Acyclic and cyclic amine derivatives

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to acyclic and cyclic amine derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.

BACKGROUND OF THE INVENTION

[0003] Neurological diseases are associated with the death of or injury to neuronal cells. Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death. A more recent approach involves the promotion of nerve regeneration by promoting neuronal growth.

[0004] Neuronal growth, which is critical for the survival of neurons, is stimulated in vitro by nerve growth factors (NGF). For example, Glial Cell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of Parkinson's disease. Insulin and insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PC12 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al., J. Neurosci., 6, pp. 1211-1219 (1986)]. Insulin and insulin-like growth factors also stimulate the regeneration of injured motor nerves in vivo and in vitro [Near et al., Proc. Natl. Acad. Sci., pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al., Cell Differ., 19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine Cytokine Res., 12, p. 135 (1993)].

[0005] There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma and they have poor drug delivery properties.

[0006] Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neuronal growth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique Toran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp. 169-78 (1996); and B. S. McEwen et al., Brain Res. Dev. Brain. Res., 87, pp. 91-95 (1995)]. The progress of Alzheimer's disease is slowed in women who take estrogen. Estrogen is hypothesized to complement NGF and other neurotrophins and thereby help neurons differentiate and survive.

[0007] Other target sites for the treatment of neurodegenerative disease are the immunophilin class of proteins. Immunophilins are a family of soluble proteins that mediate the actions of immunosuppressant drugs such as cyclosporin A, FK506 and rapamycin. Of particular interest is the 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 binds FK-506 and rapamycin, leading to an inhibition of T-cell activation and proliferation. Interestingly, the mechanism of action of FK-506 and rapamycin are different. For a review, see, S. H. Solomon et al., Nature Med., 1, pp. 32-37 (1995). It has been reported that compounds with an affinity for FKBP12 that inhibit that protein's rotomase activity possess nerve growth stimulatory activity. [Lyons et al., Proc. Natl. Acad. Sci. USA, 91, pp. 3191-3195 (1994)]. Many of these such compounds also have immunosuppressive activity.

[0008] FK506 (Tacrolimus) has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al. (1994)]. This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [B. Gold et al., J. Neurosci., 15, pp. 7509-16 (1995)].

[0009] The use of immunosuppressive compounds, however, has drawbacks in that prolonged treatment with these compounds can cause nephrotoxicity [Kopp et al., J. Am. Soc. Nephrol., 1, p. 162 (1991)], neurological deficits [P. C. DeGroen et al., N. Eng. J. Med., 317, p. 861 (1987)] and vascular hypertension [Kahan et al., N. Eng. J. Med., 321, p. 1725 (1989)].

[0010] More recently, sub-classes of FKBP binding compounds which inhibit rotomase activity, but which purportedly lack immunosuppressive function have been disclosed for use in stimulating nerve growth [see, U.S. Pat. No. 5,614,547; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner et al., Proc. Natl. Acad. Sci. USA, 94, pp. 2019-23 (1997); and G. S. Hamilton et al., Bioorg. Med. Chem. Lett., 7, pp. 1785-90 (1997)].

[0011] Stimulation of neural axons in nerve cells by piperidine derivatives is described in WO 96/41609. Clinical use of the piperidine and pyrrolidine derivatives known so far for stimulating axonal growth has not been promising, as the compounds are unstable in plasma and do not pass the blood-brain barrier in adequate amounts.

[0012] Though a wide variety of neurological degenerative diseases may be treated by promoting repair of neuronal damage, there are relatively few agents known to possess these properties. Thus, there remains a need for new compounds and compositions that have the ability to either prevent or treat neuronal damage associated with neuropathologic disorders.

SUMMARY OF THE INVENTION

[0013] The invention provides compounds of formula

[0014] and pharmaceutically acceptable derivatives thereof, wherein:

[0015] X is selected from —CH2CH2—, —CH═CH—, —C(OH)CH2—, —CH2C(OH)—, ═C(F)CH2—, —C(F)═CH2—, —NHC(O)—, —P(O)(OH)CH2—, —CH2S(O)2—, —C(S)NR1—, —C(O)CH2CH(OH)—, —C(OH)CF2—, —C(O)CF2—, —CH(F)CH2—, —C(F)2CH2—, —CH2CH(F)—, —CH2C(F)2—

[0016] A, B and R1 are independently E, (C1-C10)-straight or branched alkyl, (C2-C10)-straight or branched alkenyl or alkynyl, or (C5-C7)-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (C5-C7)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the —CH2— groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O)2—, ═N—, —N═ or —N(R3)—;

[0017] or, B and R1 are independently hydrogen;

[0018] R3 is hydrogen, (C1-C4)-straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R3 is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused;

[0019] E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R3), O, S, S(O), or S(O)2; and wherein no more than 4 ring atoms are selected from N, N(R3), O, S, S(O), or S(O)2;

[0020] wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O—[(C1-C6)-straight or branched alkyl], O—[(C3-C6)-straight or branched alkenyl], (CH2)n—N(R4)(R5), (CH2)n—NH(R4)—(CH2)n—Z, (CH2)n—N(R4—(CH2)n—Z)(R5—(CH2)n—Z), (CH2)n—Z, O—(CH2)n—Z, (CH2)n—O—Z, S—(CH2)n—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C1C6)-straight or branched alkyl], C(O)O—(CH2)n—Z or C(O)—N(R4)(R5);

[0021] each of R4 and R5 are independently hydrogen, (C1-C6)-straight or branched alkyl, (C3-C5)-straight or branched alkenyl, or wherein R4 and R5, when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, N(R3), O, S, S(O), or S(O)2; wherein said alkyl, alkenyl or alkynyl groups in R4 and R5 are optionally substituted with Z.

[0022] each n is independently 0 to 4;

[0023] each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R3), O, S, S(O), or S(O)2; and wherein no more than 4 ring atoms are selected from N, N(R3), O, S, S(O), or S(O)2;

[0024] wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C1-C3)-straight or branched alkyl, O—(C1-C3)-straight or branched alkyl, C(O)O—[(C1-C3)-straight or branched alkyl], amino, NH[(C1-C3)-straight or branched alkyl], or N—[(C1-C3)-straight or branched alkyl]2;

[0025] J is H, methyl, ethyl or benzyl;

[0026] K and K1 are independently selected from (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E;

[0027] wherein K and K1 are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O—(C1-C6)-alkyl, O—(CH2)n-Z, NO2, C(O)OH, C(O)—O—(C1-C6)-alkyl, C(O)NR4R5, NR4R5 and (CH2)n—Z; or,

[0028] J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R3), O, S, S(O), or S(O)2, wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH2— group in said alkyl, alkenyl or alkynyl substituent is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O2)—, ═N—, —N═, or —N(R3)—; and wherein said heterocyclic ring is optionally fused with E;

[0029] G, when present, is —S(O)2—, —C(O)—, —S (O)2—Y—, —C(O)—Y—, —C(O)—C(O)—, or —C(O)—C(O)—Y—;

[0030] Y is oxygen, or N(R6);

[0031] wherein R6 is hydrogen, E, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl; or wherein R6 and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, N(R3), SO, or SO2; and wherein said ring is optionally benzofused;

[0032] D is hydrogen, (C1-C7)-straight or branched alkyl, (C2-C7)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl or cycloalkenyl optionally substituted with (C1-C6)-straight or branched alkyl or (C2-C7)-straight or branched alkenyl or alkynyl, [(C1-C7)-alkyl]-E, [(C2-C7)-alkenyl or alkynyl]-E, or E;

[0033] wherein 1 to 2 of the CH2 groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by —O—, —S—, —S(O)—, —S(O2)—, ═N—, —N═, or —N(R3);

[0034] provided that when J is hydrogen or G is selected from —S(O)2—, C(O)C(O)—, SO2—Y, C(O)—Y, or C(O)C(O)—Y, wherein Y is O; then D is not hydrogen; and

[0035] x is 0 or 1.

