Compounds useful for treatment of autoimmune and inflammatory disorders

Abstract

The present invention relates to certain compounds of formula (Ia) and pharmaceutically acceptable salts thereof: # imgabs0 which exhibit useful pharmacological properties, e.g., as S1P1 receptor agonists. The invention also provides pharmaceutical compositions comprising the compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1 receptor-related disorders, such as S1P1 receptor-related disorders. The S1P1 receptor-associated condition is, for example, a lymphocyte-mediated disease or condition, an autoimmune disease or condition, an inflammatory disease or condition, an inflammatory skin disease or condition, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, or the like. Type I diabetes and acne, microbial infections or diseases and viral infections or diseases.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of September 5, 2019, application number 201980071228.0, and invention name “Compounds useful for treating autoimmune diseases and inflammatory diseases”. Technical Field

[0002] The present invention relates to certain compounds of formula (Ia) and pharmaceutically acceptable salts thereof that exhibit useful pharmacological properties (e.g., as agonists of the S1P1 receptor). The present invention also provides pharmaceutical compositions comprising the compounds of the present invention, and methods of using the compounds and compositions of the present invention to treat S1P1 receptor-related disorders, such as lymphocyte-mediated diseases or disorders, autoimmune diseases or disorders, inflammatory diseases or disorders, inflammatory skin diseases or disorders, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne, microbial infections or diseases, and viral infections or diseases. Background Art

[0003] The present invention relates to compounds that are S1P1 receptor agonists having at least immunosuppressive, anti-inflammatory and / or hemostatic activity, for example by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues and / or enhancing vascular integrity.

[0004] The present application focuses, in part, on addressing the unmet need for immunosuppressants, such as those that can be obtained orally, that 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 with underlying defects in vascular integrity or associated with angiogenesis, such as can be pathological (e.g., as can occur in inflammation, tumor development, and atherosclerosis), with fewer side effects, such as impairing immune responses to systemic infections.

[0005] S1P receptor agonists with agonist activity at the S1P1 receptor have been shown to rapidly and reversibly induce lymphopenia (also known as peripheral lymphopenia (PLL); Hale et al., Bioorg. Med. Chem. Lett., 14:3351-3355, 2004). This leads to clinically useful immunosuppression by sequestering T and B cells in secondary lymphoid tissues (lymph nodes and Ehrlich patches) and thus sequestering sites of inflammation and organ transplantation (Rosen et al., Immunol. Rev., 195:160-177, 2003; Schwab et al., Nature Immunol., 8:1295-1301, 2007). This lymphocyte sequestration, for example in lymph nodes, is thought to be the result of both agonist-driven functional antagonism of S1P1 receptors on T cells (thereby reducing the ability of S1P to mobilize T cells out of the lymph nodes) and persistent antagonism of S1P1 receptors on the lymph node endothelium (thereby increasing the barrier function against lymphocyte migration) (Matloubian et al., Nature, 427:355-360, 2004; Baumruker et al., Expert Opin. Investig. Drugs, 16:283-289, 2007). Agonism of the S1P1 receptor alone has been reported to be sufficient to achieve lymphocyte sequestration (Sauna et al., J. Biol. Chem., 279:13839-13848, 2004) and this occurs without compromising immune responses to systemic infection (Brinkmann et al., Transplantation, 72:764-769, 2001; Brinkmann et al., Transplant Proc., 33:530-531, 2001).

[0006] Agonism of endothelial S1P1 receptors has a broader role in promoting vascular integrity, with studies supporting a role for S1P1 receptors 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, such as those that may result from sepsis, severe trauma, and surgery, leading to acute lung injury or respiratory distress syndrome (Johan Groeneveld, Vascul. Pharmacol., 39:247-256, 2003).

[0007] An exemplary S1P receptor agonist with agonist activity at the S1P1 receptor is FTY720 (fingolimod, an immunosuppressant currently in clinical trials (Martini et al., Expert Opin. Investig. Drugs, 16:505-518, 2007). FTY720 acts as a prodrug that is phosphorylated in vivo; the phosphorylated derivative is an agonist at the S1P1, 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 lymphocytopenia (also known as peripheral lymphopenia). (PLL); Hale et al., Bioorg. Med. Chem. Lett., 14:3351-3355, 2004). It causes clinically useful immunosuppression by sequestering T cells and B cells in secondary lymphoid tissues (lymph nodes and Ehrlich patches) and thus isolating inflammation and organ transplant sites (Rosen et al., Immunol. Rev., 195:160-177, 2003; Schwab et al., Nature Immunol., 8:1295-1301, 2007).

