WO2009151626A1 - Dérivés de l’acide (1, 2, 4-oxadiazol-3-yl)indolin-1-yl carboxylique substitué pouvant être utilisés comme agonistes de s1p1 - Google Patents

Dérivés de l’acide (1, 2, 4-oxadiazol-3-yl)indolin-1-yl carboxylique substitué pouvant être utilisés comme agonistes de s1p1 Download PDF

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WO2009151626A1
WO2009151626A1 PCT/US2009/003530 US2009003530W WO2009151626A1 WO 2009151626 A1 WO2009151626 A1 WO 2009151626A1 US 2009003530 W US2009003530 W US 2009003530W WO 2009151626 A1 WO2009151626 A1 WO 2009151626A1
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Robert M. Jones
Sangdon Han
Jeanne V. Moody
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Arena Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to certain substituted (l,2,4-oxadiazol-3-yl)indolin-2-yl carboxylic acid derivatives of Formula (Ia) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the SlPl receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the
  • the present invention relates to compounds that are SlPl receptor agonists having at least immunosuppressive, anti-inflammatory, and/or hemostatic activities, e.g. by virtue of modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues,
  • the present application is in part focused on addressing an unmet need for immunosuppressive agents such as may be orally available which have therapeutic efficacy for at least autoimmune diseases and disorders, inflammatory diseases and disorders (e.g. , acute and chronic inflammatory conditions), transplant rejection, cancer, and/or conditions that have an
  • vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis) with fewer side effects such as the impairment of immune responses to systemic infection.
  • the sphingosine-1 -phosphate (SlP) receptors 1-5 constitute a family of G protein- coupled receptors with a seven-transmembrane domain. These receptors, referred to as SlPl to
  • S1P5 (formerly termed endothelial differentiation gene (EDG) receptor-1, -5, -3, -6, and -8, respectively; Chun et al., Pharmacological Reviews, 54:265-269, 2002), are activated via binding by sphingosine-1 -phosphate, which is produced by the sphingosine kinase-catalyzed phosphorylation of sphingosine.
  • SlPl, S1P4, and S1P5 receptors activate Gi but not Gq, whereas S1P2 and S1P3 receptors activate both Gi and Gq.
  • 35 receptor responds to an agonist with an increase in intracellular calcium.
  • lymphopenia also referred to as peripheral lymphocyte lowering (PLL); Hale et al, Bioorg. Med. Chem. Lett., 14:3351-3355, 2004.
  • lymphopenia also referred to as peripheral lymphocyte lowering (PLL); Hale et al, Bioorg. Med. Chem. Lett., 14:3351-3355, 2004.
  • This is attended by clinically useful immunosuppression by virtue of sequestering T- and B-cells in secondary lymphoid tissue (lymph nodes and Peyer's patches) and thus apart from sites of inflammation and organ grafts (Rosen et al, Immunol. Rev., 195:160-177, 2003; Schwab et al, Nature Immunol, 8:1295-1301, 2007).
  • lymphocyte sequestration for example in lymph nodes, is thought to be a consequence of concurrent agonist-driven functional antagonism of the SlPl receptor on T-cells (whereby the ability of SlP to mobilize T-cell egress from lymph nodes is reduced) and persistent agonism of the SlPl receptor on lymph node endothelium (such that barrier function opposing transmigration of lymphocytes is increased) (Matloubian et al, Nature, 427:355-360, 2004; Baumruker et al, Expert Opin. Investig. Drugs, 16:283-289, 2007).
  • agonism of the SlPl receptor alone is sufficient to achieve lymphocyte sequestration (Sanna et al, J Biol Chem., 279:13839-13848, 2004) and that this occurs without impairment of immune responses to systemic infection (Brinkmann et al, Transplantation, 72:764-769, 2001; Brinkmann et al, Transplant Proc, 33:530-531, 2001).
  • That agonism of endothelial SlPl receptors has a broader role in promoting vascular integrity is supported by work implicating the SlPl receptor in capillary integrity in mouse skin and lung (Sanna et al, Nat Chem Biol, 2:434-441, 2006).
  • Vascular integrity can be compromised by inflammatory processes, for example as may derive from sepsis, major trauma and surgery so as to lead to acute lung injury or respiratory distress syndrome (Johan Groeneveld, Vascul Pharmacol, 39:247-256, 2003).
  • SlP receptor agonist having agonist activity on the SlPl receptor is FTY720 (f ⁇ ngolimod), an immunosuppressive agent currently in clinical trials (Martini et al, Expert Opin. Investig. Drugs, 16:505-518, 2007).
  • FTY720 acts as a prodrug which is phosphorylated in vivo; the phosphorylated derivative is an agonist for SlPl, S1P3, S1P4, and S1P5 receptors (but not the S1P2 receptor) (Chiba, Pharmacology & Therapeutics, 108:308- 319, 2005).
  • FTY720 has been shown to rapidly and reversibly induce lymphopenia (also referred to as peripheral lymphocyte lowering (PLL); Hale et al, Bioorg. Med. Chem. Lett., 14:3351-3355, 2004). This is attended by clinically useful immunosuppression by virtue of sequestering T- and B-cells in secondary lymphoid tissue (lymph nodes and Peyer's patches) and thus apart from sites of inflammation and organ grafts (Rosen et al, Immunol. Rev., 195:160-177, 2003; Schwab et al, Nature Immunol, 8:1295-1301, 2007).
  • lymphopenia also referred to as peripheral lymphocyte lowering (PLL); Hale et al, Bioorg. Med. Chem. Lett., 14:3351-3355, 2004. This is attended by clinically useful immunosuppression by virtue of sequestering T- and B-cells in secondary lymphoid tissue (lymph nodes and Pe
  • FTY720 elicited an adverse event (i.e., transient asymptomatic bradycardia) due to its agonism of the S1P3 receptor (Budde et al, J. Am. Soc. Nephrol, 13: 1073-1083, 2002; Sanna et al, J. Biol. Chem., 279:13839-13848, 2004; Ogawa et al, BBRC, 361:621-628, 2007).
  • an adverse event i.e., transient asymptomatic bradycardia
  • FTY720 has been reported to have therapeutic efficacy in at least: a rat model for autoimmune myocarditis and a mouse model for acute viral myocarditis (Kiyabayashi et al, J. Cardiovasc. Pharmacol, 35:410-416, 2000; Miyamoto et al, J. Am. Coll Cardiol, 37:1713- 1718, 2001); mouse models for inflammatory bowel disease including colitis (Mizushima et al, Inflamm. Bowel Dis., 10:182-192, 2004; Deguchi et al, Oncology Reports, 16:699-703, 2006; Fujii et al, Am. J. Physiol. Gastrointest.
  • SLE systemic lupus erythematosus
  • KRP-203 an SlP receptor agonist having agonist activity on the SlPl receptor
  • SEW2871 agonism of endothelial SlPl receptors prevents proinflammatory monocyte/endothelial interactions in type I diabetic vascular endothelium
  • FTY720 has been reported to have therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE) in rats and mice, a model for human multiple sclerosis (Brinkmann et al, J. Biol. Chem., 277:21453-21457, 2002; Fujino et al, J. Pharmacol. Exp. Ther., 305:70-77, 2003; Webb et al, J. NeuroimmunoL, 153: 108-121, 2004; Rausch et al, J. Magn. Reson. Imaging, 20: 16-24, 2004; Kataoka et al, Cellular & Molecular Immunology,
  • FTY720 has been found to have therapeutic efficacy for multiple sclerosis in clinical trials. In Phase II clinical trials for relapsing-remitting multiple sclerosis, FTY720 was found to reduce the number of lesions detected by magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis
  • MRI magnetic resonance imaging
  • FTY720 has been reported to impair migration of dendritic cells infected with
  • Francisella tularensis to the mediastinal lymph node, thereby reducing the bacterial colonization of it. Francisella tularensis is associated with tularemia, ulceroglandular infection, respiratory infection and a typhoidal disease (E. Bar-Haim et al, PLoS Pathogens, 4(11): el000211. doi:10.1371/journal.ppat.l000211, 2008).
  • Agonism of the SlPl receptor has been implicated in enhancement of survival of oligodendrocyte progenitor cells. Survival of oligodendrocyte progenitor cells is a required component of the remyelination process. Remyelination of multiple sclerosis lesions is considered to promote recovery from clinical relapses. (Miron et al, Ann. Neurol, 63:61-71,
  • SlPl receptor plays a role in platelet-derived growth factor (PDGF)-induced oligodendrocyte progenitor cell mitogenesis (Jung et al, GUa, 55:1656-1667, 2007).
  • PDGF platelet-derived growth factor
  • Agonism of the SlPl receptor has also been reported to mediate migration of neural stem cells toward injured areas of the central nervous system (CNS), including in a rat model of spinal cord injury (Kimura et al, Stem Cells, 25:115-124, 2007).
  • Agonism of the SlPl receptor has been implicated in the inhibition of keratinocyte proliferation (Sauer et al, J. Biol. Chem., 279:38471-38479, 2004), consistent with reports that SlP inhibits keratinocyte proliferation (Kim et al, Cell Signal, 16:89-95, 2004).
  • the hyperproliferation of keratinocytes at the entrance to the hair follicle, which can then become blocked, and an associated inflammation are significant pathogenetic factors of acne (Koreck et al, Dermatology, 206:96-105, 2003; Webster, Cutis, 76:4-7, 2005).