[0036] In another embodiment, the invention provides pharmaceutical compositions comprising the compounds of formula (I). These compositions may be utilized in methods treating various neurological diseases which are influenced by neuronal regeneration and axon growth or for stimulating neuronal regeneration in an ex vivo nerve cell. Examples of such diseases include peripheral nerve destruction due to physical injury or diseases such as diabetes; physical injuries to the central nervous system (e.g., brain or spinal cord); stroke; neurological disturbances due to nerve degeneration, such as Parkinson's disease, Alzheimer's disease, and amylotrophic lateral sclerosis.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The invention provides compounds of formula (I):

[0038] and pharmaceutically acceptable derivatives thereof, wherein:

[0039] X is selected from —CH2CH2—, —CH═CH—, —C(OH)CH2—, —CH2C(OH)—, ═C(F)CH2—, —C(F)═CH2—, —NHC(O)—, —P(O)(OH)CH2—, —CH2S(O)2—, —C(S)NR1—, —C(O)CH2CH(OH)—, —C(OH)CF2—, —C(O)CF2—, —CH(F)CH2—, —C(F)2CH2—, —CH2CH(F)—, —CH2C(F)2—,

[0040] A, B and R1 are independently E, (C1-C10)-straight or branched alkyl, (C2-C10)-straight or branched alkenyl or alkynyl, or (C5-C7)-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (C5-C7)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the —CH2— groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O)2—, ═N—, —N═ or —N(R3)—;

[0041] or, B and R1 are independently hydrogen;

[0042] R3 is hydrogen, (C1-C4)-straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R3 is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused;

[0043] E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N (R3), O, S, S(O), or S(O)2; and wherein no more than 4 ring atoms are selected from N, N(R3), O, S, S(O), or S(O)2;

[0044] wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O—[(C1-C6)-straight or branched alkyl], O—[(C3-C6)-straight or branched alkenyl], (CH2)n—N(R4)(R5), (CH2)n—NH(R4)—(CH2)n—Z, (CH2)n—N(R4—(CH2)n—Z)(R5—(CH2)n—Z), (CH2)n—Z, O—(CH2)n—Z, (CH2)n—O—Z, S—(CH2)n—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C1-C6)-straight or branched alkyl], C(O)O—(CH2)n—Z or C(O)—N(R4)(R5);

[0045] each of R4 and R5 are independently hydrogen, (C1-C6)-straight or branched alkyl, (C3-C5)-straight or branched alkenyl, or wherein R4 and R5, when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, N(R3), O, S, S(O), or S(O)2; wherein said alkyl, alkenyl or alkynyl groups in R4 and R5 are optionally substituted with Z.

[0046] each n is independently 0 to 4;

[0047] each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R3), O, S, S(O), or S(O)2; and wherein no more than 4 ring atoms are selected from N, N(R3), O, S, S(O), or S(O)2;

[0048] wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C1-C3)-straight or branched alkyl, O—(C1-C3)-straight or branched alkyl, C(O)O—[(C1-C3)-straight or branched alkyl], amino, NH[(C1-C3)-straight or branched alkyl], or N—[(C1-C3)-straight or branched alkyl]2;

[0049] J is H, methyl, ethyl or benzyl;

[0050] K and K1 are independently selected from (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E;

[0051] wherein K and K1 are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O—(C1-C6)-alkyl, O—(CH2)n-Z, NO2, C(O)OH, C(O)—O—(C1-C6)-alkyl, C(O)NR4R5, NR4R5 and (CH2)n—Z; or,

[0052] J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R3), O, S, S(O), or S(O)2, wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH2— group in said alkyl, alkenyl or alkynyl substituent is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O2)—, ═N—, —N═, or —N(R3)—; and wherein said heterocyclic ring is optionally fused with E;

[0053] G, when present, is —S(O)2—, —C(O)—, —S(O)2—Y—, —C(O)—Y—, —C(O)—C(O)—, or —C(O)—C(O)—Y—;

[0054] Y is oxygen, or N(R6);

[0055] wherein R6 is hydrogen, E, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl; or wherein R6 and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, N(R3), SO, or SO2; and wherein said ring is optionally benzofused;

[0056] D is hydrogen, (C1-C7)-straight or branched alkyl, (C2-C7)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl or cycloalkenyl optionally substituted with (Cl-C6)-straight or branched alkyl or (C2-C7)-straight or branched alkenyl or alkynyl, [(C1-C7)-alkyl]-E, [(C2-C7)-alkenyl or alkynyl]-E, or E;

[0057] wherein 1 to 2 of the CH2 groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by —O—, —S—, —S(O)—, —S(O2)—, ═N—, —N═, or —N(R3);

[0058] provided that when J is hydrogen or G is selected from —S (O)2—, C(O)C(O)SO2—Y, C(O)—Y, or C(O)C(O)—Y, wherein Y is O; then D is not hydrogen; and

[0059] x is 0 or 1.

[0060] According to a preferred embodiment, each of A and B in formula (I) is (C1-C10) straight or branched alkyl, wherein 1-2 hydrogen atoms in said alkyl are optionally substituted with E.

[0061] In another preferred embodiment, B is hydrogen.

[0062] According to another preferred embodiment, each of A and B in formula (I) is —CH2—CH2—E or —CH2—CH2—CH2—E.

[0063] According to another preferred embodiment, D in formula (I) is (C1-C7) straight or branched alkyl, E or [(C1-C6)-straight or branched alkyl]-E.

[0064] According to a more preferred embodiment, D is an aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5-7 ring atoms independently selected from C, N, O or S, and wherein no more than 4 ring atoms are selected from N, O or S.

[0065] According to an even more preferred embodiment, D is phenyl or C1-C7straight or branched alkyl group.

[0066] According to another preferred embodiment, E in formula (I) is a monocyclic or bicyclic aromatic ring system, wherein said ring comprises 5-7 ring atoms independently selected from C, N, N(R3), O, S, S(O), or S(O)2, and wherein 1 to 4 ring atoms are independently selected from N, N(R3), O, S, S(O), or S(O)2.

[0067] Preferred embodiments of E include phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-trazinyl, 1,3,5-trithianyl, benzo[b]furanyl, benzo[b]thiophenyl, purinyl, cinnolinyl, phthalazinyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolinyl, indolizinyl, isoindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phnazinyl, phenothiazinyl, phenoxazinyl and benzothiazolyl, wherein E is optionally substituted as described above.

[0068] More preferred embodiments of E include phenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, and benzothiazolyl, wherein E is optionally substituted as described above.

[0069] According to another preferred embodiment, J is H, methyl, ethyl or benzyl; and

[0070] K is selected from (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E.

[0071] According to another preferred embodiment, J and K, taken together with the nitrogen atom, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R3), O, S, S(O), or S(O)2, wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH2— group said heterocyclic ring is optionally and independently replaced by —O—, —S—, —S(O)—, —S (O2)—, ═N—, —N═, or —N(R3)—; and wherein said heterocyclic ring is optionally fused with E.

[0072] According to yet another preferred embodiment, X is selected from —CH2CH2—, —CH═CH—, —C(OH)CH2—, —CH2C(OH)—, —C(F)═CH2—, —CH2S(O)2—, —C(S)NR1—, —C(O)CH2CH(OH)—, —C(OH)CF2—, —C(O)CF2—, —CH(F)CH2—, —C(F)2CH2—, —CH2CH(F)—, —CH2C(F)2—, or

[0073] The compounds of formula (I) may be stereoisomers, geometric isomers or stable tautomers. The invention envisions all possible isomers, such as E and Z isomers, S and R enantiomers, diastereoisomers, racemates, and mixtures of those. It is preferred that the substituent in the 2 position have the S configuration.

