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

Abstract

There are disclosed compounds of the formula 1

Description

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 cysteines are separated by a single amino acid (CXC-chemokines) or are adjacent (CC-chemokines). The CXC-chemokines include interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1), neutrophil-activating protein-2 (NAP-2), 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 an α-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 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.

[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, 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.

[0012] 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.

[0013] This invention also provedes 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).

[0014] 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.

[0015] This invention also provides novel compounds of formula IA, as described below.

[0016] 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

[0017] 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.

[0018] 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”.

[0019] “Patient” includes both human and other mammals, preferably human.

[0020] “Mammal” includes a human being, and preferably means a human being.

[0021] “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 is atoms.

[0022] “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.

[0023] “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.

[0024] “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.

[0025] “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.

[0026] “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.

[0027] “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.

[0028] “Cycloalkylalkyl” means a cycloalkyl group bound to the parent moiety through an alkyl group. Non-limiting examples include: cyclopropylmethyl and cyclohexylmethyl.

[0029] “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 is carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and norbornenyl.

[0030] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0031] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.

[0032] “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.

[0033] “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.

[0034] The term heterocyclic acidic functional group is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like.

[0035] “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.

[0036] “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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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). Also, “Bn” represents benzyl.

[0041] Representative embodiments of this invention are described below. The embodiments have been numbered for purposes of reference thereto.

[0042] The methods of this invention use a compound of formula IA: 2

[0043] and the pharmaceutically acceptable salts (e.g., sodium or calcium salt) and solvates thereof, wherein:

[0044] A is selected from the group consisting of: 345

[0045] 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; 6

[0046] 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; 7

[0047] 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 8

[0048] B is selected from the group consisting of 9

[0049] n is 0 to 6;

[0050] p is 1 to 5;

[0051] X is O, NH, or S;

[0052] Z is 1 to 3;

[0053] R2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO2NR3R14, —NHC(O)R3, —NHSO2NR13R4, —NHSO2R3, —NR3R14, —C(O)NR3R14, —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;

[0054] 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)OR3, —C(O)NHR17, —C(O)NR13R4, —SO(t)NR13R4, —SO(t)R3, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, 10

[0055] 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;

[0056] 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)R3, —C(O)OR3, —C(O)NR13R4, —SO(t)NR3R4, —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;

[0057] 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:

[0058] a) halogen,

[0059] b) —CF3,

[0060] c) —COR13,

[0061] d) —OR13,

[0062] e) —NR13R14,

[0063] f) —NO2,

[0064] g) —CN,

[0065] h) —SO2OR13,

[0066] i) —Si(alkyl)3, wherein each alkyl is independently selected,

[0067] j) —Si(aryl)3, wherein each alkyl is independently selected,

[0068] k) —(R13)2R14Si, wherein each R13 is independently selected,

[0069] l) —CO2R13,

[0070] m) —C(O)NR13R14,

[0071] n) —SO2NR13R14,

[0072] o) —SO2R13,

[0073] p) —OC(O)R13,

[0074] q) —OC(O)NR13R14,

[0075] r) —NR13C(O)R14, and

[0076] s) —NR13CO2R14;

[0077] (fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen);

[0078] R8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;

[0079] each R9 is independently selected from the group consisting of:

[0080] a) —R13,

[0081] b) halogen,

[0082] c) —CF3,

[0083] d) —COR13,

[0084] e) —OR13,

[0085] f) —NR13R14,

[0086] g) —NO2,

[0087] h) —CN,

[0088] i) —SO2R13,

[0089] j) —SO2NR3R14,

[0090] k) —NR13COR14,

[0091] l) —CONR13R14,

[0092] m) —NR13CO2R14,

[0093] n) —CO2R13,

[0094] o) 11

[0095] 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),

[0096] 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

[0097] r) —N(R13)SO2R14 (e.g., R13 is H and R14 is alkyl, such as methyl);

[0098] 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;

[0099] 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;

[0100] 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)N R15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16; or

[0101] 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., 12

[0102] each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0103] R17 is selected from the group consisting of: —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;

[0104] R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;

[0105] each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;

[0106] R30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO2, or —SO2R15 provided that R15 is not H;

[0107] 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;

[0108] each R40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and

[0109] t is 0, 1 or 2.

[0110] An embodiment of the present invention is directed to a method of treating an α-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.

[0111] Examples of chemokine mediated diseases include psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, 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, glomerulo-nephritis or thrombosis, alzheimer's disease, graft vs. host reaction, allograft rejections and malaria.

[0112] 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.

[0113] 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.

[0114] 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).

[0115] In another embodiment of the methods of this invention B is selected from the group consisting of: 13

[0116] wherein all substituents are as defined for formula IA.

[0117] In another embodiment of the methods of this invention B is: 14

[0118] wherein:

[0119] R2, R4, R5 and R6 are as defined for formula IA; and

[0120] 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)NR3R14, —SO(t)R13, —C(O)NR13OR14, 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.

[0121] In the methods of this invention:

[0122] (1) substituent A in formula IA is preferably selected from the group consisting of: 15

[0123] wherein the above rings are unsubstituted or substituted, as described for formula IA: and 16

[0124] 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

[0125] (2) substituent B in formula IA is preferably selected from the group consisting of: 17

[0126] wherein R2 to R6 and R10 to R14 are as defined above.

[0127] In the methods of this invention:

[0128] (1) substituent A in formula IA is more preferably selected from the group consisting of: 18

[0129] 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 19

[0130] 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

[0131] (2) substituent B in formula IA is more preferably selected from the group consisting of: 20

[0132] wherein

[0133] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 or and —NHSO2R13;

[0134] R3 is selected from the group consisting of: —SO2NR13R14, —NO2, cyano, —C(O)N R13R14, —SO2R13; and —C(O)OR13;

[0135] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3, halogen, and —CF3;

[0136] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano;

[0137] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0138] 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)N R13R14, —C(O)N R13OR14, —OC(O)R13, —COR13, —OR13, and cyano;

[0139] each R13 and R14 is independently selected from the group consisting of: methyl, ethyl and isopropyl; or

[0140] R13 and R14 when taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)N R13R14, —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 R13 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.

[0141] In the methods of this invention:

[0142] (1) substituent A in formula IA is even more preferably selected from the group consisting of: 21

[0143] 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 22

[0144] 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.

[0145] In the methods of this invention:

[0146] (1) substituent A in formula IA is still even more preferably selected from the group consisting of: 23

[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: 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 24

[0148] 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.

[0149] (2) substituent B in formula IA is preferably selected from the group consisting of: 25

[0150] wherein:

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

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

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

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

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

[0156] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0157] each R13 and R14 is independently selected from the group consisting of: methyl, ethyl and isopropyl; 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 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.

[0159] In the methods of this invention:

[0160] (1) substituent A in formula IA is yet even still more preferably selected from the group consisting of: 26

[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: 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 27

[0162] 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.

[0163] (2) substituent B in formula IA is preferably selected from the group consisting of: 28

[0164] wherein:

[0165] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0166] R3 is selected from the group consisting of: —C(O)NR13R14—SO2NR13R14, —NO2, cyano, and —SO2R13;

[0167] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0168] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0169] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0170] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0171] each R13 and R14 is independently selected from the group consisting of: methyl and ethyl.

[0172] In the methods of this invention:

[0173] (1) substituent A in formula IA is most preferably selected from the group consisting of: 293031

[0174] and

[0175] (2) substituent B in formula IA is preferably selected from the group consisting of: 32

[0176] wherein:

[0177] R2 is —OH;

[0178] R3 is selected from the group consisting of: —SO2NR13R14 and —CONR13R14;

[0179] R4 is selected form the group consisting of: H, —CH3 and —CF3;

[0180] R5 is selected from the group consisting of: H and cyano;

[0181] R6 is selected from the group consisting of: H, —CH3 and —CF3;

[0182] R11 is H; and

[0183] R13 and R14 are methyl.

[0184] The novel compounds of this invention are compounds of formula IA: 33

[0185] and their pharmaceutically acceptable salts (e.g., sodium or calcium salt) and solvates thereof, wherein:

[0186] A is selected from the group consisting of: 34353637

[0187] 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; 38

[0188] 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; 39

[0189] 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 40

[0190] B is selected from the group consisting of: 41

[0191] provided that R3 for this group is selected from the group consisting of: —C(O)NR13R14, 424344

[0192] n is 0 to 6;

[0193] p is 1 to 5;

[0194] X is O, NH, or S;

[0195] Z is 1 to 3;

[0196] 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;

[0197] 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)NHR7, —C(O)NR13R14, —SO(t)NR13R14, —SO(t)R3, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, 45

[0198] 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;

[0199] 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)R3, —C(O)OR3, —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;

[0200] 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:

[0201] a) halogen,

[0202] b) —CF3,

[0203] c) —COR13,

[0204] d) —OR13,

[0205] e) —NR13R14,

[0206] f) —NO2,

[0207] g) —CN,

[0208] h) —SO2OR13,

[0209] i) —Si(alkyl)3, wherein each alkyl is independently selected,

[0210] j) —Si(aryl)3, wherein each alkyl is independently selected,

[0211] k) —(R13)2R14Si, wherein each R13 is independently selected,

[0212] l) —CO2R13,

[0213] m) —C(O)NR13R14,

[0214] n) —SO2NR13R14,

[0215] o) —SO2R13,

[0216] p) —OC(O)R13,

[0217] q) —OC(O)NR13R14,

[0218] r) —NR13C(O)R14, and

[0219] s) —NR13CO2R14;

[0220] (fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen);

[0221] R8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;

[0222] each R9 is independently selected from the group consisting of:

[0223] a) —R13,

[0224] b) halogen,

[0225] c) —CF3,

[0226] d) —COR13,

[0227] e) —OR13,

[0228] f) —NR13R14,

[0229] g) —NO2,

[0230] h) —CN,

[0231] i) —SO2R13,

[0232] j) —SO2NR13R14,

[0233] k) —NR13COR14,

[0234] l) —CONR13R14,

[0235] m) —NR13CO2R14,

[0236] n) —CO2R13,

[0237] o) 46

[0238] 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),

[0239] q) alkyl substituted with one or more (e.g., one) —NR13R14 group (e.g., —(CH2)qNR3R4, wherein q is 1-6, usually 1 to 2, and preferably 1), and

[0240] r) —N(R13)SO2R14 (e.g., R13 is H and R14 is alkyl, such as methyl);

[0241] 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, —NHSO2R3, —C(O)NR13R14, —C(O)NR13OR14, —OC(O)R13 and cyano;

[0242] 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;

[0243] 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(R4)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

[0244] 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., 47

[0245] each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

[0246] R17 is selected from the group consisting of: —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;

[0247] R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;

[0248] each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;

[0249] R30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO2, or —SO2R15 provided that R15 is not H;

[0250] 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;

[0251] each R40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and

[0252] t is 0, 1 or 2.

[0253] Representative embodiments of the novel compounds of this invention are described below. The embodiments have been numbered for purposes of reference thereto.

[0254] Embodiment No. 1 is directed to the novel compounds of formula IA wherein B is selected from the group consisting of: 48

[0255] provided that R3 for this group is selected from the group consisting of: —C(O)NR13R14, 49

[0256] wherein all substituents are as defined for the novel compounds of formula IA.

[0257] Embodiment No. 2 is directed to the novel compounds of formula IA wherein B is: 50

[0258] wherein R3 is selected from the group consisting of: —C(O)NR13R14, 51

[0259] and all other substituents are as defined in formula IA.

[0260] Embodiment No. 3 is directed to the novel compounds of formula IA wherein B is: 52

[0261] and all other substituents are as defined in formula IA.

[0262] Embodiment No. 4 is directed to the novel compounds of formula IA wherein B is 53

[0263] R13 and R14 are each the same or different alkyl group, and all other substituents are as defined in formula IA.

[0264] Embodiment No. 5 is directed to the novel compounds of formula IA wherein B is 54

[0265] 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.

[0266] Embodiment No. 6 is directed to the novel compounds of formula IA wherein B is 55

[0267] R3 is selected from the group consisting of: 56

[0268] and all other substituents are as defined in formula IA.

[0269] Embodiment No. 7 is directed to the novel compounds of formula IA wherein B is 57

[0270] R3 is selected from the group consisting of: 58

[0271] R2 is —OH, and all other substituents are as defined in formula IA.

[0272] Embodiment No. 8 is directed to compounds of formula IA wherein B is: 59

[0273] R2, R13, and R14 are as defined for compounds of formula IA, and all other substituents are as defined in formula IA.

[0274] Embodiment No. 9 is directed to the novel compounds of formula IA wherein B is: 60

[0275] R2 is —OH, R13 and R14 are as defined for compounds of formula and all other substituents are as defined in formula IA.

[0276] Embodiment No. 10 is directed to the novel compounds of formula IA wherein B is: 61

[0277] 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.

[0278] Embodiment No. 11 is directed to the novel compounds of formula IA wherein B is: 62

[0279] R2 is —OH, R13 and R14 are the same or different alkyl group, and all other substituents areas defined for compounds of formula IA.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] Embodiment No. 15 is directed to novel compounds of formula IA wherein B is selected from the group consisting of: 63

[0284] wherein all substituents are as defined for formula IA.

[0285] Embodiment No. 16 is directed to compounds of formula IA wherein B is: 64

[0286] wherein all substituents are as defined for formula IA.

[0287] Embodiment No. 17 is directed to compounds of formula IA wherein B is: 65

[0288] R11 is H, and all other substituents are as defined in formula IA.

[0289] Embodiment No. 18 is directed to compounds of formula IA wherein B is: 66

[0290] R2 is —OH, and all other substituents are as defined in formula IA.

[0291] Embodiment No. 19 is directed to compounds of formula IA wherein B is: 67

[0292] R3 is —C(O)NR13R14, and all other substituents are as defined in formula IA.

[0293] Embodiment No. 20 is directed to compounds of formula IA wherein B is: 68

[0294] R3 is —S(O)tNR13R14 (e.g., t is 2), and all other substituents are as defined in formula IA.

[0295] Embodiment No. 21 is directed to compounds of formula IA wherein B is: 69

[0296] R2 is —OH, R3 is —C(O)NR13R14, and all other substituents are as defined in formula IA.

[0297] Embodiment No. 22 of this invention is directed to compounds of formula IA wherein B is: 70

[0298] R2 is —OH, and R3 is —S(O)tNR13R14 (e.g., t is 2), and all other substituents are as defined in formula IA.

[0299] Embodiment No. 23 is directed to compounds of formula IA wherein B is: 71

[0300] R2 is —OH, R3 is —C(O)NR13R14, R11 is H, and all other substituents are as defined in formula IA.

[0301] Embodiment No. 24 is directed to compounds of formula IA wherein B is: 72

[0302] 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.

[0303] Embodiment No. 25 is directed to compounds of formula IA wherein B is: 73

[0304] R2 is —OH, R3 is —C(O)NR13R14, R14 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 74

[0305] Embodiment No. 26 is directed to compounds of formula IA wherein B is: 75

[0306] R2 is —OH, R3 is —S(O)tNR13R14 (e.g., t is 2), Rat is H, and R13 and R14 are the same or different alkyl group (e.g., methyl), and all other substituents are as defined in formula IA.

[0307] Embodiment No. 27 is directed to compounds of formula IA wherein B is: 76

[0308] and all substituents are as defined in formula IA.

[0309] Embodiment No. 28 is directed to compounds of formula IA wherein B is: 77

[0310] and all substituents are as defined in formula IA.

[0311] Embodiment No. 29 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 28, 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.

[0312] Embodiment No. 30 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 28, and A is: 78

[0313] 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.