  • FTY720 has been reported to have therapeutic efficacy in inhibiting pathologic angiogenesis, such as that as may occur in tumor development. Inhibition of angiogenesis by FTY720 is thought to involve agonism of the SlPl receptor (Oo et al, J. Biol. Chem.,
  • FTY720 has been reported to have therapeutic efficacy for inhibiting primary and metastatic tumor growth in a mouse model of melanoma (LaMontagne et al, Cancer Res., 66:221-231, 2006). FTY720 has been reported to have therapeutic efficacy in a mouse model for metastatic hepatocellular carcinoma (Lee et al, Clin. Cancer Res., 11 :84588466, 2005).
  • Cyclosporin A and FK506 are drugs used to prevent rejection of transplanted organs. Although they are effective in delaying or suppressing transplant rejection, classical immunosuppressants such as cyclosporin A and FK506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, /3-cell toxicity and gastrointestinal discomfort.
  • FTY720 has been shown to have therapeutic efficacy in transplant rejection both as a monotherapy and in synergistic combination with a classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressants cyclosporin A, FK506 and RAD, FTY720 has efficacy for prolonging graft survival without inducing general immunosuppression, and this difference in drug action is believed to be relevant to the synergism observed for the combination (Brinkmann et al, Transplant Proc, 33:530-531, 2001; Brinkmann et al, Transplantation, 72:764-769, 2001).
  • a classical immunosuppressant including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressants cyclosporin A, FK506 and RAD, FTY720 has efficacy for prolonging graft survival without
  • Agonism of the SlPl receptor has been reported to have therapeutic efficacy for prolonging allograft survival in mouse and rat skin allograft models (Lima et al, Transplant Proc, 36:1015-1017, 2004; Yan et al, Bioorg. & Med. Chem. Lett., 16:3679-3683, 2006).
  • FTY720 has been reported to have therapeutic efficacy for prolonging allograft survival in a rat cardiac allograft model (Suzuki et al., Transpl. Immunol, 4:252-255, 1996).
  • FTY720 has been reported to act synergistically with cyclosporin A to prolong rat skin allograft survival (Yanagawa et al, J.
  • KRP-203 an SlP receptor agonist has been reported to have therapeutic efficacy for prolonging allograft survival in a rat skin allograft model and both as monotherapy and in synergistic combination with cyclosporin A in a rat cardiac allograft model (Shimizu et al, Circulation, 111 :222-229, 2005).
  • KRP-203 also has been reported to have therapeutic efficacy in combination with mycophenolate mofetil (MMF; a prodrug for which the active metabolite is mycophenolic acid, an inhibitor of purine biosynthesis) for prolonging allograft survival both in a rat renal allograft model and in a rat cardiac allograft model (Suzuki et al, J. Heart Lung Transplant, 25:302-209, 2006; Fujishiro et al, J. Heart Lung Transplant, 25:825-833, 2006).
  • MMF mycophenolate mofetil
  • FTY720 has been reported to have therapeutic efficacy in a mouse islet graft model (Fu et al, Transplantation, 73:1425-1430, 2002; Liu et al, Microsurgery, 27:300-304; 2007) and in a study using human islet cells to evidence no detrimental effects on human islet function (Truong et al, American Journal of Transplantation, 7:2031-2038, 2007).
  • FTY720 has been reported to reduce the nociceptive behavior in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis (O. Costu et al, Journal of Cellular and Molecular Medicine 12(3), 995-1004, 2008).
  • FTY720 has been reported to impair initiation of murine contact hypersensitivity (CHS). Adoptive transfer of immunized lymph node cells from mice treated with FTY720 during the sensitization phase was virtually incapable of inducing CHS response in recipients (D. Nakashima et al, J. Investigative Dermatology (128(12), 2833-2841, 2008). It has been reported that prophylactic oral administration of FTY720 (1 mg/kg, three times a week), completely prevented the development of experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 mice (T. Kohono et al, Biological & Pharmaceutical Bulletin, 28(4), 736-739, 2005).
  • CHS murine contact hypersensitivity
  • the present invention encompasses compounds which are agonists of the SlPl receptor having selectivity over the S1P3 receptor.
  • the S1P3 receptor and not the SlPl receptor, has been directly implicated in bradycardia (Sanna et al, J. Biol. Chem., 279:13839-13848, 2004).
  • An SlPl receptor agonist selective over at least the S1P3 receptor has advantages over current therapies by virtue of an enhanced therapeutic window, allowing better tolerability with higher dosing and thus improving efficacy as therapy.
  • the present invention encompasses compounds which are agonists of the SlPl receptor and which exhibit no or substantially no activity for bradycardia.
  • SlPl receptor agonists are useful to treat or prevent conditions where suppression of the immune system or agonism of the SlPl receptor is in order, such as diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders, and conditions that have an underlying defect in vascular integrity or that relate to angiogenesis such as may be pathologic.
  • the present invention encompasses compounds which are agonists of the SlPl receptor having good overall physical properties and biological activities and having an effectiveness that is substantially at least that of prior compounds with activity at the SlPl receptor.
  • the present invention encompasses compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the present invention encompasses compounds which are SlPl receptor agonists having at least immunosuppressive, anti-inflammatory and/or hemostatic activities, e.g. by virtue of modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and/or enhancing vascular integrity.
  • SlPl receptor agonists are useful to treat or prevent conditions where suppression of the immune system or agonism of the SlPl receptor is in order, such as diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions that have an underlying defect in vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development and atherosclerosis).
  • diseases and disorders mediated by lymphocytes transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions that have an underlying defect in vascular integrity or that are associated with angiogenesis
  • pathologic e.g., as may occur in inflammation, tumor development and atherosclerosis.
  • Such conditions where suppression of the immune system or agonism of the SlPl receptor is in order include diseases and disorders mediated by lymphocytes, conditions that have an underlying defect in vascular integrity, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), acute or chronic rejection of cells, tissue or solid organ grafts, arthritis including psoriatic arthritis and rheumatoid arthritis, diabetes including type I diabetes, demyelinating disease including multiple sclerosis, ischemia-reperfusion injury including renal and cardiac ischemia-reperfusion injury, inflammatory skin disease including psoriasis, atopic dermatitis and acne, hyperproliferative skin disease including acne, inflammatory bowel disease including Crohn's disease and ulcerative colitis, systemic lupus erythematosis, asthma, uveitis, myocarditis, allergy, atherosclerosis, brain inflammation including Alzheimer's disease and brain inflammatory reaction following traumatic brain injury, central nervous system disease including spinal cord injury or
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for treating a disorder associated with the SlPl receptor in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating a disorder associated with the SlPl receptor in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof, wherein the disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, hypertensive nephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne.
  • One aspect of the present invention pertains to methods for treating a disease or disorder mediated by lymphocytes in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating an autoimmune disease or disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating an inflammatory disease or disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating a disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof, wherein the disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne.
  • One aspect of the present invention pertains to methods for treating a microbial infection or disease associated with the SlPl receptor in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating a viral infection or disease associated with the SlPl receptor in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating psoriasis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating rheumatoid arthritis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating Crohn's disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating transplant rejection in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating multiple sclerosis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating systemic lupus erythematosus in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating ulcerative colitis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating type I diabetes in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating acne in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating gastritis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating polymyositis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating thyroiditis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating vitiligo in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating hepatitis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating biliary cirrhosis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating hypertensive nephropathy in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating glomerulosclerosis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating myocardial ischemia-reperfusion injury in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of a disorder associated with the SlPl receptor.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of a disorder associated with the SlPl receptor selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, hypertensive nephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of a disease or disorder mediated by lymphocytes.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of an autoimmune disease or disorder.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of an inflammatory disease or disorder.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of cancer.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of a microbial infection or disease associated with the SlPl receptor.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of a viral infection or disease associated with the SlPl receptor.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of a disorder associated with the SlPl receptor selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne.
  • a disorder associated with the SlPl receptor selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of psoriasis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of rheumatoid arthritis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of Crohn's disease.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of transplant rejection.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of multiple sclerosis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of systemic lupus erythematosus.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of ulcerative colitis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of type I diabetes.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of acne.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of gastritis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of polymyositis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of thyroiditis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of vitiligo.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of hepatitis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of biliary cirrhosis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of hypertensive nephropathy.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of glomerulosclerosis.
  • One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of myocardial ischemia- reperfusion injury.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a disorder associated with the SlPl receptor.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a disorder associated with the SlPl receptor selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, hypertensive nephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne.
  • a disorder associated with the SlPl receptor selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, hypertensive nephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne.
  • a disorder associated with the SlPl receptor selected from the
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of an autoimmune disease or disorder.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of an inflammatory disease or disorder.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of cancer.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a microbial infection or disease associated with the SlPl receptor.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a viral infection or disease associated with the SlPl receptor.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a disorder associated with the SlPl receptor selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of psoriasis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of rheumatoid arthritis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of Crohn's disease.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of transplant rejection.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of multiple sclerosis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of systemic lupus erythematosus.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of ulcerative colitis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of type I diabetes.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of acne.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of gastritis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of polymyositis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of thyroiditis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of vitiligo.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of hepatitis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of biliary cirrhosis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of hypertensive nephropathy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of glomerulosclerosis.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of hypertensive nephropathy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of myocardial ischemia-reperfusion injury.
