Patent Application
20070155727
Inflammation is normally an acute response by the immune system to invasion by microbial pathogens, chemicals or physical injury. In some cases, however, the inflammatory response can progress to a chronic state, and be the cause of inflammatory disease. Therapeutic control of this chronic inflammation in diverse diseases is a major medical need.
Leukotriene B4 (LTB4) is a potent pro-inflammatory activator of inflammatory cells, including neutrophils (J. Palmblad, J. Rheumatol. 1984, 13(2):163-172), eosinophils (A. M. Tager, et al., J. Exp. Med. 2000, 192(3):439-446), monocytes (N. Dugas et al., Immunol. 1996, 88(3):384-388), macrophages (L. Gagnon et al., Agents Actions 1989, 34(1-2):172-174), T cells (H. Morita et al., Biochem. Biophys. Res. Commun. 1999, 264(2):321-326) and B cells (B. Dugas et al., J. Immunol. 1990, 145(10):3405-3411). Immune cell priming and activation by LTB4 can promote chemotaxis, adhesion, free radical release, degranulation and cytokine release. LTB4 stimulates T-cell proliferation and cytokine release in response to IL-2, concanavalin-A and CD3 ligation (H. Morita et al., Biochem. Biophys. Res. Commun. 1999, 264(2):321-326). LTB4 is a chemoattractant for T-cells creating a functional link between early innate and late adaptive immune responses to inflammation (K. Goodarzi, et al., Nat. Immunol. 2003, 4:965-973; V. L. Ott, et al., Nat. Immunol. 2003, 4:974-981; A. M. Tager, et al., Nat. Immunol. 2003, 4:982-990). There is substantial evidence that LTB4 plays a significant role in the amplification of many inflammatory disease states (R. A. Lewis, et al., N. Engl. J. Med. 1990, 323:645; W. R. Henderson, Ann. Intern. Med. 1994, 121:684. ) including asthma (D. A. Munafo et al., J. Clin. Invest. 1994, 93(3):1042-1050), inflammatory bowel disease (IBD) (P. Sharon and W. F. Stenson, Gastroenterology 1984, 86(3):453-460), chronic obstructive pulmonary disease (COPD) (P. J. Barnes, Respiration 2001, 68(5):441-448), arthritis (R. J. Griffiths et al., Proc. Nat. Acad. Sci. U.S.A. 1995, 92(2):517-521; F. Tsuji et al., Life Sci. 1998 64(3):L51-L56), psoriasis (K. Ikai, J. Dermatol. Sci. 1999, 21(3):135-146; Y. I. Zhu and M. J. Stiller, Skin Pharmacol. Appl. Skin Physiol. 2000, 13(5):235-245), and atherosclerosis (E. B. Friedrich, et al., Arterioscler. Thromb. Vasc. Biol. 2003, 23:1761-1767; K. Subbarao, et al., Arterioscler. Thromb. Vasc. Biol. 2004, 24:369-375; A. Helgadottir, et al., Nat. Genet. 2004, 36:233-239; V. R. Jala, et al., Trends in Immun. 2004, 25:315-322). LTB4 also stimulates the production of various cytokines and may play a role in immunoregulation (A. W. Ford-Hutchinson, Immunology 1990, 10:1). Furthermore, it has recently been shown that LTB4 levels are elevated in brochoalveolar lavage fluid from patients with scleroderma lung disease (see Kowal-Bielecka, O. et al., Arthritis Rheum. (Nov. 30, 2005), Vol. 52, No. 12, pp. 3783-3791). Therefore, a therapeutic agent that inhibits the biosynthesis of LTB4 or the response of cells to LTB4 may be useful for the treatment of these inflammatory conditions.
The biosynthesis of LTB4 from arachidonic acid (AA) involves the action of three enzymes: phospholipase A2 (PLA2), to release AA from the membrane lipids; 5-lipoxygenase (5-LO), to form the unstable epoxide Leukotriene A4 (LTA4); and leukotriene A4 hydrolase (LTA4-h), to form LTB4 (A. W. Ford-Hutchinson, et al., Annu. Rev. Biochem. 1994, 63:383-347). The cysteinyl leukotrienes are formed by the additon of glutathione to LTA4 by the action of LTC4 synthase (Aharony, D., Am. J. Respir. Crit. Care Med. 1998, 157 (6, Pt 2), S214-S218) into the pro-inflammatory cysteinyl leukotrienes LTC4, LTD4 and LTE4. An alternative path for LTA4 is conversion via transcellular biosynthesis and the action of lipoxygenases into lipoxin A4 (LXA4) and lipoxin B4 (LXB4) (C. N. Serhan, Prostaglandins 1997, 53:107-137).
LTA4-h is a monomeric, soluble 69 kD zinc metalloenzyme. A high resolution crystal structure of recombinant LTA4-h with bound inhibitors has been obtained (M. M. Thunissen et al., Nat Struct. Biol. 2001, 8(2): 131-135). LTA4-h is a bifunctional zinc-dependent metalloenzyme of the M1 class of metallohydrolases. It catalyses two reactions: the stereospecific epoxide hydrolase reaction to convert LTA4 to LTB4 and a peptidase cleavage of chromogenic substrates. The Zn center is critical to both activities. LTA4-h is related to aminopeptidases M and B, which have no LTA4-hydrolase activity. LTA4-h has high substrate specificity, accepting only a 5,6-trans-epoxide with a free carboxylic acid at C-1 of the fatty acid. The double-bond geometry of the substrate is essential for catalysis. LTA3 and LTA5 are the only other weak substrates known to date. In contrast, LTA4-h peptidase activity appears to be promiscuous, cleaving nitroanilide and 2-naphthylamide derivatives of various amino acids, e.g. particularly alanine and arginine. Arg-Gly-Asp, Arg-Gly-Gly, and Arg-His-Phe tripeptides are hydrolyzed with specificity constants (kcat/Km) similar to the epoxide hydrolase reaction. There is no known physiological peptide substrate for LTA4-h.
LTA4-h is widely expressed as a soluble intracellular enzyme in intestine, spleen, lung and kidney. High activity levels are found in neutrophils, monocytes, lymphocytes and erythrocytes. Tissue macrophages can have high LTA4-h levels. An interesting feature is that the cellular distribution of LTA4-h and 5-LO are distinct, requiring close apposition of cells such as neutrophils and epithelial cells for efficient transcellular LTB4 synthesis. Many studies support this concept including recent data from bone marrow chimeras derived from LTA4-h−/− and 5-LO−/− mice (J. E. Fabre et al., J. Clin. Invest. 2002, 109(10):1373-1380).
These important functions of LTB4 in inflammation and potentially in autoimmunity prompted an aggressive search at numerous pharmaceutical companies to discover potent LTB4 receptor antagonists. These efforts were initiated long before the molecular identity of LTB4 receptors was known. Drug discovery efforts focused on competition binding of small molecule antagonists or agonists at [3H]-LTB4 binding sites and functional responses, e.g. chemotaxis in human neutrophils. Despite the presence of a stereospecific, high affinity [3H]-LTB4 receptor (Kd<1 nM) on human neutrophils, it was apparent from early studies that additional lower affinity LTB4 receptors (Kd>60 nM) were also present on neutrophils (D. W. Goldman and E. J. Goetzl, J. Exp. Med. 1984 159(4):1027-1041). This LTB4 receptor heterogeneity was subsequently confirmed in HL-60 leukemia cells (C. W. Benjamin et al., J. Biol. Chem. 1985, 260(26):14208-14213), alveolar macrophages (A. J. de Brum et al., Prostaglandins 1990, 40(5):515-527), peritoneal eosinophils (R. Sehmi et al., Immunol. 1992, 77(1):129-135) and other cell types.
The seminal work of Takao Shimizu and colleagues in cloning human LTB4 receptors has recently defined two pharmacologically distinct receptors (T. Shimizu et al., Ernst Schering Res. Found. Workshop 2000, (31):125-141). Human BLT1 and its mouse, rat and guinea pig orthologues represent the high affinity LTB4 receptor (Kd 0.1-0.7 nM). BLT1 has a restricted expression in inflammatory cells e.g. neutrophils, monocytes, thymus and spleen. Human and mouse BLT2 have a wider tissue expression profile than BLT1, with evidence for mRNA transcripts predominantly in spleen, liver, ovary and leukocytes and lower transcript levels in many other tissues (T. Yokomizo et al., J. Exp. Med. 2000, 192(3):421-432; and T. Yokomizo et al., J. Biol. Chem. 2001, 276(15):12454-12459). Human BLT2 had 20-fold lower affinity for LTB4 (Kd=23 nM) than BLT1 and much weaker, but measurable affinity for other eicosanoids. The distinct pharmacology of BLT1 and BLT2 receptors was shown by [3H]-LTB4 competition binding studies with industry-standard LTB4 receptor antagonists. Most known LTB4 receptor antagonists were able to compete for binding to BLT1, but not to BLT2.
These findings suggest that local concentrations of LTB4 generated at sites of inflammation will provide graded responses to different cell types based on either unique or regulated co-expression of BLT1 and BLT2 receptors. This was confirmed by co-expression of BLT1 and BLT2 in CHO cells, which exhibited a broader dose response range to LTB4-stimulated chemotaxis than either receptor alone (T. Yokomizo et al., Life Sci. 2001, 68(19-20):2207-2212). The data also suggest that the failure or success of a given LTB4 receptor antagonist in pre-clinical efficacy models of inflammatory or autoimmune disease and in human clinical trials needs to be re-examined in light of pharmacological effects at these distinct BLT1 and BLT2 receptors.
Further analysis of LTB4 receptor subtype expression in immune cells has been performed by semi-quantitative PCR analysis (T. Yokomizo et al., Life Sci. 2001, 68(19-20):2207-2212). Data suggest BLT1 mRNA expression is highest in CD14+ monocytes, while BLT2 mRNA expression is high in CD8+ cytotoxic T-, CD4+ helper T-, and CD19+ B-cells. These findings have not been corroborated with clear evidence for differential BLT1 and BLT2 expression at the protein level. Although a BLT1-specific antibody has been reported (A. Pettersson et al., Biochem. Biophys. Res. Commun. 2000, 279(2):520-525), anti-BLT2 antibody are not yet available. Nevertheless, the known responses of some of these cell types to LTB4 (see above) suggest a role for BLT2 in modulating T- and B-lymphocyte-dependent immune biology. While an LTB4 receptor antagonist may differ in its affinity for BLT1 vs BLT2, blocking the production of LTB4 using LTA4-h inhibitors would be expected to inhibit the downstream events mediated through both BLT1 and BLT2.
Studies have shown that introduction of exogenous LTB4 into normal tissues can induce inflammatory symptoms (R. D. R. Camp et al., Br. J. Pharmacol. 1983, 80(3):497-502; R. Camp et al., J. Invest. Dermatol. 1984, 82(2):202-204). Elevated levels of LTB4 have been observed in a number of inflammatory diseases including inflammatory bowel disease (IBD), chronic obstructed pulmonary disease (COPD), psoriasis, rheumatoid arthritis (RA), cystic fibrosis, multiple sclerosis (MS), and asthma (S. W. Crooks and R. S. Stockley, Int. J. Biochem. Cell Biol. 1998, 30(2):173-178). Therefore, reduction of LTB4 production by an inhibitor of LTA4-h activity would be predicted to have therapeutic potential in a wide range of diseases.
This idea is supported by a study of LTA4-h-deficient mice that, while otherwise healthy, exhibited markedly decreased neutrophil influx in arachidonic acid-induced ear inflammation and zymosan-induced peritonitis models (R. S. Byrum et al., J. Immunol. 1999, 163(12):6810-68129). LTA4-h inhibitors have been shown to be effective anti-inflammatory agents in preclinical studies. For example, oral administration of LTA4-h inhibitor SC57461 caused inhibition of ionophore-induced LTB4 production in mouse blood ex vivo, and in rat peritoneum in vivo (J. K. Kachur et al., J. Pharm. Exp. Thr. 2002, 300(2): 583-587). Eight weeks of treatment with the same inhibitor significantly improved colitis symptoms in cotton top tamarins (T. D. Penning, Curr. Pharm. Des. 2001, 7(3):163-179). The spontaneous colitis that develops in these animals is very similar to human IBD. The results therefore indicate that LTA4-h inhibitors would have therapeutic utility in this and other human inflammatory diseases.
Inflammation may be observed in any one of a plurality of conditions, such as asthma, COPD, atherosclerosis, rheumatoid arthritis, multiple sclerosis (including relapsing-remitting, primary progressive, and secondary progressive), inflammatory bowel diseases (IBD, including Crohn's disease and ulcerative colitis), or psoriasis, which are each characterized by excessive or prolonged inflammation at some stage of the disease. The connection between inflammatory diseases and cancer has been strengthened by the strong link established between a mutation of the oncogene ras and a de-novo expression of the BLT2 receptor as well as activation of LTB4 synthesis in tumor cells (M.-H. Yoo et al. 2004, Oncogene, 23, 9259). Previously it was shown in various cell models that oncogenic ras induces cytosolic phospolipase A (cPLA2) thus increasing the release of arachidonic acid (L. E. Heasley et al. 1997, J. Biol. Chem., 272, 14501) and the synthesis of LTB4. Inhibition of this pathway through an LTA4-h inhibitor would have a therapeutic utility in the treatment of cancers.
Events that elicit the inflammatory response include the formation of the pro-inflammatory mediator LTB4, which can be blocked with an LTA4-h inhibitor, thus providing the ability to prevent and/or treat leukotriene-mediated conditions, such as inflammation. The inflammatory response is characterized by pain, increased temperature, redness, swelling, or reduced function, or by a combination of two or more of these symptoms. Regarding the onset and evolution of inflammation, inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.
Background and review material on inflammation and conditions related with inflammation can be found in articles such as the following: C. Nathan, Points of control in inflammation, Nature 2002, 420:846-852; K. J. Tracey, The inflammatory reflex, Nature 2002, 420:853-859; L. M. Coussens and Z. Werb, Inflammation and cancer, Nature 2002, 420:860-867; P. Libby, Inflammation in atherosclerosis, Nature 2002, 420:868-874; C. Benoist and D. Mathis, Mast cells in autoimmune disease, Nature 2002, 420:875-878; H. L. Weiner and D. J. Selkoe, Inflammation and therapeutic vaccination in CNS diseases, Nature 2002, 420:879-884; J. Cohen, The immunopathogenesis of sepsis, Nature 2002, 420:885-891; D. Steinberg, Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime, Nature Medicine 2002, 8(11):1211-1217. Cited references are incorporated herein by reference.
The connection between members of the leukotriene pathway, particularly LTA4-h and LTB4, and myocardial infarction and acute coronary syndrome has recently been disclosed in PCT Published Patent Application WO 2004/035741, PCT Published Patent Application WO 2004/035746, PCT Published Patent Application WO 2005/027886, PCT Published Patent Application WO 2005/075022, and U.S. Published Patent Application US 2005/0113408, the pertinent disclosures of which are incorporated by reference in their entireties, and in Nature Genetics, Advanced Online Communication, Nov. 10, 2005.
Accordingly, there exists a need for inhbitors of the LTA4-h enzyme, particularly inhibitors that are useful in the inhibition of pro-inflammatory mediators, such as the LTB4 mediator. Such inhibitors would be useful in the treatment of diseases and conditions as set forth herein.
This invention is directed to compounds, as single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, solvates, polymorphs, clathrates, ammonium ions, N-oxides or prodrugs thereof, that inhibit the activity of LTA4-h and are therefore useful as pharmaceutical agents for the treatment of diseases and disorders which are ameliorated by the inhibition of LTA4-h activity.
Accordingly, in one aspect, the invention provides compounds of formula (I):
wherein:
In another aspect, this invention provides pharmaceutical compositions, which composition comprises a therapeutically effective amount of a compound of formula (I) as described above, and a pharmaceutically acceptable excipient.
In another aspect, this invention provides a method of treating a disease or disorder ameliorated by the inhibition of LTA4-h activity in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of compound of formula (I) as described above.
Definitions
Throughout this specification and the claims that follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
As used herein the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. For example, “a compound” refers to one or more of such compounds, while “the enzyme” includes a particular enzyme as well as other family members and equivalents thereof as known to those skilled in the art.
Furthermore, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
“Amino” refers to the —NH2 radical.
“Cyano” refers to the —CN radical.
“Hydroxy” refers to the —OH radical.
“Nitro” refers to the —NO2 radical.
“Oxo” refers to the ═O radical.
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms, more preferably one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted by one of the following substituents: halo, cyano, nitro, oxo, trimethylsilyl, —OR15, —OC(═O)—R15, —N(R15)2, —C(═O)R15, —C(═O)OR15, —C(═O)N(R15)2, —N(R15)C(═O)OR15, —N(R15)C(═O)R15, —N(R15)S(═O)tR15 (where t is 1 or 2), —S(═O)tOR15 (where t is 1 or 2), —S(═O)pR15 (where p is 0, 1 or 2), and —S(═O)tN(R15)2 (where t is 1 or 2) where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo or alkyl groups), aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated unless specifically defined otherwise.
“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted by one of the following substituents: cyano, nitro, oxo, trimethylsilyl, —OR15, —OC(═O)—R15, —N(R15)2, —C(═O)R15, —C(═O)OR15, —C(═O)N(R15)2, —N(R15)C(═O)OR15, —N(R15)C(═O)R15, —N(R15)S(═O)tR15 (where t is 1 or 2), —S(═O)tOR15 (where t is 1 or 2), —S(═O)pR15 (where p is 0, 1 or 2), and —S(═O)tN(R15)2 (where t is 1 or 2) where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated unless specifically defined otherwise.
“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted by one of the following substituents: cyano, nitro, oxo, trimethylsilyl, —OR15, —OC(═O)—R15, —N(R15)2, —C(═O)R15, —C(═O)OR15, —C(═O)N(R15)2, —N(R15)C(═O)OR15, —N(R15)C(═O)R15, —N(R15)S(═O)tR15 (where t is 1 or 2), —S(═O)tOR15 (where t is 1 or 2), —S(═O)pR15 (where p is 0, 1 or 2), and —S(═O)tN(R15)2 (where t is 1 or 2) where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless specifically defined otherwise.
“Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted by one of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, —OR15, —OC(═O)—R15, —N(R15)2, —C(═O)R15, —C(═O)OR15, —C(═O)N(R15)2, —N(R15)C(═O)OR15, —N(R15)C(═O)R15, —N(R15)S(═O)tR15 (where t is 1 or 2), —S(═O)tOR15 (where t is 1 or 2), —S(═O)pR15 (where p is 0, 1 or 2), and —S(═O)tN(R15)2 (where t is 1 or 2) where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated.
“Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain may be optionally substituted by one of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, —OR15, —OC(═O)—R15, —N(R15)2, —C(═O)R15, —C(═O)OR15, —C(═O)N(R15)2, —N(R15)C(═O)OR15, —N(R15)C(═O)R15, —N(R15)S(═O)tR15 (where t is 1 or 2), —S(═O)tOR15 (where t is 1 or 2), —S(═O)pR15 (where p is 0, 1 or 2), and —S(═O)tN(R15)2 (where t is 1 or 2) where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated.
“Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, for example, propynylene, n-butynylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain may be optionally substituted by one of the following substituents: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, —OR15, —OC(═O)—R15, —N(R15)2, —C(═O)R15, —C(═O)OR15, —C(═O)N(R15)2, —N(R15)C(═O)OR15, —N(R15)C(═O)R15, —N(R15)S(═O)tR15 (where t is 1 or 2), —S(═O)tOR15 (where t is 1 or 2), —S(═O)pR15 (where p is 0, 1 or 2), and —S(═O)tN(R15)2 (where t is 1 or 2) where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated.
“Alkoxy” refers to a radical of the formula —ORa where Ra is an alkyl radical as defined above containing one to twelve carbon atoms. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.
“Alkoxyalkyl” refers to a radical of the formula —Ra—O—Ra where each Ra is independently an alkyl radical as defined above. The oxygen atom may be bonded to any carbon in either alkyl radical. Each alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.
“Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, where the ring system may be partially or fully saturated. Aryl groups include, but are not limited to, groups such as fluorenyl, phenyl and naphthyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from the group consisting of alkyl, akenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)C(═O)N(R15)2, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
“Aralkyl” refers to a radical of the formula —RaRb where Ra is an alkyl radical as defined above and Rb is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. The aryl radical(s) may be optionally substituted as described above.
