material was concentrated then purified by column chromatography (6% methanol/DCM). Isolated product (0.74 g, 0.002 mol, 100%).

[1257] MS: calculated: 364.17, found: 365.1

[1258]

1
H NMR (300 MHz, CDCl3) 1.27 (t, 3H), 2.85 (m, 8H), 3.18 (1H), 3.45 (m, 3H), 4.19 (m, 3H), 3.90 (m, 3H)

[1259] Step 3

[1260] 1-(3-Amino-2-hydroxy-benzoyl)-4-dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (0.74 g, 0.002 mol) was suspended in a solution of dioxane (10 mL) and water (10 mL). Lithium hydroxide (0.26 g, 0.006 mol) was added and the mixture stirred for two hours. The solution was acidified to pH=6 with 3N HCl then extracted with butanol. The extracts were combined, dried over sodium sulfate and concentrated.

[1261] MS: calculated: 336.14, found: 337.1

[1262]

1
H NMR (300 MHz, CD3OD) 2.86 (m, 7H), 3.23 (m, 3H), 3.54 (m, 3H), 6.92 (m, 2H), 7.23 (m, 1H).

Preparative Example 106-107

[1263] Following the procedure described for Example 105, the Products listed in the table below were prepared using the amine from the Preparative Example indicated and 3-nitrosalacylic acid.

231. Yield (%)2. (M + 1)+ExampleAnilineProduct3. Note106103

1160

1. 91% 2. Not observed 3. Rainey nickel used in Step 2107104

1161

1. 24% 2. 360.0 3. For Step 1 used PyBrop/ DIEA in DCM

Preparative Example 108

[1264]

1162

[1265] Step A

[1266] 3-Nitrosalicylic acid (1.0 g, 5.5 mmol) was dissolved in ethyl acetate (20 mL). 1,3-Dicyclohexylcarbodiimide (0.568 g, 2.8 mmol) was added and the mixture was stirred for approximately 10 minutes and cooled to 0° C. During this time a precipitate formed. Azetidine (0.39 mL, 5.8 mmol) was added and the reaction was stirred overnight and allowed to warm to room temperature. After this time the reaction was cooled to 0° C. and filtered. The collected solid was washed with chilled ethyl acetate. The filtrate was concentrated and purified by column chromatography (80% EtOAc/Hex) to give the product (476 mg, 39.0%).

[1267]

1
H NMR (300 MHz, CDCl3) δ2.40(m, 2H), 4.38(m, 4H), 6.97(m, 1H), 7.62(d, 1H), 8.12(d, 1H), 12.88(m, 1H) ppm.

1163

[1268] The nitro compound (0.48 g, 2.1 mmol) from Preparative Example 32 Step A was dissolved in methanol (25 ml) and stirred with 10% Pd/C under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo to give the product (344 mg, 90%). 1H NMR (300 MHz, CDCl3) 82.52(m, 2H), 4.57(bs, 4H), 6.75(m, 1H), 6.90(m, 2H), 12.71(bs, 1H) ppm.

Preparative Example 109

[1269]

1164

[1270] In essentially the same manner as described in Preparative Example 108 above, the morpholino-amine product was obtained.

Preparative Example 110

[1271]

1165

[1272] Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL). N,N′-Dimethylcarbamoyl chloride (1.0 mL, 0.011 mol) was added dropwise to the solution at room temperature. The reaction was stirred for one hour. After this time 1N potassium hydroxide (200 mL) was added. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product, without further purification, as an oil (1.16 g, 13%).

[1273]

1
H NMR (CDCl3, 300 MHz) 1.95 (s, 1H), 2.83 (s, 6H), 2.86 (m, 4H), 3.20 (m, 4H).

[1274] MS: calculated: 157.12, found: 158.1.

Preparative Example 111

[1275]

1166

[1276] Piperazine (4.9 g, 0.057 mol) was dissolved in 1N HCl (100 mL). A solution of phenylsulfonylchloride (1.45 mL, 0.011 mol) in acetonitrile (25 mL) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time the reaction was extracted two times with ethyl acetate. The solution was then made basic with 1N potassium hydroxide and extracted three times with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (1.22 g, 9.4%).

[1277]

1
H NMR (CDCl3, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H), 7.76 (m, 2H).

[1278] MS: calculated: 226.08, found: 227.1.

Preparative Example 112

[1279]

1167

[1280] Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL). Methanesulfonyl chloride (0.85 mL, 0.011 mol) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time 1N potassium hydroxide (200 mL) was added. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product, without further purification, as a solid (1.07 g, 11%).

[1281]

1
H NMR (CDCl3, 300 MHz) 1.75 (s, 1H), 2.78 (s, 3H), 2.97 (m, 4H), 3.20 (m, 4H).

[1282] MS: calculated: 164.06, found: 165.1.

Preparative Example 113

[1283]

1168

[1284] Step A

[1285] Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100 mL). Propylisocyanate (1.51 mL, 0.0161 mol) was added to the solution at room temperature. The reaction was stirred for over night. After this time the reaction was diluted with 1N potassium hydroxide (200 mL) and extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product as a solid.

[1286] Step B

[1287] The product of Step A above, was dissolved in a 30% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time a 1N potassium hydroxide solution (200 mL) was added to the reaction. The aqueous layer was extracted a total of six times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product (1.37 g, 50%).

[1288]

1
H NMR (CDCl3, 300 MHz) 0.92 (t, 3H), 1.52 (m, 2H), 2.89 (m, 4H), 3.01 (s, 1H), 3.18 (m, 2H), 3.37 (m, 4H), 4.61 (bs, 1H).

[1289] MS: calculated: 171.14, found: 172.0.

Preparative Example 114

[1290]

1169

[1291] Piperazine (4.9 g, 0.0569 mol) was dissolved in 1N HCl (70 mL). A solution of phenylchloroformate (1.43 mL, 0.0114 mol) in acetonitrile (25 mL) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time the reaction was extracted two times with ethyl acetate. The solution was then made basic with 1N potassium hydroxide and extracted three times with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (2.12 g, 18%).

[1292]

1
H NMR (CDCl3, 300 MHz) 1.78 (s, 1H), 2.91 (m, 4H), 3.59 (m, 4H), 7.11 (2H), 7.19 (m, 1H), 7.36 (m, 2H).

[1293] MS: calculated: 206.24, found: 207.1.

Preparative Example 115-117

[1294] Following the procedure described for Example 112, the Products listed in the table below were prepared using the commercially available chloroformate shown and piperazine.

241. Yield (%)ExampleChloroformateProduct2. (M + 1)+115

1170

1171

1. 54% 2. 144.9116

1172

1173

1. 17% 2. 173.0117

1174

1175

1. 69% 2. 173.0

Preparative Example 118

[1295]

1176

[1296] Step A

[1297] Boc-Piperazine (3.01 g, 0.0161 mol) was dissolved in dichloromethane (100 mL) along with diisopropylethylamine (5.61 mL, 0.0322 mol). Benzoylchloride (1.87 mL, 0.0161 mol) was added dropwise to the solution at room temperature. The reaction was stirred for several hours. After this time the reaction was concentrated and the product was purified by column chromatography (10% MeOH/DCM). Boc-Protected product was isolated as a solid (5.21 g).

[1298]

1
H NMR (CDCl3, 300 MHz) 1.47 (s, 9H), 3.45 (m, 8H), 7.41 (m, 5H).

[1299] MS: calculated: 290.16, found: 290.8.

[1300] Step B

[1301] The product from Step A above, was dissolved in a 50% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with 1N potassium hydroxide (200 mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93 g).

[1302]

1
H NMR (CDCl3, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39 (s, 5H).

[1303] MS: calculated: 190.11, found: 191.1.

Preparative Example 119

[1304]

1177

[1305] Step A

[1306] Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100 mL) along with diisopropylethylamine (3.1 mL, 0.0177 mol). N,N′-dimethylsulfamoyl chloride (1.73 mL, 0.0161 mol) was added dropwise to the solution at room temperature. The reaction was stirred for several hours. After this time the reaction was diluted with water (100 mL). The layers were separated and the aqueous layer was extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (4.53 g).

[1307]

1
H NMR (CDCl3, 300 MHz) 1.47 (s, 9H), 2.84 (s, 6H), 3.21 (m, 4H), 3.48 (m, 4H).

[1308] MS: calculated: 293.14, found: 194.1 (M-Boc)+.

[1309] Step B

[1310] The product from Step A above, was dissolved in a 30% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with water and 1N potassium hydroxide was used to make the aqueous layer slightly basic. The aqueous layer was extracted a total of seven times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product (2.96 g).

[1311]

1
H NMR (CDCl3, 300 MHz) 2.03 (s, 1H), 2.83 (s, 6H), 2.92 (m, 4H), 3.23 (m, 4H).

[1312] MS: calculated: 193.09, found: 194.1.

Preparative Example 120

[1313]

1178

[1314] In essentially the same manner as that described in Preparative Example 105, Step 1, using 3-nitrobenzoic acid instead of 3-nitrosalicylic acid, the methyl ester product was prepared.

1179

[1315] The methyl ester (1.79 g, 6.1 mmol) from Step A above, was dissolved in dioxane/water (20 mL/15 mL) at room temperature. Lithium hydroxide (0.258 g, 6.2 mmol) was added to the solution. After a few hours more lithium hydroxide was added (0.128 g, 3.0 mmol) and the reaction was stirred for another hour. After this time the reaction was concentrated and then taken up in water. The solution was extracted two times with ether. The aqueous phase was then acidified and extracted three times with ethyl acetate. The organic fractions were then dried over sodium sulfate, filtered and concentrated. Product was isolated by column chromatography (95% EtOAc/Hex, 0.05% HOAc) to give the product (1.66 g, 98%).

[1316]

1
H NMR (300 MHz, CDCl3) 1.49(m, 2H), 1.68(m, 1H), 1.82(m, 2H), 2.44(m, 1H) 3.32(m, 1H), 3.58(m, 1H), 5.57(m, 1H), 7.65(m, 1H), 7.80(m, 1H), 8.32(m, 2H), 10.04(bs, 1 Hppm).

1180

[1317] The nitro compound was dissolved in an excess of methanol (20 mL) and covered by a blanket of argon. 5% Palladium on carbon was added (catalytic) and a hydrogen balloon was attached to the flask. The atmosphere of the system was purged under vacuum and replaced with hydrogen. This step was repeated for a total of three times. The reaction was then stirred under hydrogen overnight. After this time the balloon was removed and the solution was filtered through celite followed by several rinses with methanol. The filtrate was concentrated and dried on the vacuum line to provide the desired aniline product (1.33 g. 90%).

[1318]

1
H NMR (300 MHz, CDCl3) 1.40(m, 2H), 1.50(m, 1H), 1.68(m, 2H), 2.33(m, 1H) 3.18(m, 1H), 3.62(m, 1H), 5.39(m, 1H), 6.12(bs, 2H), 6.75(m, 2H), 7.12(m, 1H)ppm.

[1319] Mass Spectra, calculated: 248, found: 249.1 (M+1)+

Preparative Examples 121-123

[1320] Following the procedure described in Preparative Example 120, but using the commercially available amine and benzoic acid indicated, the intermediate products in the table below were obtained.

251. Yield (%)Carboxylic2. (M + 1)+Ex.AcidAmineProduct3. Note121

1181

1182

1183

1. 21% 2. 251.0122

1184

1185

1186

1. 21% 2. 265.0 3. Skipped step B123

1187

1188

1189

1. 15% 2. 264.0 3. Skipped step B

Preparative Example 124

[1321]

1190

[1322] Step A

[1323] 3-Nitrosalicylic acid (500 mg, 2.7 mmol), 1,3-dicyclohexylcarbodiimide (DCC) (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min. (R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resulting suspension was stirred at room temperature overnight. The solid was filtered off and the filtrate was either concentrated down and directly purified or washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the residue by preparative plate chromatography (silica gel, 5% MeOH/CH2Cl2 saturated with AcOH) gave the desired compound (338 mg, 46%, MH+=267).

[1324] Step B

[1325] The product from Step A above was stirred with 10% Pd/C under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 4% MeOH/CH2Cl2 saturated with NH4OH) to give the product (129 mg, 43%, MH+=237).

Preparative Examples 125-145

[1326] Following the procedure described for Preparative Example 124, but using the commercially available amine or the amine from the Preparative Example indicated and 3-nitrosalicylic acid, the products in the table below were obtained.

26AmineComm. Avail./1. Yield (%)Ex.From Prep. Ex.Product2. (M + 1)+125

1191

1192

1. 37% 2. 298.1126

1193

1194

1. 31% 2. 310.1127

1195

1196

1. 68% 2. 294.1128

1197

1198

1. 54% 2. 365.9129

1199

1200

1. 45% 2. 316.1130110

1201

1. 59% 2. 293.1131111

1202

1. 32% 2. 362.0132114

1203

1. 36% 2. 342.0133112

1204

1. 65% 2. 300.0134

1205

1206

1. 48% 2. 321.1135

1207

1208

1. 50% 2. 300.1136

1209

1210

1. 56% 2. 299.2137115

1211

1. 79% 2. 280.1138116

1212

1. 64% 2. 307.1139

1213

1214

1. 73% 2. 304.2140

1215

1216

1. 34% 2. 264.0141117

1217

1. 40% 2. 307.1142113

1218

1. 91% 2. 307.1143118

1219

1. 9.0% 2. 326.0144119

1220

1. 42% 2. 329.0145

1221

1222

1. 6.5% 2. 236.1

Preparative Example 146

[1327]

1223

[1328] Step A

[1329] To a solution of tosylaziridine [J. Am. Chem. Soc. 1998, 120, 6844-6845) (0.5 g, 2.1 mmol) and Cu(acac)2 (55 mg, 0.21 mmol) in THF (5 mL) at 0° C. was added PhMgBr (3.5 ml, 3.0 M in THF) diluted with THF (8 mL) dropwise over 20 min. The resulting solution was allowed to gradually warm to rt and was stirred for 12 h. Sat. aq. NH4Cl (5 mL), was added and the mixture was extracted with Et2O (3×15 mL). The organic layers were combined, washed with brine (1×10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by preparative TLC eluting with hexane/EtOAc (4:1) to afford 0.57 g (86% yield) of a solid. The purified tosylamine was taken on directly to the next step.