  • One aspect of the present invention pertains to processes for preparing a composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • Figure 1 shows the results of an experiment which measured the ability of Compound 1 to lower the absolute count of peripheral lymphocytes in mouse compared to saline and vehicle.
  • Figure 2 shows the results of an experiment which measured the ability of Compound 2 to lower the absolute count of peripheral lymphocytes in mouse compared to saline and vehicle.
  • Figure 3 shows a general synthetic scheme for the preparation of compounds of Formula (Ia).
  • Oxidation of the hydroxymethyl indoline starting material afforded the aldehyde which was converted via a Wittig reaction to the 3-f-butoxy-3-oxoprop-l-enyl indoline. This was further converted to the corresponding 3-/-butoxy-3-oxopropyl indoline by palladium- catalyzed reduction.
  • the cyano group was introduced by a metal-catalyzed coupling reaction and subsequently converted to the amidoxime group. Condensation of the precursor with acid chlorides, followed by deprotection, provided substituted (l,2,4-oxadiazol-3-yl)indolin-2-yl carboxylic acid derivatives of Formula (Ia).
  • an agonist is intended to mean a moiety that interacts with and activates a G- protein-coupled receptor, such as the SlPl receptor, such as can thereby initiate a physiological or pharmacological response characteristic of that receptor.
  • a G- protein-coupled receptor such as the SlPl receptor
  • an agonist may activate an intracellular response upon binding to the receptor, or enhances GTP binding to a membrane.
  • an agonist of the invention is an SlPl receptor agonist that is capable of facilitating sustained SlPl receptor internalilzation (see e.g., Matioubian et al, Nature, 427, 355).
  • antagonist is intended to mean a moietiy that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist.
  • An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • hydrate as used herein means a salt of the invention that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate as used herein means a salt of the invention that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • the term "in need of treatment” and the term “in need thereof when referring to treatment are used interchangeably to mean a judgment made by a caregiver ⁇ e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • the term "individual” is intended to mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and most preferably humans.
  • inverse agonist is intended to mean a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist, or decreases GTP binding to a membrane.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 50%.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • modulate or modulating is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • pharmaceutical composition is intended to mean a composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • terapéuticaally effective amount is intended to mean the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, caregiver or by an individual, which includes one or more of the following:
  • Preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • Inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology);
  • Ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • Cj-C 6 alkoxy is intended to mean a Ci-C 6 alkyl radical, as defined herein, attached directly to an oxygen atom. Some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons and some embodiments are 1 or 2 carbons. Examples include methoxy, ethoxy, «-propoxy, isopropoxy, /i-butoxy, tert-butoxy, isobutoxy, sec-butoxy, and the like.
  • Cj-C 6 alkyl is intended to mean a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons and some embodiments are 1 or 2 carbons.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, H-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, fert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e., -CH 2 CH(CH 3 )CH 2 CH 3 ], n-hexyl, and the like.
  • C 1 -C 6 alkylsulfonyl is intended to mean a Cj-C 6 alkyl radical attached to the sulfur of a sulfone radical having the formula: -S(O) 2 - wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, M-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, and the like.
  • Cj-C 6 alkylthio is intended to mean a Ci-C 6 alkyl radical attached to a sulfur atom (i.e., -S-) wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfanyl (i.e., CH 3 S-), ethylsulfanyl, n- propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, t- butylsulfanyl, and the like.
  • Cj-C 6 alkylamino is intended to mean one alkyl radical attached to an -NH- radical wherein the alkyl radical has the same meaning as described herein. Some examples include, but are not limited to, methylamino, ethylamino, «-propylamino, isopropylamino, n- butylamino, sec-butylamino, isobutylamino, tert-butylamino, and the like.
  • cyano is intended to mean the group -CN.
  • C 3 -C 7 cycloalkyl is intended to mean a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • C 1 -C 6 haloalkoxy is intended to mean a Q-C 6 haloalkyl, as defined herein, which is directly attached to an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.
  • Cj-C 6 haloalkyl is intended to mean an Ci-C 6 alkyl group, defined herein, wherein the alkyl is substituted with between one halogen up to fully substituted wherein a fully substituted C r C 6 haloalkyl can be represented by the formula C n L 2n+ , wherein L is a halogen and "n" is 1, 2, 3, 4, 5 or 6.
  • the halogens may be the same or different and selected from the group consisting of fluoro, chloro, bromo or iodo, preferably fluoro.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • halogen or halo is intended to mean a fluoro, chloro, bromo or iodo group.
  • heteroaryl is intended to mean an aromatic ring system containing 5 to 14 aromatic ring atoms that may be a single ring, two fused rings or three fused rings, wherein at least one aromatic ring atom is a heteroatom selected from, for example, but not limited to, the group consisting of O, S and N wherein the N is optionally substituted with H, C 1 -C 4 acyl or C r C 4 alkyl.
  • Some embodiments contain 5 to 6 ring atoms, for example, furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
  • Some embodiments contain 8 to 14 ring atoms for example quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, lH-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran, and the like.
  • the nitrogen is optionally substituted with C r C 4 acyl or Q-C 4 alkyl.
  • ring carbon atoms are optionally substituted with oxo thus forming a carbonyl group.
  • ring sulfur atoms are optionally substituted with oxo atoms thus forming a thiocarbonyl group.
  • the heterocyclic group can be attached/bonded to any available ring atom, for example, ring carbon, ring nitrogen and the like. In some embodiments the heterocyclic group is a 3-, 4-, 5-, 6- or 7- membered ring.
  • heterocyclic group examples include, but are not limited to, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin- 3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, piperzin-1-yl, piperzin-2- yl, piperzin-3-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [l,3]-dioxolan- 2-yl, thiomorpholin-4-yl, [l,4]oxazepan-4-yl, 1 , 1 -dioxothiomorpholin-4-yl, azepan-1-yl,
  • One aspect of the present invention pertains to certain compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R 2 , R 3 , Y, and Z have the same definitions as described herein, supra and infra. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group.
  • the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted" it may have up to the full valence of substitution, for example, a methyl group can be substituted by 1 , 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group.
  • the substitutents can be identical or they can be different.
  • Compounds of the invention also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
  • Y is N or CH; and Z is N or CR 1 . In some embodiments, Y is N; and Z is N. In some embodiments, Y is N; and Z is CR 1 . In some embodiments, Y is CH; and Z is N.
  • Y is CH; and Z is CR 1 .
  • Y is N.
  • Y is CH.
  • Z is N.
  • Z is CR 1 .
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, C r C 6 alkoxy, Ci-C 6 alkyl, C 1 -C 6 alkylsulfonyl, C r C 6 alkylthio, Q-C 6 alkylamino, cyano, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, and heterocyclyl, wherein said C 1 -C 6 alkyl and Q-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group.
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, C r C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, cyano, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, and heteroaryl.
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, chloro, cyano, cyclopentyl, difluoromethoxy, ethyl, methoxy, methylsulfonyl, thien-2-yl, trifluoromethoxy, and trifluoromethyl.
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, Q- C 6 alkyl, Ci-C 6 alkylsulfonyl, Q-C 6 alkylthio, C r C 6 alkylamino, cyano, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, C]-C 6 haloalkyl, halogen, heteroaryl, and heterocyclyl, wherein the Ci-C 6 alkyl and Ci-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group.
  • R 1 is selected from the group consisting of H, Q-C 6 alkoxy, Q-
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, Q- C 6 alkylsulfonyl, cyano, Q-C 6 haloalkoxy, Cj-C 6 haloalkyl, and halogen. In some embodiments, R 1 is selected from the group consisting of H, chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • R 1 is selected from the group consisting of H, chloro, cyano, methoxy, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • R 1 is H. In some embodiments, R 1 is chloro.
  • R 1 is cyano
  • R 1 is ethylamino
  • R 1 is methoxy
  • R 1 is methylthio. In some embodiments, R 1 is methylsulfonyl.
  • R 1 is trifluoromethoxy
  • R 1 is trifluoromethyl.
  • R 2 is selected from the group consisting of H, C]-C 6 alkoxy, Q-
  • R 2 is selected from the group consisting of H, Cj-C 6 alkoxy, Q- C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the Cj-C 6 alkyl and Cj-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group.
  • R 2 is selected from the group consisting of H, Ci-C 6 alkoxy, Q- C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, and heteroaryl.
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, cyclopropylmethoxy, cyclopropylmethyl, ethyl, methoxy, pyrrolidin-1-yl, thien-2- yl, and trifluoromethoxy.
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, difluoromethoxy, ethyl, methoxy, thien-2-yl, and trifluoromethoxy.
  • R 2 is H.
  • R 2 is chloro.
  • R 2 is cyclopentyl.
  • R 2 is cyclopropylmethoxy. In some embodiments, R 2 is cyclopropylmethyl. In some embodiments, R 2 is difluoromethoxy. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is methoxy.
  • R 2 is pyrrolidin-1-yl.
  • R 2 is thien-2-yl.