[0074] The compounds of the present invention may be readily prepared using known synthetic methods. For synthetic methods for the preparation of X, which are amide bond bioisosteres see: “Peptidomimetics Protocols” in Methods on Molecular Medicine, Vol 30, 1999, Humana Press, Totowa New Jersey, Kazmierski, W. M., Ed.

[0075] Examples of synthetic schemes that may be used to produce the compounds of this invention are set forth in Schemes 1 through 6 below.

[0076] a=p-toluenesulfonyl chloride; diisopropylethylamine and CH2Cl2; b=NaI and acetone; followed by PPh3 and toluene; c=NaH, and THF; followed by

[0077] Pd/C, H2 gas, and MeOH; e=HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH2)x—Br, K2CO3 and DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C(O), wherein X is 0 or 1.

[0078] HOBT, EDC, and CH2Cl2; b=Lawesson's reagent and toluene; c=HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH2)x—Br, K2CO3 and DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C(O), wherein X is 0 or 1. C(H2)x—Br, K2CO3 and DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C(O), wherein X is 0 or 1.

[0079] a=H2NNH2.H2O, and ethanol; b=NaNO2, acetic acid, and H2O; c=HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH2)x—Br, K2CO3 and DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C(O), wherein X is 0 or 1.

[0080] a=N,O-dimethylhydroxylamine hydrochloride, EDC, diisopropylethylamine, and CH2Cl2; b=3-(trimethylsilyl)propargyl magnesium bromide and THF; c=BU4NF/THF; d=aryl halide (Br or I), (Ph3P)4Pd(O), Et3N, and THF; e=5% Pd/C, H2 (1 atm), and MeOH; f=Et2N—SF3, and CH2Cl2; g=NaBH4, and MeOH, when X′═CH(OH) or DAST, and CH2Cl2, when X═CHF; h=HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH2)x—Br, K2CO3 and DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C(O), wherein x is 0 or 1; z=0 or 1; and X′═—C(O)—, —CH(OH)— or —CHF—.

[0081] a=NaH and THF; followed by aldehyde derivative; b=NBS, Bu4NF/HF, and CH2Cl2; followed by KOtBu, and Et2O; c=TMSI, and CH3CN; followed by (CH2)x—Br, K2CO3 DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C (Q), wherein x is 0 or 1.

[0082] a=N,O-dimethylhydroxylamine hydrochloride, EDC, diisopropylethylamine, and CH2Cl2;

[0083] and THF; c=Et2N—SF3, and CH2Cl2; d=NaBH4, and MeOH, when X′═CH(OH), or DAST and CH2Cl2, when X═CHF; e=HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH2)x—Br, K2CO3 and DMF if (G)x═(CH2)x; or D—C(O)—Cl, diisopropylethylamine, and CH2Cl2 if (G)x═—C(O), wherein x is 0 or 1; z=0 or 1; and X′═—C(O)—, —CH(OH)— or —CHF—.

[0084] One of skill in the art will also be well aware of analogous synthetic methods for preparing compounds of formula (I).

[0085] According to another embodiment, this invention provides compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0086] Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxy methylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0087] In another embodiment, the pharmaceutical composition of the present invention is comprised of a compound of formula (I), a pharmaceutically acceptable carrier, and a neurotrophic factor.

[0088] The term “neurotrophic factor,” as used herein, refers to compounds which are capable of stimulating growth or proliferation of nervous tissue. Numerous neurotrophic factors have been identified in the art and any of those factors may be utilized in the compositions of this invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives such as gIGF-1 and Des(1-3)IGF-I, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in the compositions of this invention is NGF.

[0089] As used herein, the described compounds used in the pharmaceutical compositions and methods of this invention, are defined to include pharmaceutically acceptable derivatives thereof. A “pharmaceutically acceptable derivative” denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote repair or prevent damage of neurons from disease or physical trauma.

[0090] If pharmaceutically acceptable salts of the described compounds are used, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

[0091] The described compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0092] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0093] Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.

[0094] The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0095] Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0096] The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0097] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0098] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0099] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0100] The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[0101] The amount of both a described compound and the optional neurotrophic factor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the described compound can be administered. If a neurotrophic factor is present in the composition, then a dosage of between 0.01 μg-100 mg/kg body weight/day of the neurotrophic factor can be administered to a patient receiving these compositions.

[0102] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredients will also depend upon the particular described compound and neurotrophic factor in the composition.

[0103] According to another embodiment, this invention provides methods for promoting repair or preventing neuronal damage or neurodegeneration in vivo or in an ex vivo nerve cell. Such methods comprise the step of treating nerve cells with any of the compounds described above. Preferably, this method promotes repair or prevents neuronal damage or neurodegeneration in a patient, and the compound is formulated into a composition additionally comprising a pharmaceutically acceptable carrier. The amount of the compound utilized in these methods is between about 0.01 and 100 mg/kg body weight/day.

[0104] According to an alternate embodiment, the method of promoting repair or preventing neuronal damage or neurodegeneration comprises the additional step of treating nerve cells with a neurotrophic factor, such as those contained in the pharmaceutical compositions of this invention. This embodiment includes administering the compound and the neurotrophic agent in a single dosage form or in separate, multiple dosage forms. If separate dosage forms are utilized, they may be administered concurrently, consecutively or within less than about 5 hours of one another.

[0105] Preferably, the methods of this invention are used to stimulate axonal growth in nerve cells. The compounds are, therefore, suitable for treating or preventing neuronal damage caused by a wide variety of diseases or physical traumas. These include, but are not limited to, Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, Tourette's syndrome, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, spinal cord injuries and facial nerve crush.

[0106] In a particularly preferred embodiment of the invention, the method is used to treat a patient suffering from trigeminal neuralgia, glosspharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome's, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, such as those caused by lead, dapsone, ticks, or porphyria, other peripheral myelin disorders, Alzheimer's disease, Gullain-Barre syndrome, Parkinson's disease and other Parkinsonian disorders, ALS, Tourette's syndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, neuropathy associated with diabetes, spinal cord injuries, facial nerve crush and other trauma, chemotherapy- and other medication-induced neuropathies, and Huntington's disease.

[0107] More preferably, the compositions of the present invention are used for treating Parkinson's disease, amylotrophic lateral sclerosis, Alzheimer's disease, stroke, neuralgias, muscular atrophies, and Guillain-Barré syndrome.

[0108] For use of the compounds according to the invention as medications, they are administered in the form of a pharmaceutical preparation containing not only the active ingredient but also carriers, auxiliary substances, and/or additives suitable for enteric or parenteral administration. Administration can be oral or sublingual as a solid in the form of capsules or tablets, as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions, or rectal in the form of suppositories, or in the form of solutions for injection which can be given subcutaneously, intramuscularly, or intravenously, or which can be given topically or intrathecally. Auxiliary substances for the desired medicinal formulation include the inert organic and inorganic carriers known to those skilled in the art, such as water, gelatin, gum arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The medicinal formulations may also contain preservatives, stabilizers, wetting agents, emulsifiers, or salts to change the osmotic pressure or as buffers.

[0109] Solutions or suspensions for injection are suitable for parenteral administration, and especially aqueous solutions of the active compounds in polyhydroxy-ethoxylated castor oil.

[0110] Surface-active auxiliary substances such as salts of gallic acid, animal or vegetable phospholipids, or mixtures of them, and liposomes or their components, can be used as carrier systems.

[0111] The neurotrophic effect of the compounds of formula (I) of the present invention and their physiologically acceptable salts can be determined by the methods of W. E. Lyons et al., Proc. Natl. Acad. Sci. USA, Vol. 91, pp. 3191-3195 (1994) and W. E. Lyons et al., Proc. Natl. Acad. Sci. USA, Vol. 91, pages 3191-3195 (1994), the disclosures of which are herein incorporated by reference.