[1330] Step B

[1331] To a solution of tosylamine (0.55 g, 1.75 mmol) in NH3 (20 mL) at −78° C. was added sodium (0.40 g, 17.4 mmol). The resulting solution was stirred at −78° C. for 2 h whereupon the mixture was treated with solid NH4Cl and allowed to warm to rt. Once the NH3 had boiled off, the mixture was partitioned between water (10 mL) and CH2Cl2 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The organic layers were combined,), dried (NaSO4), and concentrated under reduced pressure to a volume of ˜20 mL. 4N HCl in dioxane (5 mL) was added and the mixture was stirred for 5 min. The mixture was concentrated under reduced pressure and the resultant crude residue was recrystallized from EtOH/Et2O to afford 0.30 g (87% yield) of a solid.

Preparative Examples 147-156.10

[1332] Following the procedure set forth in Preparative Example 146 but using the requisite tosylaziridines and Grignard reagents listed in the Table below, the following racemic hydrochloride products were obtained.

27PrepTosylGrignardAmineEx.aziridineReagenthydrochloride1. Yield (%)147

1224

MeMgBr

1225

1. 19%148

1226

EtMgBr

1227

1. 56%149

1228

n-PrMgBr

1229

1. 70%150

1230

i-PrMgCl

1231

1. 41%151

1232

BnMgCl

1233

1. 61%152

1234

MeMgBr

1235

1. 61%153

1236

EtMgBr

1237

1. 66%154

1238

n-PrMgBr

1239

1. 80%155

1240

i-PrMgBr

1241

1. 27%156

1242

BnMgCl

1243

1. 79%156.1

1244

1245

1246

52%156.2

1247

1248

1249

49%156.3

1250

1251

1252

61%156.4

1253

1254

1255

57%156.5

1256

1257

1258

64%156.6

1259

1260

1261

64%156.7

1262

1263

1264

45%156.8

1265

1266

1267

23%156.9

1268

1269

1270

40%156.10

1271

1272

1273

15%

Preparative Example 156.11

[1333]

1274

[1334] Step A

[1335] To a solution of the amine (118 mg) from Preparative Example 148 in CH2Cl2 (10 ml) was added triethylamine (120 ul), R-Mandelic Acid (164 mg), DCC (213 mg) and DMAP (8.8 mg)and let stir for 40 hr. The mixture was diluted with CH2Cl2 and washed with saturated ammonium chloride, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by preparative plate chromatography (Hex/EtOAc 4:1) to afford both isomers (A, 86 mg, 45%) (B, 90 mg, 48%).

[1336] Step B

[1337] To isomer B (90 mg) from above in dioxane (5 ml) was added 6M H2SO4 (5 ml). The reaction was heated to 80° C. over the weekend. 2M NaOH added to basify the reaction and extracted with ether. Ether layer washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was stirred in 4N HCl in dioxane for 30 min, concentrated in vacuo and recrystallized in EtOH/ether to afford 55 mg of product (98%).

[1338] Step C

[1339] Isomer A (86 mg) was reacted following the procedure set forth in Step B above to give the amine salt.

Preparative Example 156.12

[1340]

1275

[1341] The above nitro compound was reduced following the Preparative Example 2, Step B.

Preparative Example 156.13

[1342]

1276

[1343] To a solution of 1,2-phenylenediame (1.5 g) in CH2Cl2 (30 ml) at 0° C. was added TEA (2.91 ml), followed by dropwise addition of MeSO2Cl (1.07 ml). The mixture was allowed to warm to room temperature and stir overnight. 1M HCl added and the layers were separated. The aqueous layer was adjusted to pH=11 with solid NaOH, extracted with CH2Cl2. The basified aqueous layer was then neutralized using 3N HCl and extracted with CH2Cl2, dried with Na2SO4, filtered, and concentrated in vacuo to give 1.8 g of product (71%).

Preparative Example 156.14

[1344]

1277

[1345] The above compound was prepared using the procedure set forth in Preparative Example 156.13, but using PhSO2Cl.

Preparative Example 156.15

[1346]

1278

[1347] The nitro compound was reduced following a similar procedure as in Preparative Example 2, Step B.

Preparative Example 156.16

[1348]

1279

[1349] Step A

[1350] The known acid (410 mg) above (J. Med. Chem. 1996, 34,4654.) was reacted following the procedure set forth in Preparative Example 2, Step A to yield 380 mg of an oil (80%).

[1351] Step B

[1352] The amide (200 mg) from above was reacted following the procedure set forth in Preparative Example 2, Step B to yield 170 mg of an oil (100%).

Preparative Example 156.17

[1353]

1280

[1354] Step A

[1355] To a solution of ketone (500 mg) in EtOH/water (3:1, 4 ml) at room temperature was added hydroxylamine hydrochloride (214 mg) followed by NaOH to afford a heterogenous mixture. The reaction was not complete so another equivalent of hydroxylamine hydrochloride was added and refluxed overnight. The reaction was cooled to 0° C. and treated with 3N HCl and extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 500 mg of product (92%).

[1356] Step B

[1357] To a solution of oxime (300 mg) in THF (5 ml) at 0° C. was added LiAIH4 (266 mg) portionwise. The heterogenous solution was stirred at room temperature for 14 hr and then refluxed for 8 hr. The solution was cooled to 0° C. and water, 2M NaOH, water and ether were added to the reaction. The mixture was filtered through a celite pad. The filtrate was treated with 3N HCl. The aqueous layer was cooled to 0° C., basified with NaOH pellets and extracted with ether. The ether layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product (143 mg, 69%).

Preparative Example 156.18

[1358]

1281

[1359] Step A

[1360] Methoxyacetic acid (14 mL) in CH2Cl2 (120 mL) and cooled in an ice-water bath was treated with DMF (0.9 mL) and oxalyl chloride (21 mL). After stirring at RT overnight, the mixture was concentrated in vacuo and redissolved in CH2Cl2 (120 mL). N-methyl-N-methoxylamine (20 g) was added and the mixture stirred at RT overnight. Filtration and concentration in vacuo afforded the desired amide (21 g, 89%).

[1361] Step B

[1362] To a solution of the above amide (260 mg) in THF (5 ml) at −78° C. was added a solution of 2-thienyllithium (1M in THF, 2.15 ml). The solution was stirred for 2 hr at −78° C. and warmed to −20° C. for an additional 2 hr. The reaction was quenched with saturated ammonium chloride and extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 250 mg of product (82%).

[1363] Step C

[1364] The ketone from above (250 mg) was reacted via the procedure set forth in Preparative Example 156.17 Steps A and B to yield 176 mg of the amine (79%).

Preparative Example 156.19

[1365]

1282

[1366] Step A

[1367] To a solution of 3-chlorothiophene (1.16 ml) in ether (20 ml) at −10° C. was added n-BuLi (2.5M in hexane, 5 ml). After solution was stirred at −10° C. for 20 min, propionaldehyde (0.82 ml) in ether (20 ml) was added dropwise and let warm to room temperature slowly. The reaction was quenched with saturated ammonium chloride and extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.37 g of product (62%).

[1368] Step B

[1369] The alcohol from Step A above was reacted via the procedures set forth in Preparative Example 75.75, Steps B and C to give the amine.

Preparative Example 156.20

[1370]

1283

[1371] Step A

[1372] To a solution of magnesium metal (360 mg) in THF (15 ml) at 0° C. was added 2-bromothiophene (1.45 ml) in THF (10 ml) dropwise over 20 min. The solution was warmed to room temperature for 3 hr, recooled to 0° C. whereupon a solution of cyclopropylacetonitrile (1 g) in ether (30 ml) was added dropwise via a syringe and let warm to room temperature and stir overnight. 3M HCl was added and washed with CH2Cl2. The aqueous layer was basified with NaOH pellets and extracted with ether, dried with Na2SO4, filtered, and concentrated in vacuo to give 625 mg of product (68%).

[1373] Step B

[1374] The ketone was reacted via the procedure set forth in Preparative Example 156.17 Step A to give the oxime.

[1375] Step C

[1376] The oxime from above was reacted via the procedure set forth in Preparative Example 156.17 Step B to give the amine.

Preparative Example 156.21

[1377]

1284

[1378] Step A

[1379] To a solution of CH3ONHCH3.HCl (780 mg) and acid chloride (1 g) in CH2Cl2 at 0° C. was added dry pyridine (1.35 ml) to afford a heterogenous mixture The solution was warmed to room temperature and stirred overnight. 1 M HCl was added to the reaction and the organic layer was separated, washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give 1 g of product (85%).

[1380] Step B

[1381] To a solution of Etl (614 ul) in ether (5 ml) at −78° C. was added t-BuLi (1.7M in pentane, 9 ml) dropwise. The mixture was warmed to room temperature for 1 hr, cooled to −78° C. where the amide (1 g) from Step A in THF (4 ml) was added and allowed to warm to 0° C. for 2 hr. 1M HCl was added to the reaction and extracted with CH2Cl2, washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give 500 mg of product (63%).

[1382] Step C

[1383] To a solution of ketone (800 mg) in THF/water (10:1, 20 ml) at 0° C. was added sodium borohydride (363 mg) portionwise. The solution was stirred for 2 hr at 0° C. The mixture was concentrated in vacuo, the residue was dissolved in CH2Cl2, washed with 1N NaOH and brine, dried with Na2SO4, filtered, and concentrated in vacuo to give 560 mg of product (69%).

[1384] Step D

[1385] The alcohol from above was reacted via the procedures set forth in Preparative Example 75.75, Steps B and C to give the amine (176 mg, 59%).

Preparative Example 156.22

[1386]

1285

[1387] Step A

[1388] Cyclopropylacetonitrile (12 mmol) in Et2O (50 mL) at 0° C. was treated with PhMgBr (14 mmol) and the mixture was stirred for 2 hrs at 0° C., then at RT overnight. Hydrochloric acid (3M) was added, and after stirring for an additional 12 hrs, the mixture was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired ketone (1.34 g, 70%).

[1389] Step B

[1390] Following the procedures set forth in Preparative Example 156.20 Steps B and C, the amine was prepared.

Preparative Example 156.23

[1391]

1286

[1392] The above amine was prepared using the procedures set forth in WO Patent Publication 98/11064.

Preparative Example 157

[1393]

1287

[1394] Step A

[1395] By taking the known carboxylic acid [J. Med. Chem. 1996, 39, 4654-4666] and subjecting it to the conditions outlined in Preparative Example 112, the product can be prepared.

[1396] Step B

[1397] Following a similar procedure used in Preparative Example 2, Step A, except using dimethylamine and the compound from Step A above, the product can be prepared.

[1398] Step C

[1399] Following a similar procedure used in Preparative Example 2, Step B, except using the compound from Step B above, the product can be prepared.

Preparative Example 158

[1400]

1288

[1401] Following a similar procedure used in Preparative Example 157, Steps A-C, except using trifluoromethylsulfonylchloride in Step A above, the product can be prepared.

Preparative Example 500.1

[1402]

1289

[1403] Step A

[1404] By using the nitro-amide from Preparative Example 13.3, Step A, the amidine structure can be prepared following a similar procedure to that in Tetrahedron Lett., 2000, 41 (11), 1677-1680.

[1405] Step B

[1406] By using the product from Step A and the procedure set forth in Preparative Example 2, Step B, one could obtain the desired amine-amidine.

Alternate Preparative Example 500.2

[1407]

1290

[1408] Step A

[1409] By treating the nitro-amide from Preparative Example 13.3, Step B with POCl3 and subsequently MeNH2, according to procedures known in the art, one would obtain the desired compound.

[1410] Step B

[1411] By treating the product from Step A according to the procedure set forth in Preparative Example 13.3, Step E, one could obtain the desired compound.

[1412] Step C

[1413] By using the product from Step B and the procedure set forth in Preparative Example 2 Step B, one would obtain the desired compound.

Preparative Example 500.3

[1414]

1291

[1415] Step A

[1416] By following a similar procedure as that described in Zh. Obshch. Khim., 27, 1957, 754, 757., but instead using 2,4-dichlorophenol and dimethylphosphinic chloride, one would obtain the desired compound.

[1417] Step B

[1418] By following a similar procedure as that described in J. Organomet. Chem.; 317, 1986, 11-22, one would obtain the desired compound.

[1419] Step C

[1420] By following a similar procedure as that described in J. Amer. Chem. Soc., 77, 1955, 6221, one would obtain the desired compound.

[1421] Step D

[1422] By following a similar procedure as that described in J. Med. Chem., 27, 1984, 654-659, one would obtain the desired compound.

Alternate Preparative Example 500.4

[1423]

1292

[1424] Step A

[1425] By following a similar procedure as that described in Phosphorous, Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119-129, but instead using 4-chlorophenol, one would obtain the desired compound.