  • R 2 is trifluoromethoxy
  • R 3 is selected from the group consisting of H, Ci-C 6 alkoxy, Q- C 6 alkyl, Ci-C 6 alkylsulfonyl, Ci-C 6 alkylthio, C r C 6 alkylamino, cyano, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, C]-C 6 haloalkyl, halogen, heteroaryl, and heterocyclyl, wherein the Q-C 6 alkyl and Ci-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group.
  • R 3 is selected from the group consisting of H, Q-C 6 alkoxy, Q-
  • R 3 is selected from the group consisting of H, Ci-C 6 alkoxy, Q- C 6 alkylsulfonyl, cyano, Q-C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen. In some embodiments, R 3 is selected from the group consisting of H, chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • R 3 is selected from the group consisting of H, chloro, cyano, methoxy, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • R 3 is H. In some embodiments, R 3 is chloro.
  • R 3 is cyano
  • R 3 is ethylamino. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is methylthio. In some embodiments, R 3 is methylsulfonyl. In some embodiments, R 3 is trifluoromethoxy. In some embodiments, R 3 is trifluoromethyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Y is N or CH; Z is N or CR 1 ;
  • R 1 is selected from the group consisting of H, C r C 6 alkoxy, Ci-C 6 alkylsulfonyl, C 1 -C 6 alkylthio, Ci-C 6 alkylamino, cyano, Ci-C 6 haloalkoxy, Ci-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, C r C 6 alkoxy, Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the Ci-C 6 alkyl and C r C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group; and
  • R 3 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkylsulfonyl, Ci-C 6 alkylthio, C r C 6 alkylamino, cyano, Q-C 6 haloalkoxy, Ci-C 6 haloalkyl, and halogen.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein: Y is N or CH;
  • Z is N or CR 1 ;
  • R 1 is selected from the group consisting of chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl
  • R 2 is selected from the group consisting of H, C r C 6 alkoxy, Cj-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the C 1 -C 6 alkyl and C]-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group
  • R 3 is selected from the group consisting of H, Cj-C 6 alkoxy, Ci-C 6 alkylsulfonyl, Q-C 6 alkylthio, Ci-C 6 alkylamino, cyano, Ci-C 6 haloalkoxy, Ci-C 6 haloalkyl, and hal
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • Y is N or CH; Z is N or CR 1 ;
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkylsulfonyl, C]-C 6 alkylthio, C]-C 6 alkylamino, cyano, Cj-C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, cyclopropylmethoxy, cyclopropylmethyl, ethyl, methoxy, pyrrolidin-1-yl, thien-2-yl, and trifluoromethoxy; and R 3 is selected from the group consisting of H, Cj-C 6 alkoxy, Cj-C 6 alkylsulfonyl, C]-C 6 alkylthio, Ci-C 6 alkylamino, cyano, C 1 -C 6 haloalkoxy, Cj-C 6 haloalkyl, and halogen.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • Y is N or CH; Z is N or CR 1 ;
  • R 1 is selected from the group consisting of H, Cj-C 6 alkoxy, Cj-C 6 alkylsulfonyl, Cj-C 6 alkylthio, Cj-C 6 alkylamino, cyano, Cj-C 6 haloalkoxy, Cj-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, Cj-C 6 alkoxy, Cj-C 6 alkyl, C 3 -C 7 cycloalkyl, Cj-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the Cj-C 6 alkyl and Cj-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group; and
  • R 3 is selected from the group consisting of H, chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • Z is N or CR 1 ;
  • R 1 is selected from the group consisting of chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl;
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, cyclopropylmethoxy, cyclopropylmethyl, ethyl, methoxy, pyrrolidin-1-yl, thien-2-yl, and trifluoromethoxy;
  • R 3 is selected from the group consisting of H, chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkylsulfonyl, Ci-C 6 alkylthio, Ci-C 6 alkylamino, cyano, C 1 -C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the C)-C 6 alkyl and C r C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group; and
  • R 3 is selected from the group consisting of H, C r C 6 alkoxy, Ci-C 6 alkylsulfonyl, Q-C 6 alkylthio, Q-C 6 alkylamino, cyano, Q-C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen.
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, C 1 -C 6 alkylsulfonyl, Ci-C 6 alkylthio, C]-C 6 alkylamino, cyano, Ci-C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the Ci-C 6 alkyl and Q-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group; and
  • R 3 is selected from the group consisting of H, Ci-C 6 alkoxy, Q-C 6 alkylsulfonyl, Q-C 6 alkylthio, Q-C 6 alkylamino, cyano, Ci-C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof wherein: R 1 , R 2 , and R 3 are each independently selected from the group consisting of H,
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof wherein:
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkylsulfonyl, cyano, Ci-C 6 haloalkoxy, Ci-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, Q-C 6 alkoxy, Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 haloalkoxy, halogen, and heteroaryl;
  • R 3 is selected from the group consisting of H, Ci-C 6 alkoxy, Ci-C 6 alkylsulfonyl, cyano, C)-C 6 haloalkoxy, Ci -C 6 haloalkyl, and halogen.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • R 1 is selected from the group consisting of chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifiuoromethyl;
  • R 2 is selected from the group consisting of H, Q-C 6 alkoxy, Q-C 6 alkyl, C 3 -C 7 cycloalkyl, Q-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the Ci-C 6 alkyl and Q-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group; and R 3 is selected from the group consisting of H, Cj-C 6 alkoxy, C]-C 6 alkylsulfonyl, Q-C 6 alkylthio, Ci-C 6 alkylamino, cyano, Q-C 6 haloalkoxy, Ci-C 6 haloalkyl, and halogen.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • R 1 is selected from the group consisting of H, Ci-C 6 alkoxy, Q-C 6 alkylsulfonyl, C r C 6 alkylthio, Ci-C 6 alkylamino, cyano, Q-C 6 haloalkoxy, Ci-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, cyclopropylmethoxy, cyclopropylmethyl, ethyl, methoxy, pyrrolidin-1-yl, thien-2-yl, and trifluoromethoxy;
  • R 3 is selected from the group consisting of H, Q-C 6 alkoxy, Ci-C 6 alkylsulfonyl, Q-C 6 alkylthio, C r C 6 alkylamino, cyano, Q-C 6 haloalkoxy, Q-C 6 haloalkyl, and halogen.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • R 1 is selected from the group consisting of H, C]-C 6 alkoxy, Ci-C 6 alkylsulfonyl, Q-C 6 alkylthio, C]-C 6 alkylamino, cyano, Q-C 6 haloalkoxy, Ci-C 6 haloalkyl, and halogen;
  • R 2 is selected from the group consisting of H, Q-C 6 alkoxy, Ci-C 6 alkyl, C 3 -C7 cycloalkyl, Q-C 6 haloalkoxy, halogen, heteroaryl, and heterocyclyl, wherein the Q-C 6 alkyl and Q-C 6 alkoxy are each optionally substituted with one C 3 -C 7 cycloalkyl group; and
  • R 3 is selected from the group consisting of H, chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • R 1 is selected from the group consisting of chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, cyclopropylmethoxy, cyclopropylmethyl, ethyl, methoxy, pyrrolidin-1-yl, thien-2-yl, and trifluoromethoxy; and
  • R 3 is selected from the group consisting of H, chloro, cyano, ethylamino, methoxy, methylthio, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein: R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, chloro, cyano, cyclopentyl, difluoromethoxy, ethyl, methoxy, methylsulfonyl, thien-2- yl, trifluoromethoxy, and trifluoromethyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • R 1 is selected from the group consisting of H, chloro, cyano, methoxy, methylsulfonyl, trifluoromethoxy, and trifluoromethyl;
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, difluoromethoxy, ethyl, methoxy, thien-2-yl, and trifluoromethoxy;
  • R 3 is selected from the group consisting of H, chloro, cyano, methoxy, methylsulfonyl, trifluoromethoxy, and trifluoromethyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
  • R 1 is selected from the group consisting of chloro, methoxy, methylsulfonyl, trifluoromethoxy, and trifluoromethyl;
  • R 2 is selected from the group consisting of H, chloro, cyclopentyl, difluoromethoxy, ethyl, methoxy, and thien-2-yl;
  • R 3 is H, cyano, and trifluoromethyl.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in Table A. Table A
  • individual compounds and chemical genera of the present invention encompass all pharmaceutically acceptable salts, solvates, and hydrates, thereof.
  • the present invention embraces each diastereomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers (such as, by chiral HPLC, recrystallization of diastereomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
  • the compounds of the Formula (Ia) of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working examples.
  • Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]; incorporated herein by reference in its entirety).
  • a further aspect of the present invention pertains to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations.
  • Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art.
  • Suitable pharmaceutically acceptable carriers outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.) While it is possible that, for use in the prophylaxis or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • the invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds of the invention may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or suspensions, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • active ingredient is defined in the context of a "pharmaceutical composition” and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose when using the compounds of the present invention can vary within wide limits and as is customary and known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention.
  • Representative doses of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate by the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.
  • the amount of active ingredient or an active salt, solvate or hydrate derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • one skilled in the art understands how to extrapolate in vivo data obtained in one model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors including those cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimens outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as 2, 3, 4 or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate of a compound of the invention. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc., New York, 1999, incorporated herein by reference in its entirety.
  • the suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may be from 0.5 to about 90 percent of the active compound.
  • Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein ⁇ e.g., by stirring).
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols (e.g., nasal aerosols, by inhalation), this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • aerosols e.g., nasal aerosols, by inhalation
  • a spray e.g., a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well known to the person skilled in the art.
  • Solutions or dispersions of the compounds of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or derivative thereof in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives (e.g., benzyl alcohol or other suitable preservatives), absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants (e.g., carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and the like).
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder (e.g. , a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP)).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP)
  • PVP polyvinylpyrrolidone
  • the powder composition may be presented in unit dose form (e.g., capsules, cartridges) as for gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • compositions are tablets or capsules for oral administration.
  • compositions are liquids for intravenous administration.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulf ⁇ ric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed by Berge et ah, Journal of Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein by reference in its entirety.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • Pro-drugs can be converted to "pro-drugs.”
  • the term "pro- drugs” refers to compounds that have been modified with specific chemical groups known in the art and that when administered into an individual undergo biotransformation to give the parent compound.
  • Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound.
  • the "pro-drug” approach is utilized to facilitate oral absorption.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • SlPl receptor agonists are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non- human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as SlPl receptor agonists, for the treatment of an SlPl receptor-associated disease or disorder in companionship animals (e.g., cats, dogs, etc.) and in livestock animals (e.g., cows, chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt or as a solvate or hydrate thereof. Moreover, various hydrates and solvates of the compounds of the invention and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of KJ.
  • one aspect of the present invention pertains to hydrates and solvates of compounds of the present invention and/or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-Infrared spectroscopy
  • PXRD powder X-ray diffraction
  • Karl Fisher titration high resolution X-ray diffraction
  • Another object of the present invention relates to radiolabeled compounds of the present invention that are useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the SlPl receptor in tissue samples, including human and for identifying SlPl receptor ligands by inhibition binding of a radiolabeled compound. It is a further object of this invention to develop novel SlPl receptor assays which comprise such radiolabeled compounds.
  • the present invention embraces isotopically-labeled compounds of the present invention.
  • Isotopically or radiolabeled compounds are those which are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • Suitable radionuclides that may be incorporated in compounds of the present invention include, but are not limited to, 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl, 75 Br, 76 Br, 77 Br, 82 Br, 123 1, 124 1, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radiolabeled compounds will depend on the specific application of that radiolabeled compound. For example, for in vitro SlPl receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1, 131 I or 35 S will generally be most useful.
  • radionuclide (Ia), (Ic), etc., containing at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1, 35 S and 82 Br.
  • isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • the radionuclide 3 H and/or 14 C isotopes are useful in these studies.
  • substitution with heavier isotopes such as deuterium ⁇ i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability ⁇ e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in Figure 3 and the examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Tritium Gas Exposure Labeling This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • A. Sandmeyer and like reactions This procedure transforms an aryl amine or a heteroaryl amine into a diazonium salt, such as a diazonium tetrafluoroborate salt and subsequently to 125 I labeled compound using Na 125 I.
  • a represented procedure was reported by Zhu, G-D. and co-workers in J. Org. Chem., 2002, 67, 943-948.
  • B. Ortho 125 Iodination of phenols This procedure allows for the incorporation of 125 I at the ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266.
  • Aryl and heteroaryl bromide exchange with 125 I This method is generally a two step process.
  • the first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph 3 P) 4 ] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH 3 ) 3 SnSn(CH 3 ) 3 ].
  • Pd catalyzed reaction i.e. Pd(Ph 3 P) 4
  • a tri-alkyltinhalide or hexaalkylditin e.g., (CH 3 ) 3 SnSn(CH 3 ) 3 ].
  • a newly synthesized or identified compound i.e., test compound
  • the ability of a test compound to compete with the "radiolabeled compound of Formula (Ia)" for the binding to the SlPl receptor directly correlates to its binding affinity.
  • the labeled compounds of the present invention bind to the SlPl receptor.
  • the labeled compound has an IC 50 less than about 500 ⁇ M, in another embodiment the labeled compound has an IC 5 O less than about 100 ⁇ M, in yet another embodiment the labeled compound has an IC 50 less than about 10 ⁇ M, in yet another embodiment the labeled compound has an IC 50 less than about 1 ⁇ M and in still yet another embodiment the labeled inhibitor has an ICs 0 less than about 0.1 ⁇ M.
  • Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient.
  • Proton nuclear magnetic resonance ( 1 H NMR) spectra were also recorded on a Bruker Avance-500 equipped with a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference.
  • TLC Thin-layer chromatography
  • PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063- 0.200 mm (Merck). Evaporation was done under reduced pressure on a B ⁇ chi rotary evaporator.
  • Celite ® 545 was used for filtration of palladium.
  • LCMS spec HPLC-pumps: LC-IOAD VP, Shimadzu Inc.; HPLC system controller: SCL-IOA VP, Shimadzu Inc; UV-Detector: SPD-IOA VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, ABfMDS Sciex; Software: Analyst 1.2.
  • Example 1.1 Preparation of ( ⁇ )-3-(5-(5-(3,5-Bis(trifluoromethyl)phenyl)-l,2,4-oxadiazol- 3-yl)indolin-2-yl)propanoic Acid (Compound 1).
  • Step A Preparation of (S)-tert-Butyl 2-formylindoline-l-carboxylate.
  • Step C Preparation of (R)-tert-Butyl 2-(3-terf-Butoxy-3-oxopropyl)indoline-l- carboxylate.
  • Step D Preparation of (R)-tert-Buty ⁇ 5-Bromo-2-(3-tert-butoxy-3- oxopropyl)indoline-l-carboxylate.
  • NBS (0.47 g, 2.65 mmol) was added to a solution of (R)-tert-buty ⁇ 2-(3-tert-butoxy-3- oxopropyl)indoline-l-carboxylate (0.92 g, 2.65 mmol) in DMF (3 mL) at 0 0 C.
  • the mixture was stirred for 2 h at 0 0 C and quenched with water (3 mL).
  • the reaction was extracted with EtOAc (2 x 10 mL).
  • the combined organic extracts were washed with water, brine, dried over MgSO 4 and concentrated.
  • the residue was purified by silica gel column chromatography
  • Step F Preparation of ⁇ R)-tert-Euty ⁇ 2-(3-terf-Butoxy-3-oxopropyl)-5-(W- hydroxycarbamimidoyl)indoline-l-carboxylate.
  • Step G Preparation of ( ⁇ )-tert-Butyl 5-(5-(3,5-Bis(trifiuoromethyl)phenyl)-l,2,4- oxadiazoI-3-yl)-2-(3-terf-butoxy-3-oxopropyl)indoline-l-carboxylate.
  • Step H Preparation of ( ⁇ )-3-(5-(5-(3,5-Bis(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid.
  • Example 1.2 Preparation of (S)-3-(5-(5-(3,5-Bis(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3- yl)indolin-2-yl)propanoic Acid (Compound 3).
  • the title compound was prepared from (R)-tert-butyl 2-(hydroxymethyl)indoline-l - carboxylate in a similar manner to the one described in Example 1.1.
  • Example 1.3 Preparation of ( ⁇ )-3-(5-(5-(3-Cyano-5-(trifluoromethoxy)phenyl)-l,2,4- oxadiazoI-3-yl)indolin-2-yl)propanoic Acid (Compound 2).
  • Example 1.4 Preparation of (S)-3-(5-(5-(3-Cyano-5-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 4).
  • the title compound was prepared from (R)-tert-buty ⁇ 2-(hydroxymethyl)indoline-l- carboxylate and 3-cyano-5-(trifluoromethyl)benzoyl chloride in a similar manner to the one described in Example 1.1, the title compound was obtained.
  • Example 1.5 Preparation of (i?)-3-(5-(5-(4-Chloro-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 5).
  • Step A Preparation of (l?)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(4-chloro-
  • Step B Preparation of (/?)-3-(5-(5-(4-Chloro-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 5).
  • Example 1.6 Preparation of ( ⁇ )-3-(5-(5-(4-Methoxy-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 6).
  • Step A Preparation of (R)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(4- methoxy-3-(trifluoromethoxy)phenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • the title compound was prepared from 4-methoxy-3-(trifluoromethoxy)benzoic acid using a similar method to the one described in Example 1.5, Step A.
  • LCMS m/z 606.6 [M+H] + .
  • Step B Preparation of (/?)-3-(5-(5-(4-Methoxy-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazoI-3-yl)indolin-2-yl)propanoic acid (Compound 6).
  • the title compound was prepared from (R)-tert-buty ⁇ 2-(3-ter/-butoxy-3-oxopropyl)-5-
  • Example 1.7 Preparation of ( ⁇ )-3-(5-(5-(4-(Difluoromethoxy)-3-methoxyphenyI)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 7).
  • Step A Preparation of (R)-tert-Buty ⁇ 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(4- (difluoromethoxy)-3-methoxyphenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • the title compound was prepared as an oil from 4-(difluoromethoxy)-3-methoxybenzoic acid using a similar method to the one described in Example 1.5, Step A.
  • LCMS m/z 588.4 [M+H] + .
  • Step B Preparation of ( ⁇ )-3-(5-(5-(4-(Difluoromethoxy)-3-methoxyphenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 7). From (R)-tert-buty ⁇ 2-(3-tert-butoxy-3-oxopropyl)-5-(5-(4-(difluoromethoxy)-3- methoxyphenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate using a similar method to the one described in Example 1.5, Step B.