[0008] In clinical trials, FTY720 caused adverse events (i.e., transient asymptomatic bradycardia) due to its agonistic effect on the S1P3 receptor (Budde et al., J. Am. Soc. Nephrol., 13:1073-1083, 2002; Sauna et al., J. Biol. Chem., 279:13839-13848, 2004; Ogawa et al., BBRC, 361:621-628, 2007).

[0009] FTY720 has been reported to have therapeutic efficacy in at least a rat model of autoimmune myocarditis and a mouse model of acute viral myocarditis (Kiyabayashi et al., J. Cardiovasc. Pharmacol., 35:410-416, 2000; Miyamoto et al., J. Am. Coll. Cardiol., 37:1713-1718, 2001); and a mouse model of 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. Liver Physiology, 16:699-703, 2006). =Physiol., 291: G267-G274, 2006; Daniel et al., J. Immunol., 178: 2458-2468, 2007); a rat model of progressive mesangial proliferative glomerulonephritis (Martini et al., Am. J. Physiol. Renal Physiology, 2006: G267-G274; Daniel et al., J. Immunol., 178: 2458-2468, 2007); a rat model of progressive mesangial proliferative glomerulonephritis (Martini et al., Am. J. Physiol. Renal Physiology, 2006: G267-G274, 2006 ... Based on the work using the S1P1 receptor agonist SEW2871, a mouse model of asthma that mainly acts through the S1P1 receptor was proposed (Idzko et al., Journal of Clinical Research (J. Clin. Invest.), 116: 2935-2944, 2006); a mouse model of airway inflammation and induced bronchial hyperresponsiveness (Sawicka et al., Journal of Immunology (J. Immunol.), 171: 6206-6214, 2003); a mouse model for atopic dermatitis (Kohno ... Bull. of Biology and Pharmacology, 27:1392-1396, 2004); mouse model of ischemia-reperfusion injury (Kaudel et al., Transplant. Proc., 39:499-502, 2007); mouse model of systemic lupus erythematosus (SLE) (Okazaki et al., J. Rheumatol., 29:707-716, 2002; Herzinger et al., Am. J. Clin. Dermatol.)", 8:329-336, 2007); a rat model of rheumatoid arthritis (Matsuura et al., Int. J. Immunopharmacol., 22:323-331, 2000; Matsuura et al., Inflamm. Res., 49:404-410, 2000); a rat model of autoimmune uveitis (Kurose et al., Exp. Eye Res., 70:7-15, 2000); a mouse model of type I diabetes (Fu et al., Transplantation, 73:1425-1430, 2002; Maki et al., Transplantation, 74:1684-1686, 2002; Yang et al., Clinical Immunology, 23:323-331 ... rheumatoid arthritis (Matsuura et al., Int. J. Immunopharmacol., 22:323-331, 2000; Matsuura et al., Inflamm. Res., 49:404-410, 2000); a rat model of autoimmune uveitis (Kurose et al., Exp. Eye Res., 70:7-15, 2000); a mouse model of type I diabetes (Fu et =In vitro fertilization (IVF) and inflammatory cytokines (Immunology, 107:30-35, 2003; Maki et al., Transplantation, 79:1051-1055, 2005); mouse models of atherosclerosis (Nofer et al., Circulation, 115:501-508, 2007; Keul et al., Thromb. Vasc. Biol., 27:607-613, 2007); rat models of brain inflammation after traumatic brain injury (TBI) (Zhang et al., J. Cell. Molecular Medicine, 2003; Zhang ... Maki et al., Transplantation, 79:1051-1055, 2005); mouse models of atherosclerosis (Nofer et al., Circulation, 115:501-508, 2007; Keul et al., Thromb. Vasc. Biol., 27:607-613, 2007); rat models of brain inflammation after traumatic brain injury (TBI) (Zhang et al., J. Cell. Molecular Medicine, 2003; Mol. Med., 11:307-314, 2007); and mouse models of transplant coronary artery disease and graft-versus-host disease (GVHD) (Hwang et al., Circulation, 100:1322-1329, 1999; Taylor et al., Blood, 110:3480-3488, 2007). In vitro results suggest that FTY720 may have therapeutic efficacy against β-amyloid-related inflammatory diseases including Alzheimer's disease (Kaneider et al., FASEB J., 18:309-311, 2004). KRP-203, an S1P receptor agonist with agonist activity at the S1P1 receptor, has been reported to have therapeutic efficacy in a rat model of autoimmune myocarditis (Ogawa et al., BBRC, 361:621-628, 2007). Using the S1P1 receptor agonist SEW2871, agonism of the endothelial S1P1 receptor has been shown to prevent proinflammatory monocyte / endothelial cell interactions in the vascular endothelium of type I diabetes (Whetzel et al., Circ.Res., 99:731-739, 2006) and protects the vasculature from TNFα-mediated monocyte / endothelial cell interactions (Bolick et al., Thromb. Vasc. Biol., 25:976-981, 2005).