“Aralkenyl” refers to a radical of the formula —RcRb where Rc is an alkenyl radical as defined above and Rb is one or more aryl radicals as defined above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenyl part of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group.
“Aralkynyl” refers to a radical of the formula —RdRb where Rd is an alkynyl radical as defined above and Rb is one or more aryl radicals as defined above. The aryl part of the aralkynyl radical may be optionally substituted as described above for an aryl group. The alkynyl part of the aralkynyl radical may be optionally substituted as defined above for an alkynyl group.
“Aryloxy” refers to a radical of the formula —ORb where Rb is an aryl group as defined above. The aryl part of the aryloxy radical may be optionally substituted as defined above.
“Aralkyloxy” refers to a radical of the formula —ORb where Rb is an aralkyl group as defined above. The aralkyl part of the aralkyloxy radical may be optionally substituted as defined above.
“Ammonium ion” refers to a nitrogen within a compound of the invention containing a positive charge due to the additional substitution of the nitrogen with an optionally substituted alkyl group as defined above.
“Clathrates” as used herein refers to substances which fix gases, liquids or compounds as inclusion complexes so that the complex may be handled in solid form and the included constituent (or “guest” molecule) is subsequently released by the action of a solvent or by melting. The term “clathrate” is used interchangeably herein with the phrase “inclusion molecule” or with the phrase “inclusion complex”. Clathrates used in the instant invention are prepared from cyclodextrins. Cyclodextrins are widely known as having the ability to form clathrates (i.e., inclusion compounds) with a variety of molecules. See, for example, Inclusion Compounds, edited by J. L. Atwood, J. E. D. Davies, and D. D. MacNicol, London, Orlando, Academic Press, 1984; Goldberg, I., “The Significance of Molecular Type, Shape and Complementarity in Clathrate Inclusion”, Topics in Current Chemistry (1988), Vol. 149, pp. 2-44; Weber, E. et al., “Functional Group Assisted Clathrate Formation—Scissor-Like and Roof-Shaped Host Molecules”, Topics in Current Chemistry (1988), Vol. 149, pp. 45-135; and MacNicol, D. D. et al., “Clathrates and Molecular Inclusion Phenomena”, Chemical Society Reviews (1978), Vol. 7, No. 1, pp. 65-87. Conversion into cyclodextrin clathrates is known to increase the stability and solubility of certain compounds, thereby facilitating their use as pharmaceutical agents. See, for example, Saenger, W., “Cyclodextrin Inclusion Compounds in Research and Industry”, Angew. Chem. Int. Ed. Engl. (1980), Vol. 19, pp. 344-362; U.S. Pat. No. 4,886,788 (Schering AG); U.S. Pat. No. 6,355,627 (Takasago); U.S. Pat. No. 6,288,119 (Ono Pharmaceuticals); U.S. Pat. No. 6,110,969 (Ono Pharmaceuticals); U.S. Pat. No. 6,235,780 (Ono Pharmaceuticals); U.S. Pat. No. 6,262,293 (Ono Pharmaceuticals); U.S. Pat. No. 6,225,347 (Ono Pharmaceuticals); and U.S. Pat. No. 4,935,446 (Ono Pharmaceuticals).
“Cyclodextrin” refers to cyclic oligosaccharides consisting of at least six glucopyranose units which are joined together by α(1-4) linkages. The oligosaccharide ring forms a torus with the primary hydroxyl groups of the glucose residues lying on the narrow end of the torus. The secondary glucopyranose hydroxyl groups are located on the wider end. Cyclodextrins have been shown to form inclusion complexes with hydrophobic molecules in aqueous solutions by binding the molecules into their cavities. The formation of such complexes protects the “guest” molecule from loss of evaporation, from attack by oxygen, visible and ultraviolet light and from intra- and intermolecular reactions. Such complexes also serve to “fix” a volatile material until the complex encounters a warm moist environment, at which point the complex will dissolve and dissociate into the guest molecule and the cyclodextrin. For purposes of this invention, the six-glucose unit containing cyclodextrin is specified as α-cyclodextrin, while the cyclodextrins with seven and eight glucose residues are designated as β-cyclodextrin and γ-cyclodextrin, respectively. The most common alternative to the cyclodextrin nomenclature is the naming of these compounds as cycloamyloses.
“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantine, norbornane, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)C(═O)N(R15)2, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
“Cycloalkylalkyl” refers to a radical of the formula —RaRe where Ra is an alkyl radical as defined above and Re is a cycloalkyl radical as defined above. The alkyl radical and the cycloalkyl radical may be optionally substituted as defined above.
“Cycloalkylalkenyl” refers to a radical of the formula —RcRe where Rc is an alkenyl radical as defined above and Re is a cycloalkyl radical as defined above. The alkenyl radical and the cycloalkyl radical may be optionally substituted as defined above.
“Cycloalkylalkynyl” refers to a radical of the formula —RdRe where Rd is an alkynyl radical as defined above and Re is a cycloalkyl radical as defined above. The alkynyl radical and the cycloalkyl radical may be optionally substituted as defined above.
“Halo” refers to bromo, chloro, fluoro or iodo.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
“Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. The alkenyl part of the haloalkyl radical may be optionally substituted as defined above for an alkenyl group.
“Haloalkynyl” refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. The alkynyl part of the haloalkyl radical may be optionally substituted as defined above for an alkynyl group.
“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, azepinyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, hexahydro-1H-1,4-diazepinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxiranyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)C(═O)N(R15)2, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
“N-heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical may be optionally substituted as described above for heterocyclyl radicals.
“Heterocyclylalkyl” refers to a radical of the formula —RaRf where Ra is an alkyl radical as defined above and Rf is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The alkyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkyl group. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.
“Heterocyclylalkenyl” refers to a radical of the formula —RcRf where Rc is an alkenyl radical as defined above and Rf is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkenyl radical at the nitrogen atom. The alkenyl part of the heterocyclylalkenyl radical may be optionally substituted as defined above for an alkenyl group. The heterocyclyl part of the heterocyclylalkenyl radical may be optionally substituted as defined above for a heterocyclyl group.
“Heterocyclylalkynyl” refers to a radical of the formula —RdRf where Rd is an alkynyl radical as defined above and Rf is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkynyl radical at the nitrogen atom. The alkynyl part of the heterocyclylalkynyl radical may be optionally substituted as defined above for an alkynyl group. The heterocyclyl part of the heterocyclylalkynyl radical may be optionally substituted as defined above for a heterocyclyl group.
“Heteroaryl” refers to a 3- to 18-membered fully or partially aromatic ring radical which consists of one to thirteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, acridinyl, benzimidazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)C(═O)N(R15)2, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
“N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical may be optionally substituted as described above for heteroaryl radicals.
“Heteroarylalkyl” refers to a radical of the formula —RaRg where Ra is an alkyl radical as defined above and Rg is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group. The alkyl part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkyl group.
“Heteroarylalkenyl” refers to a radical of the formula —RcRg where Rc is an alkenyl radical as defined above and Rg is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkenyl radical may be optionally substituted as defined above for a heteroaryl group. The alkenyl part of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenyl group.
“Heteroarylalkynyl” refers to a radical of the formula —RdRg where Rd is an alkynyl radical as defined above and Rg is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkynyl radical may be optionally substituted as defined above for a heteroaryl group. The alkynyl part of the heteroarylalkynyl radical may be optionally substituted as defined above for an alkynyl group.
“Hydroxyalkyl” refers to an alkyl radical, as defined above, substituted by one or more hydroxy (—OH) groups. If the hydroxyalkyl radical is attached to a hetero atom (e.g., oxygen or nitrogen), a hydroxy group can not be attached to a carbon in the alkyl group which is directly attached to the hetero atom.
“Hydroxyiminoalkyl” refers to an alkyl radical, as defined above, substituted by a hydroxyimino (═NOH) group.
“Polymorph” refers to a polymorphic form of compound of the invention. Solids exist in either amorphous or crystalline forms. In the case of crystalline forms, molecules are positioned in 3-dimensional lattice sites. When a compound recrystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as “polymorphism,” with the different crystal forms individually being referred to as a “polymorph”. Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability. In the case of a chemical substance that exists in two (or more) polymorphic forms, the unstable forms generally convert to the more thermodynamically stable forms at a given temperature after a sufficient period of time. When this transformation is not rapid, the thermodynamically unstable form is referred to as the “metastable” form. In general, the stable form exhibits the highest melting point, the lowest solubility, and the maximum chemical stability. However, the metastable form may exhibit sufficient chemical and physical stability under normal storage conditions to permit its use in a commercial form. In this case, the metastable form, although less stable, may exhibit properties desirable over those of the stable form, such as enhanced solubility or better oral bioavailability.
“Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Desiqn of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the compounds of the invention and the like.
“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
“Mammal” includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like. Preferably, for purposes of this invention, the mammal is a human.
“Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
“Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
“Pharmaceutically acceptable salt” includes both acid and base addition salts.
“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
“Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, for example, humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients.
“Solvate” refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
“Therapeutically effective amount” refers to that amount of a compound of the invention that, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease or condition of interest in the mammal, preferably a human. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on, e.g., the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy, but it can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
“Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
(i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;
(ii) inhibiting the disease or condition, i.e., arresting its development;
(iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or
(iv) stabilizing the disease or condition.
As used herein, the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as for example, but not limited to, HPLC using a chiral column. When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.
The chemical naming protocol and structure diagrams used herein employ and rely on the Chemical Abstracts Service (CAS) rules. For complex chemical names employed herein, a substituent group is named before the group to which it attaches. For example, 2-cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. In chemical structure diagrams, all bonds are identified, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
For example, a compound of formula (I) wherein r is 0; q is 1; R1a, R1b, R1c, R1d and R1e are each hydrogen; R2 is methyl; R3 is —O—; R4a and R4b are both direct bonds; R4c is methylene; R5a, R5b, R5c, R6a, R6b, and R6c are each hydrogen; R7 is methyl; R8 is 4-carboxybenzyl; and R10 is hydrogen, i.e., a compound of the following formula:
is named herein as 4-[[methyl[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]methyl]benzoic acid.
Pharmaceutical Compositions of the Invention and Administration
Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
A pharmaceutical composition of the invention may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.
A liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 50% of the compound of the invention. Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of the compound prior to dilution of the invention.
The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w/v (weight per unit volume).
The pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
The pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.
The pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
The pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.
The pharmaceutical compositions of the invention may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors and can be determined routinely by one of ordinary skill in the art. Generally, a therapeutically effective daily dose is (for a 70 kg mammal) from about 0.001 mg/kg (i.e., 0.7 mg) to about 100 mg/kg (i.e., 7.0 gm); preferaby a therapeutically effective dose is (for a 70 kg mammal) from about 0.01 mg/kg (i.e., 7 mg) to about 50 mg/kg (i.e., 3.5 gm); more preferably a therapeutically effective dose is (for a 70 kg mammal) from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).
Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations. Where separate dosage formulations are used, the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
Utility of the Compounds of the Invention
The compounds of the invention are inhibitors of LTA4-h activity and are therefore useful in treating diseases and disorders which are ameliorated by the inhibition of LTA4-h activity. Such diseases and conditions include inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation.
Accordingly, the compounds are useful in the treatment of the following diseases or disorders in mammals, particularly humans: acute or chronic inflammation, anaphylactic reactions, allergic reactions, allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, fistulas associated with Crohn's disease, pouchitis, septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndromes induced by immunotherapy of cancer, acute respiratory distress syndrome, traumatic shock, immune- and pathogen-induced pneumonias, immune complex-mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases (including ulcerative colitis, Crohn's disease and post-surgical trauma), gastrointestinal ulcers, diseases associated with ischemia-reperfusion injury (including acute myocardial ischemia and infarction, acute renal failure, ischemic bowel disease and acute hemorrhagic or ischemic stroke), immune-complex-mediated glomerulonephritis, autoimmune diseases (including insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus), acute and chronic organ transplant rejection, transplant arteriosclerosis and fibrosis, cardiovascular disorders (including hypertension, atherosclerosis, aneurysm, critical leg ischemia, peripheral arterial occlusive disease and Reynaud's syndrome), complications of diabetes (including diabetic nephropathy, neuropathy and retinopathy), ocular disorders (including macular degeneration and glaucoma), neurodegenerative disorders (including delayed neurodegeneration in stroke, Alzheimer's disease, Parkinson's disease, encephalitis and HIV dementia), inflammatory and neuropathic pain including arthritic pain, periodontal disease including gingivitis, ear infections, migraine, benign prostatic hyperplasia, and cancers (including, but not limited to, leukemias and lymphomas, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head and neck tumors and colorectal cancer).
The compounds are also useful in treating folliculitis induced by inhibitors of epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) kinase used in the treatment of solid tumors. Clinical trials have revealed folliculitis (inflammation of the hair follicle manifested by severe acne-like skin rash on the face, chest and upper back) as a major dose-limiting side effect of such treatments. Such folliculitis is associated with an infiltration of neutrophils suggesting products secreted by activated neutrophils to be the cause of the inflammation. The compounds of the invention inhibit neutrophil or eosinophil-mediated inflammation, and are therefore useful in treating such folliculitis, thereby improving the quality of life of the treated cancer patients but also allowing for the increase of the dosage of the EGF inhibitor or EGFR kinase inhibitor or the extension of the duration of the treatment, resulting in improved efficacy of the desired inhibitor.
The compounds are also useful in the treatment of pulmonary and respiratory inflammation disorders in mammals, particularly humans, including, but not limited to, asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans (including such with organizing pneumonia), allergic inflammation of the respiratory tract (including rhinitis and sinusitis), eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary diseases, adult respiratory distress syndrome, and other non-infectious inflammatory disorders of the lung characterized by eosinophil infiltration.
For example, the compounds of the invention are useful in the inhibition of: eosinophil-mediated inflammation of the lung or tissues; neutrophil-mediated inflammation of the lung; lymphocyte-mediated inflammation of the lung; airway hyper-responsiveness; and airway and vascular inflammation.
The compounds are also useful in the treatment of myocardial infarction or susceptibility to myocardial infarction in mammals, particularly humans, transient ischemic attack, transient monocular blindness, stroke or susceptibility of stroke, claudication, peripheral arterial occlusive disease or susceptibility to peripheral arterial occlusive disease, and acute coronary syndrome (such as unstable angina, non-ST-elevation myocardial infarction or ST-elevation myocardial infarction). The compounds are also useful in the methods for reducing the risk of myocardial infarction, stroke or peripheral arterial occlusive disease in mammals and reducing the risk of a second myocardial infarction or stroke.
The compounds are also useful in the treatment of atherosclerosis in mammals, particularly humans who require treatment (such as angioplasty, stents, coronary artery bypass graft) in order to restore blood flow in the arteries (such as in the coronary arteries).
The compounds are also useful in inhibiting the synthesis of leukotriene B4 in both in vitro and in vivo assays.
Testing of the Compounds of the Invention
The compounds of the invention were tested for their ability to inhibit LTA4-h by various known assays and by assays described herein. For example, the compounds were tested for their ability to inhibit LTA4-h activity by assaying the compounds in the hydrolase-homogeneous time resolved fluoroescence assay. This assay, which is a two-step assay, measures the hydrolysis of LTA4 to LTB4 by analyzing the amount of LTB4 produced. The first step involves the enzymatic conversion of LTA4 to LTB4 and the second step involves the quantification of the LTB4 formed with a homogeneous time resolved fluoroescence assay.
Since LTA4 hydrolase is grouped with the M1 family of zinc metalloproteases (see, Rudberg, P. C. et al., J. Biol. Chem. 2002, Vol. 277, page 1398-1404), the compounds of the invention can be tested in the standard hydrolase and peptidase assay to determine the compounds' kinetic constants for binding to LTA4 hydrolase and for inhibiting LTB4 synthesis (see Askonas, L. J., et al., The Journal of Pharmacology and Experimental Therapeutics 2002, 300(2): 577-582; Penning, T. D., J. Med. Chem. 2000, 43(4): 721-735; Kull, F. et al., The Journal of Biological Chemistry 1999, 274 (49): 34683-34690).
Compounds of the invention can also be tested for their ability as inhibitors of LTA4 hydrolase in the whole blood assay using human, mouse, rat or dog whole blood (see Penning, T. D. et al., J. Med. Chem. 2000, 43(4): 721-735 for a description of a human whole blood assay and a mouse whole blood assay).
A hallmark of inflammation is the adhesion and transmigration across endothelium of neutrophils, eosinophils and other inflammatory cells. A similar process is observed for the migration of cells across polarized epithelial cells that occur in the lung, gastrointestinal tract and other organs. Cell culture models of these processes are available and can be used to show the ability of the compounds of the invention to inhibit the transmigration of human neutrophils across human endothelial cells and epithelial cells, including the human intestinal epithelial cell line T84. Accordingly, one of ordinary skill in the art can test the compounds of the invention for their ability to inhibit the transmigration of human neutrophils and eosinophils across human endothelial cells and epithelial cells by performing assays similar to those described in Colgan, S. P., et al., J. Clin. Invest. 1993, Vol. 92, No. 1, pp. 75-82; Serhan, C. N., et al., Biochemistry 1995, Vol. 34, No. 44, pp.14609-14615.
The air pouch model and/or the mouse zymosan-induced peritonitis model may be used to evaluate the in vivo efficacy of the compounds of the invention in treating an inflammatory response. These are acute experimental models of inflammation characterized by infiltration of inflammatory cells into a localized area. See, e.g., the in vivo assays described in Ajuebor, M. N., et al., Immunology 1998, Vol. 95, pp. 625-630; Gronert, K., et al., Am. J. Pathol. 2001, Vol. 158, pp. 3-9; Pouliot, M., et al., Biochemistry 2000, Vol. 39. pp. 4761-4768; Clish, C. B., et al., Proc. Natl. Acad. Sci. U.S.A. 1999, Vol. 96, pp. 8247-8252; Hachicha, M., et al., J. Exp. Med. 1999, Vol. 189, pp. 1923-30.
Animal models (i.e., in vivo assays) may also be utilized to determine the efficacy of the compounds of the invention in treating asthma and related disorders of the pulmonary and respiratory tract, including, but not limited to, asthma. See, e.g., the assays described in De Sanctis, G. T. et al., Journal of Clinical Investigation 1999, Vol. 103, pp. 507-515; and Campbell, E. M., et al., J. Immunol. 1998, Vol.161, No. 12, pp. 7047-7053.
Exemplary Embodiments of the Invention
Another aspect of the invention are the compounds of Formula (I-1)), as single stereoisomers or as mixtures of stereoisomers, and the pharmaceutically acceptable salts, solvates, polymorphs, clathrates, ammonium ions, N-oxides or prodrugs thereof, as set forth above in the Summary:
Another aspect of the invention are the compounds of Formula (I-2), as single stereoisomers or as mixtures of stereoisomers, and the pharmaceutically acceptable salts, solvates, polymorphs, clathrates, ammonium ions, N-oxides or prodrugs thereof, as set forth above in the Summary:
Another aspect of the invention are the compounds of Formula (I-3), as single stereoisomers or as mixtures of stereoisomers, and the pharmaceutically acceptable salts, solvates, polymorphs, clathrates, ammonium ions, N-oxides or prodrugs thereof, as set forth above in the Summary:
Another aspect of the invention are the compounds of Formula (I-4), as single stereoisomers or as mixtures of stereoisomers, and the pharmaceutically acceptable salts, solvates, polymorphs, clathrates, ammonium ions, N-oxides or prodrugs thereof, as set forth above in the Summary:
Another aspect of the invention are the compounds of Formula (I-5), as single stereoisomers or as mixtures of stereoisomers, and the pharmaceutically acceptable salts, solvates, polymorphs, clathrates, ammonium ions, N-oxides or prodrugs thereof, as set forth above in the Summary:
Accordingly, one embodiment of the compounds of Formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a, R1b, R1c, R1d and R1e are each independently selected from the group consisting of hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; each R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11 alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; each R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Another embodiment of the compounds of formula (I-B) are those compounds wherein r is 0; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b , R1c, R1d and R1e are each independently hydrogen or halo; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain; each R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of formula (I-B) are those compounds wherein r is 0; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain; R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2);
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a, R1b, R1c, R1d and R1e are each independently selected from the group consisting of hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11 alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; or R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R7, together with the nitrogens to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Another embodiment of the compounds of formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11 alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; or R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R7, together with the nitrogens to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-B) are those compounds wherein R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl.