[1426] Step B

[1427] By using a similar procedure as that in Phosphorous, Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119-129, but instead using MeMgBr, the desired compound could be prepared.

[1428] Step C

[1429] By following a similar procedure as that described in J. Amer. Chem. Soc., 77, 1955, 6221, one would obtain the desired compound.

[1430] Step D

[1431] By following a similar procedure as that described in J. Med. Chem., 27, 1984, 654-659, one would obtain the desired compound.

Preparative Example 500.5

[1432]

1293

[1433] By following a similar procedure as that set forth in J. Org. Chem. 1998, 63, 2824-2828, but using CH3CCMgBr, one could obtain the desired compound.

Preparative Example 500.6

[1434]

1294

[1435] Step A

[1436] By following the procedure set forth in Preparative Example 13.1, Step B using 3-methoxythiophene, one can obtain the desired product.

[1437] Step B

[1438] By using the product from step A and following the procedure set forth in Preparative Example 13.19, Step E, the desired compound can be obtained.

[1439] Step C

[1440] By using the product from Step B and following the procedure set forth in Preparative Example 13.29, Step D, one can obtain the desired compound.

[1441] Step D

[1442] By using the product from Step C and following the procedure set forth in Preparative Example 13.3, Step B, the desired compound can be obtained.

[1443] Step E

[1444] By treating the product from Step D with n-BuLi at −78° C. in THF and quenching the resulting anion with CO2 according to standard literature procedure, one would obtain the desired compound following aqueous acid work up.

[1445] Step F

[1446] By using the product from Step E and the procedure set forth in Prepartive Example 13.19, Step C, one could obtain the desired compound.

[1447] Step G

[1448] By using the product from step F and following the procedure set forth in Preparative Example 13.19, Step E, the desired compound can be obtained.

[1449] Step H

[1450] By using the product from Step G and following the procedure set forth in Preparative Example 2, Step B, the desired compound can be obtained.

[1451] Step I

[1452] By using the product from Step H and following the procedure set forth in Preparative Example 19, the desired compound can be prepared.

Example 200

[1453]

1295

[1454] To a solution of the HCl salt product (83 mg, 0.50 mmol) from Preparative Example 24, in EtOH (3 mL) at room temperature was added Et3N (55 μL, 0.50 mmol) and the mixture was stirred for 10 min. The cyclobutenedione (100 mg, 0.33 mmol) from Preparative Example 19 in EtOH was then added in a single portion and the mixture was stirred for 12 h at room temperature. The mixture was concentrated under reduced pressure and was purified by preparative TLC (4×1000 μM plates) eluting with CH2Cl2/MeOH (25:1) to afford 116 mg (91% yield) of the desired product as a solid [MH+389.1, mp 241-243° C].

Examples 201-209

[1455] Following the procedure set forth in Preparative Example 200 but using the appropriate amine hydrochlorides from Preparative Examples 25-33 as identified and the cyclobutenedione intermediate from Preparative Example 19, the cyclobutenedione products in the Table below were obtained.

281. Yield (%)(Prep Ex.)2. MH+Ex.AmineProduct3. mp (° C.)201(25)

1296

1297

1. 89% 2. 375.1 3. 255.5-257.3202(26)

1298

1299

1. 92% 2. 465.1 3. 149.0-152.3203(27)

1300

1301

1. 68% 2. 451.1 3. 282-284204(28)

1302

1303

1. 74% 2. 493.1 3. 141205(29)

1304

1305

1. 48% 2. 479.1 3. 142206(30)

1306

1307

1. 41% 2. 479.1 3. 142207(31)

1308

1309

1. 59% 2. 479.1 3. 141208(32)

1310

1311

1. 34% 2. 493.1 3. 140209(33)

1312

1313

1. 40% 2. 493.1 3. 142209.1(33.1)

1314

1. 59% 2. 143-145

Example 209.2

[1456]

1315

[1457] The crude amine product from Preparative Example 33.2 and the cyclobutendione component from Preparative Example 19.1(36 mg) were dissolved in MeOH/DIEA (2.5 ml/5/1) and irradiated via microwave (50W, 1 hr). The reaction was concentrated in vacuo and purified by Gilson semi-prep. HPLC to give the final product (68%, MH+=485.2).

Examples 209.3-209.50

[1458] Following the procedure set forth in Example 209.2, but using the prepared amine from the Preparative Example indicated in the Table below, the following cyclobutenedione products were obtained.

29(Prep Ex.)1. Yield (%)Ex.AmineProduct2. MH+209.3(33.3)

1316

1. 50% 2. 541.2209.4(33.4)

1317

1. 32% 2. 549.1209.5(33.5)

1318

1. 65% 2. 493.1209.6(33.6)

1319

1. 64% 2. 491.1209.10(33.7)

1320

1. 90% 2. 457.2209.11(33.8)

1321

1. 35% 2. 505.0209.12(33.9)

1322

1. 70% 2. 493.1209.13(33.10)

1323

1. 75% 2. 480.2209.14(33.11)

1324

1. 74% 2. 465.1209.15(33.12)

1325

1. 62% 2. 479.1209.16(33.13)

1326

1. 31% 2. 466.2209.17(33.14)

1327

1. 79% 2. 495.2209.18(33.15)

1328

1. 99% 2. 479.2209.19(33.16)

1329

1. 47% 2. 466.2209.20(33.17)

1330

1. 72% 2. 479.1209.21(33.18)

1331

1. 92% 2. 493.1209.22(33.19)

1332

1. 47% 2. 499.1209.23(33.20)

1333

1. 7% 2. 490.0209.24(33.21)

1334

1. 15% 2. 533.1209.25(33.22)

1335

1. 88% 2. 451.1209.26(33.23)

1336

1. 26% 2. 523.0209.27(33.24)

1337

1. 54% 2. 433.1209.28(33.25)

1338

1. 59% 2. 466.2209.29(33.26)

1339

1. 66% 2. 560.2209.30(33.27)

1340

1. 98% 2. 495.1209.31(33.28)

1341

1. 99% 2. 471.2209.32(33.29)

1342

1. 99% 2. 471.2209.33(33.30)

1343

1. 18% 2. 524.2209.34(33.31)

1344

1. 78% 2. 479.2209.35(33.32)

1345

1. 71% 2. 459.2209.36(33.33)

1346

1. 5% 2. 491.0209.37(33.34)

1347

1. 27% 2. 501.1209.38(33.35)

1348

1. 26% 2. 533.1209.39(33.36)

1349

1. 48% 2. 451.1209.40(33.37)

1350

1. 99% 2. 455.1209.41(33.38)

1351

1. 88% 2. 527.1209.42(33.39)

1352

1. 74% 2. 485.2209.43(33.40)

1353

1. 20% 2. 492.5209.44(33.41)

1354

1. 68% 2. 541.1209.45(33.42)

1355

1. 13% 2. 508.9209.46(33.43)

1356

1. 86% 2. 479.1209.47(33.44)

1357

1. 34% 2. 507.0209.48(33.45)

1358

1. 56% 2. 429.1209.49(33.46)

1359

1. 18% 2. 495.0209.50(33.47)

1360

1. 22% 2. 501.0

Example 210

[1459]

1361

[1460] To a solution of amine (0.17 g, 1 mmol) from Preparative Example 34 in EtOH (3 mL) at room temperature was added the cyclobutenedione from Preparative Example 19 (100 mg, 0.33 mmol) in one portion. The resulting mixture was stirred for 5 h (until TLC analysis revealed reaction complete) and was concentrated under reduced pressure. The crude residue was redissolved in CH2Cl2 (15 mL) and was washed sequentially with 10% KH2PO4 (2×15 mL) and brine (1×15 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the crude adduct. The crude product was purified by prep TLC (4×1000 uM plates) eluting with CH2Cl2/MeOH (20:1) to afford 83 mg (59% yield) of the desired product as a solid.

Examples 211-260

[1461] Following the procedure set forth in Example 210 but using the commercially available amine or the prepared amine from the Preparative Example indicated in the Table below, the following cyclobutenedione products were obtained.

301. Yield (%)(Prep Ex)2. MH+Ex.AmineProduct3. mp (° C.)211

1362

1363

1. 75% 2. 412.1 3. 126212

1364

1365

1. 42% 2. 438.1 3. 106213

1366

1367

1. 73% 2. 428.1 3. 139214

1368

1369

1. 40% 2. 462.1 3. 160215

1370

1371

1. 52% 2. 408.1 3. 126216

1372

1373

1. 32% 2. 478.1 3. 176217

1374

1375

1. 50% 2. 412.1 3. 126218

1376

1377

1. 55% 2. 478.1 3. 100219

1378

1379

1. 67% 2. 438.1 3. 122220

1380

1381

1. 73% 2. 462.1 3. 118221

1382

1383

1. 67% 2. 424.1 3. 100222

1384

1385

1. 61% 2. 478.1 3. 114223

1386

1387

1. 50% 2. 408.1 3. 157-159224

1388

1389

1. 75% 2. 366.1 3. 110-112225

1390

1391

1. 81% 2. 380.1 3. 118-120226

1392

1393

1. 69% 2. 394.1 3. 123-125227

1394

1395

1. 80% 2. 367.1 3. 122-125228

1396

1397

1. 72% 2. 381.1 3. 133-135229

1398

1399

1. 81% 2. 395.1 3. 141-145230

1400

1401

1. 75% 2. 356.1 3. 103-104231

1402

1403

1. 24% 2. 370.1 3. 101232

1404

1405

1. 16% 2. 384.1 3. 70233

1406

1407

1. 72% 2. 373.4 3. 104-106234

1408

1409

1. 34% 2. 387.1 3. 99235

1410

1411

1. 48% 2. 380.1 3. 118-120236

1412

1413

1. 72% 2. 380.1 3. 119-120237

1414

1415

1. 72% 2. 398.1 3. 121-123238

1416

1417

1. 44% 2. 398.1 3. 121-123239

1418

1419

1. 60% 2. 394.1 3. 123-124240

1420

1421

1. 52% 2. 394.1 3. 122-124241

1422

1423

1. 34% 2. 428.4 3. 157-159242

1424

1425

1. 70% 2. 412.1 3. 109-112243

1426

1427

1. 69% 2. 412.1 3. 110-112244

1428

1429

1. 89% 2. 412.1 3. 126245

1430

1431

1. 81% 2. 412.1 3. 126246

1432

1433

1. 65% 2. 424.1 3. 121-124247

1434

1435

1. 73% 2. 424.1 3. 122-124248

1436

1437

1. 29% 2. 372.1 3. 219-221249

1438

1439

1. 66% 2. 394.1 3. 132-135250

1440

1441

1. 72% 2. 332251

1442

1443

1. 74% 2. 408.1 3. 121-123252

1444

1445

1. 76% 2. 408.1 3. 102-104253

1446

1447

1. 72% 2. 438.1 3. 75-77254

1448

1449

1. 80% 2. 392.1 3. 98-101255

1450

1451

1. 72% 2. 420.1 3. 200-205256

1452

1453

1. 75% 2. 434.1 3. 138-140257

1454

1455

1. 67% 2. 410.1 3. 116-118258

1456

1457

1. 76% 2. 424.1 3. 108-110259

1458

1459

1. 72% 2. 430.1 3. 125260

1460

1461

1. 78% 2. 422.1 3. 127260.1

1462

1463

1. 74% 2. 426.1 3. 114 DEC260.2

1464

1465

1. 85% 2. 436.1 3. 143 DEC260.3

1466

1467

1. 56% 2. 474.1 3. 121-123260.4

1468

1469

1. 71% 2. 500.1 3. 97 (DEC)260.6

1470

1471

1. 61% 2. 465 3. 102-107260.7

1472

1473

1. 78% 2. 422.1 3. 114 DEC260.8

1474

1475

1. 35% 2. 486.1 3. 103-105260.9

1476

1477

1. 79% 2. 470 3. 110-115260.10

1478

1479

1. 62% 2. 462.1 3. 110 DEC260.11

1480

1481

1. 61% 2. 446.1 3. 118 DEC260.12

1482

1483

1. 58% 2. 480.1 3. 111 DEC260.13

1484

1485

1. 87% 2. 438.1 3. 122260.14

1486

1487

1. 74% 2. 408.1 3. 128-130260.15

1488

1489

1. 78% 2. 430.1 3. 117 DEC260.16

1490

1491

1. 81% 2. 452.1 3. 139260.17

1492

1493

1. 85% 2. 426.1 3. 126260.18

1494

1495

1. 50% 2. 482.1 3. 114-116260.19

1496

1497

1. 64% 2. 450.1 3. 129260.20

1498

1499

1. 72% 2. 424.1 3. 116260.21

1500

1501

1. 35% 2. 434.1 3. 124260.22

1502

1503

1. 58% 2. 420.1 3. 107-109260.23

1504

1505

1. 69% 2. 440.1 3. 169260.24

1506

1507

1. 15% 2. 404.1 3. 103-105260.25

1508

1509

1. 92% 2. 434.1 3. 129260.26

1510

1511

1. 77% 2. 434.1 3. 133260.27

1512

1513

1. 73% 2. 434.1 3. 138260.28

1514

1515

1. 37% 2. 434.1 3. 133

Example 261

[1462]

1516

[1463] To a solution of the amine (77 μL, 0.66 mmol) in EtOH (3 mL) at room temperature was added the product from Preparative Example 19 (100 mg, 0.33 mmol) in one portion. The resulting mixture was stirred for 5 h (until TLC analysis revealed reaction complete) and was then concentrated under reduced pressure. The crude residue was redissolved in CH2Cl2 (15 mL) and was washed sequentially with 10% KH2PO4 (2×15 mL) and brine (1×15 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the crude adduct. The crude product was purified by prep TLC (4×1000 uM plates) eluting with CH2Cl2/MeOH (20:1) to afford 82 mg (72% yield) of the desired product as a solid. (mp 126.0-128.0° C., MH+ 346)

Examples 262-360.117

[1464] Following the procedure set forth in Example 261 but using the commercially available amine or the prepared amine from the Preparative Example indicated in the table below, the following cyclobutenedione products were obtained.