[0112] In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLE 1

Compounds 100-295

[0113] Compounds 101-296 are synthesized via the method set forth in Scheme 1, above. In all of the examples, “Ph” is phenyl.

[0114] Compounds 100-148 have the formula:

[0115] with the individual variables defined in the table below.

1Cmpd #

—(G)x—D100

—CH3101Same as above—CH2CH3102Same as above—C(═O)—CH3103Same as above—CH2—Ph104Same as above—C(═O)—Ph105Same as above—C(═O)—O—CH2—Ph106Same as above—C(═O)—C(═O)—Ph107

—CH3108Same as above—CH2CH3109Same as above—C(═O)—CH3110Same as above—CH2—Ph111Same as above—C(═O)—Ph112Same as above—C(═O)—O—CH2—Ph113Same as above—C(═O)—C(═O)—Ph114

—CH3115Same as above—CH2CH3116Same as above—C(═O)—CH3117Same as above—CH2—Ph118Same as above—C(═O)—Ph119Same as above—C(═O)—O—CH2—Ph120Same as above—C(═O)—C(═O)—Ph121

—CH3122Same as above—CH2CH3123Same as above—C(═O)—CH3124Same as above—CH2—Ph125Same as above—C(═O)—Ph126Same as above—C(═O)—O—CH2—Ph127Same as above—C(═O)—C(═O)—Ph128

—CH3129Same as above—CH2CH3130Same as above—C(═O)—CH3131Same as above—CH2—Ph132Same as above—C(═O)—Ph133Same as above—C(═O)—O—CH2—Ph134Same as above—C(═O)—C(═O)—Ph135

—CH3136Same as above—CH2CH3137Same as above—C(═O)—CH3138Same as above—CH2—Ph139Same as above—C(═O)—Ph140Same as above—C(═O)—O—CH2—Ph141Same as above—C(═O)—C(═O)—Ph142

—CH3143Same as above—CH2CH3144Same as above—C(═O)—CH3145Same as above—CH2—Ph146Same as above—C(═O)—Ph147Same as above—C(═O)—O—CH2—Ph148Same as above—C(═O)—C(═O)—Ph

[0116] Compounds 149-197 have the formula:

[0117] with the individual variables defined in the table below.

2Cmpd #

—(G)x—D149

—CH3150Same as above—CH2CH3151Same as above—C(═O)—CH3152Same as above—CH2—Ph153Same as above—C(═O)—Ph154Same as above—C(═O)—O—CH2—Ph155Same as above—C(═O)—C(═O)—Ph156

—CH3157Same as above—CH2CH3158Same as above—C(═O)—CH3159Same as above—CH2—Ph160Same as above—C(═O)—Ph161Same as above—C(═O)—O—CH2—Ph162Same as above—C(═O)—C(═O)—Ph163

—CH3164Same as above—CH2CH3165Same as above—C(═O)—CH3166Same as above—CH2—Ph167Same as above—C(═O)—Ph168Same as above—C(═O)—O—CH2—Ph169Same as above—C(═O)—C(═O)—Ph170

—CH3171Same as above—CH2CH3172Same as above—C(═O)—CH3173Same as above—CH2—Ph174Same as above—C(═O)—Ph175Same as above—C(═O)—O—CH2—Ph176Same as above—C(═O)—C(═O)—Ph177

—CH3178Same as above—CH2CH3179Same as above—C(═O)—CH3180Same as above—CH2—Ph181Same as above—C(═O)—Ph182Same as above—C(═O)—O—CH2—Ph183Same as above—C(═O)—C(═O)—Ph184

—CH3185Same as above—CH2CH3186Same as above—C(═O)—CH3187Same as above—CH2—Ph188Same as above—C(═O)—Ph189Same as above—C(═O)—O—CH2—Ph190Same as above—C(═O)—C(═O)—Ph191

—CH3192Same as above—CH2CH3193Same as above—C(═O)—CH3194Same as above—CH2—Ph195Same as above—C(═O)—Ph196Same as above—C(═O)—O—CH2—Ph197Same as above—C(═O)—C(═O)—Ph

[0118] Compounds 198-246 have the formula:

[0119] with the individual variables defined in the table below.

3Cmpd #

—(G)x—D198

—CH3199Same as above—CH2CH3200Same as above—C(═O)—CH3201Same as above—CH2—Ph202Same as above—C(═O)—Ph203Same as above—C(═O)—O—CH2—Ph204Same as above—C(═O)—C(═O)—Ph205

—CH3206Same as above—CH2CH3207Same as above—C(═O)—CH3208Same as above—CH2—Ph209Same as above—C(═O)—Ph210Same as above—C(═O)—O—CH2—Ph211Same as above—C(═O)—C(═O)—Ph212

—CH3213Same as above—CH2CH3214Same as above—C(═O)—CH3215Same as above—CH2—Ph216Same as above—C(═O)—Ph217Same as above—C(═O)—O—CH2—Ph218Same as above—C(═O)—C(═O)—Ph219

—CH3220Same as above—CH2CH3221Same as above—C(═O)—CH3222Same as above—CH2—Ph223Same as above—C(═O)—Ph224Same as above225Same as above—C(═O)—C(═O)—Ph226

—CH3227Same as above—CH2CH3228Same as above—C(═O)—CH3229Same as above—CH2—Ph230Same as above—C(═O)—Ph231Same as above—C(═O)—O—CH2—Ph232Same as above—C(═O)—C(═O)—Ph233

—CH3234Same as above—CH2CH3235Same as above—C(═O)—CH3236Same as above—CH2—Ph237Same as above—C(═O)—Ph238Same as above—C(═O)—O—CH2—Ph239Same as above—C(═O)—C(═O)—Ph240

—CH3241Same as above—CH2CH3242Same as above—C(═O)—CH3243Same as above—CH2—Ph244Same as above—C(═O)—Ph245Same as above—C(═O)—O—CH2—Ph246Same as above—C(═O)—C(═O)—Ph

[0120] Compounds 247-295 have the formula:

[0121] with the individual variables defined in the table below.

4Cmpd #

—(G)x—D247

—CH3248Same as above—CH2CH3249Same as above—C(═O)—CH3250Same as above—CH2—Ph251Same as above—C(═O)—Ph252Same as above—C(═O)—O—CH2—Ph253Same as above—C(═O)—C(═O)—Ph254

—CH3255Same as above—CH2CH3256Same as above—C(═O)—CH3257Same as above—CH2—Ph258Same as above—C(═O)—Ph259Same as above—C(═O)—O—CH2—Ph260Same as above—C(═O)—C(═O)—Ph261

—CH3262Same as above—CH2CH3263Same as above—C(═O)—CH3264Same as above—CH2—Ph265Same as above—C(═O)—Ph266Same as above—C(═O)—O—CH2—Ph267Same as above—C(═O)—C(═O)—Ph268

—CH3269Same as above—CH2CH3270Same as above—C(═O)—CH3271Same as above—CH2—Ph272Same as above—C(═O)—Ph273Same as above—C(═O)—O—CH2—Ph274Same as above—C(═O)—C(═O)—Ph275

—CH3276Same as above—CH2CH3277Same as above—C(═O)—CH3278Same as above—CH2—Ph279Same as above—C(═O)—Ph280Same as above—C(═O)—O—CH2—Ph281Same as above—C(═O)—C(═O)—Ph282

—CH3283Same as above—CH2CH3284Same as above—C(═O)—CH3285Same as above—CH2—Ph286Same as above—C(═O)—Ph287Same as above—C(═O)—O—CH2—Ph288Same as above—C(═O)—C(═O)—Ph289

—CH3290Same as above—CH2CH3291Same as above—C(═O)—CH3292Same as above—CH2—Ph293Same as above—C(═O)—Ph294Same as above—C(═O)—O—CH2—Ph295Same as above—C(═O)—C(═O)—Ph

EXAMPLE 2

Compounds 296-519

[0122] Compounds 296-519 are synthesized via the method set forth in Scheme 2, above.