Another embodiment of the compounds of Formula (I-B) are those compounds having the following formula (I-B-1):
wherein r is 0 to 4; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11 alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; each R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R6a together, R5b and R6b together, or R5c and R6c together may form an oxo; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of compounds of Formula (I-B-1) include the following: 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid;
Another embodiment of the compounds of formula (I) are those compounds wherein R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted piperazinyl or an optionally substituted tetrahydropyrimidinyl.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of Formula (I-B) are those compounds wherein R2 and R7, together with the nitrogen to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl.
Another embodiment of the compounds of Formula (I-B) are those compounds having the following formula (I-B-2):
wherein r is 0 to 4; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11 alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of compounds of Formula (I-B-2) include the following:
Another embodiment of the compounds of Formula (I-B) are those compounds wherein r is 0 to 4; q is 1 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; or R1a and R1d, together with the carbons to which they are attached, form an optionally substituted heteroaryl or optionally substituted heterocyclyl, and R1b and R1c are each independently hydrogen or halo; R2 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; each R5b, R5c, R6a, R6b and R6c is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of formula (I-B) are those compounds wherein r is 0 to 4; q is 1 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; or R1a and R1d, together with the carbons to which they are attached, form an optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; each R5a, R5b, R6a, R6b and R6c is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of Formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R2 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; each R5a, R5c, R6a, R6b and R6c is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, cyano, nitro, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, —R14—OR11, —R14—N(R11)R12, —R14—N(R11)C(═O)R11 and —R14N(R11)C(═O)OR11; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of Formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; each R5a, R5c, R6a, R6b and R6c is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of Formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl; or R2 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; each R5b, R5c, R6a, R6b and R6c is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Another embodiment of the compounds of Formula (I-B) are those compounds wherein r is 0 to 4; q is 0 to 2; R1a is hydrogen, —R14—OR11, —R14—C(═O)OR11, —R14—C(═O)R11, alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl; optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R1b, R1c, R1d and R1e are each independently hydrogen or halo; R2 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; each R5a, R5b, R6a, R6b and R6c is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is an optionally substituted straight or branched alkylene chain; and each R14 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific embodiments of this embodiment include the following compounds:
Accordingly, one embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a, R4b and R4c are each independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—O—R11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a and R4b are each a direct bond; R4c is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O))OR11; or R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11 )R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Specific examples of this embodiment include the following compounds:
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain; R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R7, together with the nitrogens to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a, R4b and R4c are each independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R7, together with the nitrogens to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl.
Another embodiment of the compounds of formula (I-C) are those compounds having the following formula(I-C-1):
wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R6a together, R5b and R6b together, or R5c and R6c together may independently form an oxo; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Specific examples of this embodiment include the following compound:
Another embodiment of the compounds of formula (I-C) are those compounds wherein R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted piperazinyl or an optionally substituted tetrahydropyrimidinyl.
Another embodiment of the compounds of formula (I-C) are those compounds wherein R2 and R7, together with the nitrogen to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl.
Another embodiment of the compounds of formula (I-C) are those compounds having the following formula (I-C-2):
wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 1 or 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 1 or 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, cyano, nitro, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, —R14—OR11, —R14—N(R11)R12, —R14—N(R11)C(═O)R11 and —R14N(R11)C(═O)OR11; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 0 to 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 1 or 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-C) are those compounds wherein n1, n2 and n3 are each independently 0 to 2; r is 0 to 4; q is 1 or 2; R1v, R1w, R1x, R1y and R1z are each independently hydrogen or fluoro; R2 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
D. Another aspect of the invention are the compounds of Formula (I) having Formula (I-D):
wherein RHet is an optionally substituted heteroaryl as defined in the Definitions hereinabove, and the remaining substituents are as described above in the Summary.
Accordingly, one embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a, R4b and R4c are each independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; R10 is selected from the group consisting of hydrogen and alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a and R4b are each a direct bond; R4c is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Specific examples of this embodiment include the following compounds:
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a and R4b are each a direct bond; R4c is a direct bond or an optionally substituted straight or branched alkylene chain; R5a and R5b, together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; or R5b and R6b, together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl; R7 is selected from the group consisting of hydrogen, —R13—R11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R7, together with the nitrogens to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4a, R4b and R4c are each independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R7, together with the nitrogens to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each a direct bond or an optionally substituted straight or branched alkylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl.
Another embodiment of the compounds of formula (I-D) are those compounds having the following formula (I-D-1):
wherein r is 0 to 4; RHet is optionally substituted heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched lkylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; or R5a and R6a together, R5b and R6b together, or R5c and R6c together may independently form an oxo; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein R2 and R7, together with the nitrogens to which they are attached, form an optionally substituted piperazinyl or an optionally substituted tetrahydropyrimidinyl.
Another embodiment of the compounds of formula (I-D) are those compounds wherein R2 and R7, together with the nitrogen to which they are attached and one of R5a, R5b and R5c, form an optionally substituted 6- to 10-membered bridged N-heterocyclyl.
Another embodiment of the compounds of formula (I-D) are those compounds having the following formula (I-D-2):
wherein r is 0 to 4; RHet is optionally substituted heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; RHet is optionally substituted heteroaryl; R2 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5b, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those wherein r is 0 to 4; q is 0 to 2; RHet is an optionally substituted heteroaryl; R2 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted piperidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; or R2 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted pyrrolidinyl or an optionally substituted piperidinyl; R3 is a direct bond, —O—R12—, or an optionally substituted straight or branched alkylene chain; R4 is a direct bond, —O—R12a—, or an optionally substituted straight or branched alkylene chain; R5a, R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl or hydroxyalkyl; R7 is selected from the group consisting of hydrogen, —R14—OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R14—N(R10)C(═O)N(R10)R11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is hydrogen or aralkyl optionally substituted with one or more substituents selected from the group consisting of —R13—OR10, —R13—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, or —R13—C(═O)N(R10)—R14—N(R10)R11; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 and R11 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R10 and R11, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R12 is an optionally substituted straight or branched alkylene chain; R12a is an optionally substituted straight or branched alkylene chain; each R13 is a direct bond or an optionally substituted straight or branched alkylene chain; and each R14 is an optionally substituted straight or branched alkylene chain.
More specific embodiments of this aspect of the invention are compounds of formula (I) having the following formulas (I-D-4) and (I-D-5):
wherein r is 0 to 4; RHet is an optionally substituted heteroaryl; R3 is a direct bond, —O—, —R12—O—, —O—R12—, —O—R12—O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R4 is a direct bond, —O—R12a—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R13—OR10, —R13—O—R14—C(═O)OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R14—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), or —R14—S(═O)pR10 (where p is 0, 1 or 2); or R8 is aralkyl optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, optionally substituted heteroaryl, hydroxyiminoalkyl, —R13—OR10, —R13—C(═O)R10, —R13—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—C(═O)N(R10)—R14—N(R10)R11, —R13—S(═O)tN(R10)R11 (where t is 1 or 2), —R13—N(R10)R11, —R13—N(R10)C(═O)R10, —R13—N(R10)C(═O)—R13—N(R10)R11, —R13—N(R10)—R14—C(═O)R10, —R13—N(R10)C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2), —R13—N(R10)C(═O)—R13—N(R10)C(═O)R10, —R13—N(R10)C(═O)—R13—N(R10)—R14—N(R10)R11, —R13—N(R10)S(═O)tN(R10)R11 (where t is 1 or 2), and —R13—O—R14—C(═O)OR10; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 and R11 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R10 and R11, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R12 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R12a is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; each R13 is a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and each R14 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain.
Specific embodiments of the compounds of formulas (I-D-4) and (I-D-5) are those compounds wherein r is 0 to 4; RHet is an optionally substituted heteroaryl; R3 is a direct bond, —O—, —R12—O—, —O—R12—, —O—R12—O—, or an optionally substituted straight or branched alkylene chain; R4 is a direct bond; R8 is selected from the group consisting of —R13—C(═O)—R14—C(═O)OR10 or —R13—C(═O)—R14—S(═O)tN(R10)R11 (where t is 1 or 2); or R8 is aralkyl optionally substituted with one or more substituents selected from the group consisting of —R13OR10, —R13—C(═O)OR10, —R13—C(═O)—R13—N(R10)R11, —R13—N(R10)C(═O)R10, and —R13—N(R10)C(═O)—R13—N(R10)R11; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 and R11 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R10 and R11, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R12 is an optionally substituted straight or branched alkylene chain; R12a is an optionally substituted straight or branched alkylene chain; each R13 is a direct bond or an optionally substituted straight or branched alkylene chain; and each R14 is an optionally substituted straight or branched alkylene chain.
More specific embodiments of the compounds of formulas (I-D-4) and (I-D-5) are those compounds wherein; r is 0; RHet is an optionally substituted monocyclic or bicyclic heteroaryl; R3 is a direct bond, —O—, —R12—O—, —O—R12—, —O—R12—O—, or an optionally substituted straight or branched alkylene chain; R4 is a direct bond; R8 is benzyl substituted with one or more of —R13—OR10 and —R13—C(═O)OR10; each R10 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; R12 is a C1-6-alkylene chain (optionally substituted with one or more substituents selected from the group consisting of —OR10); R12a is a methylene, ethylene or propylene chain (optionally substituted with one or more substituents selected from the group consisting of —OR10); and each R13 is a direct bond or an optionally substituted straight or branched alkylene chain.
Specific examples of these embodiments include the following compound:
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; RHet, is optionally substituted heteroaryl; R2 is hydrogen, —RO3—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, cyano, nitro, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, —R14—OR11, —R14—N(R11)R12, —R14—N(R11)C(═O)R11 and —R14N(R11)C(═O)OR11; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 0 to 2; RHet is optionally substituted heteroaryl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R11)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5c, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5b, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 1 or 2; RHet is optionally substituted heteroaryl; R2 is hydrogen, —R13—OR11, —R13—N(R11)R12, —R14—C(═O)OR11, —R14—C(═O)N(R12)R12, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or R2 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; or R2 and R8, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; R5b, R5c, R6a, R6b and R6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 and R5a, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11)R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (I-D) are those compounds wherein r is 0 to 4; q is 1 or 2; RHet is optionally substituted heteroaryl; R2 and R5c, together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl; R3 is a direct bond, —O—, —R13—O—, —O—R13—, —O—R13—O—, or an optionally substituted straight or branched alkylene chain; R4a, R4b and R4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain; R5a, R5b, R6a, R6b and R6c are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R14—C(═O)OR11; R7 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)R11, —R14—C(═O)OR11, —R14—C(═O)—R14—N(R11)R12, —R13—N(R11)C(═O)N(R11)R12, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, and optionally substituted heterocyclylalkyl; R8 is selected from the group consisting of hydrogen, —R13—OR11, —R14—C(═O)OR11, —R14—S(═O)pR11 (where p is 0, 1 or 2), —R14—C(═O)R12, —R14—C(═O)N(R11 )R12, —R13—O—R14—C(═O)OR11, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; each R9 is independently —O—R10, alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl; each R10 is independently hydrogen or alkyl; each R11 and R12 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or R11 and R12, together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently an optionally substituted straight or branched alkylene chain; and each R14 is independently a direct bond or an optionally substituted straight or branched alkylene chain.
Another aspect of the invention, as set forth above in the Summary, are methods of treating a disease or disorder ameliorated by the inhibition of LTA4-h activity in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of compound of Formula (I), as set forth above in the Summary.
Of this aspect, one embodiment is wherein the disease or disorder is selected from the group consisting of acute inflammation, chronic inflammation, anaphylactic reactions, allergic reactions, allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, fistulas associated with Crohn's disease, pouchitis, septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndromes induced by immunotherapy of cancer, acute respiratory distress syndrome, scleroderma lung disease, traumatic shock, immune- and pathogen-induced pneumonias, immune complex-mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, post-surgical trauma, gastrointestinal ulcers, diseases associated with ischemia-reperfusion injury, acute myocardial ischemia, infarction, acute renal failure, ischemic bowel disease, acute hemorrhagic or ischemic stroke, immune-complex-mediated glomerulonephritis, autoimmune diseases, insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, acute and chronic organ transplant rejection, transplant arteriosclerosis, transplant fibrosis, cardiovascular disorders, hypertension, atherosclerosis, aneurysm, critical leg ischemia, peripheral arterial occlusive disease, Reynaud's syndrome, diabetic nephropathy, neuropathy, retinopathy, macular degeneration, glaucoma, neurodegenerative disorders, delayed neurodegeneration in stroke, Alzheimees disease, Parkinson's disease, encephalitis, HIV dementia, inflammatory pain, neuropathic pain, arthritic pain, periodontal disease, gingivitis, ear infections, migraine, benign prostatic hyperplasia, cancer, leukemias, lymphomas, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head tumors, neck tumors and colorectal cancer.
The various embodiments described above are described in more detail herein.
Preparation of the Compounds of the Invention
The following Reaction Schemes illustrate methods to make compounds of this invention, i.e., compounds of formula (I):
where r, q, R, R2, R3, R4, R4b, R4c, R5a, R5b, R5c, R6a, R6b, R6c, R7, R8, R9 and R10 are described above in the Summary, as single stereoisomers or as a mixture of stereoisomers, and the pharmaceutically acceptable salts, solvates, polymorphs, ammonium ions, N-oxides or prodrugs thereof. It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyidiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, alkyl and the like. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include —C(═O)—R″ (where R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.
Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein.
The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds of this invention are included within the scope of the invention.
It is understood that one of ordinary skill in the art would be able to make the compounds of the invention by methods simliar to the methods described herein or by methods known to one of ordinary skill in the art. It is also understood that one of ordinary skill in the art would be able to make in a similar manner as described below other compounds of formula (I) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, compounds employed as initial starting materials in the synthesis of the compounds of the invention are well known and commercially available, e.g., from Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. To the extent that the compounds employed as initial starting materials are not commercially available, the compounds may be readily synthesized using specific references provided, or by standard procedures commonly employed by those of ordinary skill in the art and/or found in general references text (see, for example, Comprehensive Organic Transformations, VCH Publishers Inc., 1989; Compendium of Organic Synthetic Methods, Volumes 1-10, 1974-2002, Wiley Interscience; Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, Wiley Interscience, 2001; Advanced Organic Chemistry, 4th Edition, Part B, Reactions and Synthesis, Kluwer Academic/Plenum Publishers, 2000, etc.; and references cited therein).
It is also understood that the various R groups on the structures in the following Reaction Schemes are to be selected or combined in a manner consistent with the synthesis depicted in order to produce the desired product as a stable compound.
In the following Reaction Schemes and description thereof, the following common abbreviations are used:
DMF for N,N-Dimethylformamide
DIEA for diisopropylethylamine
THF for tetrahydrofuran
TFA for trifluoroacetic acid
EtOAc for ethyl acetate
TMS for trimethylsilyl
TLC for thin layer chromatography
EtOAc for ethyl acetate
MeOH for methanol
NaOH for sodium hydroxide
Boc for t-butoxycarbonyl
A. Preparation of Compounds of Formula (Ia)
Compounds of formula (Ia) are compounds of formula (I) and can be prepared as described below in Reaction Scheme 1A wherein a is 1 to 5; r, R, R3, R9 and R10 are as defined above in the Summary; R4c is a straight or branched alkylene chain; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and X is independently bromo or chloro:
Compounds of formula (A) are optionally substituted N-heterocyclics or optionally substituted bridged N-heterocyclics and include, for example, the following compounds:
Compounds of formula (A) are commercially available, or can be prepared by methods known to one skilled in the art. Compounds of formula (B) are also commercially available, or can be prepared according to methods known to one skilled in the art, or by methods disclosed herein. For example, as set forth in the following reaction scheme, compounds of formula (B) can be prepared by treating a compound of formula (Ba), which is commercially available, with the appropriate brominating or chlorinating agent under standard conditions to form a compound of formula (B) where X is bromo or chloro:
Compounds of formula (D) can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (A) are reacted with an equivalent amount of a compound of formula (B) at ambient temperatures in the presence of base to generate compounds of formula (C), which are isolated from the reaction mixture by standard isolation techniques, such as chromatography. Compounds of formula (C) can then be coupled with compounds of formula (D) at ambient temperatures in the presence of base to generate compounds of formula (Ia), which can be isolated from the reaction mixture by standard isolation techniques, such as chromatography.
Alternatively, one of the nitrogens in the compound of formula (A) can first be protected under standard nitrogen-protecting techniques. The nitrogen-protected compound of formula (A) can then be treated with the compound of formula (B) as described above to form the corresponding nitrogen-protected compound of formula (C). Prior to the reaction with the compound of formula (D) to generate the compound of formula (Ia1), the nitrogen-protecting group can be removed from the compound of formula (C) under standard nitrogen deprotection procedures to form the free base.
Alternatively, compounds of formula (Ia) can be prepared by the method disclosed in Reaction Scheme 1B below wherein a, r, R, R2, R3, R4a, R4, R4c, R5a, R5b, R5c, R7, R8, R9, R10, and X are as defined above in Reaction Scheme 1A:
Compounds of formula (A) and (F) are commercially available or can be prepared by methods known to one skilled in the art. Compounds of formula (D) can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ia) are prepared by first treating a compound of formula (A) with a compound of formula (D) under standard alkylation conditions to generate a compound of formula (E). Compounds of formula (E) are then treated under standard reductive amination conditions with a compound of formula (F) to produce a compound of formula (Ia), which can be isolated from the reaction mixture by standard isolation techniques, such as precipitation, crystallization and/or chromatography.
Compounds of formula (Ia) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ia) wherein R8b is a carboxylic acid group.
The following Reaction Schemes provide additional disclosure on how to make the compounds of the invention.
B. PreParation of Compounds of Formula (Ia1)
Compounds of formula (Ia1) are compounds of formula (I) and are prepared as described below in Reaction Scheme 2 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R4c is an alkylene chain; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each X is independently bromo or chloro:
Compounds of formula (Ia1), (1b), (2a) and (2b) are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ia1) are prepared by first treating a compound of formula (1a) with a compound of formula (1b) under standard amidation conditions to yield of a compound of formula (1), which is isolated from the reaction mixture by standard isolation procedures. The compound of formula (2a) is treated with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (2), which is isolated from the reaction mixture by standard isolation procedures. The compound of formula (1) so formed is then treated with the compound of formula (2b) so formed under standard alkylation conditions to form a compound of formula (Ia1), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ia1) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ia1) wherein R8b is a carboxylic acid group.
C. Preparation of Compounds of Formula (Ib)
Compounds of formula (Ib) are compounds of formula (I) and are prepared as described below in Reaction Scheme 3 wherein a is 1 to 5; r, R, R3, R4c, and R9 are as defined above in the Summary; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and X is bromo or chloro:
Compound of formula (3a), (2b) and (1) are commercially available, or can be prepared according to methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ib) are prepared by first treating a compound of formula (3a) with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (3b), which is isolated from the reaction mixture by standard isolation procedures. The protecting group on the compound of formula (3b) is then removed under standard deprotecting conditions to form a compound of formula (3), which is isolated from the reaction mixture by standard isolation procedures. The compound of formula (3) is then treated with a compound of formula (1) under standard alkylation conditions to produce a compound of formula (Ib), which can be isolated from the reaction mixture by standard isolation procedures.
Compounds of formula (Ib) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ib) wherein R8b is a carboxylic acid group.
D. Preparation of Compounds of Formula (Ic)
Compounds of formula (Ic) are compounds of formula (I) and are prepared as described below in Reaction Scheme 4 wherein wherein r, R, R3, and R9 are as defined above in the Summary; R8a is a straight or branched alkylene chain; R4c is an alkylene chain; and X is bromo or chloro:
Compounds of formula (1) and (4) are commercially available, or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, componds of formula (Ic) are prepared by treating a compound of formula (1) with a compound of formula (4) under standard alkylation conditions to form a compound of formula (Ic), which can be isolated from the reaction mixture by standard isolation techniques.
E. Preparation of Comnounds of Formula (Id1) and (Id2)
Compounds of formula (Id1) and (Id2) are compounds of formula (I) and are prepared as described below in Reaction Scheme 5 wherein r, q, R, R2, R3, R5a, R5b, R5c, R6a, R6b, R6c, R7, R9, R11 and R14 are as defined above in the Summary; R4c is an alkylene chain; and X is bromo or chloro:
Compounds of formula (1), (5) and (6) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Id1) and (Id2) are prepared by first treating a compound of formula (5) with a compound of formula (1) under standard alkylation conditions to form a compound of formula (Id1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Id1) is then treated with a compound of formula (6) under standard alkylation conditions to form a compound of formula (Id2), which is isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Id2) wherein R11 is not hydrogen can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Id2) wherein R11 is hydrogen.