311. Yield (%)2. MH+Ex.AmineProduct3. mp (° C.)262

1517

1518

1. 74% 2. 330.1 3. 112-115263

1519

1520

1. 64% 2. 344.1 3. 120-122264

1521

1522

1. 72% 2. 358.4 3. 129-132265

1523

1524

1.76% 2. 372.1 3. 141-143266

1525

1526

1. 57% 2. 372.1 3. 102267

1527

1528

1. 65% 2. 386.1 3. 146268

1529

1530

1. 65% 2. 464.1 3. 110-112269

1531

1532

1. 85% 2. 464.1 3. 111-113270

1533

1534

1. 49% 2. 374.1 3. 146271

1535

1536

1. 69% 2. 374.1 3. 158-162272

1537

1538

1. 54% 2. 430.1 3. 108273

1539

1540

1. 65% 2. 430.1 3. 110274

1541

1542

1. 53% 2. 388.1 3. 136275

1543

1544

1. 30% 2. 388.1 3. 114276

1545

1546

1. 53% 2. 402.1 3. 126277

1547

1548

1. 68% 2. 402.1 3. 116278

1549

1550

1. 64% 2. 372.1 3. 106279

1551

1552

1. 69% 2. 434.1 3. 141-143280

1553

1554

1. 51% 2. 434.1 3. 148-150281

1555

1556

1. 71% 2. 406.1 3. 146-148282

1557

1558

1. 66% 2. 406.1 3. 141-144283

1559

1560

1. 70% 2. 450.1 3. 97-99284

1561

1562

1. 25% 2. 360.1 3. 139285

1563

1564

1. 78% 2. 416.1 3. 94286

1565

1566

1. 49% 2. 372.1 3. 139287

1567

1568

1. 95% 2. 386.1 3. 139288

1569

1570

1. 32% 2. 348 3. 130-133289

1571

1572

1. 72% 2. 410.1 3. 138290

1573

1574

1. 72% 2. 410.1 3. 132-134291

1575

1576

1. 75% 2. 318.1 3. 96-98292

1577

1578

1. 72% 2. 430.1 3. 125293

1579

1580

1. 51% 2. 348 3. 109-111294

1581

1582

1. 84% 2. 374 3. 150.3295

1583

1584

1. 56% 2. 386 3. 142.3296

1585

1586

1. 38% 2. 382 3. 173.4297

1587

1588

1. 13% 2. 370 3. 135.1298

1589

1590

1. 47% 2. 424 3. 231.2-234.5299

1591

1592

1. 34% 2. 316 3. 209.5300

1593

1594

1. 92% 2. 392 3. 152.7301

1595

1596

1. 52% 2. 346 3. 124.7302

1597

1598

1. 51% 2. 346 3. 139.2303

1599

1600

1. 29% 2. 408 3. 105304

1601

1602

1. 24% 2. 372 3. 223.2305

1603

1604

1. 25% 2. 442 3. 219.0306

1605

1606

1. 83% 2. 386 3. 145307

1607

1608

1. 58% 2. 400 3. 99.6308

1609

1610

1. 60% 2. 414 3. 123.6309

1611

1612

1. 44% 2. 412 3. 146.7310

1613

1614

1. 39% 2. 432 3. 156.6311

1615

1616

1. 65% 2. 448 3. 162.8312

1617

1618

1. 53% 2. 449 3. 139.7313

1619

1620

1. 64% 2. 454 3. 143.2314

1621

1622

1. 35% 2. 428 3. 146.8315

1623

1624

1. 72% 2. 476 3. 139.4316

1625

1626

1. 36% 2. 402 3. 89.6317

1627

1628

1. 62% 2. 400 3. 130.2318

1629

1630

1. 46% 2. 400 3. 123.6319

1631

1632

1. 64% 2. 400 3. 132.5320

1633

1634

1. 79% 2. 406 3. 123.3321

1635

1636

1. 17% 2. 440 3. 157.6322

1637

1638

1. 58% 2. 428 3. 167.9323

1639

1640

1. 50% 2. 422 3. 150.2324

1641

1642

1. 20% 2. 462 3. 113.9325

1643

1644

1. 95% 2. 360 3. 129.2326

1645

1646

1. 97% 2. 360 3. 131.5327

1647

1648

1. 39% 2. 318 3. 138.5328

1649

1650

1. 54% 2. 408 3. 152.3329

1651

1652

1. 62% 2. 346 3. 134.8330

1653

1654

1. 55% 2. 346 3. 145.1331

1655

1656

1. 61% 2. 400 3. 137.6332

1657

1658

1. 42% 2. 374 3. 155.1333

1659

1660

1. 45% 2. 348 3. 108-110334

1661

1662

1. 29% 2. 424 3. 116335

1663

1664

1. 15% 2. 414 3. 108-110336

1665

1666

1. 75% 2. 408 3. 116337

1667

1668

1. 75% 2. 408 3. 116338

1669

1670

1. 59% 2. 424 3. 115-117339

1671

1672

1. 72% 2. 424 3. 157-159340

1673

1674

1. 19% 2. 332 3. 131341

1675

1676

1. 86% 2. 360 3. 127342

1677

1678

1. 98% 2. 346 3. 128343

1679

1680

1. 80% 2. 374 3. 131.5344

1681

1682

1. 46% 2. 374 3. 102345

1683

1684

1. 75% 2. 388 3. 104346

1685

1686

1. 76% 2. 438 3. 95347

1687

1688

1. 72% 2. 424 3. 163-165348

1689

1690

1. 73% 2. 438 3. 96-98349

1691

1692

1. 53% 2. 362 3. 89-91350

1693

1694

1. 59% 2. 362 3. 90-92351

1695

1696

1. 61% 2. 362 3. 120-122352

1697

1698

1. 70% 2. 362 3. 121-123353

1699

1700

1. 23% 2. 371 3. 126354

1701

1702

1. 79% 2. 370 3. 108355

1703

1704

1. 80% 2. 370 3. 106356

1705

1706

1. 56% 2. 450 3. 138-140357

1707

1708

1. 76% 2. 398 3. 116358

1709

1710

1. 85% 2. 384 3. 100359

1711

1712

1. 59% 2. 332 3. 138.6360

1713

1714

1. 47% 2. 332 3. 141.6360.1

1715

1716

1. 89% 2. 356.1 3. 133-135360.2

1717

1718

1. 65% 2. 334.1 3. 121-122360.3

1719

1720

1. 60% 2. 348.1 3. 94-96360.4

1721

1722

1. 29% 2. 414.1 3. 108-1103605.

1723

1724

1. 67% 2. 348.1 3. 95-96360.6

1725

1726

1. 62% 2. 414.1 3. 113-115360.7

1727

1728

1. 68% 2. 414.1 3. 114-116360.8

1729

1730

1. 74% 2. 374 3. 129.8360.9

1731

1732

1. 61% 2. 388 3. 123.1360.10

1733

1734

1. 53% 2. 388 3. 117.2360.11

1735

1736

1. 37% 2. 388 3. 129.9360.12

1737

1738

1. 62% 2. 374 3. 126.1360.13

1739

1740

1. 71% 2. 400.1 3. 106-109360.14

1741

1742

1. 66% 2. 400.1 3. 106-109360.15

1743

1744

1. 69% 2. 372 3. 138.7360.16

1745

1746

1. 54% 2. 346 3. 123.6360.17

1747

1748

1. 53% 2. 388 3. 116.9360.18

1749

1750

1. 87% 2. 384.1 3. 136360.19

1751

1752

1. 92% 2. 384.1 3. 136360.20

1753

1754

1. 27% 2. 386.1 3. 109-112360.12

1755

1756

1. 31% 2. 400.1 3. 117-120360.22

1757

1758

1. 61% 2. 396.1 3. 129360.23

1759

1760

1. 69% 2. 396.1 3. 126360.24

1761

1762

1. 74% 2. 398.1 3. 123360.25

1763

1764

1. 76% 2. 398.1 3. 123360.26

1765

1766

1. 60% 2. 384.1 3. 103-105360.27

1767

1768

1. 67% 2. 384.1 3. 104‥106360.28

1769

1770

1. 70% 2. 386.1 3. 103-105360.29

1771

1772

1. 64% 2. 400.1 3. 109-111360.30

1773

1774

1. 63% 2. 398.1 3. 99-101360.31

1775

1776

1. 57% 2. 398.1 3. 99-101360.32

1777

1778

1. 45% 2. 400 3. 104.6360.33

1779

1780

1. 44% 2. 386 3. 143360.34

1781

1782

1. 73% 2. 356.1 3. 218-220360.35

1783

1784

1. 97% 2. 406.1 3. 154360.36

1785

1786

1. 77% 2. 414.1 3. 122-124360.37

1787

1788

1. 70% 2. 412.1 3. 99-101360.38

1789

1790

1. 69% 2. 416.1 3. 107-109360.39

1791

1792

1. 43% 2. 454.1 3. 128-130360.40

1793

1794

1. 40% 2. 374.1 3. 132-136360.41

1795

1796

1. 60% 2. 345.1 3. 205-207360.42

1797

1798

1. 96% 2. 412.1 3. 112360.43

1799

1800

1. 30% 2. 434.1 3. 117-119360.44

1801

1802

1. 96% 2. 410.1 3. 139360.45

1803

1804

1. 65% 2. 384.1 3. 87-89360.46

1805

1806

1. 50% 2. 434.1 3. 123-125360.47

1807

1808

1. 74% 2. 412.1 3. 84-86360.48

1809

1810

1. 73% 2. 400.1 3. 136-140360.49

1811

1812

1. 74% 2. 412.1 3. 103-105360.50

1813

1814

1. 63% 2. 434.1 3. 114-117360.51

1815

1816

1. 74% 2. 414.1 3. 130-133360.52

1817

1818

1. 71% 2. 426.1 3. 138360.53

1819

1820

1. 41% 2. 414 3. 139-141360.54

1821

1822

1. 32% 2. 426 3. 148-150360.55

1823

1824

1. 57% 2. 428 3. 159-163360.56

1825

1826

1. 44% 2. 464.1 3. 86-88360.57

1827

1828

1. 37% 2. 442 3. 158-162360.58

1829

1830

1. 53% 2. 494.1 3. 148-151360.59

1831

1832

1. 63% 2. 528.1 3. 90-95360.60

1833

1834

1. 73% 2. 438.1 3. 116360.61

1835

1836

1. 55% 2. 494.1 3. 133-135360.62

1837

1838

1. 83% 2. 412.1 3. 119360.63

1839

1840

1. 66% 2. 440.1 3. 110360.64

1841

1842

1. 49% 2. 410.1 3. 97360.65

1843

1844

1. 40% 2. 442.1 3. 157-160360.66

1845

1846

1. 75% 2. 400 3. 136-140360.67

1847

1848

1. 63% 2. 528.1 3. 106-108360.68

1849

1850

1. 10% 2. 401.1 3. 111-113360.69

1851

1852

1. 5% 2. 426.1360.70

1853

1854

1. 56% 2. 442.1 3. 152-154360.71

1855

1856

1. 46% 2. 414.1 3. 122-124360.72

1857

1858

1. 62% 2. 385.1 3. 130-133360.73

1859

1860

1. 41% 2. 399.1 3. 83-85360.74

1861

1862

1. 70% 2. 414.1 3. 98-101360.75

1863

1864

1. 62% 2. 441.1 3. 98-102360.76

1865

1866

1. 79% 2. 464.1 3. 111360.77

1867

1868

1. 79% 2. 418.1 3. 107360.78

1869

1870

1. 65% 2. 400.1 3. 109-112360.79

1871

1872

1. 21% 2. 428.1 3. 126360.80

1873

1874

1. 55% 2. 493.1 3. 155-158360.81

1875

1876

1. 67% 2. 428.1 3. 138-140360.82

1877

1878

1. 68% 2. 426.1 3. 121-123360.83

1879

1880

1. 25% 2. 427.1 3. 139360.84

1881

1882

1. 62% 2. 413.1 3. 128360.85

1883

1884

1. 49% 2. 460.1 3. 112-114360.86

1885

1886

1. 71% 2. 434.1 3. 91-93360.87

1887

1888

1. 57% 2. 411.1 3. 125360.88

1889

1890

1. 12% 2. 400.1 3. 131-133360.89

1891

1892

1. 60% 2. 464.1 3. 111-113360.90

1893

1894

1. 60% 2. 418.1 3. 113360.91

1895

1896

1. 55% 2. 415.1 3. 140-143360.92

1897

1898

1. 55% 2. 429 3. 185-190360.93

1899

1900

1. 3% 2. 447.1360.94

1901

1902

1. 71% 2. 452.1 3. 106360.95

1903

1904

1. 44% 2. 439.1 3. 112360.96

1905

1906

1. 71% 2. 464.1 3. 111-113360.97

1907

1908

1. 70% 2. 398.1 3. 106-108360.98

1909

1910

1. 46% 2. 426.1 3. 140-142360.99

1911

1912

1. 62% 2. 399.1 3. 109-112360.100

1913

1914

1. 60% 2. 466.1 3. 129-131360.101

1915

1916

1. 49% 2. 446.1 3. 146360.102

1917

1918

1. 48% 2. 432.1 3. 116360.103

1919

1920

1. 62% 2. 418.1 3. 126360.104

1921

1922

1. 47% 2. 430.1 3. 136360.105

1923

1924

1. 42% 2. 461.1 3. 131-134360.106

1925

1926

1. 93% 2. 426.1 3. 123-125360.107

1927

1928

1. 26% 2. 454.1 3. 132-134360.108

1929

1930

1. 12% 2. 479.1 3. 129-132360.109

1931

1932

1. 67% 2. 410.1 3. 119-121360.110

1933

1934

1. 71% 2. 412 3. 102360.111

1935

1936

1. 64% 2. 440.1 3. 91-93360.112

1937

1938

1. 79% 2. 412 3. 111-113360.113

1939

1940

1. 20% 2. 440.1 3. 130 (DEC)360.114

1941

1942

1. 61% 2. 438.1 3. 117-119360.115

1943

1944

1. 61% 2. 440.1 3. 117-119360.116

1945

1946

1. 81% 2. 452 3. 118360.117

1947

1948

1. 65% 2. 466 3. 109

Examples 361-368.45

[1465] Following the procedure set forth in Example 261 but using the commercially available amine in the table below and the cyclobutenedione intermediate from the Preparative Example indicated, the following cyclobutenedione products were obtained.