[0123] Compounds 296-407 have the formula:

[0124] with the individual variables defined in the table below.

5Cmpd #

R1—(G)x—D296

H—CH3297Same as aboveH—CH2CH3298Same as aboveH—C(═O)—CH3299Same as aboveH—CH2—Ph300Same as aboveH—C(═O)—Ph301Same as aboveH—C(═O)—O—CH2—Ph302Same as aboveH—C(═O)—C(═O)—Ph303Same as aboveCH3—CH3304Same as aboveCH3—CH2CH3305Same as aboveCH3—C(═O)—CH3306Same as aboveCH3—CH2—Ph307Same as aboveCH3—C(═O)—Ph308Same as aboveCH3—C(═O)—O—CH2—Ph309Same as aboveCH3—C(═O)—C(═O)—Ph310Same as aboveCH2CH3—CH3311Same as aboveCH2CH3—CH2CH3312Same as aboveCH2CH3—C(═O)—CH3313Same as aboveCH2CH3—CH2—Ph314Same as aboveCH2CH3—C(═O)—Ph315Same as aboveCH2CH3—C(═O)—O—CH2—Ph316Same as aboveCH2CH3—C(═O)—C(═O)—Ph317Same as aboveCH2Ph—CH3318Same as aboveCH2Ph—CH2CH3319Same as aboveCH2Ph—C(═O)—CH3320Same as aboveCH2Ph—CH2—Ph321Same as aboveCH2Ph—C(═O)—Ph322Same as aboveCH2Ph—C(═O)—O—CH2—Ph323Same as aboveCH2Ph—C(═O)—C(═O)—Ph324

H—CH3325Same as aboveH—CH2CH3326Same as aboveH—C(═O)—CH3327Same as aboveH—CH2—Ph328Same as aboveH—C(═O)—Ph329Same as aboveH—C(═O)—O—CH2—Ph330Same as aboveH—C(═O)—C(═O)—Ph331Same as aboveCH3—CH3332Same as aboveCH3—CH2CH3333Same as aboveCH3—C(═O)—CH3334Same as aboveCH3—CH2—Ph335Same as aboveCH3—C(═O)—Ph336Same as aboveCH3—C(═O)—O—CH2—Ph337Same as aboveCH3—C(═O)—C(═O)—Ph338Same as aboveCH2CH3—CH3339Same as aboveCH2CH3—CH2CH3340Same as aboveCH2CH3—C(═O)—CH3341Same as aboveCH2CH3—CH2—Ph342Same as aboveCH2CH3—C(═O)—Ph343Same as aboveCH2CH3—C(═O)—O—CH2—Ph344Same as aboveCH2CH3—C(═O)—C(═O)—Ph345Same as aboveCH2Ph—CH3346Same as aboveCH2Ph—CH2CH3347Same as aboveCH2Ph—C(═O)—CH3348Same as aboveCH2Ph—CH2—Ph349Same as aboveCH2Ph—C(═O)—Ph350Same as aboveCH2Ph—C(═O)—O—CH2—Ph351Same as aboveCH2Ph—C(═O)—C(═O)—Ph352

H—CH3353Same as aboveH—CH2CH3354Same as aboveH—C(═O)—CH3355Same as aboveH—CH2—Ph356Same as aboveH—C(═O)—Ph357Same as aboveH—C(═O)—O—CH2—Ph358Same as aboveH—C(═O)—C(═O)—Ph359Same as aboveCH3—CH3360Same as aboveCH3—CH2CH3361Same as aboveCH3—C(═O)—CH3362Same as aboveCH3—CH2—Ph363Same as aboveCH3—C(═O)—Ph364Same as aboveCH3—C(═O)—O—CH2—Ph365Same as aboveCH3—C(═O)—C(═O)—Ph366Same as aboveCH2CH3—CH3367Same as aboveCH2CH3—CH2CH3368Same as aboveCH2CH3—C(═O)—CH3369Same as aboveCH2CH3—CH2—Ph370Same as aboveCH2CH3—C(═O)—Ph371Same as aboveCH2CH3—C(═O)—O—CH2—Ph372Same as aboveCH2CH3—C(═O)—C(═O)—Ph373Same as aboveCH2Ph—CH3374Same as aboveCH2Ph—CH2CH3375Same as aboveCH2Ph—C(═O)—CH3376Same as aboveCH2Ph—CH2—Ph377Same as aboveCH2Ph—C(═O)—Ph378Same as aboveCH2Ph—C(═O)—O—CH2—Ph379Same as aboveCH2Ph—C(═O)—C(═O)—Ph380

H—CH3381Same as aboveH—CH2CH3382Same as aboveH—C(═O)—CH3383Same as aboveH—CH2—Ph384Same as aboveH—C(═O)—Ph385Same as aboveH—C(═O)—O—CH2—Ph386Same as aboveH—C(═O)—C(═O)—Ph387Same as aboveCH3—CH3388Same as aboveCH3—CH2CH3389Same as aboveCH3—C(═O)—CH3390Same as aboveCH3—CH2—Ph391Same as aboveCH3—C(═O)—Ph392Same as aboveCH3—C(═O)—O—CH2—Ph393Same as aboveCH3—C(═O)—C(═O)—Ph394Same as aboveCH2CH3—CH3395Same as aboveCH2CH3—CH2CH3396Same as aboveCH2CH3—C(═O)—CH3397Same as aboveCH2CH3—CH2—Ph398Same as aboveCH2CH3—C(═O)—Ph399Same as aboveCH2CH3—C(═O)—O—CH2—Ph400Same as aboveCH2CH3—C(═O)—C(═O)—Ph401Same as aboveCH2Ph—CH3402Same as aboveCH2Ph—CH2CH3403Same as aboveCH2Ph—C(═O)—CH3404Same as aboveCH2Ph—CH2—Ph405Same as aboveCH2Ph—C(═O)—Ph406Same as aboveCH2Ph—C(═O)—O—CH2—Ph407Same as aboveCH2Ph—C(═O)—C(═O)—Ph

[0125] Compounds 408-519 have the formula:

[0126] with the individual variables defined in the table below.

6Cmpd #

R1—(G)x—D408

H—CH3409Same as aboveH—CH2CH3410Same as aboveH—C(═O)—CH3411Same as aboveH—CH2—Ph412Same as aboveH—C(═O)—Ph413Same as aboveH—C(═O)—O—CH2—Ph414Same as aboveH—C(═O)—C(═O)—Ph415Same as aboveCH3—CH3416Same as aboveCH3—CH2CH3417Same as aboveCH3—C(═O)—CH3418Same as aboveCH3—CH2—Ph419Same as aboveCH3—C(═O)—Ph420Same as aboveCH3—C(═O)—O—CH2—Ph421Same as aboveCH3—C(═O)—C(═O)—Ph422Same as aboveCH2CH3—CH3423Same as aboveCH2CH3—CH2CH3424Same as aboveCH2CH3—C(═O)—CH3425Same as aboveCH2CH3—CH2—Ph426Same as aboveCH2CH3—C(═O)—Ph427Same as aboveCH2CH3—C(═O)—O—CH2—Ph428Same as aboveCH2CH3—C(═O)—C(═O)—Ph429Same as aboveCH2Ph—CH3430Same as aboveCH2Ph—CH2CH3431Same as aboveCH2Ph—C(═O)—CH3432Same as aboveCH2Ph—CH2—Ph433Same as aboveCH2Ph—C(═O)—Ph434Same as aboveCH2Ph—C(═O)—O—CH2—Ph435Same as aboveCH2Ph—C(═O)—C(═O)—Ph436