F. Preparation of Compounds of Formula (Ie1), (Ie2) and (Ia1)
Compounds of formula (Ie1), (Ie2) and (Ia1) are compounds of formula (I) and are prepared as described below in Reaction Scheme 6 wherein wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; Pg is a nitrogen-protecting group; and R4c is an alkylene chain:
Compounds of formula (1), (7) and (2b) are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ie1), (Ie2) and (Ia1) are prepared by first treating a compound of formula (1) with a compound of formula (7) under standard alkylation conditions to form a compound of formula (Ie1), which can be isolated from the reaction mixture by standard isolation techniques. The nitrogen-protecting group is then removed from the compound of formula (Ie1) under standard conditions to form a compound of formula (Ie2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ie2) is then treated with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (Ia1), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ia1) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ia1) wherein R8b is a carboxylic acid group.
G. Preparation of Compounds of Formula (If)
Compounds of formula (If) are compounds of formula (I) and are prepared as described below in Reaction Scheme 7 wherein wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and R4c is an alkylene chain:
Compounds of formula (Ie2) and formula (9) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (If) are prepared by treating a compound of formula (Ie2) with the isocyanate compound of formula (9) under standard urea formation conditions to form a compound of formula (If), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (If) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (If) wherein R8b is a carboxylic acid group.
H. Preparation of Compounds of Formula (Ig1), (Ig2), (Ig3) and (Ig4)
Compounds of formula (Ig1), (Ig2), (Ig3) and (Ig4) are compounds of formula (I) and are prepared as described below in Reaction Scheme 8 wherein a is 1 to 5; r, q, R, R2, R3, R5a, R5b, R5c, R6a, R6b, R6c, R7, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is an oxygen-protecting group; and each X is independently bromo or chloro:
Compounds of formula (10), (1b), (12) and (13) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ig1), (Ig2), (Ig3) and (Ig4) are prepared by first treating a compound of formula (10) with a compound of formula (1b) under standard acylation conditions to form a compound of formula (11), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (II) is then treated with a compound of formula (5) under standard alkylation conditions to form a compound of formula (Ig1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ig1) is then treated with a compound of formula (12) under standard reductive amination conditions, preferably in an aprotic solvent in the presence of a selective reducing agent, such as sodium triacetoxyborohydride, at ambient temperature, to form a compound of formula (Ig2), which can be isolated from the reaction mixture by standard isolation techniques. The oxygen-protecting group is then removed from the compound of formula (Ig2) under standard conditions to yield a compound of formula (Ig3), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ig3) is then treated with a compound of formula (13) under standard Williamson ether synthesis conditions to form a compound of formula (Ig4), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ig2), (Ig3) or (Ig4) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ig2), (Ig3) or (Ig4) wherein R8b is a carboxylic acid group.
I. Preparation of Compounds of Formula (Ih1), (Ih2) and (Ih3)
Compounds of formula (Ih1), (Ih2) and (Ih3) are compounds of formula (I) and are prepared as described below in Reaction Scheme 9 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R15—N(R15) S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen protecting group; and X is bromo or chloro:
Compounds of formula (1), (14), and (15) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ih1), (Ih2) and (Ih3) are prepared by first treating a compound of formula (1) with a compound of formula (14) under standard alkylation conditions to form a compound of formula (Ih1), which can be isolated from the reaction mixture by standard isolation techniques. The nitrogen protecting group is removed from the compoundo of formula (Ih1) to form a compound of formula (Ih2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ih2) is then treated with a compound of formula (15) under standard acylation conditions to form a compound of formula (Ih3), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ih3) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ih3) wherein R8b is a carboxylic acid group.
J. Preparation of Compounds of Formula (Ii)
Compounds of formula (Ii) are compounds of formula (I) and are prepared as described below in Reaction Scheme 10 wherein a is 1 to 5; r, q, R, R2, R3, R5a, R5b, R5c, R6a, R6b, R6c, R7, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16OC(═O)—R15, —R16—N(R15)2, —R16C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and R4c is an alkylene chain:
Compounds of formula (Id1) and (9) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ii) are prepared by treating a compound of formula (Id1) with a compound of formula (9) under standard urea formation conditions to form a compound of formula (Ii), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ii) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ii) wherein R8b is a carboxylic acid group.
K. Preparation of Compounds of Formula (Ij)
Compounds of formula (Ij) are compounds of formula (I) and are prepared as described below in Reaction Scheme 11 wherein wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and X is bromo or chloro:
Compounds of formula (16), (2b), and (1) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ij) can be prepared by first treating a compound of formula (16) with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (17), which can be isolated from the reaction mixture by standard isolation techniques. The nitrogen-protecting group on the compound of formula (17) is then removed under standard conditions to form a compound of formula (18), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (18) is then treated with a compound of formula (1) under standard alkylation conditions to form a compound of formula (Ij), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ij) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ij) wherein R8b is a carboxylic acid group.
L. Preparation of Compounds of Formula (Ik1), (Ik2), (Ik3), (Ik4) and (Ik5)
Compounds of formula (Ik1), (Ik2), (Ik3), (Ik4) and (Ik5) are compounds of formula (I) and are prepared as described below in Reaction Scheme 12 wherein a is 1 to 5; r, q, R, R3, R5a, R5b, R5c. R6a, R6b, R6c, R7, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and each X is independently chloro or bromo:
Compounds of formula (1), (5a), (19), (12) and (20) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ik1), (Ik2), (Ik3), (Ik4) and (Ik5) are prepared by first treating a compound of formula (1) with a compound of formula (5a) under standard alkylation conditions to form a compound of formula (Ik1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ik1) is then treated with a compound of formula (19) under standard alkylation or acylation conditions (depending on what R7 is) to yield a compound of formula (Ik2), which can be isolated from the reaction mixture by standard isolation techniques. The nitrogen-protecting group on the compound of formula (Ik2) is then removed under standard conditions to yield a compound of formula (Ik3), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ik3) is then treated with a compound of formula (12) under standard reductive amination conditions to form a compound of formula (Ik4), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Ik4) is then treated with a compound of formula (20) under standard reductive amination conditions to produce a compound of formula (Ik5), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ik4) or (Ik5) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ik4) or (Ik5) wherein R8b is a carboxylic acid group.
M. Preparation of Compounds of Formula (II1), (II2) and (II3)
Compounds of formula (II1), (II2) and (II3) are compounds of formula (I) and are prepared as described below in Reaction Scheme 13 wherein b is 1 to 4; r, R, R3, and R9 are as defined above in the Summary; R7a is hydrogen, alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; each R8c is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and X is bromo or chloro:
Compounds of formula (21) are optionally substituted N-heterocyclics or optionally substituted bridged N-heterocyclics and include, for example, the following optionally substituted compounds:
Compounds of formula (1), (21), and (22) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (II1), (II2) and (II3) are prepared by first treating a compound of formula (1) with a compound of formula (21) under standard alkylation conditions to form a compound of formula (II1), which can be isolated from the reaction mixture by standard isolation techniques. The nitrogen-protecting group on the compound of formula (II1) is then removed under standard conditions to form a compound of formula (II2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (II2) is then treated with a compound of formula (22) under standard nucleophilic aromatic substitution conditions to form a compound of formula (II3), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (II3) wherein R8c is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (II3) wherein R8c is a carboxylic acid group.
N. Preparation of Compounds of Formula (Im)
Compounds of formula (Im) are compounds of formula (I) and are prepared as described below in Reaction Scheme 14 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R7a is alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—R15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and X is bromo or chloro:
Compounds of fornula (23) are optionally substituted N-heterocyclics or optionally substituted bridged N-heterocyclics and include, for example, the following optionally substituted compounds:
Compounds of formula (23), (2b), and (1) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Im) are prepared by first treating a compound of formula (23) with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (24), which can be isolated from the reaction mixture by standard isolation techniques. The nitrogen-protecting group on the compound of formula (24) is then removed under standard conditions to yield a compound of formula (25), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (25) is then treated with a compound of formula (1) under standard alkylation conditions to form a compound of formula (Im), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Im) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Im) wherein R8b is a carboxylic acid group.
O. Preparation of Compounds of Formula (In1) and (In2)
Compounds of formula (In1) and (In2) are compounds of formula (I) and are prepared as described below in Reaction Scheme 15 wherein a is 1 to 5; r, q, R, R3, R5a, R5b, R5c, R6a, R6b, R6c, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R2a is the same as defined for R2 above in the Summary except that R2a cannot be hydrogen; R8d is the same as defined for R8 above in the Summary, except that R8d cannot be hydrogen; R4c is an alkylene chain; and X is bromo or chloro:
Compounds of formula (1), (26) and (12) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (In1) and (In2) are prepared by first treating a compound of formula (1) with a compound of formula (26) under standard alkylation conditions to form a compound of formula (In1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (In1) is then treated with a compound of formula (12) under standard reductive amination conditions to yield a compound of formula (In2), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (In2) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (In2) wherein R8b is a carboxylic acid group.
P. Preparation of Compounds of Formula (Io1), (Io2), (Io3) and (Io4)
Compounds of formula (Io1), (Io2), (Io3) and (Io4) are compounds of formula (I) and are prepared as described below in Reaction Scheme 16 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary of the Invention; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and X is bromo or chloro:
Compounds of formula (27), (2b), and (1) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Io1), (Io2), (Io3) and (Io4) are prepared by first treating a compound of formula (27) with a strong base, preferably lithium diisopropylamide, at temperatures at about −78° C. to form the corresponding carbanion, which is then treated with a compound of formula (2b) under standard substitution conditions to form the compound of formula (28), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (28) is deprotected under standard deprotection conditions, and the resulting product is treated with a compound of formula (1) under standard alkylation conditions to produce a compound of formula (Io1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Io1) is then reduced under standard nitrile reduction conditions to form the compound of formula (Io2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Io2) is then protected under standard protection techniques and the resulting product is then treated with formaldehyde to form a compound of formula (Io3), which can be isolated from the reaction mixture by standard isolation techniques. The protecting group is removed from the compound of formula (Io3) under standard deprotection conditions to form the compound of formula (Io4), which can be isolated from the reaction mixture by standard isolation techniques.
The compound of formula (Io1), (Io2), (Io3) or (Io4) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions prior to the deprotection of the compound to form compounds of formula (Io1), (Io2), (Io3) or (Io4) wherein R8b is an carboxylic acid.
Q. Preparation of Compounds of Formula (Ip)
Compounds of formula (Ip) are compounds of formula (I) and are prepared as described below in Reaction Scheme 17 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; and X is bromo or chloro:
Compounds of formula (1) and (30) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ip) are prepared by first treating a compound of formula (1) with piperidone under standard alkylation conditions to form a compound of formula (29), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (29) is then treated with a compound of formula (30) under standard reductive amination conditions to form a compound of formula (Ip), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ip) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ip) wherein R8b is a carboxylic acid group.
R. Preparation of Compounds of Formula (Iq1), (Iq2) and (Iq3)
Compounds of formula (Iq1), (Iq2) and (Iq3) are compounds of formula (I) and are prepared as described below in Reaction Scheme 18 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R7a is alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; R4c is an alkylene chain; and X is bromo or chloro:
Compounds of formula (II2) and (31) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Iq1), (Iq2) and (Iq3) are prepared by first treating a compound of formula (II2) with a compound of formula (31) under standard substitution conditions to form a compound of formula (Iq1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Iq1) is then hydrolyzed under standard conditions to produce a compound of formula (Iq2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Iq2) in a polar solvent, preferably dioxane, is then treated with acidic conditions to form a compound of formula (Iq3), which can be isolated from the reaction mixture by standard isolation techniques.
S. Preparation of Compounds of Formula (Ir)
Compounds of formula (Ir) are compounds of formula (I) and are prepared as described below in Reaction Scheme 19 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R15—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; and X is bromo or chloro:
Compounds of formula (32), (2b), and (1) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ir) are prepared by first treating a compound of formula (32) with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (33), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (33) is then treated with a compound of formula (1) under standard alkylation conditions to form a compound of formula (Ir), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Ir) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Ir) wherein R8b is a carboxylic acid group.
T. Preparation of Compounds of Formula (Is)
Compounds of formula (Is) are compounds of formula (I) and are prepared as described below in Reaction Scheme 20 wherein r, q, R, R2, R3, R5a, R5b, R5c, R6a, R6b, R6c, R7, and R9 are as defined above in the Summary; and R4c is an alkylene chain:
Compounds of formula (1a) and (32) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Is) are prepared by treating a compound of formula (1a) with a compound of formula (34) under standard amidation conditions to form the compound of formula (Is), which can be isolated from the reaction mixture by standard isolation techniques.
U. Preparation of Compounds of Formula (It1), (It2), (It3), (It4) and (It5)
Compounds of formula (It1), (It2), (It3), (It4) and (It5) are compounds of formula (I) and are prepared as described below in Reaction Scheme 21 wherein a is 1 to 5; r, R, R3, R7 and R9 are as defined above in the Summary; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; and each X is independently bromo or chloro:
The starting materials and the compounds of formula (1), (12) and (19) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (It1), (It2), (It3), (It4) and (It5) are prepared by first treating a solution of malononitrile and 1,4-dibromobutane with a strong base, such as sodium hydride, under the appropriate conditions to formn 1,1-cyclopentanedicarbonitrile, which is then reduced under standard conditions to form 1,1-cyclopentanedimethanamine. A compound of formula (1) is then treated with 1,1-cyclopentanedimethanamine under standard alkylation conditions to form a compound of formula (It1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (It1) is then protected under standard protection procedures and then treated with a compound of formula (19) under standard alkylation conditions to form a compound of formula (It2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (It2) is then deprotected under standard deprotection procedures to yield a compound of formula (It3), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (It3) is then treated with a compound of formual (12) under standard reductive amination conditions to form a compound of formula (It4), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (It4) is then treated with formaldehyde under standard reductive amination conditions to yield a compound of formula (It5), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (It4) or (It5) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (It4) or (It5) wherein R8b is a carboxylic acid group.
Q. Preparation of Compounds of Formula (Iu1), (Iu2), (Iu3) and (Iu4)
Compounds of formula (Iu1), (Iu2), (Iu3) and (Iu4) are compounds of formula (I) and are prepared as described below in Reaction Scheme 19 wherein a is 1 to 5; r, R, R3, and R9 are as defined above in the Summary; R8a is a straight or branched alkylene chain; each R8b is independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R16—OR15, —R16—OC(═O)—R15, —R16—N(R15)2, —R16—C(═O)R15, —R16—C(═O)OR15, —R16—C(═O)N(R15)2, —R16—N(R15)C(═O)OR15, —R16—N(R15)C(═O)R15, —R16—N(R15)S(═O)tR15 (where t is 1 or 2), —R16—S(═O)tOR15 (where t is 1 or 2), —R16—S(═O)pR15 (where p is 0, 1 or 2), and —R16—S(═O)tN(R15)2 (where t is 1 or 2), where each R15 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is independently a direct bond or a straight or branched alkylene or alkenylene chain; R4c is an alkylene chain; Pg is a nitrogen-protecting group; and X is bromo or chloro:
Compounds of formula (1), (35), and (2b) are commercially available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
In general, compounds of formula (Iu1), (Iu2), (Iu3) and (Iu4) are prepared by first treating a compound of formula (1) with a compound of formula (35) under standard alkylation conditions to form a compound of formula (Iu1), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Iu1) is then treated with formaldehyde under standard reductive amination conditions to form a compound of formula (Iu2), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Iu2) is then deprotected under standard deprotection techniques to yield a compound of formula (Iu3), which can be isolated from the reaction mixture by standard isolation techniques. The compound of formula (Iu3) is then treated with a compound of formula (2b) under standard alkylation conditions to form a compound of formula (Iu4), which can be isolated from the reaction mixture by standard isolation techniques.
Compounds of formula (Iu4) wherein R8b is a carboxylic acid ester group can be hydrolyzed under the appropriate hydrolysis conditions to yield compounds of formula (Iu4) wherein R8b is a carboxylic acid group.
It is understood that other compounds of the invention not specifically disclosed in the above Reaction Schemes may be similarly prepared by one skilled in the art with the appropriate starting materials.
All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques. It is understood that all polymorphs, amorphous forms, anhydrates, hydrates, solvates and salts of the compounds of the invention are intended to be within the scope of the invention. Furthermore, all compounds of the invention which contain an ester group can be converted to the corresponding acid by methods known to one skilled in the art or by methods described herein.
To prepare the cyclodextrin clathrates of this invention, the compounds of formula (I), as defined above in the Summary of the Invention, can be dissolved in a pharmacologically acceptable solvent, e.g., in an alcohol, preferably ethanol, in a ketone, e.g., acetone or in an ether, e.g., diethyl ether, and mixed with aqueous solutions of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, preferably β-cyclodextrin, at 20° C. to 80° C.; or the acids of the compounds of formula (I) as defined above in the Summary of the Invention in the form of the aqueous solutions of their salts (e.g., Na− or K− salts) can be admixed with a cyclodextrin and after solution with the equivalent amount of an acid (e.g., HCl or H2SO4) to afford the corresponding cyclodextrin clathrate.
At this point or after cooling, the corresponding cyclodextrin clathrates separate in the form of crystals. However, it is also possible to convert oily and also crystalline compounds of formula (I), as defined above in the Summary of the Invention, by rather long stirring (e.g., for 1 hour to 14 days) at ambient temperature, by treatment with an aqueous solution of cyclodextrins, into the corresponding cyclodextrin clathrate form. The clathrates can then be isolated as solid, free-flowing crystals by suctioning off the solvents and drying.
Cyclodextrins used in this invention are commercially available, for example, from Aldrich Chemical Co., or can be prepared by methods known to those skilled in the art. See, for example, Croft, A. P. et al., “Synthesis of Chemically Modified Cyclodextrins”, Tetrahedron (1983), Vol. 39, No. 9, pp. 1417-1474. Suitable cyclodextrins will include a wide variety of those which produce clathrates of the compounds of formula (I) as set forth above. See, for example, J. E. F. Reynolds (ed.) Martindale, The Extra Pharmacopoeia 28th ed. The Pharmaceutical Press, London 1982, p. 333 and 389-390 and O.-A. Neumueller (ed.), Roempps Chemie-Lexikon, 8. Aufl. Franckh'sche Verlagshandlung, Stuttgart 1981, p. 763-764, 841, 1053-1054.
By selection of the suitable amounts of cyclodextrins and water it is possible to obtain the new clathrates in a stoichiometric composition with a reproducible content of effective substance. The clathrates can be used in a dry hygroscopic form or in a water-containing, but less hygroscopic form. Typical molar ratios of cyclodextrin to a compound of formula (I) is 2:1 (cyclodextrin:compound).
The following specific Preparations (for the preparation of starting materials and intermediates), Synthesis Examples (for the preparation of the compounds of the invention) and Biological Examples (for the assays used to demonstrate the utility of the compounds of the invention) are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention. Where one or more NMR's are given for a particular compound, each NMR may represent a single stereoisomer, a non-racemic mixture of stereoisomers or a racemic mixture of the stereoisomers of the compound.
A. A solution of 4-(2-oxazolyl)phenol (10.8 g, 11.2 mmol) in DMSO (9 mL) was stirred as potassium tert-butoxide (1.5 g, 13.4 mmol) and 4-fluoro-nitrobenzene (1.3 mL, 12.3 mmol) were added sequentially. The reaction was stirred for 17 h at ambient temperature. The reaction was poured into a cold aqueous sodium hydroxide solution (1 N). The solid was isolated by filtration to give 2.6 g of 2-[4-(4-nitrophenoxy)phenyl]oxazole.
B. A slurry of 2-[4-(4-nitrophenoxy)phenyl]oxazole (2.6 g, 9.2 mmol) in a mixture of ethyl acetate (20 mL) and methanol (100 mL) was placed under a nitrogen atmosphere before the addition of catalyst palladium (10% on C, 0.65 g). The reaction mixture was placed under a hydrogen atmosphere at atmospheric pressure. After 3 h, the reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated to give the 2.4 g of 4-[4-(2-oxazolyl)phenoxy]benzenamine.
A slurry of sodium hydride (1 g, 24 mmol) in DMF (75 mL) was stirred as 2,2,3,3,3-pentafluoropropanol (2 mL, 20 mmol) was added over 50 min. The reaction mixture was treated with 4-fluoro-1-nitrobenzene (2.1 mL, 20 mmol) and stirred for 16 h. The reaction was quenched with water and extracted with ether. Purification using flash chromatography using a gradient of ethyl acetate in hexane gave 3.7 g of 1-nitro-4-(2,2,3,3,3-pentafluoropropoxy)benzene: 1H NMR (CDCl3, 400 MHz) δ 8.21 (d, 2H), 6.94 (d, 2H), 4.43 (t, 2H).