  • Example 1.8 Preparation of (5)-3-(5-(5-(4-ChIoro-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 8).
  • Step A Preparation of (S)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(4-chloro- 3-(trifluoromethoxy)phenyl)-l,2,4-oxadiazoI-3-yl)indoline-l-carboxylate.
  • Step B Preparation of (5)-3-(5-(5-(4-Chloro-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 8).
  • Example 1.9 Preparation of (£)-3-(5-(5-(4-Methoxy-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 9).
  • Step A Preparation of (S)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyI)-5-(5-(4- methoxy-3-(trifluoromethoxy)phenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • the title compound was prepared from 4-methoxy-3-(trifluoromethoxy)benzoic acid using a similar method to the one described in Example 1.5, Step A.
  • Step B Preparation of (5)-3-(5-(5-(4-Methoxy-3-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 9).
  • Example 1.10 Preparation of (£)-3-(5-(5-(4-(Difluoromethoxy)-3-methoxyphenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 10).
  • Step A Preparation of (S)-tert-Buty ⁇ 2-(3-terf-Butoxy-3-oxopropyl)-5-(5-(4- (difluoromethoxy)-3-methoxyphenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • the title compound was prepared as an oil from 4-(difluoromethoxy)-3-methoxybenzoic acid using a similar method to the one described in Example 1.5, Step A.
  • LCMS m/z 588.6 [M+H] + .
  • Step B Preparation of (S)-3-(5-(5-(4-(Difluoromethoxy)-3-methoxyphenyI)-l,2,4- oxadiazol-3-yl)indoIin-2-yl)propanoic Acid (Compound 10).
  • the title compound was prepared from (S)-tert-buty ⁇ 2-(3-tert-butoxy-3-oxopropyl)-5-
  • Step A Preparation of (R)-tert-Butyl 5-(5-(4-Bromo-3-chlorophenyl)-l,2,4- oxadiazol-3-yl)-2-(3-tert-butoxy-3-oxopropyl)indoline-l-carboxylate.
  • the title compound was prepared from 4-bromo-3-chlorobenzoic acid using a similar method to the one described in Example 1.5, Step A and was purified using silica gel column chromatography to give a solid.
  • LCMS m/z 604.3 [M+H] + .
  • Step B Preparation of (K)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(3-chloro- 4-cyclopentylphenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • Step C Preparation of ( ⁇ )-3-(5-(5-(3-Chloro-4-cyclopentylphenyl)-l,2,4-oxadiazol- 3-yl)indolin-2-yl)propanoic Acid (Compound 11).
  • Example 1.12 Preparation of ( ⁇ )-3-(5-(5-(4-Cyclopentyl-3-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yI)indolin-2-yl)propanoic Acid (Compound 12).
  • Step A Preparation of (R)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(4-chloro- 3-(trifluoromethyI)phenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • the title compound was prepared from 4-chloro-3-(trifiuoromethyl)benzoic acid using a similar method to the one described in Example 1.5, Step A.
  • Step B Preparation of (R)-tert-Butyl 2-(3-terf-Butoxy-3-oxopropyl)-5-(5-(4- cyclopentyl-S- ⁇ rifluoromethy ⁇ pheny ⁇ -l ⁇ -oxadiazol-S-y ⁇ indoline-l-carboxylate.
  • the title compound was prepared from (R)-tert-butyl 2-(3-tert-butoxy-3-oxopropyl)-5-
  • Step C Preparation of ( ⁇ )-3-(5-(5-(4-Cyclopentyl-3-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 12).
  • Example 1.13 Preparation of ( ⁇ )-3-(5-(5-(4-Ethyl-3-(trifiuoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 13).
  • Step A Preparation of ( ⁇ )-tert-butyl 2-(3-tert-butoxy-3-oxopropyl)-5-(5-(4-ethyl-3- (trifluoromethyl)phenyl)-l,2,4-oxadiazoI-3-yl)indoline-l-carboxylate.
  • Step B Preparation of ( ⁇ )-3-(5-(5-(4-Ethyl-3-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 13).
  • Example 1.14 Preparation of ( ⁇ )-3-(5-(5-(4-Ethyl-3-(methylsulfonyI)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 14).
  • Step A Preparation of (R)-tert-Butyl 2-(3-tert-Butoxy-3-oxopropyl)-5-(5-(4-chloro- 3-(methylsulfonyl)phenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • Step B Preparation of (R)-terf-Butyl 2-(3-terf-Butoxy-3-oxopropyl)-5-(5-(4-ethyl-3- (methylsuIfonyl)phenyl)-l,2,4-oxadiazol-3-yl)indoline-l-carboxylate.
  • the title compound was prepared from 2-(3-tert-butoxy-3-oxopropyl)-5-
  • Step C Preparation of ( ⁇ )-3-(5-(5-(4-Ethyl-3-(methylsulfonyl)phenyl)-l,2,4- oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 14).
  • Example 1.15 Preparation of (i?)-3-(5-(5-(4-(thiophen-2-yl)-3-(trifluoromethyl)phenyl)- l,2,4-oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 15).
  • Step A Preparation of (R)-tert-butyl 2-(3-tert-butoxy-3-oxopropyl)-5-(5-(4-
  • Step B Preparation of (/?)-3-(5-(5-(4-(Thiophen-2-yl)-3-(trifluoromethyl)phenyl)- l,2,4-oxadiazol-3-yl)indolin-2-yl)propanoic Acid (Compound 15).
  • the title compound was prepared from (i?)-ter/-butyl 2-(3-ter/-butoxy-3-oxopropyl)-5-
  • Example 2 Homogeneous Time-Resolved Fluorescence (HTRF ® ) Assay For Direct cAMP Measurement.
  • Compounds were screened for agonists of the SlPl receptor ⁇ e.g., human SlPl receptor) using the HTRF ® assay for direct cAMP measurement (Gabriel et al, Assay and Drug Development Technologies, 1:291-303, 2003) and recombinant CHO-Kl cells stably transfected with SlPl receptors.
  • CHO-Kl cells were obtained from ATCC ® (Manassas, VA; Catalog # CCL-61).
  • HTRF ® assay An agonist of the SlPl receptor was detected in the HTRF ® assay for direct cAMP measurement as a compound which decreased cAMP concentration.
  • the HTRF ® assay also was used to determine EC 50 values for SlPl receptor agonists.
  • the HTRF ® assay kit was purchased from Cisbio-US, Inc. (Bedford, MA; Catalog # 62AM4PEC).
  • the HTRF ® assay supported by the kit is a competitive immunoassay between endogenous cAMP produced by the CHO-Kl cells and tracer cAMP labeled with the dye d2.
  • the tracer binding is visualized by a monoclonal anti-cAMP antibody labeled with Cryptate.
  • the specific signal i.e., fluorescence resonance energy transfer, FRET
  • FRET fluorescence resonance energy transfer
  • Standard curve The fluorescence ratio (665 nm/620 nm) of the standards (0.17 to 712 nM cAMP) included in the assay was calculated and used to generate a cAMP standard curve according to the kit manufacturer's instructions. The fluorescence ratio of the samples (test compound or compound buffer) was calculated and used to deduce respective cAMP concentrations by reference to the cAMP standard curve.
  • the HTRF ® assay was carried out using a two-step protocol essentially according to the kit manufacturer's instructions, in 20 ⁇ L total volume per well in 384-well plate format (ProxiPlates; PerkinElmer, Fremont, CA; catalog # 6008280).
  • To each of the experimental wells was transferred 1500 recombinant CHO-Kl cells in 5 ⁇ L phosphate buffered saline containing calcium chloride and magnesium chloride ("PBS+"; Invitrogen, Carlsbad, CA; catalog # 14040) supplemented with IBMX (250 ⁇ M) and rolipram (20 ⁇ M) (phosphodiesterase inhibitors; Sigma- Aldrich, St.
  • Compounds of the invention had activity values ranging from about 0.5 to about 2.4 nM in this assay.
  • Example 3 Cellular/Functional Ca 2+ Assay for Agonist Activity on S1P3 Receptor.
  • a compound of the invention can be shown to have no or substantially no agonist activity at the S1P3 receptor using in assay a human neuroblastoma cell line which endogenously expresses S1P3 (predominantly), S1P2 and S1P5 receptors, but not SlPl or S1P4 receptors, based on mRNA analysis (Villullas et al, J. Neurosci. Res., 73:215-226, 2003). Of these, S1P3 and S1P2 receptors respond to agonists, such as SlP, with an intracellular calcium increase.
  • No or substantially no increase of intracellular calcium in response to a test compound is indicative of the test compound exhibiting no or substantially no agonist activity on the S1P3 receptor.
  • Such an assay can be performed commercially, e.g. by Caliper LifeSciences (Hopkinton, MA).
  • the human neuroblastoma cells are washed and resuspended in physiological buffer. The cells are then loaded with dye that measures intracellular calcium. SlP is used as a reference agonist. After addition of SlP or a test compound, fluorescence is measured at 485 nm excitation / 525 nm emission every 2 s for at least 60 s. Calcium ionophore A23187 is then added as an internal positive control.
  • Example 4 Effect of compounds in Peripheral Lymphocyte Lowering (PLL) Assay.