H—CH3437Same as aboveH—CH2CH3438Same as aboveH—C(═O)—CH3439Same as aboveH—CH2—Ph440Same as aboveH—C(═O)—Ph441Same as aboveH—C(═O)—O—CH2—Ph442Same as aboveH—C(═O)—C(═O)—Ph443Same as aboveCH3—CH3444Same as aboveCH3—CH2CH3445Same as aboveCH3—C(═O)—CH3446Same as aboveCH3—CH2—Ph447Same as aboveCH3—C(═O)—Ph448Same as aboveCH3—C(═O)—O—CH2—Ph449Same as aboveCH3—C(═O)—C(═O)—Ph450Same as aboveCH2CH3—CH3451Same as aboveCH2CH3—CH2CH3452Same as aboveCH2CH3—C(═O)—CH3453Same as aboveCH2CH3—CH2—Ph454Same as aboveCH2CH3—C(═O)—Ph455Same as aboveCH2CH3—C(═O)—O—CH2—Ph456Same as aboveCH2CH3—C(═O)—C(═O)—Ph457Same as aboveCH2Ph—CH3458Same as aboveCH2Ph—CH2CH3459Same as aboveCH2Ph—C(═O)—CH3460Same as aboveCH2Ph—CH2—Ph461Same as aboveCH2Ph—C(═O)—Ph462Same as aboveCH2Ph—C(═O)—O—CH2—Ph463Same as aboveCH2Ph—C(═O)—C(═O)—Ph464

H—CH3465Same as aboveH—CH2CH3466Same as aboveH—C(═O)—CH3467Same as aboveH—CH2—Ph468Same as aboveH—C(═O)—Ph469Same as aboveH—C(═O)—O—CH2—Ph470Same as aboveH—C(═O)—C(═O)—Ph471Same as aboveCH3—CH3472Same as aboveCH3—CH2CH3473Same as aboveCH3—C(═O)—CH3474Same as aboveCH3—CH2—Ph475Same as aboveCH3—C(═O)—Ph476Same as aboveCH3—C(═O)—O—CH2—Ph477Same as aboveCH3—C(═O)—C(═O)—Ph478Same as aboveCH2CH3—CH3479Same as aboveCH2CH3—CH2CH3480Same as aboveCH2CH3—C(═O)—CH3481Same as aboveCH2CH3—CH2—Ph482Same as aboveCH2CH3—C(═O)—Ph483Same as aboveCH2CH3—C(═O)—O—CH2—Ph484Same as aboveCH2CH3—C(═O)—C(═O)—Ph485Same as aboveCH2Ph—CH3486Same as aboveCH2Ph—CH2CH3487Same as aboveCH2Ph—C(═O)—CH3488Same as aboveCH2Ph—CH2—Ph489Same as aboveCH2Ph—C(═O)—Ph490Same as aboveCH2Ph—C(═O)—O—CH2—Ph491Same as aboveCH2Ph—C(═O)—C(═O)—Ph492

H—CH3493Same as aboveH—CH2CH3494Same as aboveH—C(═O)—CH3495Same as aboveH—CH2—Ph496Same as aboveH—C(═O)—Ph497Same as aboveH—C(═O)—O—CH2—Ph498Same as aboveH—C(═O)—C(═O)—Ph499Same as aboveCH3—CH3500Same as aboveCH3—CH2CH3501Same as aboveCH3—C(═O)—CH3502Same as aboveCH3—CH2—Ph503Same as aboveCH3—C(═O)—Ph504Same as aboveCH3—C(═O)—O—CH2—Ph505Same as aboveCH3—C(═O)—C(═O)—Ph506Same as aboveCH2CH3—CH3507Same as aboveCH2CH3—CH2CH3508Same as aboveCH2CH3—C(═O)—CH3509Same as aboveCH2CH3—CH2—Ph510Same as aboveCH2CH3—C(═O)—Ph511Same as aboveCH2CH3—C(═O)—O—CH2—Ph512Same as aboveCH2CH3—C(═O)—C(═O)—Ph513Same as aboveCH2Ph—CH3514Same as aboveCH2Ph—CH2CH3515Same as aboveCH2Ph—C(═O)—CH3516Same as aboveCH2Ph—CH2—Ph517Same as aboveCH2Ph—C(═O)—Ph518Same as aboveCH2Ph—C(═O)—O—CH2—Ph519Same as aboveCH2Ph—C(═O)—C(═O)—Ph

EXAMPLE 3

Compounds 520-561

[0127] Compounds 520-561 are synthesized via the method set forth in Scheme 3, above.

[0128] Compounds 520-540 have the formula:

[0129] with the individual variables defined in the table below.

7Cmpd #

—(G)x—D520

—CH3521Same as above—CH2CH3522Same as above—C(═O)—CH3523Same as above—CH2—Ph524Same as above—C(═O)—Ph525Same as above—C(═O)—O—CH2—Ph526Same as above—C(═O)—C(═O)—Ph527

—CH3528Same as above—CH2CH3529Same as above—C(═O)—CH3530Same as above—CH2—Ph531Same as above—C(═O)—Ph532Same as above—C(═O)—O—CH2—Ph533Same as above—C(═O)—C(═O)—Ph534

—CH3535Same as above—CH2CH3536Same as above—C(═O)—CH3537Same as above—CH2—Ph538Same as above—C(═O)—Ph539Same as above—C(═O)—O—CH2—Ph540Same as above—C(═O)—C(═O)—Ph

[0130] Compounds 541-561 have the formula:

[0131] with the individual variables defined in the table below.

8Cmpd #

—(G)x—D541

—CH3542Same as above—CH2CH3543Same as above—C(═O)—CH3544Same as above—CH2—Ph545Same as above—C(═O)—Ph546Same as above—C(═O)—O—CH2—Ph547Same as above—C(═O)—C(═O)—Ph548

—CH3549Same as above—CH2CH3550Same as above—C(═O)—CH3551Same as above—CH2—Ph552Same as above—C(═O)—Ph553Same as above—C(═O)—O—CH2—Ph554Same as above—C(═O)—C(═O)—Ph555

—CH3556Same as above—CH2CH3557Same as above—C(═O)—CH3558Same as above—CH2—Ph559Same as above—C(═O)—Ph560Same as above—C(═O)—O—CH2—Ph561Same as above—C(═O)—C(═O)—Ph

EXAMPLE 4

Compounds 562-771

[0132] Compounds 562-771 are synthesized via the method set forth in Scheme 4 or Scheme 6, above.

[0133] Compounds 562-596 have the formula:

[0134] with the individual variables defined in the table below.

9Cmpd #A—(G)x—D562

—CH3563Same as above—CH2CH3564Same as above—C(═O)—CH3565Same as above—CH2—Ph566Same as above—C(═O)—Ph567Same as above—C(═O)—O—CH2—Ph568Same as above—C(═O)—C(═O)—Ph569

—CH3570Same as above—CH2CH3571Same as above—C(═O)—CH3572Same as above—CH2—Ph573Same as above—C(═O)—Ph574Same as above—C(═O)—O—CH2—Ph575Same as above—C(═O)—C(═O)—Ph576

—CH3577Same as above—CH2CH3578Same as above—C(═O)—CH3579Same as above—CH2—Ph580Same as above—C(═O)—Ph581Same as above—C(═O)—O—CH2—Ph582Same as above—C(═O)—C(═O)—Ph583

—CH3584Same as above—CH2CH3585Same as above—C(═O)—CH3586Same as above—CH2—Ph587Same as above—C(═O)—Ph588Same as above—C(═O)—O—CH2—Ph589Same as above—C(═O)—C(═O)—Ph590

—CH3591Same as above—CH2CH3592Same as above—C(═O)—CH3593Same as above—CH2—Ph594Same as above—C(═O)—Ph595Same as above—C(═O)—O—CH2—Ph596Same as above—C(═O)—C(═O)—Ph

[0135] Compounds 597-631 have the formula:

[0136] with the individual variables defined in the table below.