A solution of 1-nitro-4-(2,2,3,3,3-pentafluoropropoxy)benzene (3.7 g, 13.7 mmol) in methanol (50 mL) was deoxygenated by bubbling nitrogen through the solution before the addition of 10% Pd/C (0.37 g). The reaction mixture was stirred and placed under a hydrogen atmosphere for 16 h. The reaction was filtered through a pad of Celite and washed with methanol. The filtrates were concentrated to give 3.4 g. Purification using flash chromatography using a gradient of methylene chloride in hexane gave 2.5 g of 4-(2,2,3,3,3-pentafluoropropoxy)phenylamine: 1H NMR (CDCl3, 400 MHz) δ 6.71 (d, 2H), 6.64 (d, 2H), 4.33 (t, 2H), 3.48 (s, 2H).
A. 4-Phenoxybenzenamine (3.0 g, 16.2 mmol) was heated with chloroacetyl chloride (1.68 mL, 21.06 mmol) and triethylamine (4.5 mL, 32.4 mmol) in tetrahydrofuran (160 mL) to reflux for five hours. After cooling, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography followed by crystallization from hexane/ethyl acetate gave 3.74 g of 2-chloro-N-(4-phenoxyphenyl)acetamide: 1H NMR (300 MHz, CDCl3) □ 8.21 (s, 1H), 7.51 (d, 2H), 7.34 (dd, 2H), 7.11 (dd, 1H), 7.02 (d, 2H), 7.00 (d, 2H), 4.20 (s, 2H) ppm.
B. In a similar manner, a solution of 4-phenoxybenzenamine (1.85 g, 10 mmol), (RS)-2-bromopropanoyl bromide (1.06 mL, 10 mmol), and triethylamine (2.79 mL, 20 mmol) in THF (50 mL) was heated at reflux for 1 h. After cooling, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography gave 2.62 g of (RS)-2-bromo-N-(4-phenoxyphenyl)propanamide: 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.50 (d, 2H), 7.33 (dd, 2H), 7.10 (dd, 1H), 7.00 (d, 2H), 6.99 (d, 2H), 4.56 (q, 1H), 1.96 (d, 3H) ppm.
C. In a similar manner, a solution of 4-(phenylmethoxy)aniline (10 g, 50 mmol) in dichloromethane (0.4 L) and triethylamine (8.4 mL, 60 mmol) was stirred and cooled to 0° C. as a solution of bromoacetyl bromide (4.8 mL, 55 mmol) in dichloromethane was added dropwise. The reaction was allowed to warm to ambient temperature over 2 hours. The reaction mixture was poured into ice water and then extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate, dried, and concentrated. Purification by recrystallization from a ethyl acetate in hexane mixture gave 8 g of 2-bromo-N-(4-phenylmethoxyphenyl)acetamide.
D. In a similar manner, a solution of 4-(phenylmethoxy)aniline (10 g, 50 mmol) in dichloromethane (0.4 L) and triethylamine (8.4 mL, 60 mmol) was stirred and cooled to 0° C. as a solution of bromoacetyl bromide (4.8 mL, 55 mmol) in dichloromethane was added dropwise. The reaction was allowed to warm to ambient temperature over 2 hours. The reaction mixture was poured into ice water and the extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate, dried, and concentrated. Purification by recrystallization from a ethyl acetate in hexane mixture gave 8 g of 2-bromo-N-(4-phenylmethoxyphenyl)acetamide.
E. In a similar manner, a stirred solution of 4-phenoxyaniline (50 g, 270 mmol) and N,N-diethylaniline (45 mL) in dichloromethane (500 mL) was cooled to −5° C. and treated with a solution of bromoacetyl bromide (50 g, 250 mmol) in dichloromethane (50 mL) over 15 minutes. The cooled reaction was stirred for 1 hour, then allowed to warm to ambient temperature. The reaction mixture was washed with 1 M sulfuric acid (2×1 L), dried and concentrated. Crystallization from hexanes gave 99 g of 2-bromo-N-(4-phenoxyphenyl)acetamide.
F. In a similar manner, to a solution of 4-(4-bromophenoxy)benzenamine (2.64 g, 10 mmol) in dichloromethane (30 mL) was added DIEA (1.52 g, 15 mmol) at 0° C., followed by bromo acetyl bromide (2.22 g, 11 mmol). The reaction was kept at 0° C. for 30 minutes, then allowed to warm to ambient temperature for 1 hour. The reaction was treated with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to afford 2-bromo-N-[(4-bromophenoxy)phenyl]acetamide (3.66 g, 95%).
A solution of 4-(2,2,3,3,3-pentafluoropropoxy)phenylamine (1.9 g, 7.9 mmol) in methylene chloride was cooled to −5° C. and treated with N,N-diethylaniline (1.5 mL, 9.45 mmol) and bromoacetyl bromide (0.82 mL, 9.45 mmol). After 90 min, the reaction was treated with a 1 M aqueous sulfuric acid solution. The aqueous layer was washed with methylene chloride. The combined organic layers were dried and concentrated. Purification by chromatography using a gradient of methylene chloride in hexane gave 2.3 g of a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.48 (d, 2H), 6.93 (d, 2H), 4.40 (t, 2H), 4.01 (s, 2H).
A mixture of hexahydro-1H-1,4-diazepine (17.47 g, 174.4 mmol) and methyl 4-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was heated with triethylamine (24 mL, 174.4 mmol) in tetrahydrofuran (872 mL) to reflux for three hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 3.04 g of methyl 4-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]benzoate: 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 2H), 7.42 (d, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.67 (m, 2H), 2.66 (m, 2H), 1.77 (m, 2H) ppm.
A. A solution of 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5 g, 25.22 mmol), methyl 4-(bromomethyl)benzoate (8.67 g, 37.83 mmol), and triethylamine (10.49 mL, 75.66 mmol) in tetrahydrofuran (125 mL) was heated to reflux for two hours. After cooling, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 8.6 g of 1,1-dimethylethyl (1S,4S)-5-[[4-(methoxycarbonyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate: 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 2H), 7.42 (d, 2H), 4.38/4.25 (sbr, 1H), 3.91 (s, 3H), 3.79/3.78 (s, 2H), 3.61/3.50 (dbr, 1H), 3.44 (dbr, 1H), 3.17 (m, 1H), 2.90/2.86 (dbr, 1H), 2.71/2.52 (dbr, 1H), 1.87/1.68 (m, 2H), 1.47 (s, 9H) ppm.
B. A solution of 1,1-dimethylethyl (1S,4S)-5-[[4-(methoxycarbonyl)phenyl]methyl]-2, 5-diazabicyclo[2.2.1]heptane-2-carboxylate (8.6 g, 24.82 mmol) in 19 ml of trifluoroacetic acid (248.25 mmol) and dichloromethane (125 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was concentrated under reduced pressure and diluted with methanol. Ion exchanger III (strongly basic anion exchanger) was added until pH >8. The suspension was filtered. The filtrate was concentrated under vacuum to obtain 6.1 g of methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate: 1H NMR (300 MHz, CD3OD) δ 7.98 (d, 2H), 7.49 (d, 2H), 4.00 (sbr, 1H), 3.90 (s, 3H), 3.88 (d, 1H), 3.80 (d, 1H), 3.57 (sbr, 1H), 3.39 (ddbr, 1H), 3.03 (ddbr, 1H), 2.88 (ddbr, 1H), 2.72 (ddbr, 1H), 2.09 (dbr, 1H), 1.75 (dbr, 1H) ppm.
A. A solution of 1,1-dimethylethyl hexahydro-5-oxo-1H-1,4-diazepine-1-carboxylate (2.14 g, 10 mmol) in THF (10 mL) was cooled to 0° C. and stirred as a solution of lithium hexamethyldisilazide (1 M, 11 mL, 11 mmol) was added. After 1 hour, a solution of 4-(bromomethyl)benzoate (2.29 g, 10 mmol) was added and the reaction was allowed to warm to ambient temperature over 17 hours. The reaction was diluted with water and extracted with dichloromethane. The combined organic extracts were dried and concentrated. Purification by flash chromatography gave 3.14 g of 1,1-dimethylethyl hexahydro-4-[[4-(methoxycarbonyl)phenyl]methyl]-5-oxo-1H-1,4-diazepine-1-carboxylate.
B. A solution of 1,1-dimethylethyl hexahydro-4-[[4-(methoxycarbonyl)phenyl]methyl]-5-oxo-1H-1,4-diazepine-1-carboxylate (0.72 g, 2 mmol) in dichloromethane (2 mL) was treated with an aqueous solution of hydrochloric acid (4 N, 4 mL). The reaction was stirred for 17 hours at ambient temperature and concentrated to give 0.48 g of methyl 4-[(hexahydro-7-oxo-1H-1,4-diazepin-1-yl)methyl]benzoate.
To a solution of 1,1-dimethylethyl N-methyl-N-(4-piperidinyl)carbamoate (5 g, 23.3 mmol) in DMF (50 mL) was added DIEA (3.62 g, 28 mmol), followed by methyl 4-bromomethylbenzoate (5.34 g, 23.3 mmol). The reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried, and concentrated. Purification of the product by flash chromatography and then treatment of the product in a dichloromethane solution for 17 hours with a 4 N solution of hydrochloric acid in dioxane gave methyl 4-[[4-(methylamino)-1-piperidinyl]methyl]benzoate.
A. A solution of 1,1-dimethylethyl 4-cyano-1-piperidinecarboxylate (2.3 g, 11 mmol) in THF (50 mL) was cooled to −78° C. and stirred as a solution of lithium diisopropylamide (1 M, 11 mL, 11 mmol) was added. After 30 minutes, a solution of methyl 4-(bromomethyl)benzoate (2.7 g, 12 mmol) in THF (10 mL) was added drop-wise. The reaction was allowed to warm to ambient temperature over 17 h. The reaction was diluted with ether. The combined organic layers were washed with water and brine, dried and concentrated. Purification by flash chromatography gave 1 g of 1,1-dimethylethyl 4-cyano-4-[[4-(methoxycarbonyl)phenyl]methyl]-1-piperidinecarboxylate.
B. A solution of 1,1-dimethylethyl 4-cyano-4-[[4-(methoxycarbonyl)phenyl]methyl]-1-piperidinecarboxylate (0.6 g, 1.7 mmol) in dichloromethane (20 mL) was treated with an aqueous solution of hydrochloric acid (4 N, 10 mL). The reaction was stirred for 17 hours at ambient temperature and concentrated to give 0.4 g of methyl 4-[(4-cyano-4-piperidinyl)methyl]benzoate.
A suspension of piperidone (hydrochloride salt, 1.1 g, 7.2 mmol) in DMF (50 mL) was stirred as potassium carbonate (4.5 g, 32.6 mmol) was added. After 15 minutes, 2-bromo-N-(4-phenoxyphenyl)acetamide (2 g, 6.5 mmol) was added and the reaction was stirred at ambient temperature for 17 hours. The reaction was diluted with water and ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of ethyl acetate in dichloromethane gave 2 g of 4-oxo-N-(4-phenoxyphenyl)-1-piperidine acetamide.
A solution of N,N′-dimethyl-trans-1,2-cyclohexanediamine (1.2 mL, 10 mmol) in acetonitrile (16 mL) and DIEA (3.4 mL, 20 mmol) was stirred as a solution of methyl 4-(bromomethyl)benzoate (1.5 g, 6.5 mmol) in acetonitrile (40 mL) was added drop-wise. The reaction was stirred at ambient temperature for 17 hours. The reaction was concentrated. The residue was diluted with ethyl acetate, washed with water, dried, and concentrated. Purification by flash chromatography using a gradient of a mixture of ammonium hydroxide in methanol and dichloromethane gave 1 g of methyl 4-[[methyl-trans-2-(methylamino)cyclohexyl]amino]methyl]benzoate.
A. A slurry of sodium hydride (1.2 g, 50 mmol) in DMF (200 mL) was stirred as a solution of malononitrile (1.5 g, 23 mmol) in DMF (50 mL) and 1,4-dibromobutane (6 mL, 50 mmol) were added sequentially. After 3 hours, the reaction was poured into a mixture of ice and dilute hydrochloric acid. After 45 minutes, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with an aqueous 1 N sodium hydroxide solution and brine, dried, and concentrated to give 1.9 g of 1,1-cyclopentanedicarbonitrile.
B. A solution of 1,1-cyclopentanedicarbonitrile (1.9 g, 16 mmol) in ether (150 mL) was cooled to −5° C. and treated with lithium aluminum hydride (2.4 g, 63 mmol). The cooling bath was removed and the reaction was stirred for 4 days. Excess lithium aluminum hydride was consumed using the Fieser procedure. Isolation and concentration gave 0.8 g of 1,1-cyclopentanedimethaneamine.
A. A mixture of methyl 4-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]benzoate (285 mg, 1.146 mmol) and 2-chloro-N-(4-phenoxyphenyl)acetamide (250 mg, 0.955 mmol) was heated with triethylamine (266 μL, 1.91 mmol) in tetrahydrofuran (10 mL) to reflux for five hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 393 mg of methyl 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoate: 1H NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.00 (d, 2H), 7.54 (d, 2H), 7.43 (d, 2H), 7.32 (dd, 2H), 7.08 (dd, 1H), 7.01 (d, 2H), 6.98 (d, 2H), 3.90 (s, 3H), 3.72 (s, 2H), 3.28 (s, 2H), 2.90 (m, 2H), 2.84 (m, 2H), 2.74 (m, 2H), 2.73 (m, 2H), 1.86 (m, 2H) ppm.
B. A solution of methyl 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoate (386 mg, 0.815 mmol) in methanol (25 mL) was stirred as an aqueous sodium hydroxide solution (2 M, 4.08 mL) was added. After 17 h at ambient temperature, the reaction was concentrated under reduced pressure, diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Purification by flash chromatography gave 347 mg of 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid; 1H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.88 (d, 2H), 7.65 (d, 2H), 7.40 (d, 2H), 7.36 (dd, 2H), 7.10 (dd, 1H), 6.99 (d, 2H), 6.96 (d, 2H), 3.69 (s, 2H), 3.28 (s, 2H), 2.81 (m, 2H), 2.79 (m, 2H), 2.67 (m, 4H), 1.77 (m, 2H) ppm.
A. A mixture of methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (260 mg, 0.81 mmol) and (RS)-2-bromo-N-(4-phenoxyphenyl)propanamide (200 mg, 0.81 mmol) was heated with triethylamine (226 μl, 1.62 mmol) in tetrahydrofuran (8 mL) to reflux for six hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave methyl 4-[[(1S,4S)-5-[(RS)-1-methyl-2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate as two epimeric isomers, 52 mg of epimer A and 26 mg of epimer B: Epimer A: 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 7.99 (d, 2H), 7.53 (d, 2H), 7.42 (d, 2H), 7.31 (dd, 2H), 7.07 (dd, 1H), 6.99 (d, 2H), 6.97 (d, 2H), 3.90 (s, 3H), 3.81 (d, 1H), 3.73 (d, 1H), 3.52 (s, 1H), 3.33 (s, 1H), 3.25 (q, 1H), 2.93 (d, 1H), 2.72 (m, 3H), 1.86 (d, 1H), 1.74 (d, 1H), 1.33 (d, 3H); Epimer B: 1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 7.99 (d, 2H), 7.54 (d, 2H), 7.43 (d, 2H), 7.31 (dd, 2H), 7.08 (dd, 1H), 7.01 (d, 2H), 6.98 (d, 2H), 3.91 (s, 3H), 3.79 (d, 1H), 3.74 (d, 1H), 3.49 (s, 1H), 3.34 (s, 1H), 3.23 (q, 1H), 3.12 (d, 1H), 2.81 (d, 1H), 2.72 (dd, 1H), 2.66 (dd, 1H), 1.80 (d, 1H), 1.69 (d, 1H), 1.41 (d, 3H) ppm.
B. A solution of methyl 4-[[(1S,4S)-5-[1-methyl-2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (epimer A) (52 mg, 0.11 mmol) in aqueous sodium hydroxide solution (1 mL, 2 M) and methanol (3 mL) was stirred for 17 hours at ambient temperature. The reaction was concentrated under reduced pressure, diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Purification by flash chromatography gave 47 mg of 4-[[(1S,4S)-5-[1-methyl-2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid (epimer A); 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 2H), 7.57 (d, 2H), 7.45 (d, 2H), 7.32 (dd, 2H), 7.08 (dd, 1H), 6.95 (d, 2H), 6.95 (d, 2H), 4.05 (d, 1H), 3.93 (d, 1H), 3.41 (q, 1H), 3.68 (s, 1H), 3.65 (s, 1H), 3.15 (d, 1H), 3.01 (dd, 1H), 2.90 (d, 1H), 2.88 (dd, 1H), 2.01 (d, 1H), 1.96 (d, 1H), 1.36 (d, 3H) ppm.
B. A solution of methyl 4-[[(1S,4S)-5-[1-methyl-2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (epimer B) (26 mg, 0.05 mmol) in aqueous sodium hydroxide solution (1 mL, 2 M) and methanol (3 mL) was stirred for 17 hours at ambient temperature. The reaction was concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Purification by flash chromatography gave 24 mg of 4-[[(1S,4S)-5-[1-methyl-2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-2,5-diazabicyclo[2.2.1 ]hept-2-yl]methyl]benzoic acid (Epimer B); 1H NMR (300 MHz, CDOD) δ 7.94 (d, 2H), 7.57 (d, 2H), 7.44 (d, 2H), 7.33 (dd, 2H), 7.09 (dd, 1H), 6.96 (d, 4H), 4.01 (d, 1H), 3.90 (d, 1H), 3.38 (q, 1H), 3.69 (s, 1H), 3.62 (s, 1H), 3.16 (d, 1H), 3.12 (d, 1H), 2.85 (d, 2H), 1.95 (d, 1H) ppm.
A solution of 2-bromo-N-(4-phenylmethoxyphenyl)acetamide (0.16 g, 0.5 mmol) and 1-[(2S)-pyrrolidinylmethyl]pyrrolidine (0.08 g, 0.5 mmol) in DMF (5 mL) was stirred as diisopropylethylamine (0.43 mL) was added. The reaction was heated at 50° C. for 17 hours. Purification by preparative HPLC using a reverse phase column and a gradient of acetonitrile in water plus 0.1% TFA gave 90 mg of (S)-N-[4-(phenylmethoxy)phenyl]-3-(1-pyrrolidinylmethyl)-1-pyrrolidinacetamide; 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, 2H), 7.38 (m, 5H), 6.99 (d, 2H), 5.05 (s, 2H), 4.15 (d, 1H), 3.79 (m, 1H), 3.61 (m, 3H), 3.33 (m, 5H), 3.13 (m, 1H), 2.25 (m, 1H), 1.98 (m, 6H), 1.78 (m, 1H) ppm.
A. A suspension of N,N′-Dimethylpropylenediamine (18.4 mL, 147 mmol), 2-bromo-N-(4-phenoxyphenyl)acetamide (15 g, 49 mmol), and potassium carbonate (34 g, 245 mmol) in DMF (400 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by silica gel chromatography using a gradient of ammonium hydroxide and methanol in dichloromethane gave 10 g of 2-[methyl-[3-(methylamino]propyl]amino]-N-(4-phenoxyphenyl)-acetamide.
B. A solution of 2-[methyl-[3-(methylamino]propyl]amino]-N-(4-phenoxyphenyl)-acetamide (0.25 g, 0.8 mmol), potassium carbonate (0.81 g, 3.8 mmol) and methyl 6-bromohexanoate (0.14 mL, 0.8 mmol) in DMF (15 mL) was stirred for 17 hours. The reaction was diluted with water and ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of methanol in dichloromethane gave 0.13 g of ethyl 2-[methyl[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]hexanoate; 1H NMR (CDCl3) δ 9.36 (s, 1H), 7.57 (d, 2H), 7.29 (t, 2H), 7.05 (t, 1H), 6.98/6.94 (m, 4H), 4.08 (q, 2H), 3.19 (s, 2H), 2.61/2.49 (m, 6H), 2.36 (s, 6H), 2.26 (t, 2H), 1.76 (dt, 2H), 1.64/1.50 (m, 4H), 1.30 (dt, 2H), 1.21 (t, 3H) ppm.