  • a compound of the invention can be shown to induce peripheral lymphocyte lowering (PLL).
  • PLL peripheral lymphocyte lowering
  • mice Male BALB/c mice (6 to 7 weeks of age at start of study) (Charles River Laboratories, Wilmington, MA) were housed four per cage and maintained in a humidity- (40- 60%) and temperature- (68-72 0 F) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange, CA, Rodent Diet 8604) and water. Mice were allowed one week of habituation to the animal facility before testing.
  • mice were administered one of the following viap.o.: saline, vehicle (100% PEG400) or 1 mg/kg of Compound 1 or Compound 2 in vehicle, in a total volume of 5 mL/kg.
  • Peripheral blood samples were collected at 5 hours post dose.
  • the mice were anesthetized with isoflurane and bled retro-orbitally (300 ⁇ L) into 1.5 mL EDTA tubes.
  • a complete cell count (CBC) (including lymphocyte count) was obtained using CELL-D YN ®
  • Rats Male Sprague-Dawley rats (7 weeks of age at start of study) (Charles River Laboratories) are housed two per cage and maintained in a humidity- (40-60%) and temperature- (68-72 0 F) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange, CA, Rodent Diet 8604) and water. Rats are allowed one week of habituation to the animal facility before testing.
  • PLL Assay Rats are orally administered vehicle or test compound ⁇ e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg) in vehicle, in a total volume of 5 mL/kg.
  • Peripheral blood samples are collected at 1, 3, 5, 8, 16 and 24 hours post dose. At each time point, the rats are anesthetized with isoflurane and bled retro-orbitally (200 ⁇ L) into 1.5 mL EDTA tubes. A complete cell count (CBC) (including lymphocyte count) is obtained using CELL-D YN ® 3700 (Abbott Laboratories, Abbott Park, IL). Reduction of the peripheral blood lymphocyte count by the test compound in comparison with vehicle is indicative of the test compound exhibiting activity for inducing peripheral lymphocyte lowering.
  • CBC complete cell count
  • a compound of the invention can be shown to have therapeutic efficacy in multiple sclerosis by showing it to have therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.
  • EAE is induced in rodents by injection of myelin oligodendrocyte glycoprotein (MOG) peptide, by injection of myelin basic protein (MBP) or by injection of proteolipid protein (PLP) peptide.
  • MOG myelin oligodendrocyte glycoprotein
  • MBP myelin basic protein
  • PGP proteolipid protein
  • mice Female C57BL/6 mice (8 to 10 weeks of age at start of study) (Jackson Laboratory, Bar Harbor, ME) are housed four per cage and maintained in a humidity- (40-60%) and temperature- (68-72 0 F) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange, CA, Rodent Diet 8604) and water. Mice are allowed one week of habituation to the animal facility before testing.
  • mice are immunized subcutaneously, 50 ⁇ L per hind flank, with a total of 100 ⁇ g MOG 35-55 peptide emulsified 1:1 with Complete Freund's adjuvant containing 4 mg/mL heat-killed Mycobacterium tuberculosis. Mice also receive 200 ng pertussis toxin intraperitoneally on the day of immunization and 48 hours later.
  • Drug treatment Mice are dosed orally, with vehicle or a test compound, once a day from day 3 until day 21. Dosing volume is 5mL/kg. The test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Mice are weighed daily. Mice are monitored daily from day 7 onward for disease symptoms. After the last dose on day 21, disease progression is monitored daily for 2 more weeks. Reduction of the severity of disease symptoms by the test compound in comparison with vehicle is indicative of the test compound exhibiting therapeutic efficacy in EAE. B. PLP-induced EAE in Mice.
  • mice Female SJL/J mice (8 to 10 weeks of age at start of study) (Jackson Laboratory, Bar Harbor, ME) are housed four per cage and maintained in a humidity- (40-60%) and temperature- (68-72 0 F) controlled facility on a 12 h:12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange, CA, Rodent Diet 8604) and water. Mice are allowed one week of habituation to the animal facility before testing.
  • mice are immunized subcutaneously with 100 ⁇ g PLPi 39 _i 5 i peptide emulsified 1:1 with Complete Freund's adjuvant containing 4 mg/mL heat- killed Mycobacterium tuberculosis. Mice also receive 200 ng pertussis toxin intravenously on the day of immunization.
  • Drug treatment Mice are dosed orally, with vehicle or a test compound, once a day from day 3 until day 21. Dosing volume is 5mL/kg. The test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Mice are weighed daily. Mice are monitored daily from day 7 onward for disease symptoms. After the last dose on day 21, disease progression is monitored daily for two more weeks.
  • C MBP-induced EAE in Rats.
  • mice Male Lewis rats (325-375 g at start of study) (Harlan, San Diego, CA) are housed two per cage and maintained in a humidity- (30-70%) and temperature- (20-22 0 C) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 A.M.) with free access to food (Harlan-Teklad Western Res., Orange, CA, Rodent Diet 8604) and water. Rats are allowed one week of habituation to the animal facility before testing. During the study, rats are weighed daily prior to clinical scoring at 11 am.
  • MBP Myelin basic protein
  • guinea pig Myelin basic protein
  • ipl Intraplantar injection into both hind paws of each rat, for a total injected volume of 100 ⁇ L per rat and a total dose of 50 ⁇ g of MBP per rat.
  • Drug treatment Rats are dosed orally, with vehicle or a test compound, 1 hour prior to MBP injection on day 0 and daily thereafter, after clinical scoring, for the duration of the study. Dosing volume is 5 mL/kg. The test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Reduction of the severity of disease symptoms by the test compound in comparison with vehicle is indicative of the test compound exhibiting therapeutic efficacy in EAE.
  • Example 6 Effect of Compounds on Type I Diabetes.
  • a compound of the invention can be shown to have therapeutic efficacy in Type I diabetes using an animal model for Type I diabetes, such as cyclophosphamide induced Type I diabetes in mice.
  • Drug treatment Mice are dosed orally, with vehicle or test compound, once a day from day 0 until day 25. Compounds are suspended in 0.5% methyl cellulose vehicle using a sonicator to ensure uniform suspension. Mice are weighed twice weekly and are dosed according to weight. Dosing volume is 5 mL/kg. The test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Blood glucose is measured twice weekly. After dosing is completed at day 25, the mice continue to be monitored and blood glucose measurements are taken once a week for 3 weeks. Promotion of normoglycemia by the test compound in comparison with vehicle is indicative of the test compound exhibiting therapeutic efficacy in Type I diabetes.
  • Example 7 Allograft Survival.
  • a compound of the invention can be shown to have therapeutic efficacy in prolonging allograft survival by showing it to have therapeutic efficacy in prolonging, e.g., survival of a skin allograft in an animal model.
  • mice Female BALBc/J mice (6 to 7 weeks of age at start of study) (Jackson Laboratory, Bar Harbor, ME) are housed four per cage and maintained in a humidity- (40-60%) and temperature- (68-72 0 F) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange, CA, Rodent Diet 8604) and water.
  • Female C57BL/6 mice (8 to 10 weeks of age at start of study) (Jackson Laboratory, Bar Harbor, ME) are similarly housed and maintained. Mice are allowed one week of habituation to the animal facility before testing.
  • Balbc/J and C57BL/6 mice are used as donors and recipients, respectively, in a model of skin allograft transplantation.
  • Donor Balbc/J mice are anesthetized, and 0.5 cm - diameter full thickness areas of abdominal skin are surgically removed.
  • Skin grafts harvested from the Balbc/J mice are sutured onto the dorsum of anesthetized recipient C57BL/6 mice.
  • Sutured allografts are covered with Vaseline gauze and Bolster dressing for 7 days. The allografted mice are divided into eight groups of 8 mice each.
  • Histological analysis of the rejected graft is carried out on hematoxylin and eosin (H & E)-stained sections.
  • H & E hematoxylin and eosin
  • grafts are removed from transplanted recipients, cut into small fragments, digested with collagenase and sedimented over Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) to isolate graft-infiltrating lymphocytes, which are counted and characterized for activation markers (e.g., T-cell activation markers) by flow cytometry. Histological analysis of the graft on day 5 can be carried out on hematoxylin and eosin (H&E)- stained sections.
  • Drug treatment Mice are dosed orally, with vehicle or test compound, once a day from the day of transplantation until the end of the study, e.g. until day 14, 21 or 28.
  • Dosing volume is 5 mL/kg.
  • the test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Delay of time of rejection of the skin allograft by the test compound in comparison with vehicle is indicative of the test compound exhibiting therapeutic efficacy in prolonging skin allograft survival.
  • a compound of the invention can be shown to have therapeutic efficacy in colitis using an animal model for colitis.
  • Suitable animal models are known in the art (Boismenu et al, J. Leukoc. Biol, 67:267-278, 2000).
  • a first exemplary animal model for colitis is trinitrobenzene sulfonic acid (TNBS)-induced colitis, which presents clinical and histopathological findings that resemble those in Crohn's disease (Neurath e/ ⁇ /. , J. Exp. Med., 182: 1281-1290, 1995; Boismenu et al., J. Leukoc. Biol., 67:267-278, 2000).