321. Yield (%)Prep.2. MH+Ex.AmineEx.Product3. mp (° C.)361

1949

1950

1. 57% 2. 422 3. 172.4362

1951

1952

1. 53% 2. 408 3. 139.8363

1953

1954

1. 70% 2. 374 3. 167.8-170.1364

1955

1956

1. 21% 2. 334 3. 184.3365

1957

1958

1. 61% 2. 348 3. 205.6366

1959

21.1

1960

1. 75% 2. 344 3. 170-172367

1961

21.1

1962

1. 66% 2. 330 3. 160-162368

1963

1964

1. 31% 2. 436 3. 140-145368.1

1965

1966

1. 8% 2. 374 3. 130-133368.2

1967

23.1

1968

1. 56% 2. 372 3. 188-191368.3

1969

23.1

1970

1. 67% 2. 406 3. 142-144368.4

1971

23.2

1972

1. 69% 2. 408 3. 147-150368.5

1973

23.2

1974

1. 67% 2. 374 3. 177-180368.6

1975

23.3

1976

1. 45% 2. 385 3. 236-240368.7

1977

23.3

1978

1. 35% 2. 425 3. 248-251368.8

1979

23.2

1980

1. 66% 2. 414 3. 156-160368.9

1981

23.4

1982

1. 78% 2. 428 3. 138-140368.10

1983

23.5

1984

1. 46% 2. 428 3. 149-153368.11

1985

23.6

1986

1. 54% 2. 412 3. 136-138368.12

1987

1988

1. 30% 2. 414 3. 164-167368.13

1989

23.1

1990

1. 25% 2. 412 3. 172-177368.14

1991

23.7

1992

1. 21% 2. 434 3. 208-211368.15

1993

23.8

1994

1. 27% 2. 478 3. 216-219368.16

1995

23.9

1996

1. 63% 2. 400368.17

1997

23.9

1998

1. 61% 2. 406.1 3. 127 DEC368.18

1999

23.9

2000

1. 68% 2. 436.1 3. 128 DEC368.19

2001

23.9

2002

1. 72% 2. 404.1 3. 126 DEC368.20

2003

23.10

2004

1. 8.4% 2. 478368.21

2005

23.9

2006

1. 39% 2. 432.1 3. 151-153368.22

2007

23.12

2008

1. 78% 2. 414.1 3. 210 DEC368.23

2009

23.11

2010

1. 4% 2. 504368.24

2011

23.11

2012

1. 31% 2. 490 3. 241-245368.25

2013

23.9

2014

1. 81% 2. 420.1 3. 126-128368.26

2015

23.11

2016

1. 8% 2. 476 3. 193-198368.27

2017

23.9

2018

1. 70% 2. 434.1 3. 130 DEC368.28

2019

23.11

2020

1. 83% 2. 506 3. 222-227368.29

2021

23.11

2022

1. 17% 2. 464 3. 183-190368.30

2023

23.13

2024

1. 6.5% 2. 438.1368.31

2025

23.14

2026

1. 71% 2. 471.1 3. 149-151368.32

2027

23.14

2028

1. 58% 2. 471.1 3. 149368.33

2029

23.15A

2030

1. 33% 2. 440.1 3. 181368.34

2031

23.15A

2032

1. 56% 2. 468 3. 180368.35

2033

23.15A

2034

1. 28% 2. 480 3. 186368.36

2035

23.15A

2036

1. 48% 2. 494 3. 112.5368.37

2037

23.15B

2038

1. 58% 2. 592 3. 177-179368.38

2039

23.15C

2040

1. 69% 2. 516 3. 88-90368.39

2041

23.15D

2042

1. 80% 2. 530 3. 134-137368.40

2043

23.15E

2044

1. 57% 2. 454 3. 138-140368.41

2045

19.2

2046

1. 26% 2. 507 3. 162-164368.42323.25

2047

1. 82% 2. 466 3. 141-143368.43323.26

2048

1. 67% 2. 480 3. 139 dec368.4413.2923.16

2049

1. 29% 2. 480 3. 112-114368.4513.2923.26

2050

1. 88% 2. 508 190 dec

Examples 369-378.23

[1466] Following the procedure set forth in Example 210 but using the cyclobutenedione intermediate from Preparative Example indicated and the amine from the Preparative Example indicated in the Table below, the following cyclobutenedione products were obtained.

33Prep Ex ofCyclo-butene1. Yield (%)Prep Ex ofInter-2. MH+Ex.AminemediateProduct3. mp (° C.)369887

2051

1. 41% 2. 422 3. 135-140370987

2052

1. 60% 2. 420 3. 120-1253711087

2053

1. 59% 2. 450 3. 162-1673721287

2054

1. 34% 2. 419 3. 157.2-168.23731288

2055

1. 18% 2. 371 3. 1.42.3-144.63741387

2056

1. 41% 2. 408 3. 245.3-247.8375587

2057

1. 32% 2. 366 3. 165.7376687

2058

1. 17% 2. 380 3. 173.5377787

2059

1.48% 2. 436 3. 175.6378

2060

2061

1.62% 2. 364 3. 155-160378.1388.3

2062

1. 73% 2. 438.1 3. 116378.2388.2

2063

1. 58% 2. 454 3. 140-142378.313.387

2064

1. 43% 2. 472 206-209378.4323.16

2065

1. 69% 438.1 3. 116378.5323.17

2066

1. 73% 2. 438.1 3. 116378.613.487

2067

1. 10% 2. 470 3. 198-201 DEC378.713.587

2068

1. 16% 2. 471 3. 246-248378.813.323.16

2069

1. 30% 2. 516/518 3. 234-240 DEC378.913.1923.16

2070

1. 65% 2. 444.1378.10323.20

2071

1. 78% 2. 488 3. 137-140378.11

2072

88.1

2073

1. 24% 2. 371 3. 254-260 DEC378.1213.688.1

2074

1. 3% 2. 542378.1313.788.1

2075

1. 9% 2. 542378.14

2076

88.1

2077

1. 48% 2. 434 3. 150-152378.15323.19

2078

1. 71% 2. 488 3. 136-138378.16323.22

2079

1. 35% 2. 424.1 3. 132378.1713.988.1

2080

1. 13% 2. 440 3. 219-223378.1813.1088.1

2081

1. 25% 2. 406 3. 242-249 DEC378.1913.888.1

2082

1. 18% 2. 395378.20323.18

2083

1. 53% 2. 478.1 3. 126378.21323.21

2084

1. 66% 2. 466 3. 106378.22323.24

2085

1. 73% 2. 502.1 3. 121378.23323.23

2086

1. 57% 2. 458.1 3. 129

Examples 378.25-378.89

[1467] Following the procedure set forth in Example 210 but using the cyclobutenedione intermediate from Preparative Example indicated and the amine from the Preparative Example indicated in the Table below, the following cyclobutenedione products were obtained.

34PrepEx ofCy-clo-bu-teneInter-1. YieldPrep Exmedi-(%)Ex.of AmineateProduct2. MH+378.2511.1087.1

2087

1. 71% 2. 480.0378.2610.2887.1

2088

1. 60% 2. 449.9378.2711.1188.4

2089

1. 25% 2. 540.1 [M +Na+]378.2810.3687.1

2090

1. 16% 2. 465.0378.2910.788.5

2091

1. 46% 2. 440.4378.3010.988.4

2092

1. 43% 2. 934.9 [dimer +1]30 378.3111.1288.4

2093

1. 48% 2. 464.0378.3210.3587.1

2094

1. 17% 2. 437378.3310.887.1

2095

1. 10% 2. 481.9378.3411.1387.1

2096

1. 55% 2. 463.9378.3510.2987.1

2097

1. 34% 2. 471.9378.3610.4887.1

2098

1. 4% 2. 433.9378.36 A10.1087.1

2099

1. 85% 2. 451.9378.3710.3187.1

2100

1. 36% 2. 423.8378.3810.1787.1

2101

1. 85% 2. 521.1378.3910.3287.1

2102

1. 63% 2. 409.9378.40

2103

87.1

2104

1. 44% 2. 323.1378.4110.3387.1

2105

1. 20% 2. 486.0378.4210.1387.1

2106

1. 47% 2. 520.1378.4310.3487.1

2107

1. 18% 2. 449.9378.4411.1487.1

2108

1. 13% 2. 424.0378.452.1387.1

2109

1. 13% 2. 423.8378.4612.187.1

2110

1. 51% 2. 487.1378.4710.3888.4

2111

1. 72% 2. 437.7378.4811.1587.1

2112

1. 29% 2. 477.9378.4910.1487.1

2113

1. 61% 2. 560.2378.5011.1887.1

2114

1. 25% 2. 480.0378.5110.1887.1

2115

1. 51% 2. 466.0378.5212.287.1

2116

1. 32% 2. 380.9378.5310.1987.1

2117

1. 14% 2. 461.4378.5411.187.1

2118

1. 41% 2. 463.9378.5511.287.1

2119

1. 5% 2. 409.9378.5610.2087.1

2120

1. 70% 2. 478.1378.5710.4987.1

2121

1. 17% 2. 421.9378.5810.1587.1

2122

1. 51% 2. 582.1378.5910.4687.1

2123

1. 18% 2. 477.9378.6011.1688.4

2124

1. 54% 2. 455.1378.6110.2187.1

2125

1. 84% 2. 485.9378.6210.4087.1

2126

1. 4% 2. 506.1378.652.887.1

2127

1. 34% 2. 480378.6610.2287.1

2128

1. 16% 2. 486.0378.672.1087.1

2129

1. 44% 2. 545378.6810.2387.1

2130

1. 26% 2. 493.9378.692.1487.1

2131

1. 60% 2. 437.9378.7010.2487.1

2132

1. 64% 2. 469.9378.7110.1888.4

2133

1. 64% 2. 471.1378.7210.3988.4

2134

1. 41% 2. 451.7378.7310.3087.1

2135

1. 60% 2. 464.0378.7410.2587.1

2136

1. 63% 2. 470.1378.7510.2687.1

2137

1. 10% 2. 448.0378.7610.5087.1

2138

1. 5% 2. 477.0378.7710.4288.4

2139

1. 57% 2. 467.7378.7811.1787.1

2140

1. 75% 2. 478.0378.792.987.1

2141

1. 21% 2. 561378.8010.4387.1

2142

1. 69% 2. 437.9378.8110.4187.1

2143

1. 3% 2. 436.0378.8210.4487.1

2144

1. 90% 2. 454.0378.8310.1388.4

2145

1. 29% 2. 524.1378.8410.4588.4

2146

1. 46% 2. 511.7378.8610.3787.1

2147

1. 53% 2. 452.0378.8810.4787.1

2148

1. 61% 2. 506.1378.8910.1687.1

2149

1. 30% 2. 568.1

Example 378.90

[1468]

2150

[1469] The above compound from Preparative Example 378.68 was stirred with 4N HCl/dioxane to yield the product (23%, MH+=437.9).

Example 378.91

[1470]

2151

[1471] Using the procedure set forth in Preparative Example 2, Step A, but using Preparative Example 2.16 and Preparative Example 2.15, the title compound was prepared (20%, MH+=472.9).

Examples 379-393

[1472] Following the procedure set forth in Example 210 but using the amine from the Preparative Example indicated and the ethoxy squarate intermediate from Preparative Example 87, the following cyclobutenedione products were obtained.

351. Yield (%)Ex.AnilineProduct2. (MH+)379109

2152

1. 29% 2. 436.0380105

2153

1. 6.3% 2. 550.0381106

2154

1. 12% 2. 557.0382107

2155

1. 8.6% 2. 573.0383143

2156

1. 3.2% 2. 497.0384135

2157

1. 36% 2. 529.0385130

2158

1. 33% 2. 506.1387145

2159

1. 27% 2. 449.1388140

2160

1. 25% 2. 477.038998

2161

1. 66% 2. 542.139096

2162

1. 60% 2. 545.039197

2163

1. 66% 2. 540.1392100

2164

1. 47% 2. 512.139399

2165

1. 60% 2. 528.1

Examples 394-404.4

[1473] Following the procedure set forth in Example 261 but using the amines from the Preparative Examples indicated in the table below and the cyclobutenedione derivative from Preparative Example 19, the following cyclobutenedione products were obtained as racemic mixtures.