C. A solution of ethyl 2-[methyl[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]hexanoate (0.08 g, 0.2 mmol) in methanol (3 mL) was stirred and aqueous solution of 1 N sodium hydroxide (2 mL) was added. The reaction was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated. Purification by preparative HPLC gave 0.06 g of 2-[methyl[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]hexanoic acid; 1H NMR (DMSO-d6) δ 10.66 (s, 1H), 9.95 (sbr, 1H), 9.63 (sbr, 1H), 7.59 (dt, 2H), 7.36 (qt, 2H), 7.10 (tt, 1H), 7.02 (dt, 2H), 6.95 (d, 2H), 3.94 (s, 2H), 3.24/2.99 (m, 4H), 2.86 (s, 3H), 2.75 (s, 3H), 2.03 (t, 2H), 2.04 (sbr, 2H), 1.66/1.56 (m, 2H), 1.51 (dt, 2H), 1.28 (dt, 2H) ppm.
A. A suspension of 2-bromo-N-(4-phenoxyphenyl)acetamide (5 g, 16.4 mmol), 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (3.7 g, 24.2 mmol), and potassium carbonate (5 g, 36.2 mmol) in acetonitrile (70 mL) was stirred at ambient temperature overnight. The suspension was filtered. The filtrate was concentrated. Purification by column chromatography using a gradient of hexane in ethyl acetate gave 6.2 g of 1,1-dimethylethyl hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepine-1-carboxylate.
B. A solution of 1,1-dimethylethyl hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepine-1-carboxylate (6.2 g, 15 mmol) in dichloromethane (100 mL) was treated with 4.0 M hydrochloric acid solution (in 1,4-dioxane, 20 mL) and stirred overnight at ambient temperature. The resulting white suspension was filtered and the filter cake was washed with dichloromethane and air-dried to give 5.2 g of hexahydro-N-(4-phenoxyphenyl)-1H-1,4-diazepine-1-acetamide; 1H NMR (DMSO-d6, 400 MHz) δ 10.9 (s, 1H), 9.88 (s, 1H), 7.63 (d, 2H), 7.36 (t, 2H), 7.11 (t, 1H), 7.02 (q, 2H), 6.97 (q, 2H), 4.22 (sbr, 2H), 3.76 (sbr, 2H), 3.53 (sbr, 4H), 3.23 (sbr, 2H), 2.19 (sbr, 2H) ppm.
C. A suspension of hexahydro-N-(4-phenoxyphenyl)-1H-1,4-diazepine-1-acetamide (500 mg, 1.25 mmol), methyl 4-(bromomethyl)benzoate (350 mg, 1.52 mmol), and potassium carbonate (700 mg, 5.1 mmol) in acetonitrile (10 mL) was stirred overnight at ambient temperature. The suspension was filtered and the filtrate was concentrated to give the crude residue. Purification by prep HPLC gave 0.9 g of methyl 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepinyl]methyl]-benzoate as a yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 10.4 (s, 1H), 8.03 (d, 2H), 7.63 (d, 2H), 7.55 (d, 2H), 7.36 (t, 2H), 7.11 (t, 1H), 7.01 (q, 2H), 6.97 (q, 2H), 4.36 (sbr, 2H), 4.03 (sbr, 2H), 3.83 (s, 3H), 3.51 (dbr, 4H), 3.28 (dbr, 4H), 2.08 (sbr, 2H) ppm.
D. A solution of methyl 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepinyl]methyl]benzoate (0.5 g, 0.6 mmol) in aqueous THF (1:1, 40 mL) was treated with lithium hydroxide. The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum. Purification by prep HPLC gave 0.4 g of 4-[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid; 1H NMR (DMSO-d6, 400 MHz) δ 10.6 (sbr, 1H), 7.98 (d, 2H), 7.61 (m, 4H), 7.36 (t, 2H), 7.09 (t, 1H), 7.01 (d, 2H), 6.94 (d, 2H), 4.40 (s, 2H), 4.16 (sbr, 2H), 3.59 (dbr, 4H), 3.33 (dbr, 4H), 2.16 (sbr, 2H) ppm.
A suspension of hexahydro-N-(4-phenoxyphenyl)-1H-1,4-diazepine-1-acetamide (500 mg, 1.25 mmol), methyl 4-isocyanatobenzoate (270 mg, 1.52 mmol), and DIEA (0.9 mL, 5.2 mmol) in THF (10 mL) was stirred overnight at room temperature. Concentration and purification by reverse phase chromatography by prep HPLC gave 0.69 g of methyl 4-[[[hexahydro-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]carbonyl]amino]benzoate; 1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1H), 8.62 (s, 1H), 7.80 (d, 2H), 7.62 (m, 4H), 7.34 (t, 2H), 7.06 (t, 1H), 6.93 (m, 4H), 3.78 (s, 3H), 3.56 (m, 4H), 3.24 (m, 2H), 2.81 (m, 2H), 2.73 (m, 2H), 1.83 (m, 2H) ppm; LC/MS, 502.
A. A suspension of N,N′-dimethylpropylenediamine (9.4 mL, 75 mmol), 2-bromo-N-(4-phenylmethoxyphenyl)acetamide (8 g, 25 mmol), and potassium carbonate (17 g, 125 mmol) in DMF (100 mL) was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of ammonium hydroxide and methanol in dichloromethane gave 5.3 g of 2-[methyl-[3-(methylamino]propyl]amino]-N-(4-phenylmethoxyphenyl)-acetamide.
B. A solution of 2-[methyl-[3-(methylamino]propyl]amino]-N-(4-phenylmethoxyphenyl)-acetamide (5.3 g, 15.5 mmol) in ethyl acetate (10 mL) was stirred as methyl 4-formylbenzoate (2.6 g, 15.5 mmol) and sodium triacetoxyborohydride (6.6 g, 31 mmol) were added sequentially. After 22 hours, the reaction was treated with saturated aqueous potassium carbonate and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by reverse phase preparative HPLC gave 2 g of methyl 4-[[methyl[2-[methyl[2-oxo-2-[[4-(phenylmethoxy)phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate.
C. A solution of methyl 4-[[methyl[2-[methyl[2-oxo-2-[[4-(phenylmethoxy)phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate (1.5 g, 3 mmol) in methanol (100 mL) was degassed with nitrogen, treated with palladium on carbon (10% w/w, 50 mg), and placed under a hydrogen atmosphere (45 psi) on a Parr hydrogenator. After 17 hours, the reaction was filtered. The filtrate was concentrated. Purification by reverse phase preparative HPLC gave 0.8 g of methyl 4-[[methyl[2-[methyl[2-oxo-2-[[4-hydroxyl-phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate.
D. A suspension of methyl 4-[[methyl[2-[methyl[2-oxo-2-[[4-hydroxyl-phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate (0.2 g, 0.5 mmol), 2-bromoethylbenzene (0.15 mL, 1 mmol), and potassium carbonate (0.17 g, 1.25 mmol) in DMF (5 mL) was heated at 80° C. ambient temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by reverse phase preparative HPLC using a gradient of acetonitrile in water gave 80 mg of methyl 4-[[methyl[2-[methyl[2-oxo-2-[[4-(2-phenylethoxy)phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate.
E. A solution of methyl 4-[[methyl[2-[methyl[2-oxo-2-[[4-(2-phenylethoxy)phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate (0.1 g, 0.2 mmol) in aqueous methanol (5 mL) was treated with a 1 N solution of sodium hydroxide (5 mL) and stirred for 17 hours at ambient temperature. The reaction mixture was concentrated and acidified with TFA. Purification by reverse phase preparative HPLC using a gradient of acetonitrile in water plus 0.1% TFA gave 40 mg of 4-[[methyl[3-[methyl[2-oxo-2-[[4-(2-phenylethoxy)phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoic acid, as the TFA salt; 1H NMR (CD3OD) δ 8.02 (d, 2H), 7.54 (d, 2H), 7.37 (dt, 2H), 7.18 (d, 4H), 7.12/7.06 (m, 1H), 6.79 (dt, 2H), 4.36 (s, 2H), 4.10/4.04 (m, 4H), 3.23/3.18 (m, 4H), 2.95 (t, 2H), 2.90 (s, 3H), 2.75 (s, 3H), 2.21 (dt, 2H) ppm.
A. A suspension of 2-bromo-N-(4-phenoxyphenyl)acetamide (5 g, 16.4 mmol), 1,1-dimethylethyl piperazine-1-carboxylate (3.7 g, 24.2 mmol), and potassium carbonate (5 g, 36.2 mmol) in acetonitrle (70 mL) was stirred at ambient temperature for 17 hours. The suspension was filtered and the filtrate was concentrated. Purification by column chromatography using a gradient of hexane in ethyl acetate gave 6.2 g of 1,1-dimethylethyl 4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-piperazine-1-carboxylate.
B. A solution of 1,1-dimethylethyl 4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]piperazine-1-carboxylate (6.2 g) in dichloromethane (100 mL) was treated with 4.0 M HCl solution (in 1,4-dioxane, 20 mL) and stirred at ambient temperature for 17 hours. N-(4-Phenoxyphenyl)-1-piperazine acetamide (5.2 g) was isolated by filtration; 1H NMR (DMSO-d6, 400 MHz) δ 10.8 (sbr, 1H), 9.81 (sbr, 1H), 7.63 (d, 2H), 7.34 (t, 2H), 7.11 (t, 1H), 7.02 (q, 2H), 6.96 (q, 2H), 4.13 (sbr, 2H), 3.48 (sbr, 4H), 3.38 (sbr, 4H) ppm.
C. A solution of N-(4-phenoxyphenyl)-1-piperazine acetamide (500 mg, 1.28 mmol), 1-methyl 1,4-benzenedicarboxylate (347 mg, 1.9 mmol), HATU (732 mg, 1.9 mmol), and DIEA (0.9 mL, 5.1 mmol) in DMF (10 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was quenched with ice-water and extracted with ethyl acetate. The combined organic layers were concentrated. Purification by reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.1% trifluoroacetic acid gave 0.56 g of methyl 4-[[4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1-piperazinyl]carbonyl]benzoate as the TFA salt: 1H NMR (DMSO-d6, 400 MHz) δ 10.6 (s, 1H), 8.02 (d, 2H), 7.59 (d, 4H), 7.37 (t, 2H), 7.11 (t, 1H), 7.02 (q, 2H), 6.98 (q, 2H), 4.17 (sbr, 2H), 3.83 (s, 3H), 3.46 (dbr, 8H) ppm.
E. A solution of methyl 4-[[4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1-piperazinyl]carbonyl]benzoate (0.5 g, 0.71 mmol) in aqueous THF (1:1, 40 mL) and treated with lithium hydroxide. The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum and purified by prep HPLC to give 0.35 g of 4-[[4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1-piperazinyl]carbonyl]benzoic acid; 1H NMR (DMSO-d6, 400 MHz) δ 10.6 (s, 1H), 8.02 (d, 2H), 7.56 (t, 4H), 7.48 (t, 2H), 7.12 (t, 1H), 7.02 (d, 2H), 6.98 (d, 2H), 4.14 (sbr, 2H), 3.61 (sbr, 2H), 3.31 (sbr, 6H) ppm.
A. A suspension of N,N′-Dimethylpropylenediamine (18.4 mL, 147 mmol), 2-bromo-N-(4-phenoxyphenyl)acetamide (15 g, 49 mmol), and potassium carbonate (34 g, 245 mmol) in DMF (400 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by silica gel chromatography using a gradient of ammonium hydroxide and methanol in dichloromethane gave 10 g of 2-[methyl-[3-(methylamino]propyl]amino]-N-(4-phenoxyphenyl)acetamide.
B. A solution of 2-[methyl-[3-(methylamino]propyl]amino]-N-(4-phenoxyphenyl)acetamide (0.24 g, 0.7 mmol) in dichloromethane (5 mL) was stirred as methyl 4-isocyanatobenzoate (0.13 g, 0.7 mmol) was added. After 17 hours, the reaction was treated with methanol and purified by reverse phase preparative HPLC to give 0.3 g of methyl 4-[[[methyl[3-[methyl-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]carbonyl]amino]benzoate.
C. A solution of methyl 4-[[[methyl[3-[methyl-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]carbonyl]amino]benzoate (0.3 g, 0.6 mmol) in aqueous methanol (10 mL) was treated with a 1 N solution of sodium hydroxide (6 mL) and stirred for 17 h at ambient temperature. The reaction mixture was concentrated and acidified with TFA. Purification by reverse phase preparative HPLC using a gradient of acetonitrile in water plus 0.1% TFA gave 0.3 g of 4-[[[methyl[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]carbonyl]amino]-benzoic acid, as the TFA salt; 1H NMR (CD3OD) δ 7.89 (d, 2H), 7.55 (d, 2H), 7.52 (d, 2H), 7.33 (dd, 2H), 7.09 (t, 1H), 6.96/6.93 (m, 4H), 4.15 (sbr, 2H), 3.97 (s, 1H), 3.52 (sbr, 2H), 3.35/3.31 (m, 2H), 3.11 (s, 3H), 3.01 (s, 3H), 2.09 (dt, 2H) ppm.
A. A solution of methyl 4-[(hexahydro-7-oxo-1H-1,4-diazepin-1-yl)methyl]benzoate (0.36 g, 1 mmol) in DMF (2 mL) and diisopropylethylamine (0.26 g, 2 mmol) was stirred for 1 hour before the addition of a solution of 2-bromo-N-(4-phenoxyphenyl)acetamide (0.3 g, 1 mmol) in DMF (1 mL). The reaction was stirred at ambient temperature for 17 hours. The reaction was diluted with water and extracted with dichloromethane. The combined organic extracts were dried and concentrated. Purification by flash chromatography gave 0.38 g of methyl 4-[(hexahydro-7-oxo-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl)methyl]benzoate.
B. A solution of methyl 4-[(hexahydro-7-oxo-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl)methyl]benzoate (0.26 g, 0.5 mmol) in aqueous methanol (5 mL) was stirred and treated with lithium hydroxide (5 mmol). The reaction was stirred for 17 hours at ambient temperature. Concentration and purification by preparative HPLC on a reverse phase column using a gradient of acetonitrile in water plus 0.1% TFA gave 0.12 g of 4-[[hexahydro-7-oxo-4-[2-oxo-2-[[(4-phenoxyphenyl)amino]ethyl]-1H-1, 4-diazepin-1-yl]methyl]benzoic acid.
A. A solution of 1,1-dimethylethyl 3-aminopropanecarbamoate (3.5 g, 20 mmol) in DMF (10 mL) and diisopropylethylamine (40 mmol) was stirred for 1 hour before the addition of a solution of 2-bromo-N-(4-phenoxyphenyl)acetamide (6.1 g, 20 mmol) in DMF (5 mL). The reaction was stirred for 17 hours at ambient temperature. The reaction was poured into ice water and extracted with dichloromethane. The combined organic layers were dried and concentrated. Purification by flash chromatography gave 6 g of 1, 1-dimethylethyl [3-[[2-oxo-2-[(4-phenoxyphenyl)amino]propyl]carbamoate.
B. A solution of 1,1-dimethylethyl [3-[[2-oxo-2-[(4-phenoxyphenyl)amino]propyl]carbamoate (6 g, 15 mmol) in DMF (20 ml) and DIEA (22.5 mmol) was stirred as iodomethane (16.5 mmol) was added. The reaction was stirred at ambient temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried, and concentrated to afford 3.8 g of 1,1-dimethylethyl [3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]propyl]carbamoate.
C. A solution of 1,1-dimethylethyl [3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]propyl]carbamoate (3.8 g, 9.2 mmol) in dichloromethane (20 mL) was treated with an aqueous solution of hydrochloric acid (4 N, 10 mL). The reaction was stirred for 17 hours at ambient temperature and concentrated to give 2.7 g of 2-[(3-aminopropyl)methylamino]-N-(4-phenoxyphenyl)acetamide.
D. A solution of 2-[(3-aminopropyl)methylamino]-N-(4-phenoxyphenyl)acetamide (2.7 g, 6.4 mmol) in methanol (20 mL) was treated with methyl 4-formylbenzoate (1.4 g, 8.5 mmol) and diisopropylethylamine (6.4 mmol). The reaction was stirred for 2 hours, cooled to 0° C., and treated with sodium borohydride (0.4 g, 1.5 mmol). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with ethyl acetate. The combined organic layers were dried, and concentrated. Purification by flash chromatography gave 1.5 g of methyl 4-[[[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]methyl]benzoate.
E. A solution of methyl 4-[[[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl]amino]methyl]benzoate (0.23 g, 0.5 mmol) in dichloroethane (10 mL) was treated with 2-formylpyrrole (0.09 g, 1 mmol), acetic acid (1.5 mmol), and sodium triacetoxyborohydride (0.4 g, 2 mmol) sequentially. The resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate. The combined organic layers were dried, and concentrated. Purification by flash chromatography using a gradient of methanol in dichloromethane gave 0.16 g of methyl 4-[[[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl](1H-pyrrol-2-ylmethyl)amino]methyl]benzoate.
F. A solution of methyl 4-[[[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl](1H-pyrrol-2-ylmethyl)amino]methyl]benzoate (0.14 g, 0.25 mmol) in aqueous methanol (5 mL) was stirred and treated with lithium hydroxide (2.5 mmol). The reaction was stirred for 17 hours at ambient temperature. The reaction was concentrated, pH adjusted to neutrality with an aqueous solution of ammonium chloride, and extracted with dichloromethane. The combined organic extracts were dried and concentrated. Purification by flash chromatography gave 0.012 g of 4-[[[3-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]propyl](1H-pyrrol-2-ylmethyl)amino]methyl]benzoic acid; 1H NMR (CD3OD) δ 8.01 (d, 2H), 7.60 (d, 2H), 7.55 (d, 2H), 7.37 (t, 2H), 7.09 (t, 1H), 6.98 (m, 4H), 6.82 (br, 1H), 6.31 (br, 1H), 6.15 (br, 1H), 4.24 (s, 2H), 4.19 (s, 2H), 3.40 (s, 2H), 3.06 (t, 2H), 2.60 (t, 2H), 2.23 (s, 3H), 1.94 (br, 2H) ppm.
A. A solution of 2-bromo-N-(4-phenoxyphenyl)acetamide (10 g, 33 mmol) and 1,1-dimethylethyl 4-(methylamino)-1-piperidinecarboxylate (7 g, 33 mmol) in DMF (200 mL) was stirred and treated with potassium carbonate (34 g, 163 mmol). After 1 hour, the reaction was poured into ice water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by recrystallization from a mixture of ethyl acetate and hexane gave 13.4 g of 1,1-dimethylethyl 4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]-1-piperidinecarboxylate. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.52 (d, 2H), 7.32 (m, 2H), 7.06 (t, 1H), 6.96 (m, 4H), 4.21 (s, 2H), 3.17 (s, 2H), 2.64 (m, 3H), 2.39 (s, 3H), 1.80 (s, 2H), 1.42 (m, 1H) ppm.
B. A solution of 1,1-dimethylethyl 4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]-1-piperidinecarboxylate (8 g, 18 mmol) in dichloromethane (25 mL) was treated with trifluoroacetic acid (14 mL). After 1 hour, solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with 1 N sodium hydroxide and water. The combined organic layers were washed with water and extracted with 1 N hydrochloric acid (60 mL). The acidic layer was concentrated to give 7.5 g of 2-(methyl-4-piperidinylamino)-N-(4-phenoxyphenyl)acetamide as the dihydrochloride salt; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.42 (s, 1H), 9.17 (m, 1H), 7.65 (d, 2H), 7.35 (d, 2H), 7.06 (t, 1H), 7.02 (d, 2H), 6.93 (d, 2H), 4.18 (m, 2H), 3.64 (s, 1H), 3.4 (m, 2H), 2.9 (m, 5H), 2.22 (m, 2H), 1.98 (m, 2H) ppm.
C. A slurry of 2-(methyl-4-piperidinylamino)-N-(4-phenoxyphenyl)acetamide dihyrochloride salt (0.25 g, 0.6 mmol) and potassium carbonate (0.64 g, 3 mmol) in DMF (7.5 mL) was stirred as methyl 2-chloronicotinate (0.11 g, 0.7 mmol) was added. The reaction was heated at 80° C. for 17 h. The reaction was allowed to cool, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of methanol in dichloromethane gave 0.3 g of methyl 6-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-3-pyridinecarboxylate; 1H NMR (400 MHz, CDCl3) δ 9.19 (m, 1H), 8.03 (d, 2H), 7.55 (d, 2H), 7.32 (m, 2H), 7.02 (m, 5H), 6.61 (d, 1H), 5.28 (s, 2H), 4.58 (d, 2H), 3.84 (s, 3H), 3.22 (s, 2H), 2.91 (s, 2H), 2.78 (m, 1H), 2.42 (s, 3H), 1.96 (m, 2H), 1.57 (m, 2H) ppm.