  • a second exemplary animal model for colitis is dextran sulfate sodium (DSS)-induced colitis, which presents clinical and histopathological findings that resemble those in ulcerative colitis (Okayasu et al,
  • mice Male BALB/c mice (6 weeks of age at start of study) (Jackson Laboratory, Bar Harbor, ME) are housed four per cage and maintained in a humidity- (40-60%) and temperature- (68-72 0 F) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange CA, Rodent Diet 8604) and water. Mice are allowed one week of habituation to the animal facility before testing.
  • TNBS induction of colitis Mice are weighed for baseline body weights and fasted later that day beginning at 6 : 15 pm j ust prior to lights-out (day 0) . Body weights are taken again the following morning (day 1) at approximately 7:30 am. Mice are anesthetized with isoflurane prior to induction of colitis. Colitis is induced in the mice by intracolonic injection of about 150 mg/kg TNBS in 50% ethanol (in a volume of 150 ⁇ L) using an intubation needle (22 guage, 1.5 in) inserted completely into the anus with the mouse held by the tail in a vertical position. The mouse is held vertically for 30 additional seconds to allow thorough absorption and minimize leakage, after which the mouse is returned to its cage. Mice are then fed, following the preceding approximately 14 hour of fasting. Each morning thereafter, the mice are weighed. In control experiments, mice receive 50% ethanol alone using the same protocol.
  • Drug treatment begins on day 2. Mice are dosed orally, with vehicle or a test compound, once a day from day 2 until the conclusion of the experiment on, e.g., day 7, 14 or 21. Dosing volume is 5 mL/kg. The test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg.
  • colons are extracted and measured. Mice are euthanized with CO 2 and colon is removed from anus to cecum. Excised colon is measured for entire length, length from anus to end of inflamed area and length of inflamed
  • Rats are housed two per cage and maintained in a humidity- (40-60%) and temperature- (68-72 0 F) controlled facility on a 12 h:12 h light/dark cycle (lights on at 6:30am) with free access to food (Harlan Teklad, Orange CA, Rodent Diet 8604) and water. Rats are allowed one week of habituation to the animal facility before testing.
  • TNBS induction of colitis Rats are weighed for baseline body weights and fasted later that day beginning at 6: 15 pm just prior to lights-out (day 0). Body weights are taken again the following morning (day 1) at approximately 7:30 am. Rats are anesthetized with isoflurane prior to induction of colitis.
  • Colitis is induced in the rats by intracolonic injection of about 60 mg/kg TNBS in 50% ethanol (in a volume of 500 ⁇ L) using a fabricated intubation needle (7.5 Fr umbilical catheter and 14 g hub) inserted 8cm into the anus with the rat held by the tail in a vertical position. The rat is held vertically for an additional 30 seconds to allow thorough absorption and minimize leakage, after which the rat is returned to its cage. Rats are then fed, following the preceding approximately 14 h of fasting. Each morning thereafter, the rats are weighed. In control experiments, rats receive 50% ethanol alone using the same protocol.. Drug treatment: Drug treatment begins on day 2.
  • Rats are dosed orally, with vehicle or test compound, once a day from day 2 until the conclusion of the experiment on, e.g., day 7, 14 or 21.
  • Dosing volume is 5 mL/kg.
  • Test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg.
  • colons are extracted and measured. Rats are euthanized with CO 2 and colon is removed from anus to cecum. Excised colon is measured for entire length, length from anus to end of inflamed area, and length of inflamed (affected) area. After measurements, colon is cleared of excrement by flushing with saline and then cut open to clear more thoroughly. Colon is then weighed and preserved in neutral buffered formalin (NBF; 10% formalin, pH 6.7-7.0). The colon tissue is embedded in paraffin and processed for hematoxylin and eosin (H & E)-stained sections.
  • NNF neutral buffered formalin
  • Rats Male Sprague-Dawley rats (250-300 g at time of surgery) are implanted by Charles River Laboratories (Wilmington, MA) with cardiac transmitting devices (Data Sciences PhysioTel C50-PXT) into the peritoneal space, with a pressure-sensing catheter inserted into the descending aorta. Rats are allowed at least one week to recover. Rats are housed in individual cages and maintained in a humidity- (30-70%) and temperature- (20-22 0 C) controlled facility on a 12 h: 12 h light/dark cycle (lights on at 7:00 am) with free access to food (Harlan-Teklad, Orange, CA, Rodent Diet 8604) and water. Rats are allowed one week of habituation to the animal facility before testing.
  • the implanted transmitting devices transmit continuous measurements of blood pressure (systolic, diastolic, mean arterial, pulse), heart rate, body temperature, and motor activity in freely moving conscious animals. These data are transmitted via radiofrequency to a computer which bin the data into 1 minute averages using DataSciences ART software. Telemetry recording occus over a 21-h period, starting at noon and continuing until 9:00 am the following day. A maximum of eight rats are tested at a time, and the same eight rats are utilized for all treatment groups in a within-subject design.
  • Rats are injected orally with vehicle or compound at 1 :00pm.
  • a full study (vehicle + 3 doses) requires four separate testing sessions, which occur on Mondays- Tuesdays and Thursdays-Fridays.
  • Exemplary bradycardia assay It is expressly contemplated that the rats can be used to show that a compound of the invention has no or substantially no activity for bradycardia.
  • the rats are administered vehicle or a test compound and heart rate is then measured over a 120 minute period. No or substantially no reduction of heart rate in response to the test compound in comparison with vehicle is indicative of the test compound exhibiting no or substantially no activity for bradycardia.

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Abstract

La présente invention concerne certains dérivés de l’acide (1,2,4-oxadiazol-3-yl)indolin-1-yl carboxylique substitué de formule (Ia) et leurs sels pharmaceutiquement acceptables, qui présentent des propriétés pharmacologiques utiles, par exemple, comme agonistes du récepteur S1P1. La présente invention concerne également des compositions pharmaceutiques contenant les composés de l’invention, et des procédés d’utilisation des composés et des compositions de l’invention dans le traitement d’affections associées au récepteur S1P1, par exemple, le psoriasis, la polyarthrite rhumatoïde, la maladie de Crohn, le rejet de greffe, la sclérose en plaques, le lupus érythémateux disséminé, la rectocolite hémorragique, le diabète de type I, l’acné, des infections ou maladies microbiennes et des infections ou maladies virales.
PCT/US2009/003530 2008-06-13 2009-06-12 Dérivés de l’acide (1, 2, 4-oxadiazol-3-yl)indolin-1-yl carboxylique substitué pouvant être utilisés comme agonistes de s1p1 WO2009151626A1 (fr)

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US8415484B2 (en) 2008-08-27 2013-04-09 Arena Pharmaceuticals, Inc. Substituted tricyclic acid derivatives as S1P1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders
US8580841B2 (en) 2008-07-23 2013-11-12 Arena Pharmaceuticals, Inc. Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders
US8853419B2 (en) 2010-01-27 2014-10-07 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof
US9085581B2 (en) 2010-03-03 2015-07-21 Arena Pharmaceuticals, Inc. Processes for the preparation of S1P1 receptor modulators and crystalline forms thereof
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US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11478448B2 (en) 2017-02-16 2022-10-25 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11555015B2 (en) 2018-09-06 2023-01-17 Arena Pharmaceuticals, Inc. Compounds useful in the treatment of autoimmune and inflammatory disorders

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US9522133B2 (en) 2008-07-23 2016-12-20 Arena Pharmaceuticals, Inc. Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders
US8580841B2 (en) 2008-07-23 2013-11-12 Arena Pharmaceuticals, Inc. Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders
US9126932B2 (en) 2008-07-23 2015-09-08 Arena Pharmaceuticals, Inc. Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders
US9108969B2 (en) 2008-08-27 2015-08-18 Arena Pharmaceuticals, Inc. Substituted tricyclic acid derivatives as S1P1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders
US8415484B2 (en) 2008-08-27 2013-04-09 Arena Pharmaceuticals, Inc. Substituted tricyclic acid derivatives as S1P1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders
US9447041B2 (en) 2010-01-27 2016-09-20 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[B]indol-3-yl)acetic acid and salts thereof
US8853419B2 (en) 2010-01-27 2014-10-07 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof
US11149292B2 (en) 2010-01-27 2021-10-19 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[B]indol-3-yl)acetic acid and salts thereof
US9175320B2 (en) 2010-01-27 2015-11-03 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[B]indol-3-yl)acetic acid and salts thereof
US11674163B2 (en) 2010-01-27 2023-06-13 Arena Pharmaceuticals, Inc. Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof
US9085581B2 (en) 2010-03-03 2015-07-21 Arena Pharmaceuticals, Inc. Processes for the preparation of S1P1 receptor modulators and crystalline forms thereof
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
US11896578B2 (en) 2015-01-06 2024-02-13 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US10301262B2 (en) 2015-06-22 2019-05-28 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compund1) for use in SIPI receptor-associated disorders
US11091435B2 (en) 2015-06-22 2021-08-17 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3, 4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(compound1) for use in S1P1 receptor-associated disorders
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US10676435B2 (en) 2015-06-22 2020-06-09 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound 1) for use in SIPI receptor-associated disorders
US11478448B2 (en) 2017-02-16 2022-10-25 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11555015B2 (en) 2018-09-06 2023-01-17 Arena Pharmaceuticals, Inc. Compounds useful in the treatment of autoimmune and inflammatory disorders

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