[0314] Embodiment No. 31 is directed to novel compounds of formula IA wherein B is described in any one of the Embodiment Nos. 1 to 28, and A is 79

[0315] wherein the furan ring is substituted and all other substituents are as defined for formula IA.

[0316] 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 28, and A is 80

[0317] 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.

[0318] Embodiment No. 33 is directed to novel compounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 28, A is 81

[0319] wherein the furan ring is substituted with one alkyl group and all other substituents are as defined for formula IA.

[0320] 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 28, and A is 82

[0321] 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.

[0322] 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 28, and A is 83

[0323] as defined in any one of the Embodiment Nos. 30 to 34, except that R7 and R8 are the same or different and each is selected from the group consisting of: H and alkyl.

[0324] 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 28, and A is 84

[0325] as defined in any one of the Embodiment Nos. 30 to 34, except that R7 is H, and R8 is alkyl (e.g., ethyl or t-butyl).

[0326] Embodiment No. 37 is directed to the novel compounds of formula IA wherein:

[0327] (1) substituent A in formula IA is preferably selected from the group consisting of: 85

[0328] wherein the above rings are unsubstituted or substituted, as described for formula IA: and 86

[0329] 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)NR3R14, d) —SO2NR13R14, e) —NO2, f) —CF3, g) —OR13, h) —NR3R14, i) —OC(O)R13, j) —OC(O)NR13R14, and k) halogen; and R8a and R9 are as defined in formula IA; and

[0330] (2) substituent B in formula IA is preferably selected from the group consisting of: 87

[0331] wherein R2 to R6 and R10 to R14 are as defined above for the novel compounds of formula IA.

[0332] Embodiment No. 38 is directed to the novel compounds of formula IA wherein:

[0333] (1) substituent A in formula IA is more preferably selected from the group consisting of: 88

[0334] 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 89

[0335] 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

[0336] (2) substituent B in formula IA is more preferably selected from the group consisting of: 90

[0337] wherein

[0338] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 or and —NHSO2R13;

[0339] R3 is selected from the group consisting of: —SO2NR13R14, —NO2, cyano, —C(O)NR13R14, —SO2R13; and —C(O)OR13;

[0340] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3, halogen, and —CF3;

[0341] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano;

[0342] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0343] 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)N R13R14—SO2R13, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —C(O)NR13R14, —C(O)NR13OR4, —OC(O)R3, —COR13, —OR13, and cyano;

[0344] each R13 and R14 is independently selected from the group consisting of: methyl, ethyl and isopropyl; or

[0345] R13 and R14 when taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR3R14, —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.

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

[0347] (1) substituent A in formula IA is even more preferably selected from the group consisting of: 91

[0348] 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 92

[0349] 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.

[0350] Embodiment No. 40 is directed to the novel compounds of formula IA wherein:

[0351] (1) substituent A in formula IA is still even more preferably selected from the group consisting of: 93

[0352] 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 94

[0353] 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.

[0354] (2) substituent B in formula IA is preferably selected from the group consisting of: 95

[0355] wherein:

[0356] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0357] R3 is selected from the group consisting of: —C(O)NR13R14, —SO2NR13R14, —NO2, cyano, —SO2R13; and —C(O)OR13;

[0358] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0359] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0360] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0361] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0362] each R13 and R14 is independently selected from the group consisting of: methyl, ethyl and isopropyl; or

[0363] 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.

[0364] Embodiment No. 41 is directed to the novel compounds of formula IA wherein:

[0365] (1) substituent A in formula IA is yet even still more preferably selected from the group consisting of: 96

[0366] 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 97

[0367] 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;

[0368] (2) substituent B in formula IA is yet even still more preferably selected from the group consisting of: 98

[0369] wherein:

[0370] R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13;

[0371] R3 is selected from the group consisting of: —C(O)NR13R14—SO2NR13R14, —NO2, cyano, and —SO2R13;

[0372] R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3;

[0373] R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and

[0374] R6 is selected from the group consisting of: H, alkyl and —CF3;

[0375] R11 is selected from the group consisting of: H, halogen and alkyl; and

[0376] each R13 and R14 is independently selected from the group consisting of: methyl and ethyl.

[0377] Embodiment No. 42 is directed to the novel compounds of formula IA wherein:

[0378] (1) substituent A in formula IA is most preferably selected from the group consisting of: 99100

[0379] (2) substituent B in formula IA is most preferably selected from the group consisting of: 101

[0380] wherein:

[0381] R2 is —OH;

[0382] R3 is selected from the group consisting of: —SO2NR13R14 and —CONR13R14;

[0383] R4 is selected form the group consisting of: H, —CH3 and —CF3;

[0384] R5 is selected from the group consisting of: H and cyano;

[0385] R6 is selected from the group consisting of: H, —CH3 and —CF3;

[0386] R11 is H; and

[0387] R13 and R14 are methyl.

[0388] Embodiment No. 43 is directed to compounds of formula IA wherein B is selected from the group consisting of: 102

[0389] provided that R3 for this group is selected from the group consisting of: —C(O)NR13R14, 103104

[0390] wherein all other substituents are as defined for formula IA.

[0391] Embodiment No. 44 is directed to compounds of formula IA wherein B is selected from the group consisting of: 105

[0392] wherein all substituents are as defined for formula IA.

[0393] Embodiment No. 45 is directed to compounds of formula IA wherein B is: 106

[0394] wherein all substituents are as defined for formula IA.

[0395] Embodiment No. 46 is directed to compounds of formula IA wherein B is: 107

[0396] wherein all substituents are as defined for formula IA.

[0397] Embodiment No. 47 is directed to compounds of formula IA wherein B is: 108

[0398] wherein all substituents are as defined for formula IA.

[0399] Embodiment No. 48 is directed to compounds of formula IA wherein B is: 109

[0400] wherein all substituents are as defined for formula IA.

[0401] Embodiment No. 49 is directed to compounds of formula IA wherein B is: 110

[0402] wherein all substituents are as defined for formula IA.

[0403] Embodiment No. 50 is directed to compounds of formula IA wherein B is: 111

[0404] wherein all substituents are as defined for formula IA.

[0405] Embodiment No. 51 is directed to compounds of formula IA wherein B is: 112

[0406] wherein all substituents are as defined for formula IA.

[0407] Embodiment No. 52 is directed to compounds of formula IA wherein B is: 113

[0408] wherein all substituents are as defined for formula IA.

[0409] Embodiment No. 53 is directed to compounds of formula IA wherein B is: 114

[0410] wherein all substituents are as defined for formula IA.

[0411] Embodiment No. 54 is directed to compounds of formula IA wherein B is selected from the group consisting of: 115

[0412] wherein all substituents are as defined for formula IA.

[0413] Embodiment No. 55 is directed to compounds of formula IA wherein B is described in any of Embodiment Nos. 43 to 54 and A is as described in any of Embodiments Nos. 2942.

[0414] Embodiment No. 56 is directed to any one of the Embodiment Nos. 1 to 55 is wherein the novel compound of formula IA is a pharmaceutically acceptable salt.

[0415] Embodiment No. 57 is directed to any one of the Embodiment Nos. 1 to 55 wherein the novel compound of formula IA is a sodium salt.

[0416] Embodiment No. 58 is directed to any one of the Embodiment Nos. 1 to 55 wherein the novel compound of formula IA is a calcium salt.

[0417] Embodiment No. 59 is directed to a pharmaceutically acceptable salt of any one of the representative novel compounds described below.

[0418] Embodiment No. 60 is directed to a sodium salt of any one of the representative novel compounds described below.

[0419] Embodiment No. 61 is directed to a calcium salt of any one of the representative novel compounds described below.

[0420] Embodiment No. 62 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 61 in combination with a pharmaceutically acceptable carrier (or diluent).

[0421] Embodiment No. 63 is directed to a method of treating any one of the diseases described herein (e.g., the α-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 61.

[0422] Representative compounds of the invention include but are not limited to: 116117118119120121122123124125126127128129130131132133134135136137

[0423] Preferred compounds of the invention include: 138139140141142143144145146

[0424] A more preferred group of compounds includes: 147148149

[0425] A most preferred group of compounds includes: 150151

[0426] 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.

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] Preferably the compound is administered orally.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] 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.

[0447] 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.

[0448] 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.

[0449] Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

[0450] 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.

[0451] 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.

[0452] Microtubule affecting agents useful in the invention are well known to those of skill in the art and include, but are not limited to allocoichicine (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.

[0453] 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).

[0454] 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).

[0455] 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. 41:37-47).

[0456] 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.).

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] 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.

[0468] 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.

[0469] 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

[0470] 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.

[0471] Receptor Binding Assays:

[0472] CXCR1 SPA Assay

[0473] 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 II test compound or DMSO, 40 μl CXCR1 assay buffer or IL-8 stock, 100 II 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.

[0474] CXCR2 SPA Assay

[0475] 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 II 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—(X (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.

[0476] Calcium Fluorescence Assay (FLIPR)

[0477] HEK 293 cells stably transfected with hCXCR2 and Gat/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.

[0478] 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.

[0479] 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.

[0480] Chemotaxis Assays for 293-CXCR2

[0481] 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:

[0482] 1. Inserts are coated with collagenIV (2 ug/ml) for 2 hrs at 37° C.

[0483] 2. The collagen is removed and inserts are allowed to air dry overnight.

[0484] 3. Cells are labeled with 10 uM calcein AM (Molecular Probes) for 2 hrs. Labeling is done in complete media with 2% FBS.

[0485] 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.

[0486] 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.

[0487] Cytotoxicity Assays

[0488] 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:

[0489] 1. 293-CXCR2 cells are plated overnight at a concentration of 5000 cells per well in complete media.

[0490] 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.

[0491] Soft Agar Assay

[0492] 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.

[0493] 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.

[0494] A general procedure for the preparation of compounds of formula IA is as follows: 152153

[0495] Scheme 1

[0496] 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).

[0497] Scheme 2

[0498] 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. 154155

[0499] Scheme 3

[0500] 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.

[0501] Scheme 4

[0502] 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. 156157

[0503] Scheme 5

[0504] Indazole structures of Formula (I) or IA can be prepared according to Scheme 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).

[0505] Scheme 6

[0506] 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).

[0507] 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

[0508] 158

[0509] 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 1 N 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

[0510] 159

[0511] Step A

[0512] 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 1 M NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1 M 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.

[0513] Step B

[0514] 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

[0515] 160

[0516] 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

[0517] 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.

Prep
Ex.	Amine	Isocyanate	Amine
2.2	161	162	163
2.3	164	165	166
2.4	167	168	169
2.5	170	171	172
2.6	173	174	175

Preparative Example 2.7

[0518] 176

[0519] 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

[0520] 177

[0521] Step A

[0522] 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.

[0523] Step B

[0524] 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 1 N 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).

[0525] Step C

[0526] 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

[0527] 178

[0528] Step A

[0529] 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).

[0530] Step B

[0531] 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).

[0532] Step C

[0533] 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

[0534] 179

[0535] Step A

[0536] 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.

[0537] Step B

[0538] 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%).

[0539] Step C

[0540] 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

[0541] 180

[0542] Step A

[0543] 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).

[0544] Step B

[0545] Following a similar procedure as in Preparative Example 2, Step B, but using is the product from Step A above, the title compound was obtained (95%, MH+=116).

Preparative Example 2.12

[0546] 181

[0547] Step A

[0548] To N-benzyl-N-methylamine (20 mmol) dissolved in acetone (50 mL) was added concentrated HCl (20 mmol), paratormaldehyde (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.

[0549] Step B

[0550] 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.

[0551] Step C

[0552] 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

[0553] 182

[0554] Step A

[0555] 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 1 N 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%).

[0556] Step B

[0557] 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

[0558] 183

[0559] Step A

[0560] Following a similar procedure as in Preparative Example 2.13, Step A except using methyl N-methylglycinate, the desired product was obtained (18%).

[0561] Step B

[0562] 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

[0563] 184

[0564] 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

[0565] 185

[0566] 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

[0567] 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.

				1. Coupling
				Agent
Prep	Carboxylic			2. % Yield
Ex.	acid	Amine	Product	3. MH+
3	186	187	188	1. PyBrop 2. 87%, 86% 3.181
4	189	190	191	1. PyBroP 2. 49% 3. 209
5	192	NH3	193	1. PyBroP 2. 95% 3. 153
6	194	—NH2	195	1. PyBroP 2. 83% 3. 167
7	196	197	198	1. PyBroP 2. 76% 3. 223
8	199	200	201	1. PyBroP 2. 65, 53 3. 209
9	202	203	204	1. PyBroP 2. 59, 69 3. 207
10	205	206	207	1. PyBroP 2. 49, 86 3. 237
10.1	208	209	210	1. PyBroP 2. 30, 88 193
10.2	211	212	213	1. PyBroP 2. 26, 87 3. 195
10.3	214	215	216	1. PyBroP 2. 38 3. 209
10.4	217	218	219	1. PyBroP 2. 29 3. 209
10.5	220	221	222	1. PyBroP 2. 38 3. 223
10.6	223	224	225	1. PyBroP 2. 32, 99 3. 367.9
10.7	226	227	228	1. PyBroP 2. 35, 99 3. 237
10.8	229	230	231	1. DCC 2. 30, 99 3. 269
10.9	232	233	234	1. PyBroP 2. 58, 95 3. 233.1
10.10	235	236	237	1. PyBroP 2. 42, 95 3. 238.9
10.13	238	239	240	1. PyBroP 2. 51, 95 3. 307
10.14	241	242	243	1. PyBroP 2. 55 3. 347
10.15	244	245	246	1. PyBroP 2. 41 3. 369.1
10.16	247	248	249	1. PyBroP 2. 56 3. 354.9
10.17	250	251	252	1. PyBroP 2. 56 3. 308
10.18	253	254	255	1. PyBroP 2. 10, 95 3. 252.9
10.19	256	257	258	1. PyBroP 2. 42, 95 3. 249
10.20	259	260	261	1. PyBroP 2. 15, 95 3. 264.9
10.21	262	263	264	1. PyBroP 2. 64, 95 3. 273
10.22	265	266	267	1. PyBroP 2. 45, 95 3. 273
10.23	268	269	270	1. PyBroP 2. 44, 95 3. 281
10.24	271	272	273	1. PyBroP 2. 41, 95 3. 281.1
10.25	274	275	276	1. PyBroP 2. 48, 95 3. 257
10.26	277	278	279	1. DCC 2. 15, 99 3. 235
10.28	280	281	282	1. PyBroP 2. 52, 95 3. 237.1
10.29	283	284	285	1. PyBroP 2. 31, 95 3. 259.1
10.30	286	287	288	1. PyBroP 2. 54, 95 3. 250.9
10.31	289	290	291	1. PyBroP 2. 64, 95 3. 210.9
10.32	292	293	294	1. PyBroP 2. 47, 95 3. 197
10.33	295	296	297	1. PyBroP 2. 47, 95 3. 273
10.34	298	299	300	1. PyBroP 2. 51, 95 3. 237.1
10.35	301	302	303	1. PyBroP 2. 60, 90 3. 224
10.36	304	305	306	1. PyBroP 2. 65, 99 3. 252
10.37	307	308	309	1. PyBroP 2. 58, 99 3. 239
10.38	310	311	312	1. PyBroP 2. 35, 99 3. 221.1
10.39	313	314	315	1. PyBroP 2. 42, 99 3. 235.2
10.40	316	317	318	1. DCC 2. 32, 99 3. 293.1
10.41	319	320	321	1. PyBroP 2. 45, 99 3. 223.1
10.42	322	323	324	1. PyBroP 2. 55, 81 3. 251.1
10.43	325	326	327	1. PyBroP 2. 68, 66 3. 224.9
10.44	328	329	330	1. PyBroP 2. 68, 66 3. 241.1
10.45	331	332	333	1. PyBroP 2. 44, 40 3. 295
10.46	334	335	336	1. DCC 2. 37, 81 3. 265
10.47	337	338	339	1. PyBroP 2. 71, 95 3. 293.1
10.48	340	341	342	1. PyBroP 2. 35, 99 3. 220.9
10.49	343	344	345	1. DCC 2. 16, 99 3. 209.0
10.50	346	347	348	1. DCC 2. 18, 99 3. 264.0

Preparative Example 10.55

Alternative Procedure for Preparative Example 3

[0568] 349

[0569] 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. 350

[0570] 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 1 M 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%). 351

[0571] 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

[0572] 352

[0573] Step A

[0574] 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).