D. A solution of methyl 6-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-3-pyridinecarboxylate (0.3 g, 6 mmol) in methanol (10 mL) was stirred as 1 N sodium hydroxide (1 mL) was added. The reaction was stirred for 2 days. Concentration and purification by preparative HPLC on a reverse phase column using a gradient of acetonitrile in water plus 0.1% TFA gave 6-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-3-pyridinecarboxylic acid as a TFA salt. The aqueous solution was neutralized and extraction using a 1 to 4 mixture of isopropanol and dichloromethane isolated after concentration 0.18 g of 6-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-3-pyridinecarboxylic acid; 1H NMR (DMSO-d6) δ 9.65 (s, 1H), 8.58 (d, 1H), 7.87 (dd, 1H), 7.64 (dt, 2H), 7.34 (qt, 2H), 7.07 (tt, 1H), 6.98/6.92 (m, 4H), 6.85 (d, 1H), 4.49 (d, 2H), 3.17 (s, 2H), 2.87 (t, 2H), 2.74 (tt, 1H), 2.29 (s, 3H), 1.87 (d, 2H), 1.38 (qd, 2H) ppm.
A. To a suspension of methyl 4-[[4-(methylamino)-1-piperidinyl]methyl]benzoate (1.74 g, 5.19 mmol) in DMF (30 mL) was added DIEA (1.01 g, 7.79 mmol). After stirring for 10 minutes, 2-bromo-N-[(4-bromophenoxy)phenyl]acetamide (2 g, 5.19 mmol) was added in one portion. The reaction was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried, and concentrated. Purification by column chromatography afforded methyl 4-[[4-[[2-[[4-(4-bromophenoxy)phenyl]amino]-2-oxoethyl]methylamino]-1-piperidinyl]methylbenzoate (2.35 g, 80%).
B. A mixture of methyl 4-[[4-[[2-[[4-(4-bromophenoxy)phenyl]amino]-2-oxoethyl]methylamino]-1-piperidinyl]methylbenzoate (370 mg, 0.65 mmol), 3-furanyl boronic acid (73 mg, 0.65 mmol), bis(triphenylphosphine)palladium(II) chloride (46 mg, 0.07 mmol), and an aqueous solution of 2 N sodium carbonate (3 mL) in isopropanol was degassed in vacuum and recharged with nitrogen three times. The reaction mixture was heated at reflux for 24 hours. The reaction mixture was concentrated and then diluted with a mixture of ethyl acetate and brine. The combined organic extracts were dried and concentrated. Purification by chromatography afforded methyl 4-[[4-[[2-[[4-[4-(2-furanyl)phenoxy)phenyl]amino]-2-oxoethyl]methylamino]-1-piperidinyl]methylbenzoate (270 mg, 78%).
C. A solution of methyl 4-[[4-[[2-[[4-[4-(2-furanyl)phenoxy)phenyl]amino]-2-oxoethyl]methylamino]-1-piperidinyl]methylbenzoate (0.27 g, 0.5 mmol) in a mixture of methanol and THF (1:1, 10 mL) was treated with an aqueous 2 N solution of lithium hydroxide (2 mL). The reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was acidified with an aqueous 2 N solution hydrochloric acid and concentrated. Purification by preparative HPLC gave 4-[[4-[[2-[[4-[4-(3-furanyl)phenoxy]phenyl]amino]-2-oxoethyl]methylamino]-1-piperidinyl]methyl]benzoic acid, as a TFA salt (120 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.78 (br s, 1H), 8.09 (t, 1H), 7.96 (d, 2H), 7.75 (t, 1H), 7.58 (m, 6H), 7.02 (d, 2H), 6.93 (d, 2H), 6.84 (m, 1H), 4.32 (br s, 2H), 4.01 (br, s, 2H), 3.55 (m, 4H), 2.95 (m, 1H), 2.76 (s, 3H), 2.17 (m, 2H), 1.94 (m, 2H) ppm.
A. A solution of N,N-dimethylethylenediamine (32.3 mL, 294 mmol) in ether (150 mL) was stirred and cooled to 0° C. and treated with a solution of 2-bromo-N-(4-phenoxyphenyl)acetamide (9 g, 29 mmol) in ether (500 mL). After 4 hours, the reaction mixture is diluted with ethyl acetate, washed with potassium carbonate, dried, and concentrated. Purification by flash chromatography using a gradient of methanol in dichloromethane gave 3.6 g of 2-[[(2-dimethylamino)ethyl]amino]-N-(4-phenoxyphenyl)-acetamide.
B. A solution of 2-[[(2-dimethylamino)ethyl]amino]-N-(4-phenoxyphenyl)-acetamide (2 g, 6.4 mmol) in dichloroethane (20 mL) was treated with methyl 4-formylbenzoate (1.15 g, 7 mmol) and sodium triacetoxyborohydride (1.6 g, 7.7 mmol) sequentially. The resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The combined organic layers were dried, and concentrated. Purification by flash chromatography using a gradient of methanol in dichloromethane gave 3 g of methyl 4-[[[2-(dimethylamino)ethyl][2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]-benzoate.
C. A solution of methyl 4-[[[2-(dimethylamino)ethyl][2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]benzoate (3 g, 6 mmol) in methanol (5 mL) was stirred as 1 N sodium hydroxide (65 mL) was added. The reaction was stirred for 3 days. The reaction mixture was concentrated and the pH of the aqueous residue was adjusted to neutrality with 1 N hydrochloric acid. Extraction with a mixture of 2-propanol and dichloromethane (1 to 4) and concentration gave 2.3 g of 4-[[methyl[2-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]ethyl]amino]methyl]benzoic acid; 1H NMR (DMSO-d6) δ 10.26 (s, 1H), 7.86 (d, 2H), 7.55 (d, 2H), 7.46 (d, 2H), 7.34 (qt, 2H), 7.08 (t, 1H), 6.99/6.91 (m, 4H), 3.83 (s, 2H), 3.24 (s, 2H), 2.73 (t, 2H), 2.50 (sbr, 2H), 2.26 (s, 6H) ppm.
A. A suspension of methyl 4-[(4-cyano-4-piperidinyl)methyl]benzoate (0.36 g, 1.4 mmol) in DMF (50 mL) was stirred as diisopropylethylamine (2 mL) was added. After 15 minutes, 2-bromo-N-(4-phenoxyphenyl)acetamide (0.5 g, 1.6 mmol) was added and the reaction was stirred at ambient temperature for 17 hours. The reaction was diluted with water and ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of ethyl acetate in dichloromethane gave 0.7 g of methyl 4-[[4-cyano-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoate.
B. A solution of methyl 4-[[4-cyano-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoate (0.6 g, 1.2 mmol) in acetic acid (20 mL) was degassed with nitrogen, treated with platinum oxide (50 mg), and placed under a hydrogen atmosphere (45 psi) on a Parr hydrogenator. After 17 hours, the reaction was filtered. The filtrate was concentrated. Purification by flash chromatography gave 0.24 g of methyl 4-[[4-(aminomethyl)-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoate.
C. A solution of methyl 4-[[4-(aminomethyl)-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoate (0.24 g, 0.5 mmol) in dichloromethane (10 mL) was treated with 2,4,6-trimethoxybenzaldehyde (0.15 g, 0.75 mmol), acetic acid, and sodium triacetoxyborohydride (0.2 g, 1 mmol) sequentially. The reaction was stirred at ambient temperature for 17 hours. The reaction mixture was extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of ethyl acetate in dichloromethane gave 0.33 g of methyl 4-[[1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-[[[(2,4,6-trimethoxyphenyl)methyl]amino]methyl]-4-piperidinyl]methyl]benzoate.
D. A solution of methyl 4-[[1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-[[[(2,4,6-trimethoxyphenyl)methyl]amino]methyl]-4-piperidinyl]methyl]benzoate (0.33 g, 0.5 mmol) in dichloromethane (4 mL), methanol (1 mL), and acetic acid (0.5 mL) was added formaldehyde (37% in water, 0.28 mL, 5 mmol). After 30 minutes, sodium cyanoborohydride (0.13 g, 1 mmol) was added. After 17 hours, the reaction was diluted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by flash chromatography gave 0.21 g of methyl 4-[[4-[[methyl[(2,4,6-trimethoxyphenyl)methyl]amino]methyl]-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoate.
E. A solution of methyl 4-[[4-[[methyl [(2,4,6-trimethoxyphenyl)methyl]amino]methyl]-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoate (0.15 g, 0.2 mmol) in aqueous methanol (5 mL) was stirred and treated with lithium hydroxide (2 mmol). The reaction was stirred for 17 hours at ambient temperature. The reaction was concentrated, pH adjusted to neutrality with an aqueous solution of ammonium chloride, and extracted with dichloromethane. The combined organic extracts were dried and concentrated. Purification by preparative HPLC gave 0.07 g of 4-[[4-[[methyl[(2,4,6-trimethoxyphenyl)methyl]amino]methyl]-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoic acid.
F. A solution of 4-[[4-[[methyl[(2,4,6-trimethoxyphenyl)methyl]amino]methyl]-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoic acid (0.05 g, 0.07 mmol) in anisole (2.5 mL) and trifluoroacetic acid (1 mL) was stirred for 2 hours at 70° C. The reaction was concentrated. Purification by preparative HPLC gave 0.02 g of 4-[[4-[(methylamino)methyl]-1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]methyl]benzoic acid; 1H NMR (DMSO-d6) δ 10.58 (sbr, 1H), 7.92 (d, 2H), 7.55 (d, 2H), 7.35 (t, 2H), 7.24 (d, 2H), 7.12 (t, 1H), 7.00 (d, 2H), 6.94 (d, 2H), 4.10 (sbr, 2H), 4.04 (sbr, 2H), 3.22 (br, 2H), 2.83 (s, 3H), 2.70/2.62 (br, 4H), 1.78/1.60 (br, 4H) ppm.
A. A solution of 4-oxo-N-(4-phenoxyphenyl)-1-piperidine acetamide (0.5 g, 1.5 mmol) in dichloroethane (10 mL) and acetic acid (2 mL) was stirred as methyl 4-aminobenzoate (0.23 g, 1.5 mmol) was added. After 1 hour, sodium triacetoxyborohydride (0.39 g, 1.8 mmol) was added and the reaction was stirred at ambient temperature for 17 hours. After adjusting the pH of the reaction mixture to 14 with an aqueous solution of sodium hydroxide, the reaction mixture was extracted with dichloromethane. The combined organic layers were dried and concentrated. Purification by flash chromatography using a gradient of ethyl acetate in dichloromethane gave 0.44 g of methyl 4-[[1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]amino]benzoate.
B. A solution of methyl 4-[[1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]amino]benzoate (0.44 g, 1 mmol) in a mixture of THF and methanol (10 ml) was stirred an aqueous solution of 1 N sodium hydroxide (9 mL) was added. The reaction was stirred at ambient temperature for 3 days. The reaction mixture was concentrated. Purification by preparative HPLC gave 0.22 g of 4-[[1-[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]-4-piperidinyl]amino]benzoic acid; 1H NMR (DMSO-d6) δ 9.73 (s, 1H), 7.63 (d, 2H), 7.34 (qt, 2H), 7.07 (t, 1H), 6.99/6.92 (m, 4H), 6.56 (d, 2H), 6.30 (d, 1H), 3.10 (s, 2H), 2.84 (d, 2H), 2.50/2.47 (m, 1H), 2.29 (t, 2H), 1.89 (d, 2H), 1.49 (q, 2H) ppm.
A. A slurry of sodium hydride (60% in oil, 2.7 g) in THF (500 mL) was stirred at −5° C. under N2 as 2-methoxybenzyl alcohol (16 g) was added dropwise. After 1 hour, the reaction mixture was cooled to −10° C. and ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylic acid (25 g) was added. The reaction was allowed to warm to ambient temperature over 17 hours. The reaction was diluted with a saturated aqueous solution of ammonium chloride (10 mL) and concentrated. The residue was diluted with dichloromethane (500 mL), washed with brine, dried, filtered, and concentrated. Purification by recrystallization from hexanes gave 21 g of a thio ether. Oxidation of a dichloromethane solution of the thio ether (700 mL) at −5° C. with m-chloroperoxybenzoic acid (70%, 35 g) for 17 hours, followed by aqueous work-up gave 15.2 g of ethyl 4-[(2-methoxyphenyl)methoxy]-2-(methylsulfonyl)-5-pyrimidinecarboxylate after recrystallization from ether.
B. A solution of ethyl 4-[(2-methoxyphenyl)methoxy]-2-(methylsulfonyl)-5-pyrimidinecarboxylate (1 g, 2.5 mmol) and potassium carbonate (1 g, 4.7 mmol) in dichloromethane (75 mL) was stirred as a solution of 2-(methyl-4-piperidinylamino)-N-(4-phenoxyphenyl)acetamide (0.85 g, 2.5 mmol) in dichloromethane (10 ML) was added. The reaction was heated at ambient temperature for 22 hours. The reaction mixture was washed with a 10% aqueous solution of potassium carbonate, dried, and concentrated to give ethyl 4-[(2-methoxyphenyl)methoxy]-2-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-5-pyrimidinecarboxylate.
C. A solution of ethyl 4-[(2-methoxyphenyl)methoxy]-2-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-5-pyrimidinecarboxylate in an equivolume mixture of THF and methanol (100 mL) was treated with lithium hydroxide (1.05 g) in water and the mixture was warmed to 50° C. for 18 h. The reaction mixture was neutralized with an aqueous solution of 1 N hydrochloric acid (25 mL) and concentrated. The residue was dissolved in dichloromethane, washed with brine, dried, filtered, and concentrated to give 4-[(2-methoxyphenyl)methoxy]-2-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-5-pyrimidinecarboxylic acid.
D. A solution of 4 N solution of hydrochloric acid in dioxane (100 mL) was stirred as a solution of 4-[(2-methoxyphenyl)methoxy]-2-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-5-pyrimidinecarboxylic acid in dichloromethane (100 mL) was added. After stirring for 24 hours at ambient temperature, the solids were filtered and washed sequentially with ethanol, acetonitrile, and ether to afford 0.8 g of 3,4-dihydro-2-[4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]-4-oxo-5-pyrimidinecarboxylic acid; 1H NMR (DMSO-d6) δ 11.00 (m, 1H), 10.47 (m, 1H), 8.58 (s, 1H), 7.63 (d, 2H), 7.34 (d, 2H), 7.17 (m, 1H), 7.02 (d, 2H), 6.93 (d, 2H), 4.93 (m, 2H), 4.2 (m, 2H), 3.92 (s, 3H), 2.96 (t, 1H), 2.82 (s, 2H), 2.17 (m, 2H), 1.63 (m, 2H) ppm.
A. A solution of methyl 4-[[methyl-trans-2-(methylamino)cyclohexyl]amino]methyl]benzoate (0.49 g, 1.7 mmol) in DMF (10 mL) was stirred as potassium carbonate (1.2 g, 8.4 mmol) was added. After 40 minutes, the reaction mixture was treated with 2-bromo-N-(4-phenoxyphenyl)acetamide (0.96 g, 3.1 mmol) and stirred for 17 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate and water. The combined organic layers were washed with water, dried, and concentrated. Purification by preparative HPLC gave 0.26 g of methyl 4-[[methyl-trans-2-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]cyclohexyl]-amino]methyl]benzoate.
B. A solution of methyl 4-[[methyl-trans-2-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]cyclohexyl]amino]methyl]benzoate (0.26 g, 0.5 mmol) in methanol (8 mL) and THF (4 mL) was stirred as a 1 N aqueous solution of sodium hydroxide (11 mL) was added and the reaction was stirred for 17 hours at ambient temperature. The reaction was acidified and concentrated. Purification by preparative HPLC gave 0.2 g of 4-[[methyl[(1R-trans)-2-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]cyclohexyl]amino]methyl]benzoic acid; 1H NMR (CDCl3) δ 7.96 (d, 2H), 7.45 (d, 2H), 7.35 (sbr, 2H), 7.27 (t, 2H), 7.02 (t, 1H), 6.92 (d, 2H), 6.81 (d, 2H), 3.59 (d, 1H), 3.32 (d, 1H), 3.08/3.03 (m, 1H), 2.65/2.59 (m, 3H), 2.39 (s, 3H), 2.29 (s, 3H), 2.01 (d, 1H), 1.93 (d, 1H), 1.79 (t, 2H), 1.37/1.04 (m, 4H) ppm.
A. A solution of 4-[4-(2-oxazolyl)phenoxy]benzeneamine (250 mg, 0.99 mmol), methyl 4-[[[3-[(carboxymethyl)methylamino]propyl]methylamino]methyl]benzoate (550 mg, 1.78 mmol), HATU (600 mg, 1.58 mmol), and DIEA (0.9 mL, 5.17 mmol) in DMF (20 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was treated a mixture of ice, water, and ethyl acetate. The combined organic layers were concentrated and purified by prep HPLC to give 0.57 g of methyl 4-[[methyl[3-[methyl[2-oxo-2-[[4-[4-(2-oxazolyl)phenoxy]phenyl]amino]ethyl]amino]propyl]amino]-methyl]benzoate as a TFA salt.
B. A solution of methyl 4-[[methyl[3-[methyl[2-oxo-2-[[4-[4-(2-oxazolyl)phenoxy]phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoate (0.5 g, 0.59 mmol) in aqueous THF (1:1, 40 mL) was treated with excess lithium hydroxide and stirred at ambient temperature for 17 hours. The reaction mixture was concentrated under vacuum and purified by prep HPLC to give 0.366 g of 4-[[methyl[3-[methyl[2-oxo-2-[[4-[4-(2-oxazolyl)phenoxy]phenyl]amino]ethyl]amino]propyl]amino]methyl]benzoic acid; 1H NMR (DMSO-d6, 400 MHz) δ 10.8 (s, 1H), 8.19 (s, 1H), 8.02 (d, 2H), 7.97 (d, 2H), 7.63 (t, 4H), 7.32 (s, 1H), 7.13 (d, 2H), 7.07 (d, 2H), 4.39 (sbr, 2H), 4.14 (sbr, 2H), 3.18 (sbr, 4H), 2.87 (s, 3H), 2.71 (s, 3H), 2.13 (sbr, 2H) ppm.
A. A solution of 1,1-cyclopentanedimethaneamine (0.8 g, 6.4 mmol) in acetonitrile (40 ml) and DIEA (1.5 mL, 8.5 mmol) was stirred as 2-bromo-N-(4-phenoxyphenyl)acetamide (1.3 g, 4.2 mmol) was added. The reaction was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of potassium carbonate. The combined organic layers were washed with brine, dried, and concentrated. Purification by column chromatography afforded 1.1 g of 2-[[[1-(aminomethyl)cyclopentyl]methyl]amino]-N-(4-phenoxyphenyl)acetamide.
B. A solution of 2-[[[1-(aminomethyl)cyclopentyl]methyl]amino]-N-(4-phenoxyphenyl)acetamide (1.1 g, 3.1 mmol) in dichloromethane (30 ml) and DIEA (1.1 mL, 6.2 mmol) was stirred as Boc-anhydride (0.7 g, 3.4 mmol) was added. The reaction was stirred at ambient temperature for 17 hours. The reaction mixture was concentrated. Purification by column chromatography afforded 1.1 g of 1,1-dimethylethyl [[1-[[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]-methyl]carbamoate.
C. A solution of 1,1-dimethylethyl [[1-[[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]carbamoate (1.1 g, 2.4 mmol) in DMF (20 ml) and DIEA (0.84 mL, 4.8 mmol) was stirred as iodomethane (0.15 mL, 2.4 mmol) was added. The reaction was stirred at ambient temperature for 6 hours. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The combined organic layers were washed with water and brine, dried, and concentrated. Purification by column chromatography afforded 0.9 g of 1,1-dimethylethyl [[1-methyl[[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]carbamoate.
D. A solution of 1,1-dimethylethyl [[1-methyl[[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]carbamoate (0.9 g, 1.9 mmol) in dichloromethane (10 ml) was stirred as trifluoroacetic acid (1.5 mL, 19 mmol) was added. The reaction was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated. A solution of the residue in dichloromethane was washed with an aqueous 1 N sodium hydroxide solution, dried, and concentrated to afford 0.66 g of 2-[[[1-(aminomethyl)cyclopentyl]methyl]methylamino]-N-(4-phenoxyphenyl)acetamide.