361. Yield (%)Prep Ex.2. MH+Ex.of AmineProduct3. mp (° C.)394147

2166

1. 64% 2. 358.1 3. 137395148

2167

1. 23% 2. 372.1 3. 126396149

2168

1. 94% 2. 386.1 3. 108397150

2169

1. 86% 2. 386.1 3. 134398146

2170

1. 87% 2. 420.1 3. 136399151

2171

1. 84% 2. 434.1 3. 129400152

2172

1. 90% 2. 372.1 3. 154401153

2173

1. 86% 2. 386.1 3. 156402154

2174

1. 90% 2. 400.1 3. 153403155

2175

1. 91 2. 400.1 3. 153404156

2176

1. 83% 2. 448.1 3. 138404.1

2177

2178

1. 30% 2. 426.1 3. 132404.2

2179

2180

1. 74% 2. 412.1 3. 127404.3

2181

2182

1. 73.4% 2. 372.1 3. 128404.4

2183

2184

1. 72% 2. 372.1 3. 128

Example 405

[1474]

2185

[1475] To a solution of the amine from Preparative Example 75.1 (11.3 g) in EtOH (100 mL) at room temperature was added the product from Preparative Example 19 (16.4 g) in one portion. The resulting mixture was stirred at reflux overnight and then concentrated under reduced pressure. The crude residue was redissolved in CH2Cl2 (80 mL) and was washed with 10% KH2PO4 (120 mL). The solid precipitate that was generated was filtered, washed with water and dried under vacuo. The residue was recrystallized from methanol-methylene chloride to give a cream colored solid (16 g, 75% yield). (mp 105-108° C., MH+ 398.1).

Examples 1101-1112.10

[1476] If one were to follow the procedure set forth in Example 210 but using the ethoxysquarate from the Preparative Example indicated and the amines from the Preparative Example indicated in the Table below, the following cyclobutenedione products can be obtained.

37Prep Ex ofPrep Ex ofEx.AmineSquarateProduct1101 1587

2186

1102 1588

2187

1103 1687

2188

1104 1688

2189

1105 1787

2190

1106 1788

2191

1107 1887

2192

1108 1888

2193

110915787

2194

111015788

2195

111115887

2196

111215888

2197

1112.1500.3 or 500.488.1

2198

1112.2500.1 or 500.288.1

2199

1112.3500.519

2200

1112.4 75.923.11

2201

1112.5 10.1988.4

2202

1112.6 75.4423.14

2203

1112.7 75.4923.14

2204

1112.8 75.5023.14

2205

1112.9 75.44500.6

2206

1112.10 75.49500.6

2207

Examples 1120.1-1120.12

[1477] Following the procedure set forth in Example 210 but using the amine from the Preparative Example indicated and the ethoxy squarate intermediate from the Preparative Example indicated, the following cyclobutenedione products were obtained.

38Prep Ex1. Yield (%)Prep Ex ofof2. MH+Ex.AmineSquarateProduct3. mp (° C.)1120.1156.1687

2208

1. 9% 2. 393.1 3. 154-1581120.2

2209

88.1

2210

1. 55% 2. 355.1 3. 199-2011120.3156.1288.1

2211

1. 37% 2. 355.1 3. 210-2131120.4

2212

88.1

2213

1. 30% 2. 391.1 3. 70-731120.5156.1488.1

2214

1. 73% 2. 466 3. 105-1081120.6

2215

88.1

2216

1. 21% 2. 391 3. 79-821120.7

2217

88.1

2218

1. 15% 2. 369 3. 167-1701120.8

2219

88.1

2220

1. 47% 2. 354 3. 121-1241120.9

2221

88.1

2222

1. 15% 2. 356 3. 200-2021120.10

2223

88.1

2224

1. 25% 2. 468 3. 154-1561120.11156.1388.1

2225

1. 57% 2. 404 3. 92-941120.12156.1588.1

2226

1. 61% 2. 351 3. 155-157

Example 1125

[1478]

2227

2228

[1479] Step A

[1480] If one were to use a similar procedure to that used in Preparative Example 13.3 Step B, except using the hydroxy acid from Bioorg. Med. Chem. Lett. 6(9), 1996, 1043, one would obtain the desired methoxy compound.

[1481] Step B

[1482] If one were to use a similar procedure to that used in Preparative Example 13.19 Step B, except using the product from Step A above , one would obtain the desired compound.

[1483] Step C

[1484] If one were to use a similar procedure to that used in Synth. Commun. 1980, 10, p. 107, except using the product from Step B above and t-butanol, one would obtain the desired compound.

[1485] Step D

[1486] If one were to use a similar procedure to that used in Synthesis, 1986, 1031, except using the product from Step C above, one would obtain the desired sulfonamide compound.

[1487] Step E

[1488] If one were to use a similar procedure to that used in Preparative Example 13.19 Step E, except using the product from Step D above, one would obtain the desired compound.

[1489] Step F

[1490] If one were to use a similar procedure to that used in Preparative Example 19, except using the product from Step E above and adding potassium carbonate as base, one would obtain the desired compound.

[1491] Step G

[1492] If one were to follow the procedure set forth in Example 210, except using the product from Step F above and the amine from Preparative Example 75.9, then one would obtain the title compound.

Example 1130

[1493]

2229

[1494] Step A

[1495] If one were to treat the product from Step C of 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

2230

[1496] Step B

[1497] If one were to use the product of Step A above and one were to follow Steps E, F and G of Example 1125, except using the amine from Preparative Example 75.49 in Step G, then one would obtain the title compound.

Example 1131

[1498]

2231

2232

[1499] Step A

[1500] To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at −78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture was stirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, the mixture was poured carefully into crushed ice, and extracted with dichloromethane. The extracts were washed with brine, dried over magnesium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.2 g).

[1501] Step B

[1502] 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).

[1503] Step C

[1504] The product from Step B above (4.3 g) was dissolved in dichloromethane (125 mL) and cooled in a −78° C. bath. A solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirred for 4 h while the temperature was increased slowly from −78° C. to 10° C. H2O was added, the two layers were separated, and the aqueous layer was extracted with dichloro-methane. The combined organic layer and extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.96 g of the desired hydroxy-compound.

[1505] Step D

[1506] 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 H2O. The aqueous mixture was adjusted 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.

[1507] Step E

[1508] 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.

[1509] Step F

[1510] The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D.

[1511] Step G

[1512] 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. H2O (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. The residue was dissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) and hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. The mixture was poured into an aqueous mixture of sodium hydroxide (1.0 M aq, 50 mL) and ether (100 mL). The two layers were separated. The aqueous layer was washed with ether three times. The combined ether washings were re-extracted with H2O once. The aqueous layers were combined, washed once with dichloromethane, adjusted to pH˜6 using 3.0 M and 0.5 M hydrogen chloride aqueous solutions, and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 1.2 g of desired amine compound.

[1513] Step H

[1514] The product from step F (122 mg) was stirred with diethyoxysquarate (0.25 mL) and potassium carbonate (75 mg) in 5 mL of ethanol at room temperature for 5 h. The mixture was diluted with dichloromethane, filtered through a Celite pad, and concentrated to an oily residue, which was separated by preparative TLC (CH2Cl2-M OH=15:1, v/v) to give 91 mg of the desired product.

[1515] Step I

[1516] Following the procedure set forth in Example 210, and using the amine from Preparative Example 75.9, the product (43 mg) from Step H was converted to the desired compound (20 mg).

Preparative Example 600

[1517]

2233

[1518] Step A

[1519] Following the procedure set forth in Preparative Example 13.19 Step D, the imine was prepared from the known bromoester (1.0 g) to yield 1.1 g (79%) as a yellow solid.

[1520] Step B

[1521] The product of step A (0.6 g) was reacted following the procedure set forth in Preparative Example 13.19 Step E to give the amine product 0.19 g (64%).

[1522] Step C

[1523] The product of Step B (1.0 g) was reacted following the procedure set forth in Preparative Example 13.19 Step B to give the acid as yellow solid 0.9 g (94%).

[1524] Step D

[1525] The product of Step C (0.35 g) was reacted following the procedure set forth in Preparative Example 13.19 Step E to give the amino acid as yellow solid 0.167 g (93%).

Preparative Example 601

[1526]

2234

[1527] Step A

[1528] To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38 mL) at −78° C. and stirred at room temperature for half an hour. The reaction mixture again cooled to −78° C. and quenched with cyclopropyl amide 1 and stirred for two hours at −78° C. and slowly warmed to room temperature. The reaction mixture stirred for three hours at room temperature and quenched with the addition of saturated ammonium chloride solution. The mixture was taken to a separatory funnel, washed with water, brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent afforded the crude ketone, which was purified by using column chromatography to afford the ketone 3.0 g (87%) as a pale yellow oil.

[1529] Step B

[1530] To a solution of ketone (1.0 g) from Step A above in THF (5.0 mL) at 0° C. was added R-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwise followed by addition of a solution of borane complexed with dimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30 minutes 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. The residue was extracted with ether, washed with water, 1M HCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and removal of solvent afforded the crude alcohol which was purified by silica gel chromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 602

[1531]

2235

[1532] Step A

[1533] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) was mixed with SnCl4 (0.05 mL) and heated at 100° C. for 3 hours. After cooling the reaction mixture, water (10 mL) 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 0.9 g (43%) as a yellow oil.

[1534] Step B

[1535] The title alcohol was obtained following a similar procedure set forth in Preparative Example 601.

Preparative Example 603

[1536]

2236

[1537] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and 3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indium powder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture was stirred over night, diluted with water and extracted with ether. The ether layer was washed with water, brine and purified by silica gel chromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 604-611

[1538] Following a similar procedure set forth in Preparative Examples 13.25 or 601 the following Alcohols were prepared.

39PrepExFuranElectrophileAlcoholYield604

2237

2238

2239

86%605

2240

2241

2242

69%606

2243

2244

2245

84%607

2246

2247

2248

82%608

2249

2250

2251

60%609

2252

2253

2254

65%610

2255

2256

2257

82%611

2258

2259

2260

89%

Preparative Examples 620-631

[1539] Following a similar procedure set forth in Preparative Examples 13.25 the following Amines were prepared from the corresponding Alcohols.

40Prep ExALCOHOLAMINE% YIELD620

2261

2262

28%621

2263

2264

58%622

2265

2266

69%623

2267

2268

81%624

2269

2270

82%625

2271

2272

45%626

2273

2274

57%627

2275

2276

58%628

2277

2278

54%629

2279

2280

53%630

2281

2282

50%631

2283

2284

Preparative Examples 640-641

[1540] Following the procedures set forth in Preparative Example 19 but using the amine from the Preparative Example indicated in the Table below, the cyclobutenedione intermediates were obtained.

41Amine from1. Yield (%)Prep Ex.Prep Ex.Product2. MH+640600 Step B

2285

1. 60% 2. 138641600 Step D

2286

1. 66% 2. 138

Examples 1200-1211

[1541] Following the procedure set forth in Example 261 but using the commercially available amine or the prepared amine from the Preparative Example indicated in the table below, the following cyclobutenedione products were obtained.

421. Yield (%)2. MH+Ex.AmineProduct3. mp (° C.)1200

2287

2288

1. 61.3% 2. 451.4 3. 108.61201

2289

2290

1. 54% 2. 439.5 3. 117.81202

2291

2292

1. 80% 2. 439.5 3. 128-131.81203

2293

2294

1. 75% 2. 423.4 3. 118-1191204

2295

2296

1. 74% 2. 447.4 3. 108-1111205

2297

2298

1. 42% 2. 415.42 3. 136-1401206

2299

2300

1. 46% 2. 423.4 3. 114-1171207

2301

2302

1. 35% 2. 433.1 3. 123-1281208

2303

2304

1. 42% 2. 423.4 3. 118-1211209

2305

2306

1. 51% 2. 415.4 3. 112-1171210

2307

2308

1. 44% 2. 415.4% 3. 115-1201211

2309

2310

1. 48% 2. 445.4 3. 105-110

Examples 1300-13011

[1542] Following the procedure set forth in Example 261 but using the commercially available amine in the table below and the cyclobutenedione intermediate from the Preparative Example indicated, the following cyclobutenedione products were obtained.

431. Yield (%)Prep.2. MH+Ex.AmineEx.Product3. mp (° C.)1300

2311

640

2312

1. 35% 2. 390.4 3. 1001301

2313

641

2314

1. 78% 2. 390.4 3. 1301302

2315

23.9

2316

1. 48% 2. 483.4 3. 1161303

2317

23.9

2318

1. 46% 2. 443.5 3. 1061304

2319

23.9

2320

1. 40% 2. 445.54 3. 1021305

2321

23.9

2322

1. 51% 2. 413.4 3. 981306

2323

23.9

2324

1. 78% 2. 405.5 3. 2461307

2325

23.9

2326

1. 83% 2. 439.5 3. 1291308

2327

23.15A

2328

1. 11% 2. 519.47 3. 1231309

2329

23.15A

2330

1. 47% 2. 475 3. 1131310

2331

640

2332

1. 55% 2. 496.1 3. 123-1251311

2333

640

2334

1. 74% 2. 468.1 3. 116-118

Preparative Example 1001

[1543]

2335

[1544] Step A

[1545] Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (prepared according to known method, see: EP0897904B1), N,N-dimethylformamide (0.3 mL), and dichloromethane (40 mL) with stirring at rt. The reaction mixture was stirred overnight. Evaporation of solvent and excess oxalyl chloride and drying under vacuum afforded 2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was used without purification.