10Cmpd #A—(G)x—D597

—CH3598Same as above—CH2CH3599Same as above—C(═O)—CH3600Same as above—CH2—Ph601Same as above—C(═O)—Ph602Same as above—C(═O)—O—CH2—Ph603Same as above—C(═O)—C(═O)—Ph604

—CH3605Same as above—CH2CH3606Same as above—C(═O)—CH3607Same as above—CH2—Ph608Same as above—C(═O)—Ph609Same as above—C(═O)—O—CH2—Ph610Same as above—C(═O)—C(═O)—Ph611

—CH3612Same as above—CH2CH3613Same as above—C(═O)—CH3614Same as above—CH2—Ph615Same as above—C(═O)—Ph616Same as above—C(═O)—O—CH2—Ph617Same as above—C(═O)—C(═O)—Ph618

—CH3619Same as above—CH2CH3620Same as above—C(═O)—CH3621Same as above—CH2—Ph622Same as above—C(═O)—Ph623Same as above—C(═O)—O—CH2—Ph624Same as above—C(═O)—C(═O)—Ph625

—CH3626Same as above—CH2CH3627Same as above—C(═O)—CH3628Same as above—CH2—Ph629Same as above—C(═O)—Ph630Same as above—C(═O)—O—CH2—Ph631Same as above—C(═O)—C(═O)—Ph

[0137] Compounds 632-666 have the formula:

[0138] with the individual variables defined in the table below.

11Cmpd #A—(G)x—D632

—CH3633Same as above—CH2CH3634Same as above—C(═O)—CH3635Same as above—CH2-Ph636Same as above—C(═O)-Ph637Same as above—C(═O)—O—CH2-Ph638Same as above—C(═O)—C(═O)-Ph639

—CH3640Same as above—CH2CH3641Same as above—C(═O)—CH3642Same as above—CH2-Ph643Same as above—C(═O)-Ph644Same as above—C(═O)—O—CH2-Ph645Same as above—C(═O)—C(═O)-Ph646

—CH3647Same as above—CH2CH3648Same as above—C(═O)—CH3649Same as above—CH2-Ph650Same as above—C(═O)-Ph651Same as above—C(═O)—O—CH2-Ph652Same as above—C(═O)—C(═O)-Ph653

—CH3654Same as above—CH2CH3655Same as above—C(═O)—CH3656Same as above—CH2-Ph657Same as above—C(═O)-Ph658Same as above—C(═O)—O—CH2-Ph659Same as above—C(═O)—C(═O)-Ph660

—CH3661Same as above—CH2CH3662Same as above—C(═O)—CH3663Same as above—CH2-Ph664Same as above—C(═O)-Ph665Same as above—C(═O)—O—CH2-Ph666Same as above—C(═O)—C(═O)-Ph

[0139] Compounds 667-701 have the formula:

[0140] with the individual variables defined in the table below.

12Cmpd #A—(G)x—D667

—CH3668Same as above—CH2CH3669Same as above—C(═O)—CH3670Same as above—CH2-Ph671Same as above—C(═O)-Ph672Same as above—C(═O)—O—CH2-Ph673Same as above—C(═O)—C(═O)-Ph674

—CH3675Same as above—CH2CH3676Same as above—C(═O)—CH3677Same as above—CH2-Ph678Same as above—C(═O)-Ph679Same as above—C(═O)—O—CH2-Ph680Same as above—C(═O)—C(═O)-Ph681

—CH3682Same as above—CH2CH3683Same as above—C(═O)—CH3684Same as above—CH2-Ph685Same as above—C(═O)-Ph686Same as above—C(═O)—O—CH2-Ph687Same as above—C(═O)—C(═O)-Ph688

—CH3689Same as above—CH2CH3690Same as above—C(═O)—CH3691Same as above—CH2-Ph692Same as above—C(═O)-Ph693Same as above—C(═O)—O—CH2-Ph694Same as above—C(═O)—C(═O)-Ph695

—CH3696Same as above—CH2CH3697Same as above—C(═O)—CH3698Same as above—CH2-Ph699Same as above—C(═O)-Ph700Same as above—C(═O)—O—CH2-Ph701Same as above—C(═O)—C(═O)-Ph

[0141] Compounds 702-736 have the formula:

[0142] with the individual variables defined in the table below.

13Cmpd #A—(G)x—D702

—CH3703Same as above—CH2CH3704Same as above—C(═O)—CH3705Same as above—CH2-Ph706Same as above—C(═O)-Ph707Same as above—C(═O)—O—CH2-Ph708Same as above—C(═O)—C(═O)-Ph709

—CH3710Same as above—CH2CH3711Same as above—C(═O)—CH3712Same as above—CH2-Ph713Same as above—C(═O)-Ph714Same as above—C(═O)—O—CH2-Ph715Same as above—C(═O)—C(═O)-Ph716

100

—CH3717Same as above—CH2CH3718Same as above—C(═O)—CH3719Same as above—CH2-Ph720Same as above—C(═O)-Ph721Same as above—C(═O)—O—CH2-Ph722Same as above—C(═O)—C(═O)-Ph723

101

—CH3724Same as above—CH2CH3725Same as above—C(═O)—CH3726Same as above—CH2-Ph727Same as above—C(═O)-Ph728Same as above—C(═O)—O—CH2-Ph729Same as above—C(═O)—C(═O)-Ph730

102

—CH3731Same as above—CH2CH3732Same as above—C(═O)—CH3733Same as above—CH2-Ph734Same as above—C(═O)-Ph735Same as above—C(═O)—O—CH2-Ph736Same as above—C(═O)—C(═O)-Ph

[0143] Compounds 737-771 have the formula:

103

[0144] with the individual variables defined in the table below.

14Cmpd #A—(G)x—D737

104

—CH3738Same as above—CH2CH3739Same as above—C(═O)—CH3740Same as above—CH2-Ph741Same as above—C(═O)-Ph742Same as above—C(═O)—O—CH2-Ph743Same as above—C(═O)—C(═O)-Ph744

105

—CH3745Same as above—CH2CH3746Same as above—C(═O)—CH3747Same as above—CH2-Ph748Same as above—C(═O)-Ph749Same as above—C(═O)—O—CH2-Ph750Same as above—C(═O)—C(═O)-Ph751

106

—CH3752Same as above—CH2CH3753Same as above—C(═O)—CH3754Same as above—CH2-Ph755Same as above—C(═O)-Ph756Same as above—C(═O)—O—CH2-Ph757Same as above—C(═O)—C(═O)-Ph758

107

—CH3759Same as above—CH2CH3760Same as above—C(═O)—CH3761Same as above—CH2-Ph762Same as above—C(═O)-Ph763Same as above—C(═O)—O—CH2-Ph764Same as above—C(═O)—C(═O)-Ph765

108

—CH3766Same as above—CH2CH3767Same as above—C(═O)—CH3768Same as above—CH2-Ph769Same as above—C(═O)-Ph770Same as above—C(═O)—O—CH2Ph771Same as above—C(═O)—C(═O)-Ph

EXAMPLE 5

Compounds 772-967

[0145] Compounds 772- are synthesized via the method set forth in Scheme 5, above.