E. A solution of 2-[[[1-(aminomethyl)cyclopentyl]methyl]methylamino]-N-(4-phenoxyphenyl)acetamide (0.67 g, 1.8 mmol) in dichloroethane (20 mL) was stirred as methyl 4-formylbenzoate (0.3 g, 1.8 mmol) and sodium triacetoxyborohydride (0.5 g, 2.2 mmol) were added sequentially. After 17 hours, the reaction was treated with an aqueous 1 N sodium hydroxide solution and extracted with dichloromethane. The combined organic layers were dried and concentrated. Purification by flash chromatography gave 0.72 g of methyl 4-[[[[1-[[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]amino]methyl]benzoate.
F. A solution of methyl 4-[[[[1-[[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]amino]methyl]benzoate (0.72 g, 1.4 mmol) in acetic acid (15 mL) was treated with formaldehyde (37% in water, 2.8 mL, 35 mmol). After 30 minutes, sodium cyanoborohydride (0.88 g, 7 mmol) was added. After 1 hour, the reaction was poured into a mixture of ice and an aqueous 1 N sodium hydroxide solution. After adjusting the pH of the solution to 14 with an aqueous sodium hydroxide solution, the reaction mixture was extracted with dichloromethane. The combined organic layers were dried and concentrated. Purification by flash chromatography gave 0.5 g of methyl 4-[[methyl[[1-[[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]amino]methyl]benzoate.
G. A solution of methyl 4-[[methyl[[1-[[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]amino]methyl]benzoate (0.5 g, 0.9 mmol) in a mixture of THF and methanol (10 ml) was stirred an aqueous solution of 1 N sodium hydroxide (2 mL, 4.7 mmol) was added. The reaction was stirred at ambient temperature for 17 hours. The reaction mixture was concentrated. Purification by preparative HPLC gave 0.34 g of 4-[[methyl[[1-[[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]methyl]cyclopentyl]methyl]amino]methyl]benzoic acid; 1H NMR (DMSO-d6) δ 12.77 (sbr, 1H), 9.65 (s, 1H), 7.85 (d, 2H), 7.57 (d, 2H), 7.40 (d, 2H), 7.33 (qt, 2H), 7.07 (t, 1H), 6.98/6.91 (m, 4H), 3.60 (s, 2H), 3.28 (s, 2H), 2.56 (s, 2H), 2.46 (s, 2H), 2.38 (s, 3H), 2.10 (s, 3H), 1.59/1.37 (m, 8H) ppm.
A. A suspension of 1,1-dimethylethyl 4-amino-4-methyl-1-piperidinecarboxylate (500 mg, 2.3 mmol), 2-bromo-N-(4-phenoxyphenyl)acetamide (820 mg, 2.8 mmol), potassium carbonate (570 mg, 4.7 mmol), and sodium iodide (20 mg, 0.1 mmol) in DMF (10 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was filtered and concentrated to give 1 g of 1,1-dimethylethyl 4-methyl-4-[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinecarboxylate.
B. A solution of 1,1-dimethylethyl 4-methyl-4-[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinecarboxylate (1 g, 2.27 mmol) in dichloromethane (60 mL) was treated with formaldehyde (37% in water, 0.8 mL, 14.6 mmol), acetic acid (0.27 mL, 4.7 mmol), and sodium triacetoxyborohydride (945 mg, 4.4 mmol). The resulting solution was stirred vigorously at ambient temperature for 17 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic layer was separated, dried, and concentrated to give 0.89 g of 1,1-dimethylethyl 4-methyl-4-[methyl[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinecarboxylate.
C. A solution of 1,1-dimethylethyl 4-methyl-4-[methyl[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinecarboxylate (0.89 g, 1.9 mmol) in dichloromethane (80 mL) was treated with a solution of hydrochloric acid (4 M in 1,4-dioxane, 2 mL) and stirred at ambient temperature for 17 hour. The resulting white solid was isolated by filtration to give 0.82 g of 4-methyl-4-[methyl[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]piperidine.
D. A solution of 4-methyl-4-[methyl[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]piperidine (400 mg, 0.68 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate (200 mg, 0.81 mmol), DIEA (0.6 mL, 3.44 mmol) in acetonitrile (10 mL) was stirred at ambient temperature for 17 hours. The crude reaction mixture was concentrated and purified by preparative HPLC gave 0.36 g of methyl 3-fluoro-4-[[4-methyl-4-[methyl[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]piperidinyl]methyl-benzoate as a TFA salt.
E. A slurry of methyl 3-fluoro-4-[[4-methyl-4-[methyl[[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]methyl-benzoate (0.36 g, 0.68 mmol) in aqueous THF (1:1, 40 mL) was treated with excess lithium hydroxide. The resulting mixture was stirred at ambient temperature for 17 h. The reaction mixture was concentrated under vacuum and purified by prep HPLC to give 0.21 g of 3-fluoro-4-[[4-methyl-4-[methyl[2-oxo-2-[(4-phenoxyphenyl)amino]ethyl]amino]-1-piperidinyl]methyl]benzoic acid; 1H NMR (DMSO-d6, 400 MHz) δ 7.83 (d, 1H), 7.72 (m, 2H), 7.60 (d, 2H), 7.38 (t, 2H), 7.11 (t, 1H), 7.02 (q, 2H), 6.98 (q, 2H), 4.39 (sbr, 2H), 3.56 (s, 3H), 3.36 (sbr, 2H), 3.19 (s, 3H), 2.72 (sbr, 2H), 2.09 (m, 4H), 1.42 (sbr, 2H) ppm.
A solution of 2-bromo-N-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]acetamide (0.4 g, 1.1 mmol) and methyl 4-[[(methyl[2-(methylamino)ethyl]amino]methylbenzoate (0.26 g, 1.1 mmol) in DMF (10 mL) was treated with solid potassium carbonate (0.61 g, 4.4 mmol) and the reaction was stirred for 3 h. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated. Purification by chromatography using a gradient of methanol in methylene chloride gave 0.33 g of methyl 4-[[[2-[[2-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]amino]-2-oxoethyl](methyl)amino]ethyl]-(methyl)amino]methyl]benzoate; 1H-NMR (CDCl3, 400 MHz) δ 9.71 (s, 1H), 7.95 (d, 2H), 7.47 (d, 2H), 7.40 (d, 2H), 6.85 (d, 2H), 4.38 (t, 2H), 3.9 (s, 3H), 3.59 (s, 2H), 3.16 (s, 2H), 2.95 (s, 1H), 2.87 (d, 1H), 2.60 (t, 2H), 2.46 (t, 2H), 2.31 (s, 3H), 2.21 (s, 3H), 1.61 (s, 3H).
A solution of methyl 4-[[[2-[[2-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]amino]-2-oxoethyl](methyl)amino]ethyl](methyl)amino]methyl]benzoate (0.33 g, 0.64 mmol) in methanol (5 mL) was treated with a 1 N aqueous sodium hydroxide solution (2 mL, 2 mmol). The reaction was stirred for 16 h. The reaction was concentrated and the product was isolated by preparative HPLC using a gradient of acetonitrile in water (both contain 0.1% trifluoroacetic acid). The pH of the combined fractions was adjusted to 8 with a saturated ammonium hydroxide solution and concentrated. Product was isolated by partition between a methanol to methylene chloride mixture (1 to 20) and brine, and the organic layer was dried and concentrated to give 0.22 g of 4-[[[2-[[2-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-amino]-2-oxoethyl](methyl)amino]ethyl](methyl)amino]methyl]benzoic acid; 1H NMR (DMSO-d6, 400 MHz) δ 9.82 (s, 1H), 7.85 (d, 2H), 7.52 (d, 2H), 7.43 (d, 2H), 6.97 (d, 2H), 4.75 (t, 2H), 3.65 (s, 2H), 3.18 (s, 2H), 2.64 (s, 2H), 2.55 (s, 2H), 2.28 (s, 3H), 2.18 (s, 3H).
A mixture of methyl 4-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]benzoate (0.3 g 1.2 mmol) and 2-chloro-N-(4-trifluoromethoxyphenyl)acetamide (0.2 g, 1 mmol) in a mixture of triethylamine (0.3 mL, 2 mmol) and tetrahydrofuran (10 mL) was heated at reflux for 5 h. Purification by flash chromatography gave 0.3 g of methyl 4-[[hexahydro-4-[2-oxo-2-[(4-trifluoromethoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoate.
A solution of methyl 4-[[hexahydro-4-[2-oxo-2-[(4-trifluoromethoxyphenyl)amino]-ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoate (0.15 g) in methanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1 mL, 1 mmol). The reaction was stirred for 16 h. The reaction was concentrated. Purification by flash chromatography using a mixture of methylene chloride, methanol, and ammonium hydroxide gave 0.09 g of 4-[[hexahydro-4-[2-oxo-2-[(4-trifluoromethoxyphenyl)amino]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid; 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 7.98 (d, 2H), 7.66 (d, 2H), 7.61 (d, 2H), 7.34 (d, 2H), 4.35 (s, 2H), 4.02 (2H), 3.51 (m, 4H), 3.28 (m, 2H), 2.08 (s, 2H).
Following the general procedures described herein and exemplified in Synthetic Examples 1-23, the following compounds, as well as other compounds encompassed within Formula (I) can be synthesized utilizing the appropriate starting materials:
Compounds of the invention were tested in the LTA4 hydrolase homogeneous time resolved fluorescence (HTRF) assay to determine their ability to inhibit the hydrolysis of LTA4 to LTB4. The assay analyzes the amount of LTB4 produced.
LTA4 HTRF assay is a two-step assay involving enzymatic conversion of LTA4 to LTB4, and subsequent quantification of LTB4, product with HTRF assay.
The enzymatic conversion of LTA4 to LTB4 was performed in 384-well plates at ambient temperature in a reaction mixture containing 50 mM HEPES (pH 7.5), 0.5% BSA (fatty acid free), 18 nM recombinant human LTA4 hydrolase, 150 nM LTA4, 1% DMSO in the absence or presence of a compound of the invention. Reaction was stopped after 10 minutes incubation by diluting the incubation mixture 10-fold in 50 mM phosphate, 0.1% casein buffer (pH 7.0).
LTB4 formed was quantified with the HTRF assay in which free LTB4 competes with LTB4-XL665 conjugate (acceptor) for anti-LTB4 monoclonal antibody labeled with Europium cryptate (donor), thereby inhibiting the fluorescence energy transfer.
The LTB4 HTRF 384-well assay was carried out by incubating LTB4 samples or standards with LTB4-XL665 conjugate (7.5 ng/well) and anti-LTB4 monoclonal antibody-Europium cryptate conjugate (0.5 ng/well) in 50 mM phosphate, 0.4 M KF and 0.1% casein, buffer (pH 7.0) for two hours at ambient temperature. Plates were read in a RubyStar plate reader (BmG Labtechnologies Inc., NC) simultaneously at 620 nm and 665 nm to obtain signal ratios of 665 nm/620 nm. Results of energy transfer were expressed as delta F (%) which equaled [(signal ratio of sample−signal ratio of negative control)/(signal ratio of negative control)]×100%. Negative controls were control samples without LTB4 or LTB4-XL665.
Sample LTB4 concentrations were calculated from the LTB4 standard curve using the 4-parameter fit equation. For determination of IC50 values for a particular compound of the invention, eight serially diluted compound concentrations (at 1:3.16 dilution) were used in this assay. Controls without a compound of the invention or with a reference compound were run parallel in the same assay plate.
Compounds of the invention, when tested in this assay, demonstrated the ability to inhibit LTA4 hydrolase activity at IC50 values of less than 100 μM, preferably at less than 1 μM.
Inhibition of peptidase activity was measured for the compounds of the invention by using methods similar to those described in Kull, F. et al., The Journal of Biological Chemistry 1999, 274 (49): 34683-34690. In particular, the peptidase activity of the compounds was measured by inhibition of the hydrolysis of L-alanine-p-nitroanilide to L-alanine and highly colored nitro-aniline as set forth below in the following reaction:
In brief, the enzyme (29 nM) was incubated with L-alanine-p-nitroanilide (1 mM) in 50 mM HEPES (pH 7.5), 100 mM KCL, 1% DMSO in the absence or presence of a compound of the invention for 1 hour at ambient temperature. Reaction was terminated by addition of acetic acid (1%). Formation of colored nitro-aniline was measured by the increase in absorbance at 405 nm in a Victor 2 plate reader (Wallac). Spontaneous hydrolysis of the substrate was corrected for by subtracting the absorbance of control incubations without enzyme. The compounds of the invention, when tested in this assay, demonstrated the ability to inhibit peptidase activity at IC50 values of less than 100 μM, preferably less than 1 μM.
Compounds of the invention were tested for their ability as inhibitors of LTA4 hydrolase in a whole blood assay using human, mouse, rat or dog whole blood in a manner similar to that described in Penning, T. D. et al., J. Med. Chem. (2000), 43(4): 721-735. In this assay, compounds were tested for their ability to inhibit LTB4 release upon stimulation with calcium ionophore. The LTB4 levels in supernatants were measured by ELISA.
Compounds of the invention inhibited the release of LTB4 upon addition of calcium ionophore in a dose-dependent manner from whole blood in all species tested.
The compounds of the invention were tested for their efficacy in the acute Lewis Rat experimental autoimmune encephalomyelitis (EAE)assay by the following protocol:
Animals and Materials:
1. Eight-week old female Lewis Rats (Charles River).
2. Test compound vehicle (20 g Aldrich HPBCD/100 ml with saline); dose volume: 0.5 mL/injection; route: intraperitoneal; frequency: twice a day (BID) beginning on the morning of immunizations.
3. Compound of the invention; dose level: 30 mg/kg, 10 mg/kg; dose volume: 0.5 mL/injection; route: intraperitoneal; frequency: BID or once a day beginning on the morning of immunizations.
4. Prednisolone (solutions made weekly, stored at 5° C.) (Sigma Cat #P-6004); vehicle: A 1:1 solution of sterile PBS and 40% Hydroxypropyl-B-Cyclodextrin (Sigma Aldrich, St. Louis Mo.), prepared weekly. The prednisolone was first dissolved in the cyclodextrin vehicle by heat sonication (˜30 minutes), and then the equal volume of PBS was added; dose Level: 1.5 mg/kg BID; dose volume: 0.1 mL; route: intraperitoneal; frequency: twice a day beginning on the morning of the immunization.
5. Spinal cord homogenate preparation (from male Hartley guinea pigs, Charles River): 500-700 g guinea pigs were euthanized with CO2. The spinal cords were removed and rinsed in saline, blotted once, and stored at −80° C. until the day of use. Spinal cords are then weighed and homogenized with saline at 1 g per mL of saline.
6. Antigen Emulsion: Guinea pig spinal cord homogenate was mixed 1:1 with CFA (Complete Freund's Adjuvant, Difco, Detroit, Mich.) with 1 mg/mL Mycobacterium tuberculosis (ground with a mortar and pestle); dose volume: 0.05 mL into each hind limb footpad for a total of 0.1 mL per rat; frequency: Single bolus injections on day 1 of immunizations.
Experiment:
On day 1, 70 female Lewis rats were immunized with a 0.05 mL subcutaneous injection into each hind footpad with the following mixture: whole guinea pig spinal cord homogenized and mixed 1 g:1 mL saline. The homogenate was then mixed 1:1 with Freund's complete adjuvant containing 1 mg/mL Mycobacterium tuberculosis. Rats were weighed and scored every few days up to day 10, then weighed and scored daily (once on weekends) up to day 21.
Clinical Evaluation:
Rats which were borderline in scores were given a one half score, such as 3.5. Moribund mice were euthanized.
Groups (n=10):
1. Vehicle
2. Compound of the invention, 30 mg/kg BID
3. Compound of the invention, 10 mg/kg BID
4. Compound of the invention, 30 mg/kg once a day
5. 1.5 mg/kg Prednisolone
Endpoint Analysis:
On day 21 of the assay, serum was collected from the groups for pharmacokinetics analysis. Spinal cords were collected from the highest scoring rats in each group for histopathologic analysis.
Results:
Compounds of the invention, when tested for their efficacy in this assay, demonstrated the ability in preventing cumulative disease burden at the doses tested.
Compounds of the invention were tested for their efficacy in the mouse adoptive experimental autoimmune encephalomyelitis (EAE) assay by the following protocol:
Animals and Materials:
1. 8 week old female SJL mice (Jackson Laboratories)
2. Myelin proteolipid protein fragment 139-151 (HCLGKWLGHPDKF)(PLP139-151), which was reconstituted to 3 mg/mL in saline and mixed 1:1 with CFA (Complete Freund's Adjuvant, Difco, Detroit, Mich.) with 4 mg/mL Mycobacterium tuberculosis H37Ra (ground with a mortar and pestle).
3. Test compound vehicle (20 g Aldrich HPBCD/100 mL with saline); dose volume: 0.2 mL/injection; route: intraperitoneal; frequency: BID beginning on the morning of immunizations.
4. Compound of the invention: Dose level: 30 mg/kg, 10 mg/kg; dose volume: 0.2 mL/injection; route: intraperitoneal (IP); frequency: BID or once a day beginning on the morning of immunizations
6. Prednisolone (Sigma Cat #P-6004); vehicle: a 1:1 solution of sterile PBS and 40% Hydroxypropyl-B-Cyclodextrin (Sigma Aldrich, St. Louis Mo.), prepared weekly. The prednisolone was first dissolved in the cyclodextrin vehicle by heat sonication (˜30 minutes), and then an equal volume of PBS was added; dose level: 2.5 mg/kg BID; dose volume: 0.1 mL; route: intraperitoneal; frequency: BID daily, beginning on the morning of the immunizations.
7. Rosswell Park Memorial Institute (RPMI) 1640, with L-glu & 25 mM HEPES, 1×, 0.1 micron filtered (Life Technologies, Cat #22400-089).
8. FBS, defined (Hyclone, Cat #SH30070.01), heat inactivated.
9. MEM Non-essential amino acids solution, 10 mM, 100× (Life Technologies, Cat #11140-050).
10. 2-mercaptoethanol, 1000×, 5.5×10−2 M in D-PBS (Life Technologies, Cat #21985-023).
11. Penicillin/Streptomycin (Pen/Strep), 10000 U/ug per ml (Bio*Whittaker, Cat #17-602E).
12. Hank's Balanced Salt Solution (HBSS), 1×, 0.1 micron filtered (Life Technologies, Cat #24020-117).
Experiment:
1. Forty 8-week-old female SJL mice were immunized with 0.1 mL subcutaneous (divided between base of tail & upper back) injection containing 150 μg PLP in CFA w/200 μg Mycobacterium tuberculosis H37Ra (ground).
2. Axial, brachial and inguinal lymph node cells were collected 11 days later. The cells were placed in sterile petri dishes with HBSS. A single cell suspension of lymph node cells was obtained by pressing lymph nodes through a metal sieve and flushing with the following media:
3. The cells were cultured at 6×106 cells/mL.
4. PLP was added to the remaining cells to obtain a final concentration of 50 μg/mL.
5. The cell cultures were incubated for 72 hours at 37° C., 7% CO2.
6. The cells were harvested and washed twice in HBSS.
7. Lymph node cell viability was checked by trypan blue exclusion.
8. The concentration was adjusted to 3.6×107 lymph node cells per mL. 1.6×107 lymph node cells were injected per mouse into naive 8 week old female SJL mice; dose volume=0.5 mL/mouse, IP.
9. Mice were weighed and scored.
Clinical Evaluation:
Rats which were borderline in scores were given a one half score, such as 3.5. Moribund mice were euthanized.
Groups (n=10):
1. Vehicle
2. Compound of the invention, 30 mg/kg BID
3. Compound of the invention, 10 mg/kg BID
4. Compound of the invention, 30 mg/kg once a day
5. 1.5 mg/kg Prednisolone
Results:
Compounds of the invention, when tested in this assay, demonstrated the ability to prevent cumulative disease burden in the assay at the doses tested.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.
This application claims the benefit of U.S. Provisional Patent Application No. 60/755,732, filed Dec. 29, 2005, and of U.S. Provisional Patent Application No. 60/835,489, filed Aug. 4, 2006, whereby the disclosures of both applications are incorporated herein by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 60755732 | Dec 2005 | US | |
| 60835489 | Aug 2006 | US |