[1546] Step B

[1547] A solution of 2-methoxy-6-(trifluoromethyl)benzoyl chloride (ca. 6.81 mmol) from Step A above in dichloromethane (20 mL) was added dropwise to a mixture of 4-(dimethylamino)pyridine (42 mg, 0.34 mmol), triethylamine (2.8 mL, 20.09 mmol), and 2 M dimethylamine solution in tetrahydrofuran (7 mL, 14 mmol), and dichloromethane (30 mL) with stirring at rt. The reaction mixture was stirred overnight. A mixture of dichloromethane and water was added. The organic phase was separated, washed with 1N HCl solution, water, and saturated sodium bicarbonate solution and concentrated. The residue was purified by column chromatography (ethyl acetate:hexanes, 3:1 v/v) to give the product as a white solid (1.24 g. 74% over two steps).

[1548] Step C

[1549] A mixture of the amide from Step B above (1.8 g, 7.28 mmol), carbon tetrachloride (25 mL), and iron powder (305 mg, 5.46 mmol) was cooled to 0° C. Bromine (0.94 mL, 18.34 mmol) was added dropwise with stirring. After addition, the mixture was stirred at rt for 1 h and at 50° C. for 3 h. The mixture was cooled to rt, diluted with dichloromethane, and slowly poured to a cold 10% NaHSO3 solution. After stirring at rt for 0.5 h, the organic layer was separated and concentrated to give the product as a white solid (2.26 g, 95%).

[1550] Step D

[1551] Concentrated sulfuric acid (10 mL) was added dropwise to a flask charged with the bromide from Step C above (600 mg, 1.84 mmol) at 0° C. with stirring. A mixture of nitric acid (0.2 mL, 4.76 mmol) and concentrated sulfuric acid (0.3 mL) was then added dropwise. After addition, the mixture was stirred at rt for 3 h. The mixture was added to ice-water, neutralized with 15% NaOH solution to pH 7, and extracted with dichloromethane. The organic layer was concentrated to give the product as a white solid (621 mg, 91%). mp 92° C., m/e 371 (MH+).

[1552] Step E

[1553] A solution of the compound from Step D above (1.2 g, 3.23 mmol) in dichloromethane (50 mL) was cooled to −75° C. 1 M BBr3 solution in dichloromethane (7.5 mL, 7.5 mmol) was added dropwise with stirring. The mixture was stirred at −75° C. for 2 h. The mixture was added to ice-water. After stirring at rt for 0.5 h, the mixture was extracted with dichloromethane. The organic was concentrated and the residue was purified by column chromatography (dichloromethane-methanol, 9:1 v/v) to give the product as a yellow solid (1.05 g, 91%). m/e 357 (MH+).

[1554] Step F

[1555] A mixture of the compound from Step E above (1.08 g, 3.02 mmol), methanol (30 mL), and 10% Pd—C (250 mg) was subjected to hydrogenation at 50 psi at rt for 6 h. The mixture was filtered through a layer of Celite. The filtrate was concentrated to give the title compound as a pale yellow solid (930 mg, 96%). mp 132° C., m/e 249.

Preparative Example 1002

[1556]

2336

[1557] Step A

[1558] To a cooled (−70° C.) etherial (45 mL dry) solution of 3-bromothiophene (3.8 mL) was added BuLi (30 mL of 1.6M in hexane) dropwise, and the mixture was stirred at −70° C. for 20 min. Acetophenone (4.6 mL) in ether (6 mL) was added dropwise with stirring at 31 70° C. After 3 hrs, the mixture was warmed to RT and sat. NH4Cl (aq) was added and the mixture was extracted with ether. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound which was used in Step B without further purification.

[1559] Step B

[1560] The crude product from Step A above was stirred with oxalic acid (0.375 g) at 70° C. under reduced pressure for 3 hr, then cooled to RT and extracted with ether. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the product as a pale yellow liquid (5.7 g, 78% for Steps A-B )

[1561] Step C

[1562] To the product from Step B above (4.2 g) diluted with dichloromethane (30 mL) and containing triethylsilane (6 mL) was added TFA (3 mL) in dichloromethane (7.5 mL). After stirring at RT for 10 min, the mixture was concentrated in vacuo to give the product as a colorless liquid (4.61 g, 80%).

[1563] Step D

[1564] To an etherial (3.5 mL dry) solution of the thiophene product (1.5 g) from Step C above was added BuLi (3.2 mL of 2.5M), and the mixture was heated at reflux for 15 min, cooled to RT, and DMF (0.8 mL) in ether (3.5 mL) was added dropwise. After stirring for 30 min, sat. NH4Cl (aq) was added and the mixture was extracted with ether. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (1.71 g, 98%).

Preparative Example 1003

[1565]

2337

[1566] Step A

[1567] The aldehyde (0.50 g) was combined with ethylene glycol (1 mL), benzene (40 mL) and pTSA monohydrate (30 mg) and stirred at reflux for 20 hr. Cool to room temperature, add EtOAc and sat. NaHCO3 (aq) solution, separate the organic phase, concentrate in vacuo, and purify by silica gel chromatography (EtOAc-Hex, 1:4) to give a colorless liquid (60 mg)

[1568] Step B

[1569] The product from Step A above (0.607 g) was stirred at 45° C. overnight with 1N NaOH (aq), then cooled to room temperature, acidified with 3N HCl and extracted with EtOAc. Washing with brine and concentration in vacuo gave a solid (5.0 g).

[1570] Step C

[1571] Following a similar procedure as that used in Preparative Example 1, except using the product from Step B above and dimethylamine in THF (2M), the product was obtained (1.21 g crude).

[1572] Step D

[1573] The product from Step C above was dissolved in THF and stirred with 0.3N HCl (aq) and stirred at RT for 4 hr. Concentration in vacuo gave a pale yellow oil (1.1 g, 67%).

Preparative Example 1004

[1574]

2338

[1575] Step A

[1576] To a cooled (−78° C.) solution of methoxybenzofuran-2-carboxylic acid (1 g) was added DIBAL (30 mL, 1M in THF). After stirring for 20 min, the mixture was warmed to RT and stirred for 4 hr, then poured into sat. NH4Cl (aq) (35 mL). After stirring at RT for 20 min, 6M HCl (aq) was added and the mixture was extracted with EtOAc, the organic phase dried and then concentrated in vacuo. Purification by silica gel chromatography (EtOAc-hexane, 3:7) afforded the alcohol as a solid (0.4 g, 97%).

[1577] Step B

[1578] A mixture of the product from Step A above (0.9 g), EtOAc (50 mL) and MnO2 (5.2 g) was stirred at RT for 22 h, then filtered and concentrated in vacuo. The solid was redissolved in EtOAc (50 mL), MnO2 (5.2 g) was added and the mixture was stirred for 4 additional hrs. Filtration, concentration and silica gel purification (EtOAc-Hexane, 1:3) gave the title compound as a solid (0.60 g, 67%).

Preparative Example 1005

[1579]

2339

[1580] Following a similar procedure as that detailed in Preparative Example 1004, except using 5-chlorobenzofuran-2-carboxylic acid (1.5 g), the title compound was obtained (solid, 0.31 g, 24%).

Preparative Example 1006

[1581]

2340

[1582] Step A

[1583] The sulfonyl chloride from Preparative Example 13.29 Step A (1.5 g) was stirred with AlCl3 and benzene for 15 min at 20° C. Treatment with NaOH, extraction with Et2O, concentration in vacuo, and purification by column chromatography (silica, hexane-EtOAc, 5:2) gave the phenylsulfone (1.5 g, 84%, MH+=255).

[1584] Step B

[1585] Following similar procedures as those used in Preparative Example 13.29 Steps C-G, except using the sulfone from Step A above, the title compound was prepared (0.04 g, 27%, MH+=256).

Preparative Examples 1007-1029

[1586] Following a similar procedure set forth in Preparative Example 19.1 of WO 02/083624, published Oct. 24, 2002, or Preparative Example 19.2, but using the Amine (Anilines) listed in the Table below, the following squarate intermediates were prepared.

441. Yield (%)ExampleAmine/AnilineProduct2. (M + 1)+1007

2341

2342

1. 95% 2. 3591008

2343

2344

1. 99% 2. 3331009

2345

2346

1. 99% 2. 3331010

2347

2348

1. 99% 2. 3111011

2349

2350

1. 99% 2. 2751012

2351

2352

1. 99% 2. 3331013

2353

2354

1. 72% 2. 353.01014

2355

2356

1. 60% 2. 355.11015

2357

2358

1. 70% 2. 303.11016

2359

2360

1. 45% 2. 327.01017

2361

2362

1. 70% 2. 367.01019

2363

2364

1. 32% 2. 4091020

2365

2366

1. 48% 2. 4661021

2367

2368

1. ˜60% (crude)1022

2369

2370

1. 21%1023

2371

2372

1. 45% 2. 3891024

2373

2374

1. 30% 2. 3801027

2375

2376

1. 44% 2. 2641028

2377

2378

1. 56% 2. 2781029

2379

2380

1. 47% 2. 292

Preparative Example 1030

[1587]

2381

[1588] Step A

[1589] The product of Preparative Example 34.18 Step B (2 g, 8 mmol) was stirred with morpholine (0.9 mL, 10.29 mmol) and K2CO3 (2.2 g, 15.9 mmol) in 50 mL of acetone at RT to obtain the morpholinobutylfuran derivative (1.22 g,73%).

[1590] Step B

[1591] Following a similar procedure as in Preparative Example 34.18 Step D, but using the product (1.2 g) from Step A above, the title aldehyde was prepared (0.9 g,66%, 1:0.7 regioisomeric mixture).

Preparative Example 1031

[1592]

2382

[1593] A solution of 5-bromobenzofuran (950 mg, 4.82 mmol) in anhydrous-ether.(12 mL) was cooled to −78° C. 1.7 M tert-BuLi solution in pentane (6 ml, 10.2 mmol) was added dropwise under argon. After addition, the mixture was stirred at −78 ° C. for 20 min, followed by addition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture was allowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added. The mixture was poured to saturated ammonium chloride solution. The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate-hexanes, 1:5 v/v) to give the title compound as a pale yellow solid (490 mg, 70%).

Preparative Examples 1040-1054

[1594] Following the procedure set forth in Preparative Example 64 of WO 02/083624, published Oct. 24, 2002, but using the commercially available (or prepared) aldehyde, aminoalcohols, and organolithium reagents in the Table below, the optically pure amine products in the Table below were obtained.

45Prep.AminoOrgano-1. Yield (%)Ex.AldehydeAlcohollithiumProduct2. (M + 1)+1040

2383

2384

EtLi

2385

1. 24% 2. 2671041

2386

2387

EtLi

2388

1. 94% 2. 176 (m/e)1042

2389

2390

EtLi

2391

1. 67% 2. 229 (M − 16)1043

2392

2393

i-PrLi

2394

1. 60% 2. 151 [M −16]1044

2395

2396

EtLi

2397

1. 74% 2. 194 (M − 16)1045

2398

2399

EtLi

2400

1. 33% 2. 165 [M −NH2]+1046

2401

2402

EtLi

2403

1. 31 2. 179 [M −NH2]+1047

2404

2405

t-BuLi

2406

1. 31% 2. 1881048

2407

2408

t-BuLi

2409

1. 10% 2. 1541049

2410

2411

EtLi

2412

1. 73% 2. 137 [M −NH2]+1051

2413

2414

t-BuLi

2415

1. 17%1054

2416

2417

t-BuLi

2418

1. 79% 2. 151 (M − 16)

Preparative Examples 1100-1126

[1595] Following the procedure set forth in Preparative Example 34 of WO 02/083624, published Oct. 24, 2002, but using the commercially available aldehydes and Grignard/Organolithium reagents listed in the Table below, the amine products were obtained.

46Prep.Organo-metallic1. Yield (%)Ex.AldehydeReagentProduct2. (M + 1)+1100

2419

t-BuLi

2420

1. 83% 2. 190 (M − 16)1101

2421

t-BuLi

2422

1. 46% 2. 2041102

2423

t-BuLi

2424

1. 48% 2. 1941103

2425

t-BuLi

2426

1. 51% 2. 1941104

2427

t-BuLi

2428

1. 12% 2. 2381105

2429

t-BuLi

2430

1. 39% 2. 2341106

2431

t-BuLi

2432

1. 44% 2. 194 (m/e)1107

2433

t-BuLi

2434

1. 57% 2. 150 (M − 16)1108

2435

t-BuLi

2436

1. 31% 2. 2241109

2437

t-BuLi

2438

1. 11% 2. 2241110

2439

t-BuLi

2440

1. 57% 2. 2241111

2441

t-BuLi

2442

1. 21% 2. 2241112

2443

c-Pentyl-Li

2444

1. 58% 2. 1901113

2445

t-BuLi

2446

1. 20% 2. 2481114

2447

t-BuLi

2448

1. 24% 2. 2321115

2449

EtLi

2450

1. 32% 2. 177 (M −NH2)1116

2451

t-BuLi

2452

1. 26% 2. 205 (M −NH2)1117

2453

t-BuLi

2454

1. 50% 2. 190 (M −NH2)1118

2455

t-BuLi

2456

1. 29% 2. 2001119

2457

t-BuLi

2458

1. 28% 2. 2321120

2459

t-BuLi

2460

1. 76% 2. 2241121

2461

t-BuLi

2462

1. 40% 2. 2061122

2463

t-BuLi

2464

1. 38% 2. 2361123

2465

t-BuLi

2466

1. 70% 2. 1921124

2467

t-BuLi

2468

1. 81% 2. 2041125

2469

t-BuLi

2470

33%1126

2471

t-BuLi

2472

50%

Preparative Examples 1200-1203

[1596] Following the procedure set forth in Preparative Example 13.29 but using the commercially available amines, the hydroxyaminothiophene products listed in the Table below were obtained.