[0146] Compounds 772-820 have the formula:

109

[0147] with the individual variables defined in the table below

15Cmpd #

110

—(G)x—D772

111

—CH3773Same as above—CH2CH3774Same as above—C(═O)—CH3775Same as above—CH2-Ph776Same as above—C(═O)-Ph777Same as above—C(═O)—O—CH2-Ph778Same as above—C(═O)—C(═O)-Ph779

112

—CH3780Same as above—CH2CH3781Same as above—C(═O)—CH3782Same as above—CH2-Ph783Same as above—C(═O)-Ph784Same as above—C(═O)—O—CH2-Ph785Same as above—C(═O)—C(═O)-Ph786

113

—CH3787Same as above—CH2CH3788Same as above—C(═O)—CH3789Same as above—CH2Ph790Same as above—C(═O)-Ph791Same as above—C(═O)—O—CH2-Ph792Same as above—C(═O)—C(═O)-Ph793

114

—CH3794Same as above—CH2CH3795Same as above—C(═O)—CH3796Same as above—CH2-Ph797Same as above—C(═O)-Ph798Same as above—C(═O)—O—CH2-Ph799Same as above—C(═O)—C(═O)-Ph800

115

—CH3801Same as above—CH2CH3802Same as above—C(═O)—CH3803Same as above—CH2-Ph804Same as above—C(═O)-Ph805Same as above—C(═O)—O—CH2-Ph806Same as above—C(═O)—C(═O)-Ph807

116

—CH3808Same as above—CH2CH3809Same as above—C(═O)—CH3810Same as above—CH2-Ph811Same as above—C(═O)-Ph812Same as above—C(═O)—O—CH2-Ph813Same as above—C(═O)—C(═O)-Ph814

117

—CH3815Same as above—CH2CH3816Same as above—C(═O)—CH3817Same as above—CH2-Ph818Same as above—C(═O)-Ph819Same as above—C(═O)—O—CH2-Ph820Same as above—C(═O)—C(═O)-Ph

[0148] Compounds 821-869 have the formula:

118

[0149] with the individual variables defined in the table below

16Cmpd #

119

—(G)x—D821

120

—CH3822Same as above—CH2CH3823Same as above—C(═O)—CH3824Same as above—CH2-Ph825Same as above—C(═O)-Ph826Same as above—C(═O)—O—CH2-Ph827Same as above—C(═O)—C(═O)-Ph828

121

—CH3829Same as above—CH2CH3830Same as above—C(═O)—CH3831Same as above—CH2-Ph832Same as above—C(═O)-Ph833Same as above—C(═O)—O—CH2-Ph834Same as above—C(═O)—C(═O)-Ph835

122

—CH3836Same as above—CH2CH3837Same as above—C(═O)—CH3838Same as above—CH2-Ph839Same as above—C(═O)-Ph840Same as above—C(═O)—O—CH2-Ph841Same as above—C(═O)—C(═O)-Ph842

123

—CH3843Same as above—CH2CH3844Same as above—C(═O)—CH3845Same as above—CH2-Ph846Same as above—C(═O)-Ph847Same as above—C(═O)—O—CH2-Ph848Same as above—C(═O)—C(═O)-Ph849

124

—CH3850Same as above—CH2CH3851Same as above—C(═O)—CH3852Same as above—CH2-Ph853Same as above—C(═O)-Ph854Same as above—C(═O)—O—CH2-Ph855Same as above—C(═O)—C(═O)-Ph856

125

—CH3857Same as above—CH2CH3858Same as above—C(═O)—CH3859Same as above—CH2-Ph860Same as above—C(═O)-Ph861Same as above—C(═O)—O—CH2-Ph862Same as above—C(═O)—C(═O)-Ph863

126

—CH3864Same as above—CH2CH3865Same as above—C(═O)—CH3866Same as above—CH2-Ph867Same as above—C(═O)-Ph868Same as above—C(═O)—O—CH2-Ph869Same as above—C(═O)—C(═O)-Ph

[0150] Compounds 870-918 have the formula:

127

[0151] with the individual variables defined in the table below

17Cmpd #

128

—(G)x—D870

129

—CH3871Same as above—CH2CH3872Same as above—C(═O)—CH3873Same as above—CH2-Ph874Same as above—C(═O)-Ph875Same as above—C(═O)—O—CH2-Ph876Same as above—C(═O)—C(═O)-Ph877

130

—CH3878Same as above—CH2CH3879Same as above—C(═O)—CH3880Same as above—CH2-Ph881Same as above—C(═O)-Ph882Same as above—C(═O)—O—CH2-Ph883Same as above—C(═O)—C(═O)-Ph884

131

—CH3885Same as above—CH2CH3886Same as above—C(═O)—CH3887Same as above—CH2-Ph888Same as above—C(═O)-Ph889Same as above—C(═O)—O—CH2-Ph890Same as above—C(═O)—C(═O)-Ph891

132

—CH3892Same as above—CH2CH3893Same as above—C(═O)—CH3894Same as above—CH2-Ph895Same as above—C(═O)-Ph896Same as above—C(═O)—O—CH2-Ph897Same as above—C(═O)—C(═O)-Ph898

133

—CH3899Same as above—CH2CH3900Same as above—C(═O)—CH3901Same as above—CH2-Ph902Same as above—C(═O)-Ph903Same as above—C(═O)—O—CH2-Ph904Same as above—C(═O)—C(═O)-Ph905

134

—CH3906Same as above—CH2CH3907Same as above—C(═O)—CH3908Same as above—CH2-Ph909Same as above—C(═O)-Ph910Same as above—C(═O)—O—CH2-Ph911Same as above—C(═O)—C(═O)-Ph912

135

—CH3913Same as above—CH2CH3914Same as above—C(═O)—CH3915Same as above—CH2-Ph916Same as above—C(═O)-Ph917Same as above—C(═O)—O—CH2-Ph918Same as above—C(═O)—C(═O)-Ph

[0152] Compounds 919-967 have the formula:

136

[0153] with the individual variables defined in the table below

18Cmpd #

137

—(G)x—D919

138

—CH3920Same as above—CH2CH3921Same as above—C(═O)—CH3922Same as above—CH2-Ph923Same as above—C(═O)-Ph924Same as above—C(═O)—O—CH2-Ph925Same as above—C(═O)—C(═O)-Ph926

139

—CH3927Same as above—CH2CH3928Same as above—C(═O)—CH3929Same as above—CH2-Ph930Same as above—C(═O)-Ph931Same as above—C(═O)—O—CH2-Ph932Same as above—C(═O)—C(═O)-Ph933

140

—CH3934Same as above—CH2CH3935Same as above—C(═O)—CH3936Same as above—CH2-Ph937Same as above—C(═O)-Ph938Same as above—C(═O)—O—CH2-Ph939Same as above—C(═O)—C(═O)-Ph940

141

—CH3941Same as above—CH2CH3942Same as above—C(═O)—CH3943Same as above—CH2-Ph944Same as above—C(═O)-Ph945Same as above—C(═O)—O—CH2-Ph946Same as above—C(═O)—C(═O)-Ph947

142

—CH3948Same as above—CH2CH3949Same as above—C(═O)—CH3950Same as above—CH2-Ph951Same as above—C(═O)-Ph952Same as above—C(═O)—O—CH2-Ph953Same as above—C(═O)—C(═O)-Ph954

143

—CH3955Same as above—CH2CH3956Same as above—C(═O)—CH3957Same as above—CH2-Ph958Same as above—C(═O)-Ph959Same as above—C(═O)—O—CH2-Ph960Same as above—C(═O)—C(═O)-Ph961

144

—CH3962Same as above—CH2CH3963Same as above—C(═O)—CH3964Same as above—CH2-Ph965Same as above—C(═O)-Ph966Same as above—C(═O)—O—CH2-Ph967Same as above—C(═O)—C(═O)-Ph

[0154] While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the products, processes and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific embodiments which have been presented by way of example.

Acyclic and cyclic amine derivatives

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