[0575] Step B

[0576] 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).

[0577] Step C

[0578] 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

[0579] 353

[0580] Step A

[0581] 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%).

[0582] Step B

[0583] 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 100 mg of product (56%, MH+=251).

Preparative Example 11.2

[0584] 354

[0585] 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

[0586] 355

[0587] Step A

[0588] 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).

[0589] Step B

[0590] Following the procedure set forth in Preparative Example 2, Step B, the amine was prepared (99%, MH+=267).

Preparative Example 11.11-11.18

[0591] 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.

Prep	Carboxylic			1. % Yield
Ex.	acid	Amine	Product	2. MH+
11.11	356	357	358	1. 45, 92 2. 310.0
11.12	359	360	361	1. 45, 95 2. 247.2
11.13	362	363	364	1. 85, 85 2. 251.1
11.14	365	366	367	1. 99, 92 2. 211.1
11.15	368	369	370	1. 48, 84 2. 265
11.16	371	372	373	1. 78, 91 2. 238.1
11.17	374	375	376	1. 67, 90 2. 265.1
11.18	377	378	379	1. 28, 99 2. 267

Preparative Example 12

[0592] 380

[0593] Step A

[0594] 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.

[0595] Step B

[0596] 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 1 M 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).

[0597] Step C

[0598] 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).

[0599] Step D

[0600] 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).

[0601] Step E

[0602] BBr3 (1.3 mL, 1 M 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).

[0603] Step F

[0604] 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

[0605] 381

[0606] Step A

[0607] 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%).

[0608] Step B

[0609] 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).

[0610] Step C

[0611] 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

[0612] 382

[0613] Step A

[0614] 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%).

[0615] Step B

[0616] 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+=167.9).

Preparative Example 12.3

[0617] 383

[0618] 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

[0619] 384

[0620] To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0° C. was added a solution of borane.THF complex (1 N, 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

[0621] 385

[0622] Step A

[0623] 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%).

[0624] Step B

[0625] 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 1 M 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).

[0626] Step C

[0627] 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).

[0628] Step D

[0629] 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

[0630] 386

[0631] Step A

[0632] 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).

[0633] Step B

[0634] 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).

[0635] Step C

[0636] 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 SnCl2O.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

[0637] 387

[0638] Step A

[0639] 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).

[0640] Step B

[0641] 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).

[0642] Step C

[0643] 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 SnCl2O.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

[0644] 388

[0645] Step A

[0646] 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 1 N NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1 N 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).

[0647] Step B

[0648] 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 1 N NaOH, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 3.3 g of an oil (99%, MH+=225).

[0649] Step C

[0650] 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).

[0651] Step D

[0652] 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).

[0653] Step E

[0654] 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

[0655] 389

[0656] Step A

[0657] 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 1 N 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).

[0658] Step B

[0659] 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

[0660] 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.

			1. Yield (%)
Prep Ex.	Boronic Acid	Product	2. MH+
13.5	390	391	1. 15% 2. 258
13.6	392	393	1. 32% 2. 325
13.7	394	395	1. 18% 2. 325

Preparative Example 13.8

[0661] 396

[0662] Step A

[0663] 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).

[0664] Step B

[0665] 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).

[0666] Step C

[0667] 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 of a solid (62%, MH+=178).

Preparative Example 13.9

[0668] 397

[0669] The amine was prepared following the procedure disclosed in WO Patent Application 01/68570.

Preparative Example 13.10

[0670] 398

[0671] The amine was prepared following the procedure disclosed in WO Patent Application 01/68570.

Preparative Example 13.11

[0672] 399

[0673] Step A

[0674] Following the procedure described in Preparative Example 88.2, Step A, the ketone was prepared (6.4 g, 36%).

[0675] Step B

[0676] To a solution of ketone (1 g) and 2-R-methylbenzylamine (0.73 ml) in anhydrous toluene (20 ml) was added 1 N 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%).

[0677] Step C

[0678] 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%).

[0679] Step D

[0680] 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

[0681] 400

[0682] 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

[0683] 401

[0684] Step A

[0685] 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 12 h. 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%).

[0686] Step B

[0687] 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%).

[0688] Step C

[0689] Following the procedures described in Preparative Example 13.11, Steps B, C and D, the amine salt was prepared.

Preparative Examples 13.15-13.17

[0690] 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.

Prep
Ex.	Aldehyde	Amine	Product	Yield (%)
13.15	402	403	404	20%
13.16	405	406	407	31%
13.17	408	409	410	66%
13.17A	411	412	413	38%
13.17B	414	415	416	31%

Preparative Example 13.18

[0691] 417

[0692] 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

[0693] 418

[0694] Step A

[0695] 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).

[0696] Step B

[0697] 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).

[0698] Step C

[0699] 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).

[0700] Step D

[0701] 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).

[0702] Step E

[0703] 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 0.48 g 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

[0704] 419

[0705] Step A

[0706] 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%).

[0707] Step B

[0708] 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

[0709] 420

[0710] Step A

[0711] 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 (CH2Cl2MeOH=70:1 to 50:1) to afford the product (111 mg, 43%).

[0712] Step B

[0713] 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

[0714] 421

[0715] Step A

[0716] 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%).

[0717] Step B

[0718] 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

[0719] 422

[0720] Step A

[0721] 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).

[0722] Step B

[0723] 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).

[0724] Step C

[0725] 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%)

[0726] Step D

[0727] 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

[0728] 423

[0729] Step A

[0730] 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%)

[0731] Step B

[0732] 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.

[0733] Step C

[0734] 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

[0735] 424

[0736] Step A

[0737] 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%).

[0738] Step B

[0739] The alcohol from above was reacted to form the azide using the procedure set forth in Preparative Example 75.75 Step B.

[0740] Step C

[0741] 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

[0742] 425

[0743] Step A

[0744] Following the procedure set forth in Preparative Example 13.26, Step A, the alcohol was prepared (100%).

[0745] Step B

[0746] 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%)

[0747] Step C

[0748] 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 (1 M 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.

[0749] The residue was dissolved in CH2Cl2 and washed with 1 N 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%).

[0750] Step D

[0751] 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.

[0752] Step E

[0753] 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

[0754] 426

[0755] Step A

[0756] 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%).

[0757] Step B

[0758] 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%).

[0759] Step C

[0760] 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%).

[0761] Step D

[0762] To the above product (854 mg) in THF (25 ml) was added dropwise a solution of tetrabutylammonium fluoride (1 M 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%).

[0763] Step E

[0764] 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%).

[0765] Step F

[0766] To the product from step E (310 mg) in dimethoxyethane (12 ml) was added dropwise a solution of LAH (1 M 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

[0767] 427

[0768] Step A

[0769] To a solution of 3-methoxythiophene (39) 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 (4.29).

[0770] Step B

[0771] 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).

[0772] Step C

[0773] 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.

[0774] Step D

[0775] 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 addjusted 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.

[0776] Step E

[0777] 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.

[0778] Step F

[0779] 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.

[0780] Step G

[0781] 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 (1.59) 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

[0782] Following the procedures set forth in Example 13.N1, but using commercially available amines, hydroxy-amino-thiophene products in the Table below were obtained.

Prep			Yield (%)
Ex.	Amine	Product	MH+
13.30	Bn2NH	428	10% 375.1
13.31	MeBnNH	429	14% 299.0
13.32	EtBnNH	430	22%

Preparative Example 13.33

[0783] 431

[0784] Step A

[0785] 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.N1, Step B.

[0786] Step B

[0787] 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).

[0788] Step C

[0789] 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%).

[0790] Step D

[0791] 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%).

[0792] Step E

[0793] The product from Step D above (4.82 g, 12.36 mmol) was stirred with concentrated sulfuric acid (5 mL) at room temperature ro 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).

[0794] Step F

[0795] 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).

[0796] Step G

[0797] 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.

[0798] Step H

[0799] 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

[0800] 432

[0801] Step A

[0802] 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 conentrated 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.

[0803] Step B

[0804] 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.

[0805] Step C

[0806] 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).

[0807] Step D

[0808] 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%).

[0809] Step E

[0810] 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).

[0811] Step F

[0812] 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.

[0813] Step G

[0814] 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

[0815] 433

[0816] Step A

[0817] 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.

[0818] Step B

[0819] To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. was added R-methyl oxazoborolidine (1.2MI, 1 M 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, 1 M 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

[0820] 434

[0821] Step A

[0822] 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.

[0823] Step B

[0824] The step B alcohol was obtained following a similar procedure set forth in the preparative example 13.35 Step B.

Preparative Example 13.37

[0825] 435

[0826] Step A:

[0827] 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

[0828] 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.

Prep. ex	Furan	Electrophile	Alcohol	Yield
13.38	436	437	438	86%
13.39	439	440	441	69%
13.40	442	443	444	84%
13.41	445	446	447	82%
13.42	448	449	450	60%
13.43	451	452	453	65%
13.44	454	455	456	82%
13.45	457	458	459	89%

Preparative Examples 13.50-13.61

[0829] 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.

PREP. EX.	ALCOHOL	AMINE	% YIELD
13.50	13.45	460	28%
13.51	13.38	461	58%
13.52	13.36	462	69%
13.53	13.35	463	81%
13.54	13.37	464	82%
13.55	13.39	465	45%
13.56	13.41	466	57%
13.57	13.40	467	58%
13.58	13.44	468	54%
13.59	13.42	469	53%
13.60	13.43	470	50%
13.61	13.37	471	82%

Preparative Example 13.70

[0830] 472

[0831] Step A

[0832] 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%).

[0833] Step B

[0834] 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%).

[0835] Step C

[0836] 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%)

[0837] Step D

[0838] 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

[0839] 473

[0840] Step A

[0841] 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.

[0842] Step B

[0843] 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

[0844] 474

[0845] Step A

[0846] 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. I. in Zh. Obs. Khim. (Journal of General Chemistry of the USSR) 1982, 52, 2592, and refs cited therein.

[0847] Step B

[0848] 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).

[0849] Step C

[0850] 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)

[0851] Step D

[0852] 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 layerwas 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).

[0853] Step E

[0854] 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

[0855] 475

[0856] Step A

[0857] 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.

[0858] Step B

[0859] 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.

[0860] Step C

[0861] Following a similar procedure used in Preparative Example 11, Step A except using the compound from Step B above, the product can be prepared.

[0862] Step D

[0863] 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

[0864] 476

[0865] Step A

[0866] Following a similar procedure used in Preparative Example 11, Step A except using the known 4-hydroxynicotinic acid, the product can be prepared.

[0867] Step B

[0868] Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared.

[0869] Step C

[0870] 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

[0871] 477

[0872] Step A

[0873] Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared.

[0874] Step B

[0875] 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

[0876] 478

[0877] 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

[0878] 479

[0879] The amine from Preparative 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

[0880] 480

[0881] 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 20-23.14

[0882] 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.

	Amine from		1. Yield (%)
Prep Ex.	Prep Ex.	Product	2. MH+
20	4	481	1. 85% 2. 333
21	11	482	1. 44% 2. 319
21.1	6	483	1. 9% 2. 291
22	2	484	1. 38% 2. 347
23	14	485	1. 51% 2. 259
23.1	10.1	486	1. 62% 2. 317
23.2	10.2	487	1. 61% 2. 319
23.3	12	488	1. 40% 2. 330
23.4	10.3	489	1. 42% 2. 333
23.5	10.4	490	1. 40% 2. 333
23.6	10.5	491	1. 37% 2. 347
23.7	13.2	492	1. 39% 2. 339
23.8	13.1	493	1. 42% 2. 383/385
23.9	13.19	494	1. 51% 2. 311
23.10	13.20	495	1. 67% 2. 389.1, 390
23.11	13.3	496	1. 52% 2. 383/385
23.12	13.21	497	1. 76% 2. 325.1
23.13	13.22	498	1. 54%
23.14	13.23	499	1. 62% 2. 378
23.14A	13.70 Step B	500	1.60% 2. 138
23.14B	13.70 Step D	501	1. 65%

Preparative Example 23.15A-23.15E

[0883] 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.

	Amine from		1. Yield (%)
Prep Ex.	Prep Ex.	Product	2. MH+
23.15A	13.29	502	1. 66% 2. 347
23.15B	13.30	503	1. 21% 2. 499
23.15C	13.31	504	1. 41% 2. 423
23.15D	13.32	505	1. 26% 2. 437
23.15E	13.33	506	1. 2.

Preparative Example 23.16-23.26

[0884] 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.

	Amine from
Prep Ex.	Prep Ex.	Product	Yield (%)
23.16	13.11	507	91%
23.17	13.12	508	81%
23.18	13.17	509	47%
23.19	13.27	510	21%
23.20	13.26	511	10%
23.21	13.25	512	49%
23.22	13.13	513	80%
23.23	13.15	514	63%
23.24	13.16	515	64%
23.25	13.17A	516	48%
23.26	13.17B	517	66%

Preparative Example 24

[0885] 518

[0886] Step A

[0887] 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.

[0888] Step B

[0889] 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

[0890] 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.

Prep				1. Yield
Ex.	Amino acid	Amine	Product	(%)
25	519	NH3	520	1. 70%
26	521	522	523	1. 71%
27	524	525	526	1. 66%
28	527	528	529	1. 65%
29	530	531	532	1. 90%
30	533	534	535	1. 68%
31	536	537	538	1. 68%
32	539	540	541	1. 97%
33	542	543	544	1. 97%
33.1	545	546	547	1. 20%

Preparative Example 33.2

[0891] 548

[0892] Step A

[0893] 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.

[0894] Step B

[0895] 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

[0896] 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.

Prep
Ex.	Amino acid	Amine	Product
33.3	549	550	551
33.4	552	553	554
33.5	555	556	557
33.6	558	559	560
33.7	561	562	563
33.8	564	565	566
33.9	567	568	569
33.10	570	571	572
33.11	573	574	575
33.12	576	577	578
33.13	579	580	581
33.14	582	583	584
33.15	585	586	587
33.16	588	589	590
33.17	591	592	593
33.18	594	595	596
19	597	598	599
33.20	600	601	602
33.21	603	604	605
33.22	606	607	608
33.23	609	610	611
33.24	612	613	614
33.25	615	616	617
33.26	618	619	620
33.27	621	622	623
33.28	624	625	626
33.29	627	628	629
33.30	630	631	632
33.31	633	634	635
33.32	636	637	638
33.33	639	640	641
33.34	642	643	644
33.35	645	646	647
33.36	648	649	650
33.37	651	652	653
33.38	654	655	656
33.39	657	658	659
33.40	660	661	662
33.41	663	664	665
33.42	666	667	668
33.43	669	670	671
33.44	672	673	674
33.45	675	676	677
33.46	678	679	680
33.47	681	682	683

Preparative Example 34

[0897] 684

[0898] 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

[0899] 685

[0900] 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

[0901] 686

[0902] 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

[0903] 687

[0904] Step A

[0905] 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%).