47Prep.1. Yield (%)Ex.AmineProduct2. (M + 1)+1200

2473

2474

1. 3% 2. 3421201

2475

2476

1. 41% 2. 2651202

2477

2478

1. 17% 2. 2371203

2479

2480

1. 1%

Preparative Example 1300

[1597]

2481

[1598] The title compound from Preparative Example 13.32 (0.35 g) was treated with concentrated sulfuric acid (3 mL) for 6 hrs, then poured on ice, and the pH adjusted to 4 with NaOH. Extraction with EtOAc, and drying of the organic phase over Na2SO4 gave the title compound (159 mg, 64%, MH+=223).

Preparative Example 1301

[1599]

2482

[1600] Following the procedure set forth in Preparative Example 605 but using the commercially available fluoroisopropylester, the alcohol product was obtained (1.2 g, 84%, M-OH=155).

[1601] Step B

[1602] Following the procedure set forth in Preparative Example 625 but using the alcohol from Step A above, the amine product was obtained (350 mg, 35%, M-NH2=155).

Preparative Example 1302

[1603]

2483

[1604] Step A

[1605] Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available arylsulfonylchloride (0.15 g) and diethylamine (2.2 eq), the dimethylsulfonamide was obtained (0.12 g, 71%, MH+=323).

[1606] Step B

[1607] Following a similar procedure as that used in Preparative Example 13.29 Step C, except using the product from Step A above (0.12 g), the phenol was obtained (0.112 g, 98%).

[1608] Step C

[1609] Following a similar procedure as that used in Preparative Example 10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using the product from Step B above (0.112 g), the title compound was obtained (0.1 g, 99%, MH+=245).

Preparative Example 1303

[1610]

2484

[1611] Following a similar procedure as that used in Preparative Example 1302 Steps A-C, except using piperidine in Step A (0.078 g) instead of diethylamine, the title compound was obtained (0.070 g, 35%, MH+=257).

Preparative Example 1304

[1612]

2485

[1613] Following a similar procedure as that used in Preparative Example 1302 Steps A-C, except using dimethylamine (2M in THF) in Step A instead of diethylamine, the title compound was obtained (1.92 g, 72%, MH+=217).

Preparative Example 1305

[1614]

2486

[1615] Step A

[1616] Following a similar procedure as that used in Preparative Example 1302 Step A, except using the phenethylamine indicated (4.99 g), the product was obtained (5.96 g, 86%, MH+=210).

[1617] Step B

[1618] The compound from Step A above (5.0 g) was added to 30 g of PPA at 150° C. and the resulting mixture stirred for 20 min, before being poured on ice and extracted with dichloromethane. The organic phase was dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (EtOAc:MeOH, 95:5) to give the product (0.5 g, 9%).

[1619] Step C

[1620] Following a similar procedure as that used in Preparative Example 13.3 Step D, of WO 02/083624, published Oct. 24, 2002, except using the compound from Step B above (0.14 g), the product was obtained (0.18 g, 87%, MH+=256).

[1621] Step D

[1622] Following a similar procedure as that used in Preparative Example 11 Step B, of WO 02/083624, published Oct. 24, 2002, except using the compound from Step C above (0.18 g), the product was obtained (0.17 g).

[1623] Step E

[1624] Following a similar procedure as that used in Preparative Example 13.3 Step B, of WO 02/083624, published Oct. 24, 2002, except using the compound from Step D above (0.17 g), the product was obtained (0.17 g, 95%, MH+=315).

[1625] Step F

[1626] Following a similar procedure as that used in Preparative Example 13.29 Step C, except using the product from Step E above (0.17 g), the nitrophenol was obtained (0.165 g, 99%, MH+=303).

[1627] Step G

[1628] Following a similar procedure as that used in Preparative Example 10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using the product from Step F above (0.165 g), the title compound was obtained (0.128 g, 86%, MH+=193).

Preparative Example 1306

[1629]

2487

[1630] Step A

[1631] Following a similar procedure as that used in Preparative Example 11 Step B, of WO 02/083624, published Oct. 24, 2002, except using the lactam (0.179 g), the title compound was obtained (0.25 g, 25%).

[1632] Step B

[1633] Following a similar procedure as that used in Preparative Example 13.29 Step C, except using the product from Step A above (0.055 g), the phenol was obtained (0.045 g, 99%).

[1634] Step C

[1635] Following a similar procedure as that used in Preparative Example 10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using the product from Step B above (0.045 g), the title compound was obtained (0.022 g, 57%, MH+=179).

Preparative Example 1307

[1636]

2488

[1637] Following a similar procedure as that used in Preparative Example 2, of WO 02/083624, published Oct. 24, 2002, except using 3(R)-hydroxypyrrolidine HCl (1.36 g), the title compound was obtained (2.25 g, 89%).

Preparative Example 1308

[1638]

2489

[1639] Following a similar procedure as that used in Preparative Example 2, of WO 02/083624, published Oct. 24, 2002, except using morpholine, the title compound was obtained (3.79 g).

Preparative Example 1309

[1640]

2490

[1641] Step A

[1642] Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available nitrophenylsulfonylchloride and diethylamine (2.2 eq), the dimethylsulfonamide was obtained (90%, MH+=231).

[1643] Step B

[1644] Following a similar procedure as that used in Preparative Example 10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using the product from Step B above, the title compound was obtained (45%, MH+=201).

Preparative Example 1310

[1645]

2491

[1646] Step A

[1647] Following a similar procedure as that used in Preparative Example 13.29 Step B, except using the commercially available nitrobenzoylchloride and the commercially available amine indicated, the benzamide was obtained (13%, MH+=253).

[1648] Step C

[1649] Following a similar procedure as that used in Preparative Example 10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using the product from Step B above, the title compound was obtained (94%, MH+=223).

Preparative Example 1311

[1650]

2492

[1651] Step A

[1652] To a benzene (20 mL) solution of methoxythiophenesulfonylchloride (1.5 g) was added AlCl3 (2.0 g) at RT. After 15 min, the mixture was added to 0.1N HCl (aq) with stirring, then extracted with Et2O. Washing the organic phase with bring, drying over MgSO4, concentration in vacuo and purification by silica gel chromatography (Hexane:EtOAc, 5:2) gave the title compound (1.5 g, 84%).

[1653] Step B

[1654] Following a similar procedure as that used in Preparative Example 13.29 Steps C-G, except using the product from Step A above, the title compound was obtained (3%, MH+=380).

Preparative Example 1312

[1655]

2493

[1656] Step A

[1657] Following a similar procedure as that used in Preparative Example 1311 Step A, except using the commercially available sulfonylchloride, the diphenylsulfone was obtained (880 mg, 80%).

[1658] Step B

[1659] Following a similar procedure as that used in Preparative Example 11 Step B, of WO 02/083624, published Oct. 24, 2002, except using the product from Step A above, the title compound was obtained (0.90 g, 97%).

[1660] Step C

[1661] Following a similar procedure as that used in Preparative Example 10.55 Step C, of WO 02/083624, published Oct. 24, 2002, except using the product from Step B above (0.16 g), the title compound was obtained (0.106 g, 95%).

Preparative Example 1313

[1662]

2494

[1663] Step A

[1664] Following a similar procedure as that used in Preparative Example 1311 Step A, except using the commercially available phenol (2 g), the nitroacid was obtained (˜13 mmol).

[1665] Step B

[1666] Oxallyl chloride (3.5 mL) and two drops of DMF was added to the product from Step A above (˜13 mmol) dissolved in dichloromethane (100 mL). After stirring at RT overnight, the mixture was concentrated in vacuo, diluted with dichloromethane (50 mL), cooled to 0° C. Dimethylamine in THF (20 mL of 2N) and TEA (8 mL) were added. After 3 hr of stirring, the mixture was concentrated in vacuo, aq NaOH (1M) was added, and the mixture was extracted with dichloromethane. The pH of the aq is layer was adjusted to pH=2 using 6N HCl (aq), and extracted with dichloromethane. The combiuned organic extracts were washed with brine, dried, concentrated in vacuo, and the product purified by silica gel chromatography (700 mL dichloromethane/20 mL MeOH/1 mL AcOH) to give the title compound (800 mg, 27% for two steps).

[1667] Step C

[1668] Following a similar procedure as that used in Preparative Example 10.55 Step C, WO 02/083624, published Oct. 24, 2002, except using the product from Step B above (780 mg), the title compound was obtained (0.46 g, 68%).

Examples 2001-2088

[1669] Following a similar procedure set forth in Example 210, of WO 02/083624, published Oct. 24, 2002, but using the cyclobutenedione intermediate and amine indicated in the Table below, the following cyclobutenedione products were obtained. See WO 02/083624, published Oct. 24, 2002, for Preparative Examples 19, 19.2, 23.14 and 87.1.

48Prep Ex of intermediate1. Yield (%)Exampleand AmineProduct2. (M + 1)+200119 and

2495

2496

3. 65% 4. 465200219 and

2497

2498

1. 5% 2. 422200319 and

2499

2500

1. 47% 2. 462200419 and

2501

2502

1. 74% 2. 452200519 and

2503

2504

1. 71% 2. 45220061007 and

2505

2506

1. 18% 2. 494200719 and

2507

2508

1. 36% 2. 434200819 and

2509

2510

1. 19% 2. 440200919 and

2511

2512

1. 45% 2. 504201019 and

2513

2514

1. 57% 2. 426201119 and

2515

2516

1. 6% 2. 469201219 and

2517

2518

1. 4% 2. 462201319 and

2519

2520

1. 29% 2. 496201419 and

2521

2522

1. 17% 2. 49220151007 and

2523

2524

1. 65% 2. 466201619 and

2525

2526

1. 72% 2. 452201719 and

2527

2528

1. 22% 2. 412201819 and

2529

2530

1. 5% 2. 425201919 and

2531

2532

1. 82% 2. 48220201008 and

2533

2534

1. 49% 2. 436202122 and

2535

2536

1. 45% 2. 440202219 and

2537

2538

1. 35% 2. 48220241010 and

2539

2540

1. 16% 2. 414202619 and

2541

2542

1. 46% 2. 48220271010 and

2543

2544

1. 13% 2. 41820281012 and

2545

2546

1. 39% 2. 440202919 and

2547

2548

1. 55% 2. 382203019 and

2549

2550

1. 39% 2. 378203319 and

2551

2552

1. 71% 2. 48220341013 and

2553

2554

1. 45% 2. 487.920351014 and

2555

2556

1. 22% 2. 461.820361015 and

2557

2558

1. 27% 2. 405.9203787.1 and

2559

2560

1. 26% 2. 392.020381016 and

2561

2562

1. 28% 2. 433.820391017 and

2563

2564

1. 34% 2. 473.9204019 and

2565

2566

1. 34% 2. 525204123.15E and

2567

2568

1. 67% 2. 48220421300 and 1027

2569

1. 33% 2. 44020431203 and 1027

2570

1. 24% 2. 468204419 and

2571

2572

1. 26% 2. 466204619.2 and

2573

2574

1. 27% 2. 535204723.15F and

2575

2576

1. 74% 2. 468204823.15F and

2577

2578

1. 68% 2. 468204919 and

2579

2580

1. 31% 2. 462205023.15F and

2581

2582

1. 41% 2. 496205119 and

2583

2584

1. 66% 2. 490205219 and

2585

2586

1. 43% 2. 490205319 and

2587

2588

1. 76% 2. 44020541024 and

2589

2590

1. 15% 2. 473205519 and

2591

2592

1. 87% 2. 454205623.15F and

2593

2594

1. 52% 2. 5162056A23.15F and

2595

2596

1. 62% 2. 482205723.15F and

2597

2598

1. 40% 2. 482205823.15F and

2599

2600

1. 71% 2. 48220591023 and

2601

2602

1. 67% 2. 48220601023 and

2603

2604

1. 60% 2. 524206119 and

2605

2606

1. 34% 2. 448206219 and

2607

2608

1. 43% 2. 506206319 and

2609

2610

1. 53% 2. 490206419 and

2611

2612

1. 25% 2. 452206519 and

2613

2614

1. 24% 2. 480206619 and

2615

2616

1. 37% 2. 465206719 and

2617

2618

1. 38% 2. 458206819 and

2619

2620

1. 35% 2. 490206919 and

2621

2622

1. 73% 2. 482207019 and

2623

2624

1. 69% 2. 464207119 and

2625

2626

1. 71% 2. 49420721022 and

2627

2628

1. 54% 2. 467207413.32A and 1028

2629

1. 42% 2. 482207519 and

2630

2631

1. 78% 2. 450207619 and

2632

2633

1. 25% 2. 402

	Number	Date	Country
Parent	10241326	Sep 2002	US
Child	10630258	Jul 2003	US
Parent	10208412	Jul 2002	US
Child	10241326	Sep 2002	US
Parent	10122841	Apr 2002	US
Child	10208412	Jul 2002	US

3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands

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Date Filed

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Inventors

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CPC

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International Classifications

Abstract

Description

Claims

CROSS REFERENCE TO RELATED APPLICATION

Provisional Applications (1)

Continuation in Parts (3)