[0906] Step B

[0907] 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

[0908] 688

[0909] Step A

[0910] 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 1 N NaOH and brine, dried with MgSO4, filtered and concentrated in vacuo to give 8.4 g of crude product (100%)

[0911] Step B

[0912] 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%)

[0913] Step C

[0914] 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%).

[0915] Step D

[0916] To a solution of aldehyde (400 g) in ether (10 ml) was added LiN(TMS)2 (1 M 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

[0917] 689

[0918] 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

[0919] 690

[0920] 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

[0921] 691

[0922] Step A

[0923] 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%).

[0924] Step B

[0925] 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.

[0926] Step C

[0927] 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

[0928] 692

[0929] Step A

[0930] 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%).

[0931] Step B

[0932] 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%).

[0933] Step C

[0934] 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 1 M 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%).

[0935] Step D

[0936] 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 1 N 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

[0937] 693

[0938] Step A

[0939] 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%).

[0940] Step B

[0941] 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. 1 M 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%).

[0942] Step C

[0943] 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 1 N NaOH and brine, dried with Na2SO4, and concentrated in vacuo to afford 510 mg of product.

[0944] Step D

[0945] 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

[0946] 694

[0947] 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

[0948] 695

[0949] Step A

[0950] 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.

[0951] Step B

[0952] 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

[0953] 696

[0954] Step A

[0955] 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).

[0956] Step B

[0957] 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

[0958] 697

[0959] The above compound was prepared according to the procedure set forth in EP 0 555 153 A1.

Preparative Example 34.14

[0960] 698

[0961] 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

[0962] Following the procedures set forth in Preparative Example 34.8 but using the nitroalkanes indicated in the table below, the aldehydes were prepared.

34.15	699	700	17%
34.16	701	702	21%

Preparative Example 34.17

[0963] 703

[0964] Step A

[0965] 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.

[0966] Step B

[0967] 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.

[0968] Step C

[0969] 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.

[0970] Step D

[0971] 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.

[0972] Step E

[0973] 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

[0974] 704

[0975] Step A

[0976] 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.

[0977] Step B

[0978] 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.

[0979] Step C

[0980] 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.

[0981] Step D

[0982] 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

[0983] 705

[0984] Step A

[0985] 3-Ethylfuran was prepared from 3-hydroxymethylfuran according to literature procedure: J. Org. Chem., 1983, 48,1106-1107.

[0986] Step B

[0987] 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

[0988] 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.

Prep		Grignard		1. Yield (%)
Ex.	Aldehyde	Reagent	Amine	2. MH+
35	706	EtMgBr	707	1. 65% 2. 154
36	708	EtMgBr	709	1. 75% 2. 180
37	710	EtMgBr	711	1. 78% 2. 170
38	712	EtMgBr	713	1. 34% 2. 204
39	714	EtMgBr	715	1. 68% 2. 150
40	716	EtMgBr	717	1. 40% 2. 220
41	718	EtMgBr	719	1. 73% 2. 154
42	720	EtMgBr	721	1. 53% 2. 220
43	722	EtMgBr	723	1. 55% 2. 180
44	724	EtMgBr	725	1. 20% 2. 204
45	726	EtMgBr	727	1. 80% 2. 166
46	728	EtMgBr	729	1. 35% 2. 220
47	730	i-PrMgBr	731	1. 20% 2. 150
48	732	EtMgBr	733	1. 77% 2. [M—NH2]+ =149
49	734	EtMgBr	735	1. 77% 2. 172
50	736	EtMgBr	737	1. 78% 2. [M—NH2]+ =147
51	738	EtLi	739	1. 10% 2. 116
51.2	740	EtMgBr	741	1. 37% 2. 161
51.3	742	EtMgBr	743	1. 63% 2. 216
51.4	744	EtMgBr	745	1. 71% 2. 228
51.5	746	EtMgBr	747	1. 89% 2. 168
51.6	748	EtMgBr	749	1. 20% 2. 228
51.8	750	EtMgBr	751	1. 36% 2. 222
51.10	752	MgBr	753	1. 95% 2. 152.1
51.11	754	EtMgBr	755	1. 61% 2. 138.1 MH+—H2O
51.12	756	EtMgBr	757	1. 70% 2. 184.1
51.18	758	EtMgBr	759	1. 42% 2. 147 [M—NH2]+
51.19	760	EtMgBr	761	1. 67% 2. 204
51.20	762	EtMgBr	763	1. 33% 2. 188

Preparative Examples 51.25-51.31

[0989] 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.

Prep		Grignard		Yield
Ex.	Aldehyde	Reagent	Amine	(%)
51.25	764	EtMgBr	765	20%
51.26	766	767	768	77%
51.27	769	EtMgBr	770	51%
51.28	771	772	773	56%
51.29	774	775	776	54%
51.30	777	EtMgBr	778	80%
51.31	779	—≡—MgBr	780	10%

Preparative Example 52

[0990] 781

[0991] Step A

[0992] 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.

[0993] Step B

[0994] 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

[0995] 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.

Prep			1. Yield (%)
Example	Ketone	Amine	2. MH+
53	782	783	1. 11% 2. 128
54	784	785	1. 33% 2. 142
55	786	787	1. 49% 2. 156
56	788	789	1. 5% 2. 154
57	790	791	1. 47% 2. 174
58	792	793	1. 71% 2. 190
59	794	795	1. 78% 2. 191
60	796	797	1. 80% 2. 190
61	798	799	1. 9% 2. 156

Preparative Example 62

[0996] 800

[0997] 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.

[0998] 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

[0999] 801

[1000] 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

[1001] 802

[1002] Step A

[1003] 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.

[1004] Step B

[1005] 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.

[1006] Step C

[1007] 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.

[1008] Step D

[1009] 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 H5106 (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

[1010] 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.

Prep		Amino	Organo		1. Yield (%)
Ex.	Aldehyde	Alcohol	lithium	Product	2. MH+
65	803	804	EtLi	805	1. 62% 2. 154
66	806	807	EtLi	808	1. 70% 2. 154
67	809	810	811	812	1. 54% 2. 166
68	813	814	815	816	1. 67% 2. 166
69	817	818	EtLi	819	1. 67% 2. 154
70	820	821	EtLi	822	1. 42% 2. 142
71	823	824	EtLi	825	1. 36% 2. 142
72	826	827	828	829	1. 62% 2. 148
73	830	831	t-BuLi	832	1. 27% 2. 256
74	833	834	t-BuLi	835	1. 15% 2. 164
75	836	837	838	839	1. 7% 2. 204
75.1	840	841	EtLi	842	1. 65% 2. 123 [M—NH2]+
75.2	843	844	EtLi	845	1. 62% 2. 123 [M—NH2]+
75.3	846	847	EtLi	848	1. 93% 2. 139 [M—NH2]+
75.4	849	850	tBuLi	851	1. 50% 2. 167 [M—NH2]+
75.5	852	853	tBuLi	854	1. 48% 2. 167 [M—NH2]+
75.6	855	856	EtLi	857	1. 97% 2. 139 [M—NH2]+
75.7	858	859	iPrLi	860	1. 87% 2. 153 [M—NH2]+
75.8	861	862	863	864	1. 94% 2. 151 [M—NH2]+
75.9	865	866	EtLi	867	1. 75% 2. 151 [M—NH2+
75.10	868	869	tBuLi	870	1. 30% 2. 179 [M—NH2]+
75.10A	871	872	873	874	1. 61% 2. 135 [M—NH2]+
75.10B	875	876	EtLi	877	1. 24% 2. 154
75.10C	878	879	EtLi	880	1. 32% 2. 165 [M—NH2]+
75.10D	881	882	MeLi	883	1. 47% 2. 137 [M—NH2]+
75.10E	884	885	iPrLi	886	1. 30% 2. 165 [M—NH2]+
75.10F	887	888	889	890	1. 67% 2. 163.0 [M—NH2]+
75.10G	891	892	EtLi	893	1. 24% 2. 165 [M—NH2]+
75.10H	894	895	EtLi	896	1. 70% 2. 194
75.10J	897	898	EtLi	899	1. 54% 2. 208

Preparative Examples 75.11-75.59

[1011] 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.

Prep		Amino	Organo
Ex.	Aldehyde	Alcohol	lithium	Product	Yield (%)
76.11	900	901	902	903	52%
75.12	904	905	906	907	50%
75.13	908	909	iPrLi	910	57%
75.14	911	912	iPrLi	913	54%
75.15	914	915	iPrLi	916	58%
75.16	917	918	919	920	61%
75.17	921	922	EtLi	923	72%
75.18	924	925	926	927	68%
75.19	928	929	iPrLi	930	77%
75.20	931	932	t-BuLi	933	15%
75.21	934	935	MeLi	936	50%
75.22	937	938	EtLi	939	23%
75.24	940	941	EtLi	942	20%
75.27	943	944	EtLi	945	65%
75.28	946	947	iPrLi	948	61%
75.29	949	950	EtLi	951	90%
75.30	952	953	iPrLi	954	62%
75.31	955	956	iPrLi	957	43%
75.32	958	959	960	961	50%
75.33	962	963	964	965	50%
75.34	966	967	tBuLi	968	51%
75.35	969	970	MeLi	971	51%
75.36	972	973	tBuLi	974	57%
75.37	975	976	tBuLi	977	60%
75.38	978	979	EtLi	980	73%
75.39	981	982	MeLi	983	48%
75.41	984	985	986	987	52%
75.42	988	989	EtLi	990	40%
75.43	991	992	tBuLi	993	20%
75.44	994	995	t-BuLi	996	79%
75.45	997	998	iPrLi	999	55%
75.46	1000	1001	tBuLi	1002	39%
75.47	1003	1004	iPrLi	1005	55%
75.48	1006	1007	1008	1009	34%
75.49	1010	1011	EtLi	1012	61%
75.50	1013	1014	tBuLi	1015	25%
75.51	1016	1017	iPrLi	1018	33%
75.52	1019	1020	tBuLi	1021	30%
75.53	1022	1023	EtLi	1024	39%
75.54	1025	1026	1027	1028	38%
75.55	1029	1030	EtLi	1031	64%
75.56	1032	1033	EtLi	1034	46%
75.57	1035	1036	EtLi	1037	62%
75.58	1038	1039	iPrLi	1040	24%
75.59	1041	1042	EtLi	1043	70%

Preparative Example 75.75

[1012] 1044

[1013] Step A

[1014] 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%)

[1015] Step B

[1016] 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, 1 N 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%).

[1017] Step C

[1018] 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 1 N 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%).

[1019] Step D

[1020] To a solution of azide in THF at −10° C. was added LiAlH4 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

[1021] Following a similar procedure set forth in Preparative Example 75.75, and using the reduction procedure indicated, the following amines were obtained.

Prep		Reducing
Ex.	Aldehyde	Step	Product	% Yield
75.76	1045	D	1046	43%
75.77	1047	C	1048	36%
75.78	1049	D	1050	32%
75.79	1051	C	1052	42%
75.80	1053	D	1054	56%
75.81	1055	D	1056	35%
75.82	1057	C	1058	13%
75.83	1059	C	1060	42%
75.84	1061	C	1062	39%
75.85	1063	C	1064	26%
75.86	1065	C	1066	25%
75.87	1067	C	1068	14%
75.88	1069	C	1070	49%
75.89	1071	C	1072	34%
75.90	1073	C	1074	44%

Preparative Example 76

[1022] 1075

[1023] The desired compound was prepared according to methods previously described in J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 76.1

[1024] 1076

[1025] Step A

[1026] 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%).

[1027] Step B

[1028] 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%).

[1029] Step C

[1030] 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

[1031] Following the procedures set forth in Preparative Example 76.1, but using the commercially available boronic acids, the indicated amines were prepared.

Prep Ex.	Boronic Acid	Product	Yield (%)
76.2	1077	1078	70%
76.3	1079	1080	35%

Preparative Example 76.10

[1032] 1081

[1033] Step A

[1034] 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%).

[1035] Step B

[1036] 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 MeOH (10 ml). After stirring for 20 min, the reaction was concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with 1 M 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%).

[1037] Step C

[1038] The chiral alcohol from Step B above was reacted via the Preparative Example 75.75 Step B to give the azide.

[1039] Step D

[1040] 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

[1041] 1082

[1042] 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

[1043] 1083

[1044] The desired compound was prepared according to methods previously described in J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 78

[1045] 1084

[1046] The desired compound was prepared according to methods previously described in Chem. Pharm. Bull. 1991, 39,181-183.

Preparative Example 78.1

[1047] 1085

[1048] The desired compound was prepared according to methods previously described in J. Organometallic Chem. 1998, 567, 31-37.

Preparative Example 79

[1049] 1086

[1050] The desired compound was prepared according to methods previously described in Chem. Pharm. Bull. 1991, 39,181-183.

Preparative Example 80

[1051] 1087

[1052] 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

[1053] 1088

[1054] 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

[1055] 1089

[1056] The desired compound was prepared according to methods previously described in J. Med. Chem. 1988, 31, 2176-2186.

Preparative Example 83

[1057] 1090

[1058] 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 O OC 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

[1059] 1091

[1060] The corresponding cyclopropyl analog was prepared according to the procedure outlined in Preparative Example 83.

Preparative Example 85

[1061] 1092

[1062] The corresponding cyclohexyl analog was prepared according to the procedure outlined in Preparative Example 83.

Preparative Example 86

[1063] 1093

[1064] The desired compound was prepared according to methods previously described in J. Org. Chem. 1978, 43,892-898.

Preparative Example 87

[1065] 1094

[1066] 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

[1067] 1095

[1068] (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

[1069] 1096

[1070] 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

[1071] 1097

[1072] 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

[1073] 1098

[1074] Step A

[1075] 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%).

[1076] Step B

[1077] 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 1 N HCl, extracted with ether, dried with MgSO4, filtered and concentrated in vacuo to give 4.58 g of the product (93%, MH+=210).

[1078] Step C

[1079] 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 1 N NaOH, extracted with ether, dried with MgSO4, filtered and concentrated in vacuo to give 3.43 g of the product (80%).

[1080] Step D

[1081] 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

[1082] 1099

[1083] 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

[1084] 1100

[1085] 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

[1086] 1101

[1087] 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

[1088] 1102

[1089] 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

[1090] 1103

[1091] 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

[1092] 1104

[1093] 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

[1094] 1105

[1095] 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

[1096] 1106

[1097] The desired compound was prepared according to methods previously described in J. Org. Chem. 1987, 52, 4437-4444.

Preparative Example 92

[1098] 1107

[1099] The desired compound was prepared according to methods previously described in Bull. Chem. Soc. Jpn. 1962, 35,11-16.

Preparative Example 93

[1100] 1108

[1101] 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

[1102] 1109

[1103] 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

[1104] 1110

[1105] Step A

[1106] Lithium hexamethyldisilylazide (34 mL, 1 M 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., 1 M 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).

[1107] Step B

[1108] 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.

[1109] Step C

[1110] 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

[1111] 1111

[1112] Step A

[1113] 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, 1H), 7.79 (d, 1H).

[1114] Step B

[1115] 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).

[1116] Step C

[1117] 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 1 N 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).

[1118] Step D

[1119] 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

[1120] 1112

[1121] Step A

[1122] 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).

[1123] Step B

[1124] 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).

[1125] Step C

[1126] 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 1 N 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).

[1127] Step D

[1128] 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%).

[1129] 1 H 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

[1130] 1113

[1131] Step A

[1132] 1-Methyl-2-pyrrolecarboxylic acid (2.5 g, 20.0 mmol) was dissolved in dichloromethane (50 mL). After addition of PyBrOP (16.3 g, 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 1 N 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).

[1133] Step B

[1134] 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).

[1135] Step C

[1136] 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 1 N 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).

[1137] Step D

[1138] 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

[1139] 1114

[1140] Step A

[1141] 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).

[1142] Step B

[1143] 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).

[1144] Step C

[1145] 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 1 N 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%).

[1146] LCMS calculated: 344.1, found: (M+1)+345.1

[1147] Step D

[1148] 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%).

[1149] LCMS calculated: 314.14, found: (M+1)+315.1

Preparative Example 100

[1150] 1115

[1151] Step A

[1152] 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).

[1153] Step B

[1154] 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).

[1155] Step C

[1156] 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 1 N 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).

[1157] Step D

[1158] 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

[1159] 1116

[1160] Step 1

[1161] 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

[1162] 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).

[1163] Step 2

[1164] 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%).

[1165] 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

[1166] 1117

[1167] 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).

[1168] MS: calculated: 229.14, found: 230.1

[1169] 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

[1170] 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.

			1. Yield (%)
Example	Chloride	Product	2. (M + 1)+
103	1118	1119	1. 99% 2. 237.1
104	1120	1121	1. 62% 2. 253.1

Preparative Example 105

[1171] 1122

[1172] Step 1

[1173] 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 0.1 N 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).

[1174] MS: calculated: 394.15, found: 395.0

[1175] 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).

[1176] Step 2

[1177] 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%).

[1178] MS: calculated: 364.17, found: 365.1

[1179] 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)

[1180] Step 3

[1181] 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, 0.0061 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.

[1182] MS: calculated: 336.14, found: 337.1

[1183] 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

[1184] 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.

			1. Yield (%)
			2. (M + 1)+
Example	Aniline	Product	3. Note
106	103	1123	1. 91% 2. Not observed 3. Rainey nickel used in Step 2
107	104	1124	1. 24% 2. 360.0 3. For Step 1 used PyBrop/ DIEA in DCM

Preparative Example 108

[1185] 1125

[1186] Step A

[1187] 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. to The filtrate was concentrated and purified by column chromatography (80% EtOAc/Hex) to give the product (476 mg, 39.0%).

[1188] 1 H NMR (300 MHz, CDCl3) δ 2.40(m, 2H), 4.38(m, 4H), 6.97(m, 1H), 7.62(d, 1H), 8.12(d, 1H), 12.88(m, 1H) ppm.

[1189] Step B 1126

[1190] 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) δ 2.52(m, 2H), 4.57(bs, 4H), 6.75(m, 1H), 6.90(m, 2H), 12.71 (bs, 1H) ppm.

Preparative Example 109

[1191] 1127

[1192] In essentially the same manner as described in Preparative Example 108 above, the morpholino-amine product was obtained.

Preparative Example 110

[1193] 1128

[1194] Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL). N,N′-Dimethylcarbamoyl chloride (11.0 mL, 0.011 mol) was added dropwise to the solution at room temperature. The reaction was stirred for one hour. After this time 1 N 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%).

[1195] 1 H NMR (CDCl3, 300 MHz) 1.95 (s, 1H), 2.83 (s, 6H), 2.86 (m, 4H), 3.20 (m, 4H).

[1196] MS: calculated: 157.12, found: 158.1.

Preparative Example 111

[1197] 1129

[1198] Piperazine (4.9 g, 0.057 mol) was dissolved in 1 N HCl (100 mL). A solution of phenylsulfonylchloride (1.45 mL, 0.01 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 1 N 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%).

[1199] 1 H NMR (CDCl3, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H), 7.76 (m, 2H).

[1200] MS: calculated: 226.08, found: 227.1.

Preparative Example 112

[1201] 1130

[1202] 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 1 N 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%).

[1203] 1 H NMR (CDCl3, 300 MHz) 1.75 (s, 1H), 2.78 (s, 3H), 2.97 (m, 4H), 3.20 (m, 4H). MS: calculated: 164.06, found: 165.1.

Preparative Example 113

[1204] 1131

[1205] Step A

[1206] 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 1 N 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.

[1207] Step B

[1208] The product of Step A above, was dissolved in a 30% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time a 1 N 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%).

[1209] 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).

[1210] MS: calculated: 171.14, found: 172.0.

Preparative Example 114

[1211] 1132

[1212] Piperazine (4.9 g, 0.0569 mol) was dissolved in 1 N 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 1 N 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%).

[1213] 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).

[1214] MS: calculated: 206.24, found: 207.1.

Preparative Example 115-117

[1215] Following the procedure described for Example 112, the Products listed in the table below were prepared using the commercially available chloroformate shown and piperazine.

			1. Yield (%)
Example	Chloroformate	Product	2. (M + 1)+
115	1133	1134	1. 54% 2. 144.9
116	1135	1136	1. 17% 2. 173.0
117	1137	1138	1. 69% 2. 173.0

Preparative Example 118

[1216] 1139

[1217] Step A

[1218] 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).

[1219] 1 H NMR (CDCl3, 300 MHz) 1.47 (s, 9H), 3.45 (m, 8H), 7.41 (m, 5H). MS: calculated: 290.16, found: 290.8.

[1220] Step B

[1221] 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 1 N 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).

[1222] 1 H NMR (CDCl3, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39 (s, 5H).

[1223] MS: calculated: 190.11, found: 191.1.

Preparative Example 119

[1224] 1140

[1225] Step A

[1226] 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).

[1227] 1 H NMR (CDCl3, 300 MHz) 1.47 (s, 9H), 2.84 (s, 6H), 3.21 (m, 4H), 3.48 (m, 4H).

[1228] MS: calculated: 293.14, found: 194.1 (M-Boc)+.

[1229] Step B

[1230] 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 1 N 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).

[1231] 1 H NMR (CDCl3, 300 MHz) 2.03 (s, 1H), 2.83 (s, 6H), 2.92 (m, 4H), 3.23 (m, 4H).

[1232] MS: calculated: 193.09, found: 194.1.

Preparative Example 120

[1233] Step A 1141

[1234] 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.

[1235] Step B 1142

[1236] 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%).

[1237] 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).

[1238] Step C 1143

[1239] 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%).

[1240] 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. Mass Spectra, calculated: 248, found: 249.1 (M+1)+

Preparative Examples 121-123

[1241] 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.

				1. Yield (%)
	Carboxylic			2. (M + 1)+
Ex.	Acid	Amine	Product	3. Note
121	1144	1145	1146	1. 21% 2. 251.0
122	1147	1148	1149	1. 21% 2. 265.0 3. Skipped step B
123	1150	1151	1152	1. 15% 2. 264.0 3. Skipped step B

Preparative Example 124

[1242] 1153

[1243] Step A

[1244] 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 1 N 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).

[1245] Step B

[1246] The product from Step A above was stirred with 10% Pd/C under a hydrogen to 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

[1247] 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.

	Amine		1 .Yield (%)
	Comm. Avail./
Ex.	From Prep. Ex.	Product	2. (M + 1)+
125	1154	1155	1. 37% 2. 298.1
126	1156	1157	1. 31% 2. 310.1
127	1158	1159	1. 68% 2. 294.1
128	1160	1161	1. 54% 2. 365.9
129	1162	1163	1. 45% 2. 361.1
130	110	1164	1. 59% 2. 293.1
131	111	1165	1. 32% 2. 362.0
132	114	1166	1. 36% 2. 342.0
133	112	1167	1. 65% 2. 300.0
134	1168	1169	1. 48% 2. 321.1
135	1170	1171	1. 50% 2. 300.1
136	1172	1173	1. 56% 2. 299.2
137	115	1174	1. 79% 2. 280.1
138	116	1175	1. 64% 2. 307.1
139	1176	1177	1. 73% 2. 304.2
140	1178	1179	1. 34% 2. 264.0
141	117	1180	1. 40% 2. 307.1
142	113	1181	1. 91% 2. 307.1
143	118	1182	1. 9.0% 2. 326.0
144	119	1183	1. 42% 2. 329.0
145	1184	1185	1. 6.5% 2. 236.1

Preparative Example 146

[1248] 1186

[1249] Step A

[1250] 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.

[1251] Step B

[1252] 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

[1253] 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 amine hydrochloride products were obtained.

Prep	Tosyl	Grignard	Amine
Ex.	aziridine	Reagent	hydrochloride	1. Yield (%)
147	1187	MeMgBr	1188	1. 19%
148	1189	EtMgBr	1190	1. 56%
149	1191	n-PrMgBr	1192	1. 70%
150	1193	i-PrMgCl	1194	1. 41%
151	1195	BnMgCl	1196	1. 61%
152	1197	MeMgBr	1198	1. 61%
153	1199	EtMgBr	1200	1. 66%
154	1201	n-PrMgBr	1202	1. 80%
155	1203	i-PrMgBr	1204	1. 27%
156	1205	BnMgCl	1206	1.79%
156.1	1207	1208	1209	52%
156.2	1210	1211	1212	49%
156.3	1213	1214	1215	61%
156.4	1216	1217	1218	57%
156.5	1219	1220	1221	64%
156.6	1222	1223	1224	64%
156.7	1225	1226	1227	45%
156.8	1228	1229	1230	23%
156.9	1231	1232	1233	40%
156.10	1234	1235	1236	15%

Preparative Example 156.11

[1254] 1237

[1255] Step A

[1256] 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%).

[1257] Step B

[1258] 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%).

[1259] Step C

[1260] Isomer A (86 mg) was reacted following the procedure set forth in Step B above to give the amine salt.

Preparative Example 156.12

[1261] 1238

[1262] The above nitro compound was reduced following the Preparative Example 2, Step B.

Preparative Example 156.13

[1263] 1239

[1264] 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. 1 M 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

[1265] 1240

[1266] The above compound was prepared using the procedure set forth in Preparative Example 156.13, but using PhSO2Cl.

Preparative Example 156.15

[1267] 1241

[1268] The nitro compound was reduced following a similar procedure as in Preparative Example 2, Step B.

Preparative Example 156.16

[1269] 1242

[1270] Step A

[1271] 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%).

[1272] Step B

[1273] 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

[1274] 1243

[1275] Step A

[1276] 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%).

[1277] Step B

[1278] To a solution of oxime (300 mg) in THF (5 ml) at 0° C. was added LiAlH4 (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

[1279] 1244

[1280] Step A

[1281] 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%).

[1282] Step B

[1283] To a solution of the above amide (260 mg) in THF (5 ml) at −78° C. was added a solution of 2-thienyllithium (1 M 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%).

[1284] Step C

[1285] 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

[1286] 1245

[1287] Step A

[1288] 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%).

[1289] Step B

[1290] 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

[1291] 1246

[1292] Step A

[1293] 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%).

[1294] Step B

[1295] The ketone was reacted via the procedure set forth in Preparative Example 156.17 Step A to give the oxime.

[1296] Step C

[1297] 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

[1298] 1247

[1299] Step A

[1300] 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%).

[1301] Step B

[1302] 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. 1 M 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%).

[1303] Step C

[1304] 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 1 N NaOH and brine, dried with Na2SO4, filtered, and concentrated in vacuo to give 560 mg of product (69%).

[1305] Step D

[1306] 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

[1307] 1248

[1308] Step A

[1309] 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 (3 M) 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%).

[1310] Step B

[1311] Following the procedures set forth in Preparative Example 156.20 Steps B and C, the amine was prepared.

Preparative Example 156.23

[1312] 1249

[1313] The above amine was prepared using the procedures set forth in WO Patent Publication 98/11064.

Preparative Example 157

[1314] 1250

[1315] Step A

[1316] 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.

[1317] Step B

[1318] 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.

[1319] Step C

[1320] 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

[1321] 1251

[1322] 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

[1323] 1252

[1324] Step A

[1325] 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.

[1326] Step B

[1327] 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

[1328] 1253

[1329] Step A

[1330] 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.

[1331] Step B

[1332] 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.

[1333] Step C

[1334] 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

[1335] 1254

[1336] Step A

[1337] 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.

[1338] Step B

[1339] By following a similar procedure as that described in J. Organomet. Chem.; 317, 1986, 11-22, one would obtain the desired compound.

[1340] Step C

[1341] By following a similar procedure as that described in J. Amer. Chem. Soc., 77, 1955, 6221, one would obtain the desired compound.

[1342] Step D

[1343] 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

[1344] 1255

[1345] Step A

[1346] 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.

[1347] Step B

[1348] 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.

[1349] Step C

[1350] By following a similar procedure as that described in J. Amer. Chem. Soc., 77, 1955, 6221, one would obtain the desired compound.

[1351] Step D

[1352] 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

[1353] 1256

[1354] 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

[1355] 1257

[1356] Step A

[1357] By following the procedure set forth in Preparative Example 13.1, Step B using 3-methoxythiophene, one can obtain the desired product.

[1358] Step B

[1359] 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.

[1360] Step C

[1361] 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.

[1362] Step D

[1363] 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.

[1364] Step E

[1365] 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.

[1366] Step F

[1367] By using the product from Step E and the procedure set forth in Preparative Example 13.19, Step C, one could obtain the desired compound.

[1368] Step G

[1369] 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.

[1370] Step H

[1371] 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.

[1372] Step I

[1373] 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

[1374] 1258

[1375] 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

[1376] 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.

			1. Yield (%)
	(Prep Ex.)		2. MH+
Ex.	Amine	Product	3. mp (° C.)
201	1259	1260	1. 89% 2. 375.1 3. 255.5-257.3
202	1261	1262	1. 92% 2. 465.1 3. 149.0-152.3
203	1263	1264	1. 68% 2. 451.1 3. 282-284
204	1265	1266	1. 74% 2. 493.1 3. 141
205	1267	1268	1. 48% 2. 479.1 3. 142
206	1269	1270	1. 41% 2. 479.1 3. 142
207	1271	1272	1. 59% 2. 479.1 3. 141
208	1273	1274	1. 34% 2. 493.1 3. 140
209	1275	1276	1. 40% 2. 493.1 3. 142
209.1	(33.1)	1277	1. 59% 2. 143-145

Example 209.2

[1377] 1278

[1378] 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

[1379] 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.

	(Prep Ex.)		1. Yield (%)
Ex.	Amine	Product	2. MH+
209.3	(33.3)	1279	1. 50% 2. 541.2
209.4	(33.4)	1280	1. 32% 2. 549.1
209.5	(33.5)	1281	1. 65% 2. 493.1
209.6	(33.6)	1282	1. 64% 2. 491.1
209.10	(33.7)	1283	1. 90% 2. 457.2
209.11	(33.8)	1284	1. 35% 2. 505.0
209.12	(33.9)	1285	1. 70% 2. 493.1
209.13	(33.10)	1286	1. 75% 2. 480.2
209.14	(33.11)	1287	1. 74% 2. 465.1
209.15	(33.12)	1288	1. 62% 2. 479.1
209.16	(33.13)	1289	1. 31% 2. 466.2
209.17	(33.14)	1290	1. 79% 2. 495.2
209.18	(33.15)	1291	1. 99% 2. 479.2
209.19	(33.16)	1292	1. 47% 2. 466.2
209.20	(33.17)	1293	1. 72% 2. 479.1
209.21	(33.18)	1294	1. 92% 2. 493.1
209.22	(33.19)	1295	1. 47% 2. 499.1
209.23	(33.20)	1296	1. 7% 2. 490.0
209.24	(33.21)	1297	1. 15% 2. 533.1
209.25	(33.22)	1298	1. 88% 2. 451.1
209.26	(33.23)	1299	1. 26% 2. 523.0
209.27	(33.24)	1300	1. 54% 2. 433.1
209.28	(33.25)	1301	1. 59% 2. 466.2
209.29	(33.26)	1302	1. 66% 2. 560.2
209.30	(33.27)	1303	1. 98% 2. 495.1
209.31	(33.28)	1304	1. 99% 2. 471.2
209.32	(33.29)	1305	1. 99% 2. 471.2
209.33	(33.30)	1306	1. 18% 2. 524.2
209.34	(33.31)	1307	1. 78% 2. 479.2
209.35	(33.32)	1308	1. 71% 2. 459.2
209.36	(33.33)	1309	1. 5% 2. 491.0
209.37	(33.34)	1310	1. 27% 2. 501.1
209.38	(33.35)	1311	1. 26% 2. 533.1
209.39	(33.36)	1312	1. 48% 2. 451.1
209.40	(33.37)	1313	1. 99% 2. 455.1
209.41	(33.38)	1314	1. 88% 2. 527.1
209.42	(33.39)	1315	1. 74% 2. 485.2
209.43	(33.40)	1316	1. 20% 2. 492.5
209.44	(33.41)	1317	1. 68% 2. 541.1
209.45	(33.42)	1318	1. 13% 2. 508.9
209.46	(33.43)	1319	1. 86% 2. 479.1
209.47	(33.44)	1320	1. 34% 2. 507.0
209.48	(33.45)	1321	1. 56% 2. 429.1
209.49	(33.46)	1322	1. 18% 2. 495.0
209.50	(33.47)	1323	1. 22% 2. 501.0

Example 210

[1380] 1324

[1381] 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

[1382] 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.

			1. Yield (%)
	(Prep Ex)		2. MH+
Ex.	Amine	Product	3. mp (° C.)
211	1325	1326	1. 75% 2. 412.1 3. 126
212	1327	1328	1. 42% 2. 438.1 3. 106
213	1329	1330	1. 73% 2. 428.1 3. 139
214	1331	1332	1. 40% 2. 462.1 3. 160
215	1333	1334	1. 52% 2. 408.1 3. 126
216	1335	1336	1. 32% 2. 478.1 3. 176
217	1337	1338	1. 50% 2. 412.1 3. 126
218	1339	1340	1. 55% 2. 478.1 3. 110
219	1341	1342	1. 67% 2. 438.1 3. 122
220	1343	1344	1. 73% 2. 462.1 3. 118
221	1345	1346	1. 67% 2. 424.1 3. 100
222	1347	1348	1. 61% 2. 478.1 3. 114
223	1349	1350	1. 50% 2. 408.1 3. 157-159
224	1351	1352	1. 75% 2. 366.1 3. 110-112
225	1353	1354	1. 81% 2. 380.1 3. 118-120
226	1355	1356	1. 69% 2. 394.1 3. 123-125
227	1357	1358	1. 80% 2. 367.1 3. 122-125
228	1359	1360	1. 72% 2. 381.1 3. 133-135
229	1361	1362	1. 81% 2. 395.1 3. 141-143
230	1363	1364	1. 75% 2. 356.1 3. 103-104
231	1365	1366	1. 24% 2. 370.1 3. 101
232	1367	1368	1. 16% 2. 384.1 3. 70
233	1369	1370	1. 72% 2. 373.4 3. 104-106
234	1371	1372	1. 34% 2. 387.1 3. 99
235	1373	1374	1. 48% 2. 380.1 3. 118-120
236	1375	1376	1. 72% 2. 380.1 3. 119-120
237	1377	1378	1. 72% 2. 398.1 3. 121-123
238	1379	1380	1. 44% 2. 398.1 3. 121-123
239	1381	1382	1. 60% 2. 394.1 3. 123-124
240	1383	1384	1. 52% 2. 394.1 3. 122-124
241	1385	1386	1. 34% 2. 428.4 3. 157-159
242	1387	1388	1. 70% 2. 412.1 3. 109-112
243	1389	1390	1. 69% 2. 412.1 3. 110-112
244	1391	1392	1. 89% 2. 412.1 3. 126
245	1393	1394	1. 81% 2. 412.1 3. 126
246	1395	1396	1. 65% 2. 424.1 3. 121-124
247	1397	1398	1. 73% 2. 424.1 3. 122-124
248	1399	1400	1. 29% 2. 372.1 3. 219-221
249	1401	1402	1. 66% 2. 394.1 3. 132-135
250	1403	1404	1. 72% 2. 332
251	1405	1406	1. 74% 2. 408.1 3. 121-123
252	1407	1408	1. 76% 2. 408.1 3. 102-104
253	1409	1410	1. 72% 2. 438.1 3. 75-77
254	1411	1412	1. 80% 2. 392.1 3. 98-101
255	1413	1414	1. 72% 2. 420.1 3. 200-205
256	1415	1416	1. 75% 2. 434.1 3. 138-140
257	1417	1418	1. 67% 2. 410.1 3. 116-118
258	1419	1420	1. 76% 2. 424.1 3. 108-110
259	1421	1422	1. 72% 2. 430.1 3. 125
260	1423	1424	1. 78% 2. 422.1 3. 127
260.1	1425	1426	1. 74% 2. 426.1 3. 114 DEC
260.2	1427	1428	1. 85% 2. 436.1 3. 143 DEC
260.3	1429	1430	1. 56% 2. 474.1 3. 121-123
260.4	1431	1432	1. 71% 2. 500.1 3. 97(DEC)
260.6	1433	1434	1. 61% 2. 465 3. 102-107
260.7	1435	1436	1. 78% 2. 422.1 3. 114 DEC
260.8	1437	1438	1. 35% 2. 486.1 3. 103-105
260.9	1439	1440	1. 79% 2. 470 3. 110-115
260.10	1441	1442	1. 62% 2. 462.1 3. 110 DEC
260.11	1443	1444	1. 61% 2. 446.1 3. 118 DEC
260.12	1445	1446	1. 58% 2. 480.1 3. 111 DEC
260.13	1447	1448	1. 87% 2. 438.1 3. 122
260.14	1449	1450	1. 74% 2. 408.1 3. 128-130
260.15	1451	1452	1. 78% 2. 430.1 3. 117 DEC
260.16	1453	1454	1. 81% 2. 452.1 3. 139
260.17	1455	1456	1. 85% 2. 426.1 3. 126
260.18	1457	1458	1. 50% 2. 482.1 3. 114-116
260.19	1459	1460	1. 64% 2. 450.1 3. 129
260.20	1461	1462	1. 72% 2. 424.1 3. 116
260.21	1463	1464	1. 35% 2. 434.1 3. 124
260.22	1465	1466	1. 58% 2. 420.1 3. 107-109
260.23	1467	1468	1. 69% 2. 440.1 3. 169
260.24	1469	1470	1. 15% 2. 404.1 3. 103-105
260.25	1471	1472	1. 92% 2. 434.1 3. 129
260.26	1473	1474	1. 77% 2. 434.1 3. 133
260.27	1475	1476	1. 73% 2. 434.1 3. 138
260.28	1477	1478	1. 37% 2. 434.1 3. 133

Example 261

[1383] 1479

[1384] 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 262-360.108

[1385] 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.

			1. Yield (%)
			2. MH+
Ex.	Amine	Product	3. mp (° C.)
262	1480	1481	1. 74% 2. 330.1 3. 112-115
263	1482	1483	1. 64% 2. 344.1 3. 120-122
264	1484	1485	1. 72% 2. 358.4 3. 129-132
265	1486	1487	1. 76% 2. 372.1 3. 141-143
266	1488	1489	1. 57% 2. 372.1 3. 102
267	1490	1491	1. 65% 2. 386.1 3. 146
268	1492	1493	1. 65% 2. 464.1 3. 110-112
269	1494	1495	1. 85% 2. 464.1 3. 111-113
270	1496	1497	1. 49% 2. 374.1 3. 146
271	1498	1499	1. 69% 2. 374.1 3. 158-162
272	1500	1501	1. 54% 2. 430.1 3. 108
273	1502	1503	1. 65% 2. 430.1 3. 110
274	1504	1505	1. 53% 2. 388.1 3. 136
275	1506	1507	1. 30% 2. 388.1 3. 114
276	1508	1509	1. 53% 2. 402.1 3. 126
277	1510	1511	1. 68% 2. 402.1 3. 116
278	1512	1513	1. 64% 2. 372.1 3. 106
279	1514	1515	1. 69% 2. 434.1 3. 141-143
280	1516	1517	1. 51% 2. 434.1 3. 148-150
281	1518	1519	1. 71% 2. 406.1 3. 146-148
282	1520	1521	1. 66% 2. 406.1 3. 141-144
283	1522	1523	1. 70% 2. 450.1 3. 97-99
284	1524	1525	1. 25% 2. 360.1 3. 139
285	1526	1527	1. 78% 2. 416.1 3. 94
286	1528	1529	1. 49% 2. 372.1 3. 139
287	1530	1531	1. 95% 2. 386.1 3. 139
288	1532	1533	1. 32% 2. 348 3. 130-133
289	1534	1535	1. 72% 2. 410.1 3. 138
290	1536	1537	1. 72% 2. 410.1 3. 132-134
291	1538	1539	1. 75% 2. 318.1 3. 96-98
292	1540	1541	1. 72% 2. 430.1 3. 125
293	1542	1543	1. 51% 2. 348 3. 109-111
294	1544	1545	1. 84% 2. 374 3. 150.3
295	1546	1547	1. 56% 2. 386 3. 142.3
296	1548	1549	1. 38% 2. 382 3. 173.4
297	1550	1551	1. 13% 2. 370 3. 135.1
298	1552	1553	1. 47% 2. 424 3. 231.2-234.5
299	1554	1555	1. 34% 2. 316 3. 209.5
300	1556	1557	1. 92% 2. 392 3. 152.7
301	1558	1559	1. 52% 2. 346 3. 124.7
302	1560	1561	1. 51% 2. 346 3. 139.2
303	1562	1563	1. 29% 2. 408 3. 105
304	1564	1565	1. 24% 2. 372 3. 223.2
305	1566	1567	1. 25% 2. 442 3. 219.0
306	1568	1569	1. 83% 2. 386 3. 145
307	1570	1571	1. 58% 2. 400 3. 99.6
308	1572	1573	1. 60% 2. 414 3. 123.6
309	1574	1575	1. 44% 2. 412 3. 146.7
310	1576	1577	1. 39% 2. 432 3. 156.6
311	1578	1579	1. 65% 2. 448 3. 162.8
312	1580	1581	1. 53% 2. 449 3. 139.7
313	1582	1583	1. 64% 2. 454 3. 143.2
314	1584	1585	1. 35% 2. 428 3. 146.8
315	1586	1587	1. 72% 2. 476 3. 139.4
316	1588	1589	1. 36% 2. 402 3. 89.6
317	1590	1591	1. 62% 2. 400 3. 130.2
318	1592	1593	1. 46% 2. 400 3. 123.6
319	1594	1595	1. 64% 2. 400 3. 132.5
320	1596	1597	1. 79% 2. 406 3. 123.3
321	1598	1599	1. 17% 2. 440 3. 157.6
322	1600	1601	1. 58% 2. 428 3. 167.9
323	1602	1603	1. 50% 2. 422 3. 150.2
324	1604	1605	1. 20% 2. 462 3. 113.9
325	1606	1607	1. 95% 2. 360 3. 129.2
326	1608	1609	1. 97% 2. 360 3. 131.5
327	1610	1611	1. 39% 2. 318 3. 138.5
328	1612	1613	1. 54% 2. 408 3. 152.3
329	1614	1615	1. 62% 2. 346 3. 134.8
330	1616	1617	1. 55% 2. 346 3. 145.1
331	1618	1619	1. 61% 2. 400 3. 137.6
332	1620	1621	1. 42% 2. 374 3. 155.1
333	1622	1623	1. 45% 2. 348 3. 108-110
334	1624	1625	1. 29% 2. 424 3. 116
335	1626	1627	1. 15% 2. 414 3. 108-110
336	1628	1629	1. 75% 2. 408 3. 116
337	1630	1631	1. 75% 2. 408 3. 116
338	1632	1633	1. 59% 2. 424 3. 115-117
339	1634	1635	1. 72% 2. 424 3. 157-159
340	1636	1637	1. 19% 2. 332 3. 131
341	1638	1639	1. 86% 2. 360 3. 127
342	1640	1641	1. 98% 2. 346 3. 128
343	1642	1643	1. 80% 2. 374 3. 131.5
344	1644	1645	1. 46% 2. 374 3. 102
345	1646	1647	1. 75% 2. 388 3. 104
346	1648	1649	1. 76% 2. 438 3. 95
347	1650	1651	1. 72% 2. 424 3. 163-165
348	1652	1653	1. 73% 2. 438 3. 96-98
349	1654	1655	1. 53% 2. 362 3. 89-91
350	1656	1657	1. 59% 2. 362 3. 90-92
351	1658	1659	1. 61% 2. 362 3. 120-122
352	1660	1661	1. 70% 2. 362 3. 121-123
353	1662	1663	1. 23% 2. 371 3. 126
354	1664	1665	1. 79% 2. 370 3. 108
355	1666	1667	1. 80% 2. 370 3. 106
356	1668	1669	1. 56% 2. 450 3. 138-140
357	1670	1671	1. 76% 2. 398 3. 116
358	1672	1673	1. 85% 2. 384 3. 100
359	1674	1675	1. 59% 2. 332 3. 138.6
360	1676	1677	1. 47% 2. 332 3. 141.6
360.1	1678	1679	1. 89% 2. 356.1 3. 133-135
360.2	1680	1681	1. 65% 2. 334.1 3. 121-122
360.3	1682	1683	1. 60% 2. 348.1 3. 94-96
360.4	1684	1685	1. 29% 2. 414.1 3. 108-110
360.5	1686	1687	1. 67% 2. 348.1 3. 95-96
360.6	1688	1689	1. 62% 2. 414.1 3. 113-115
360.7	1690	1691	1. 68% 2. 414.1 3. 114-116
360.8	1692	1693	1. 74% 2. 374 3. 129.8
360.9	1694	1695	1. 61% 2. 388 3. 123.1
360.10	1696	1697	1. 53% 2. 388 3. 117.2
360.11	1698	1699	1. 37% 2. 388 3. 129.9
360.12	1700	1701	1. 62% 2. 374 3. 126.1
360.13	1702	1703	1. 71% 2. 400.1 3. 106-109
360.14	1704	1705	1. 66% 2. 400.1 3. 106-109
360.15	1706	1707	1. 69% 2. 372 3. 138.7
360.16	1708	1709	1. 54% 2. 346 3. 123.6
360.17	1710	1711	1. 53% 2. 388 3. 116.9
360.18	1712	1713	1. 87% 2. 384.1 3. 136
360.19	1714	1715	1. 92% 2. 384.1 3. 136
360.20	1716	1717	1. 27% 2. 386.1 3. 109-112
360.21	1718	1719	1. 31% 2. 400.1 3. 117-120
360.22	1720	1721	1. 61% 2. 396.1 3. 129
360.23	1722	1723	1. 69% 2. 396.1 3. 126
360.24	1724	1725	1. 74% 2. 398.1 3. 123
360.25	1726	1727	1. 76% 2. 398.1 3. 123
360.26	1728	1729	1. 60% 2. 384.1 3. 103-105
360.27	1730	1731	1. 67% 2. 384.1 3. 104-106
360.28	1732	1733	1. 70% 2. 386.1 3. 103-105
360.29	1734	1735	1. 64% 2. 400.1 3. 109-111
360.30	1736	1737	1. 63% 2. 398.1 3. 99-101
360.31	1738	1739	1. 57% 2. 398.1 3. 99-101
360.32	1740	1741	1. 45% 2. 400 3. 104.6
360.33	1742	1743	1. 44% 2. 386 3. 143
360.34	1744	1745	1. 73% 2. 356.1 3. 218-220
360.35	1746	1747	1. 97% 2. 406.1 3. 154
360.36	1748	1749	1. 77% 2. 414.1 3. 122-124
360.37	1750	1751	1. 70% 2. 412.1 3. 99-101
360.38	1752	1753	1. 69% 2. 416.1 3. 107-109
360.39	1754	1755	1. 43% 2. 454.1 3. 128-130
360.40	1756	1757	1. 40% 2. 374.1 3. 132-136
360.41	1758	1759	1. 60% 2. 345.1 3. 205-207
360.42	1760	1761	1. 96% 2. 412.1 3. 112
360.43	1762	1763	1. 30% 2. 434.1 3. 117-119
360.44	1764	1765	1. 96% 2. 410.1 3. 139
360.45	1766	1767	1. 65% 2. 384.1 3. 87-89
360.46	1768	1769	1. 50% 2. 434.1 3. 123-125
360.47	1770	1771	1. 74% 2. 412.1 3. 84-86
360.48	1772	1773	1. 73% 2. 400.1 3. 136-140
360.49	1774	1775	1. 74% 2. 412.1 3. 103-105
360.50	1776	1777	1. 63% 2. 434.1 3. 114-117
360.51	1778	1779	1. 74% 2. 414.1 3. 130-133
360.52	1780	1781	1. 71% 2. 426.1 3. 138
360.53	1782	1783	1. 41% 2. 414 3. 139-141
360.54	1784	1785	1. 32% 2. 426 3. 148-150
360.55	1786	1787	1. 57% 2. 428 3. 159-163
360.56	1788	1789	1. 44% 2. 464.1 3. 86-88
360.57	1790	1791	1. 37% 2. 442 3. 158-162
360.58	1792	1793	1. 53% 2. 494.1 3. 148-151
360.59	1794	1795	1. 63% 2. 528.1 3. 90-95
360.60	1796	1797	1. 73% 2. 438.1 3. 116
360.61	1798	1799	1. 55% 2. 494.1 3. 133-135
360.62	1800	1801	1. 83% 2. 412.1 3. 119
360.63	1802	1803	1. 66% 2. 440.1 3. 110
360.64	1804	1805	1. 49% 2. 410.1 3. 97
360.65	1806	1807	1. 40% 2. 442.1 3. 157-160
360.66	1808	1809	1. 75% 2. 400 3. 136-140
360.67	1810	1811	1. 63% 2. 528.1 3. 106-108
360.68	1812	1813	1. 10% 2. 401.1 3. 111-113
360.69	1814	1815	1. 5% 2. 426.1
360.70	1816	1817	1. 56% 2. 442.1 3. 152-154
360.71	1818	1819	1. 46% 2. 414.1 3. 122-124
360.72	1820	1821	1. 62% 2. 385.1 3. 130-133
360.73	1822	1823	1. 41% 2. 399.1 3. 83-85
360.74	1824	1825	1. 70% 2. 414.1 3. 98-101
360.75	1826	1827	1. 62% 2. 441.1 3. 98-102
360.76	1828	1829	1. 79% 2. 464.1 3. 111
360.77	1830	1831	1. 79% 2. 418.1 3. 107
360.78	1832	1833	1. 65% 2. 400.1 3. 109-112
360.79	1834	1835	1. 21% 2. 428.1 3. 126
360.80	1836	1837	1. 55% 2. 493.1 3. 155-158
360.81	1838	1839	1. 67% 2. 428.1 3. 138-140
360.82	1840	1841	1. 68% 2. 426.1 3. 121-123
360.83	1842	1843	1. 25% 2. 427.1 3. 139
360.84	1844	1845	1. 62% 2. 413.1 3. 128
360.85	1846	1847	1. 49% 2. 460.1 3. 112-114
360.86	1848	1849	1. 71% 2. 434.1 3. 91-93
360.87	1850	1851	1. 57% 2. 411.1 3. 125
360.88	1852	1853	1. 12% 2. 400.1 3. 131-133
360.89	1854	1855	1. 60% 2. 464.1 3. 111-113
360.90	1856	1857	1. 60% 2. 418.1 3. 113
360.91	1858	1859	1. 55% 2. 415.1 3. 140-143
360.92	1860	1861	1. 55% 2. 429 3. 185-190
360.93	1862	1863	1. 3% 2. 447.1
360.94	1864	1865	1. 71% 2. 452.1 3. 106
360.95	1866	1867	1. 44% 2. 439.1 3. 112
360.96	1868	1869	1. 71% 2. 464.1 3. 111-113
360.97	1870	1871	1. 70% 2. 398.1 3. 106-108
360.98	1872	1873	1. 46% 2. 426.1 3. 140-142
360.99	1874	1875	1. 62% 2. 399.1 3. 109-112
360.100	1876	1877	1. 60% 2. 466.1 3. 129-131
360.101	1878	1879	1. 49% 2. 446.1 3. 146
360.102	1880	1881	1. 48% 2. 432.1 3. 116
360.103	1882	1883	1. 62% 2. 418.1 3. 126
360.104	1884	1885	1. 47% 2. 430.1 3. 136
360.105	1886	1887	1. 42% 2. 461.1 3. 131-134
360.106	1888	1889	1. 93% 2. 426.1 3. 123-125
360.107	1890	1891	1. 26% 2. 454.1 3. 132-134
360.108	1892	1893	1. 12% 2. 479.1 3. 129-132
360.109	1894	1895	1. 67% 2. 410.1 3. 119-121
360.110	1896	1897	1. 71% 2. 412 3. 102
360.111	1898	1899	1. 64% 2. 440.1 3. 91-93
360.112	1900	1901	1. 79% 2. 412 3. 111-113
360.113	1902	1903	1. 20% 2. 440.1 3. 130 (DEC)
360.114	1904	1905	1. 61% 2. 438.1 3. 117-119
360.115	1906	1907	1. 61% 2. 440.1 3. 117-119
360.116	1908	1909	1. 81% 2. 452 3. 118
360.117	1910	1911	1. 65% 2. 466 3. 109

Examples 361-368.31

[1386] 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.

				1. Yield (%)
		Prep.		2. MH+
Ex.	Amine	Ex.	Product	3. mp (° C.)
361	1912	20	1913	1. 57% 2. 422 3. 172.4
362	1914	21	1915	1. 53% 2. 408 3. 139.8
363	1916	21	1917	1. 70% 2.374 3. 167.8-170.1
164	1918	23	1919	1. 21% 2. 334 3. 184.3
165	1920	23	1921	1. 61% 2. 348 3. 205.6
366	1922	21.1	1923	1. 75% 2. 344 3. 170-14 172
367	1924	21.1	1925	1. 66% 2. 330 3. 160-162
368	1926	22	1927	1. 31% 2. 436 3. 140-145
368.1	1928	20	1929	1. 8% 2. 374 3. 130-133
368.2	1930	23.1	1931	1. 56% 2. 372 3. 188-191
368.3	1932	23.1	1933	1. 67% 2. 406 3. 142-144
368.4	1934	23.2	1935	1. 69% 2. 408 3. 147-150
368.5	1936	23.2	1937	1. 67% 2. 374 3. 177-180
368.6	1938	23.3	1939	1. 45% 2. 385 3. 236-240
368.7	1940	23.3	1941	1. 35% 2. 425 3. 248-251
368.8	1942	23.2	1943	1. 66% 2. 414 3. 156-160
368.9	1944	23.4	1945	1. 78% 2. 428 3. 138-140
368.10	1946	23.5	1947	1. 46% 2. 428 3. 149-153
368.11	1948	23.6	1949	1. 54% 2. 412 3. 136-138
368.12	1950	21	1951	1. 30% 2. 414 3. 164-167
368.13	1952	23.1	1953	1. 25% 2. 412 3. 172-177
368.14	1954	23.7	1955	1. 21% 2. 434 3. 208-211
368.15	1956	23.8	1957	1. 27% 2. 478 3. 216-219
368.16	1958	23.9	1959	1. 63% 2. 400
368.17	1960	23.9	1961	1. 61% 2. 406.1 3. 127 DEC
368.18	1962	23.9	1963	1. 68% 2. 436.1 3. 128 DEC
368.19	1964	23.9	1965	1. 72% 2. 404.1 3. 126 DEC
368.20	1966	23.10	1967	1. 8.4% 2. 478
368.21	1968	23.9	1969	1. 39% 2. 432.1 3. 151-153
368.22	1970	23.12	1971	1. 78% 2. 414.1 3. 210 DEC
368.23	1972	23.11	1973	1. 4% 2. 504
368.24	1974	23.11	1975	1. 31% 2. 490 3. 241-245
368.25	1976	23.9	1977	1. 81% 2. 420.1 3. 126-128
368.26	1978	23.11	1979	1. 8% 2. 476 3. 193-198
368.27	1980	23.9	1981	1. 70% 2. 434.1 3. 130 DEC
368.28	1982	23.11	1983	1. 83% 2. 506 3. 222-227
368.29	1984	23.11	1985	1. 17% 2. 464 3. 183-190
368.30	1986	23.13	1987	1. 6.5% 2. 438.1
368.31	1988	23.14	1989	1. 71% 2. 471.1 3. 149-151
368.32	1990	23.14	1991	1. 58% 2. 471.1 3. 149
368.33	1992	23.15A	1993	1. 33% 2. 440.1 3. 181
368.34	1994	23.15A	1995	1. 56% 2. 468 3. 180
368.35	1996	23.15A	1997	1. 28% 2. 480 3. 186
368.36	1998	23.15A	1999	1. 48% 2. 494 3. 112.5
368.37	2000	23.15B	2001	1. 58% 2. 592 3. 177-179
368.38	2002	23.15C	2003	1. 69% 2. 516 3. 88-90
368.39	2004	23.15D	2005	1. 80% 2. 530 3. 134-137
368.40	2006	23.15E	2007	1. 57% 2. 454 3. 138-140
368.41	2008	19.2	2009	1. 26% 2. 507 3. 162-164
368.42	3	23.25	2010	1. 82% 2. 466 3. 141-143
368.43	3	23.26	2011	1. 67% 2. 480 3. 139 dec
368.44	13.29	23.16	2012	1. 29% 2. 480 3. 112-114
368.45	13.29	23.26	2013	1. 88% 2. 508 3. 190 dec

Examples 369-378.23

[1387] 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.

		Prep Ex of
		Cyclo-	1. Yield (%)
	Prep Ex of	butene	2. MH+
Ex.	Amine	Intermediate	Product	3. mp (° C.)
369	8	87	2014	1. 41% 2. 422 3. 135-140
370	9	87	2015	1. 60% 2. 420 3. 120-125
371	10	87	2016	1. 59% 2. 450 3. 162-167
372	12	87	2017	1. 34% 2. 419 3. 157.2-168.2
373	12	88	2018	1. 18% 2. 371 3. 142.3-144.6
374	13	87	2019	1. 41% 2. 408 3. 245.3-247.8
375	5	87	2020	1. 32% 2. 366 3. 165.7
376	6	87	2021	1. 17% 2. 380 3. 173.5
377	7	87	2022	1. 48% 2. 436 3. 175.6
378	2023	87	2024	1. 62% 2. 364 3. 155-160
378.1	3	88.3	2025	1. 73% 2. 438.1 3. 116
378.2	3	88.2	2026	1. 58% 2. 454 3. 140-142
378.3	13.3	87	2027	1. 43% 2. 472 3. 206-209
378.4	3	23.16	2028	1. 69% 2. 438.1 3. 116
378.5	3	23.17	2029	1. 73% 2. 438.1 3. 116
378.6	13.4	87	2030	1. 10% 2. 470 3. 198-201 DEC
378.7	13.5	87	2031	1. 16% 2. 471 3. 246-248
378.8	13.3	23.16	2032	1. 30% 2. 516/518 3. 234-240 DEC
378.9	13.19	23.16	2033	1. 65% 2. 444.1
378.10	3	23.20	2034	1. 78% 2. 488 3. 137-140
378.11	2035	88.1	2036	1. 24% 2. 371 3. 254-260 DEC
378.12	13.6	88.1	2037	1. 3% 2. 542
378.13	13.7	88.1	2038	1. 9% 2. 542
378.14	2039	88.1	2040	1. 48% 2. 434 3. 150-152
378.15	3	23.19	2041	1. 71% 2. 488 3. 136-138
378.16	3	23.22	2042	1. 35% 2. 424.1 3. 132
378.17	13.9	88.1	2043	1. 13% 2. 440 3. 219-223
378.18	13.10	88.1	2044	1. 26% 2. 406 3. 242-249 DEC
378.19	13.8	88.1	2045	1. 18% 2. 395
378.20	3	23.18	2046	1. 53% 2. 478.1 3. 126
378.21	3	23.21	2047	1. 66% 2. 466 3. 106
378.22	3	23.24	2048	1. 73% 2. 502.1 3. 121
378.23	3	23.23	2049	1. 57% 2. 458.1 3. 129

Examples 378.25-378.89

[1388] 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.

		Prep Ex
		of
		Cyclo-
		butene
	Prep Ex	Inter-		1. Yield (%)
Ex.	of Amine	mediate	Product	2. MH+
378.25	11.10	87.1	2050	1. 71% 2. 480.0
378.26	10.28	87.1	2051	1. 60% 2. 449.9
378.27	11.11	88.4	2052	1. 25% 2. 540.1 [M + Na+]
378.28	10.36	87.1	2053	1. 16% 2. 465.0
378.29	10.7	88.5	2054	1. 46% 2. 440.4
378.30	10.9	88.4	2055	1. 43% 2. 934.9 [dimer + 1]+
378.31	11.12	88.4	2056	1. 48% 2. 464.0
378.32	10.35	87.1	2057	1. 17% 2. 437
378.33	10.8	87.1	2058	1. 10% 2. 481.9
378.34	11.13	87.1	2059	1. 55% 2. 463.9
378.35	10.29	87.1	2060	1. 34% 2. 471.9
378.36	10.48	87.1	2061	1. 4% 2. 433.9
378.36	10.10	87.1	2062	1. 85% 2. 451.9
378.37	10.31	87.1	2063	1. 36% 2. 423.8
378.38	10.17	87.1	2064	1. 85% 2. 521.1
378.39	10.32	87.1	2065	1. 63% 2. 409.9
378.40	2066	87.1	2067	1. 44% 2. 323.1
378.41	10.33	87.1	2068	1. 20% 2. 486.0
378.42	10.13	87.1	2069	1. 47% 2. 520.1
378.43	10.34	87.1	2070	1. 18% 2. 449.9
378.44	11.14	87.1	2071	1. 13% 2. 424.0
378.45	2.13	87.1	2072	1. 13% 2. 423.8
378.46	12.1	87.1	2073	1. 51% 2. 487.1
378.47	10.38	88.4	2074	1. 72% 2. 437.7
378.48	11.15	87.1	2075	1. 29% 2. 477.9
378.49	10.14	87.1	2076	1. 61% 2. 560.2
378.50	11.18	87.1	2077	1. 25% 2. 480.0
378.51	10.18	87.1	2078	1. 51% 2. 466.0
378.52	12.2	87.1	2079	1. 32% 2. 380.9
378.53	10.19	87.1	2080	1. 14% 2. 461.4
378.54	11.1	87.1	2081	1. 41% 2. 463.9
378.55	11.2	87.1	2082	1. 5% 2. 409.9
378.56	10.20	87.1	2083	1. 70% 2. 478.1
378.57	10.49	87.1	2084	1. 17% 2. 421.9
378.58	10.15	87.1	2085	1. 51% 2. 582.1
378.59	10.46	87.1	2086	1. 18% 2. 477.9
378.60	11.16	88.4	2087	1. 54% 2. 455.1
378.61	10.21	87.1	2088	1. 84% 2. 485.9
378.62	10.40	87.1	2089	1. 4% 2. 506.1
378.65	2.8	87.1	2090	1. 34% 2. 480
378.66	10.22	87.1	2091	1. 16% 2. 486.0
378.67	2.10	87.1	2092	1. 44% 2. 545
378.68	10.23	87.1	2093	1. 26% 2. 493.9
378.69	2.14	87.1	2094	1. 60% 2. 437.9
378.70	10.24	87.1	2095	1.64% 2. 469.9
378.71	10.18	88.4	2096	1. 64% 2. 471.1
378.72	10.39	88.4	2097	1. 41% 2. 451.7
378.73	10.30	87.1	2098	1. 60% 2. 464.0
378.74	10.25	87.1	2099	1. 63% 2. 470.1
378.75	10.26	87.1	2100	1. 10% 2. 448.0
378.76	10.50	87.1	2101	1. 5% 2. 477.0
378.77	10.42	88.4	2102	1. 57% 2. 467.7
378.78	11.17	87.1	2103	1. 75% 2. 478.0
378.79	2.9	87.1	2104	1. 21% 2. 561
378.80	10.43	87.1	2105	1. 69% 2. 437.9
378.81	10.41	87.1	2106	1. 3% 2. 436.0
378.82	10.44	87.1	2107	1. 90% 2. 454.0
378.83	10.13	88.4	2108	1. 29% 2. 524.1
378.84	10.45	88.4	2109	1. 29% 2. 511.7
378.86	10.37	87.1	2110	1. 53% 2. 452.0
378.88	10.47	87.1	2111	1. 61% 2. 506.1
378.89	10.16	87.1	2112	1. 30% 2. 568.1

Example 378.90

[1389] 2113

[1390] 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

[1391] 2114

[1392] 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

[1393] 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.

			1. Yield (%)
Ex.	Aniline	Product	2. (MH+)
379	109	2115	1. 29% 2. 436.0
380	105	2116	1. 6.3% 2. 550.0
381	106	2117	1. 12% 2. 557.0
382	107	2118	1. 8.6% 2. 573.0
383	143	2119	1. 3.2% 2. 497.0
384	135	2120	1. 36% 2. 529.0
385	130	2121	1. 33% 2. 506.1
387	145	2122	1. 27% 2. 449.1
388	140	2123	1. 25% 2. 477.0
389	98	2124	1. 66% 2. 542.1
390	96	2125	1. 60% 2. 545.0
391	97	2126	1. 66% 2. 540.1
392	100	2127	1. 47% 2. 512.1
393	99	2128	1. 60% 2. 528.1

Examples 394-404.4

[1394] 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.

			1. Yield (%)
	Prep Ex.		2. MH+
Ex.	of Amine	Product	3. mp (° C.)
394	147	2129	1. 64% 2. 358.1 3. 137
395	148	2130	1. 23% 2. 372.1 3. 126
396	149	2131	1. 94% 2. 386.1 3. 108
397	150	2132	1. 86% 2. 386.1 3. 134
398	146	2133	1. 87% 2. 420.1 3. 136
399	151	2134	1. 84% 2. 434.1 3. 129
400	152	2135	1. 90% 2. 372.1 3. 154
401	153	2136	1. 86% 2. 386.1 3. 156
402	154	2137	1. 90% 2. 400.1 3. 153
403	155	2138	1. 91 2. 400.1 3. 153
404	156	2139	1. 83% 2. 448.1 3. 138
404.1	2140	2141	1. 30% 2. 426.1 3. 132
404.2	2142	2143	1. 74% 2. 412.1 3. 127
404.3	2144	2145	1. 73.4% 2. 372.1 3. 128
404.4	2146	2147	1. 72% 2. 372.1 3. 128

Example 405

[1395] 2148

[1396] 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

[1397] 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.

	Prep Ex of	Prep Ex of
Ex.	Amine	Squarate	Product
1101	15	87	2149
1102	15	88	2150
1103	16	87	2151
1104	16	88	2152
1105	17	87	2153
1106	17	88	2154
1107	18	87	2155
1108	18	88	2156
1109	157	87	2157
1110	157	88	2158
1111	158	87	2159
1112	158	88	2160
1112.1	500.3 or 500.4	88.1	2161
1112.2	500.1 or 500.2	88.1	2162
1112.3	500.0	19	2163
1112.4	75.9	23.11	2164
1112.5	10.19	88.4	2165
1112.6	75.44	23.14	2166
1112.7	75.49	23.14	2167
1112.8	75.50	23.14	2168
1112.9	75.44	500.6	2169
1112.10	75.49	500.6	2170

Examples 1120.1-1120.12

[1398] 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.

		Prep Ex		1. Yield (%)
	Prep Ex of	of		2. MH+
Ex.	Amine	Squarate	Product	3. mp (° C.)
1120.1	156.16	87	2171	1. 9% 2. 393.1 3. 154-158
1120.2	2172	88.1	2173	1. 55% 2. 355.1 3. 199-201
1120.3	156.12	88.1	2174	1. 37% 2. 355.1 3. 210-213
1120.4	2175	88.1	2176	1. 30% 2. 391.1 3. 70-73
1120.5	156.14	88.1	2177	1. 73% 2. 466 3. 105-108
1120.6	2178	88.1	2179	1. 21% 2. 391 3. 79-82
1120.7	2180	88.1	2181	1. 15% 2. 369 3. 167-170
1120.8	2182	88.1	2183	1. 47% 2. 354 3. 121-124
1120.9	2184	88.1	2185	1. 15% 2. 356 3. 200-202
1120.10	2186	88.1	2187	1. 25% 2. 468 3. 154-156
1120.11	156.13	88.1	2188	1. 57% 2. 404 3. 92-94
1120.12	156.15	88.1	2189	1. 61% 2. 351 3. 155-157

Example 1125

[1399] 2190 2191

[1400] Step A

[1401] 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.

[1402] Step B

[1403] 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.

[1404] Step C

[1405] 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.

[1406] Step D

[1407] 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.

[1408] Step E

[1409] 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.

[1410] Step F

[1411] 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.

[1412] Step G

[1413] 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

[1414] 2192

[1415] Step A

[1416] 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 2193

[1417] Step B

[1418] 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

[1419] 2194 2195

[1420] Step A

[1421] 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).

[1422] Step B

[1423] 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).

[1424] Step C

[1425] 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 wahed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.96 g of the desired hydroxy-compound.

[1426] Step D

[1427] 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 addjusted to pH˜5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with brine, dried over sodium sulfate, and filtered through a celite pad. The filtrate was concentrated in vacuo to afford 4.2 g of the desired bromo-compound.

[1428] Step E

[1429] 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.

[1430] Step F

[1431] 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.

[1432] Step G

[1433] 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.

[1434] Step H

[1435] 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-MeOH=15:1, v/v) to give 91 mg of the desired product.

[1436] Step I

[1437] 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).

[1438] While the present invention has been described in conjunction with specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A compound of the formula:

2. The compound of claim 1 wherein B is selected from the group consisting of:

3. The compound of claim 1 wherein B is:

4. The compound of claim 1 wherein B is:

5. The compound of claim 1 wherein B is:

6. The compound of claim 1 wherein B is

7. The compound of claim 1 wherein B is:

8. The compound of claim 1 wherein B is

9. The compound of claim 1 wherein B is

10. The compound of claim 1 wherein B is

11. The compound of claim 10 wherein R2 is —OH.

12. The compound of claim 10 wherein R13 and R14 are the same or different alkyl group.

13. The compound of claim 12 wherein the R2 substituent is —OH.

14. The compound of claim 12 wherein R13 and R14 methyl.

15. The compound of claim 14 wherein the R2 substituent is —OH.

16. The compound of claim 1 wherein B is selected from the group consisting of:

17. The compound of claim 1 wherein B is

18. The compound of claim 17 wherein R11 is H.

19. The compound of claim 17 wherein R2 is —OH.

20. The compound of claim 17 wherein R3 is —C(O)NR13R14.

21. The compound of claim 17 wherein R2 is —OH and R3 is —C(O)NR13R14.

22. The compound of claim 17 wherein R2 is —OH, R3 is —C(O)NR13R14, and R11 is H.

23. The compound of claim 22 wherein R13 and R14 are each independently is selected from the group consisting of: alkyl, unsubstituted heteroaryl and substituted heteroaryl.

24. The compound of claim 17 wherein R3 is —S(O)tNR3R14.

25. The compound of claim 24 wherein R2 is —OH.

26. The compound of claim 25 wherein the R13 and R14 substituents are the same or different alkyl group.

27. The compound of claim 1 wherein B is

28. The compound of claim 1 wherein B is

29. The compound of claim 1 wherein A is

30. The compound of claim 1 wherein A is

31. The compound of claim 1 wherein A is

32. The compound of claim 29 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

33. The compound of claim 32 wherein R7 is H, and R8 is alkyl.

34. The compound of claim 31 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

35. The compound of claim 34 wherein R7 is H, and R8 is alkyl.

36. The compound of claim 1 wherein A is selected from the group consisting of:

37. The compound of claim 4 wherein A is

38. The compound of claim 4 wherein A is

39. The compound of claim 38 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

40. The compound of claim 39 wherein R7 is H and R8 is alkyl.

41. The compound of claim 5 wherein A is

42. The compound of claim 4 wherein A is

43. The compound of claim 42 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

44. The compound of claim 43 wherein R7 is H and R8 is alkyl.

45. The compound of claim 10 wherein A is

46. The compound of claim 10 wherein A is

47. The compound of claim 46 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

48. The compound of claim 47 wherein R7 is H and R8 is alkyl.

49. The compound of claim 11 wherein A is

50. The compound of claim 11 wherein A is

51. The compound of claim 50 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

52. The compound of claim 51 wherein R7 is H and R8 is alkyl.

53. The compound of claim 13 wherein A is

54. The compound of claim 13 wherein A is

55. The compound of claim 54 wherein R7 and R8 are independently selected from the group consisting of: H and alkyl.

56. The compound of claim 55 wherein R7 is H and R8 is alkyl.

57. The compound of claim 1 wherein: (1) A is selected from the group consisting of: 2240wherein 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 2241wherein 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; (2) B is selected from the group consisting of: 2242wherein: R2 is selected from the group consisting of: H, OH, —NHC(O)R13 and —NHSO2R13; R3 is selected from the group consisting of: —C(O)NR13R14—SO2NR13R14, —NO2, cyano, and —SO2R13; R4 is selected from the group consisting of: H, —NO2, cyano, —CH3 or —CF3; R5 is selected from the group consisting of: H, —CF3, —NO2, halogen and cyano; and R6 is selected from the group consisting of: H, alkyl and —CF3; R11 is selected from the group consisting of: H, halogen and alkyl; and each R13 and R14 is independently selected from the group consisting of: methyl and ethyl.

58. The compound of claim 1 wherein (1) A is selected from the group consisting of: 2243(2) B is selected from the group consisting of: 2244wherein: R2 is —OH; R3 is selected from the group consisting of: —SO2NR13R14 and —CONR13R14; R4 is selected form the group consisting of: H, —CH3 and —CF3; R5 is selected from the group consisting of: H and cyano; R6 is selected from the group consisting of: H, —CH3 and —CF3; R11 is H; and R13 and R14 are methyl.

59. The compound of claim 1 wherein said compound is a calcium salt.

60. The compound of claim 1 wherein said compound is a sodium salt.

61. The compound of claim 1 wherein said compound is selected from the group consisting of:

62. The compound of claim 1 selected from the group consisting of:

63. The compound of claim 1 selected from the group consisting of:

64. The compound of claim 1 selected from the group consisting of:

65. The compound of claim 64 wherein said compound is a calcium or sodium salt.

66. The compound of claim 1 wherein said compound is:

67. The compound of claim 1 wherein said compound is:

68. The compound of claim 1 wherein said compound is:

69. The compound of claim 1 wherein said compound is:

70. The compound of claim 1 wherein said compound is:

71. The compound of claim 1 wherein said compound is:

72. The compound of claim 1 wherein said compound is:

73. The compound of claim 1 wherein said compound is:

74. The compound of claim 1 wherein said compound is:

75. The compound of claim 1 wherein said compound is:

76. The compound of claim 1 wherein said compound is:

77. The compound of claim 1 wherein said compound is:

78. The compound of claim 1 wherein said compound is:

79. The compound of claim 1 wherein said compound is:

80. The compound of claim 1 wherein said compound is:

81. The compound of claim 76 wherein said compound is a calcium or sodium salt.

82. A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in said patient, comprising administering to said patient an effective amount of at least one compound of claim 1.

83. A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXC receptor in said patient, comprising administering to said patient an effective amount of at least one compound of claim 1.

84. The method of claim 82 wherein the chemokine mediated disease is selected from the group consisting of psoriasis, atopic dermatitis, acne, asthma, chronic obstructive pulmonary disease, 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 or thrombosis, Alzheimer's disease, graft vs. host reaction, allograft rejections, cystic fibrosis, malaria, acute respiratory distress syndrome, delayted type hypersensitivity reaction, atherosclerosis and cerebral and cardiac ischemia.

85. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1.

86. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1 in combination with the administration of at least one anticancer agent.

87. The method of claim 86 wherein said anticancer agent is selected from the group consisting of: alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids, and synthetics.

88. 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 claim 1.

89. 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 claim 1 in combination with the administration an effective amount of at least one anti-angiogenesis compound.

90. 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 claim 1.

91. The method of claim 82 wherein the chemokine mediated disease is an angiogenic ocular disease.

92. The method of claim 91 wherein said angiogenic ocular disease is selected from the group consisting of: ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization.

93. The method of claim 85 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.

94. The method of claim 86 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.

95. The method of claim 87, wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.

96. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

97. The compound of claim 1 wherein said compound is:

98. A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in said patient, comprising administering to said patient an effective amount of at least one compound of formula IA:

99. The method of claim 98 wherein the chemokine mediated disease is selected from the group consisting of psoriasis, atopic dermatitis, acne, asthma, chronic obstructive pulmonary disease, 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 or thrombosis, Alzheimer's disease, graft vs. host reaction, allograft rejections, cystic fibrosis, malaria, acute respiratory distress syndrome, delayted type hypersensitivity reaction, atherosclerosis and cerebral and cardiac ischemia.

100. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of formula IA:

101. The method of claim 100 wherein said compound of formula IA is administered in combination with the administration of at least one anticancer agent.

102. The method of claim 101 wherein said anticancer agent is selected from the group consisting of: alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids, and synthetics.

103. 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:

104. The method of claim 103 wherein said compound of formula IA is administered in combination with the administration an effective amount of at least one anti-angiogenesis compound.

105. 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:

106. The method of claim 98 wherein the chemokine mediated disease is an angiogenic ocular disease.

107. The method of claim 106 wherein said angiogenic ocular disease is selected from the group consisting of: ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization.

108. The method of claim 100 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.

109. The method of claim 101 wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.

110. The method of claim 102, wherein the cancer treated is melanoma, gastric carcinoma, or non-small cell lung carcinoma.

111. The compound of claim 1 selected from the group consisting of the final compounds of Examples 1 to 1131.