[0010] In addition, FTY720 has been reported to have therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE) in rats and mice (a model of 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, 20:16-24, 2004).

[0065] FTY720 is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. It is a novel antagonist of FTY720. In a Phase II clinical trial 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 (Kappos et al., N. Engl. J. Med., 355: 1124-1140, 2006; Martini et al., Expert Opin. Investig. Drugs, 16: 505-518, 2007; Zhang et al., Mini-Reviews in Medicinal Chemistry, 7: 845-850, 2007; Brinkmann, Pharmacology & Therapeutics, 115: 84-105, 2007).FTY720 is currently in Phase III studies for remitting-relapsing multiple sclerosis (Brinkmann, Pharmacology & Therapeutics, 115:84-105, 2007; Baumruker et al., Expert Opin. Investig. Drugs, 16:283-289, 2007; Dev et al., Pharmacology & Therapeutics, 117:77-93, 2008).

[0011] Recently, FTY720 was reported to have antiviral activity. Specific data have been presented in the lymphocytic choriomeningitis virus (LCMV) mouse model, in which mice were infected with the Armstrong or clone 13 strains of LCMV (Premenko-Lanier et al., Nature, 454, 894, 2008).

[0012] FTY720 was reported to impair the migration of dendritic cells infected with Francisella tularensis to mediastinal lymph nodes, thereby reducing their bacterial colonization. Francisella tularensis is associated with tularemia, ulcer and lymphopathic infections, respiratory tract infections, and typhoid fever (E. Bar-Haim et al., PLoS Pathogens, 4(11):e1000211.doi:10.1371 / journal.ppat.1000211, 2008).

[0013] It has also been recently reported that short-term high doses of FTY720 rapidly reduced ocular infiltration in experimental autoimmune uveoretinitis. Administration of FTY720 in the early stages of ocular inflammation can rapidly prevent retinal damage. It is reported to not only prevent infiltration of target organs, but also reduce existing infiltration (Raveney et al., Arch. Ophthalmol, 126(10), 1390, 2008).

[0014] Treatment with FTY720 reportedly alleviates ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to bone surfaces. The data provide evidence that S1P controls the migratory behavior of osteoclast precursors, dynamically regulating bone mineral homeostasis (Ishii et al., Nature, Online First Publication, February 8, 2009, doi: 10.1038 / nature07713).

[0015] The agonism of S1P1 receptors is related to the survival of oligodendrocyte progenitor cells. The survival of oligodendrocyte progenitor cells is an essential component of the remyelination process. Remyelination of multiple sclerosis lesions is considered to promote the recovery of clinical relapses (Miron et al., "Annuals of Neurology (Ann. Neurol.)", 63: 61-71, 2008; Coelho et al., "J Pharmacol. Exp. Ther. (J Pharmacol. Exp. Ther.), 323: 626-635, 2007; Dev et al., "Pharmacology and Therapeutics (Pharmacology and Therapeutics)", 117: 77-93, 2008). It is also shown that S1P1 receptors play a role in the occurrence of oligodendrocyte progenitor cell mitosis induced by platelet-derived growth factor (PDGF) (Jung et al., "Glia (Glia)", 55: 1656-1667, 2007).

[0016] Agonism of the S1P1 receptor has also been reported to mediate the migration of neural stem cells to 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).

[0017] Agonism of the S1P1 receptor is associated with inhibition of keratinocyte proliferation (Sauer et al., J. Biol. Chem., 279:38471-38479, 2004), which is consistent with reports that S1P inhibits keratinocyte proliferation (Kim et al., Cell Signal, 16:89-95, 2004). Excessive proliferation of keratinocytes at the entrance of the hair follicle (which can be subsequently blocked) and the associated inflammation are important pathogenic factors of acne (Koreck et al., Dermatology, 206:96-105, 2003; Webster, Cutis, 76:4-7, 2005).

[0018] FTY720 is reported to have therapeutic efficacy in inhibiting pathological angiogenesis, such as that which may occur in tumor development. Inhibition of angiogenesis by FTY720 is thought to involve agonism of the S1P1 receptor (Oo et al., J. Biol. Chem., 282; 9082-9089, 2007; Schmid et al., J. Cell Biochem, 101: 259-270, 2007). FTY720 is reported to have therapeutic efficacy in inhibiting primary and metastatic tumor growth in a mouse model of melanoma (LaMontagne et al., Cancer Res., 66: 221-231, 2006). FTY720 is reported to have therapeutic efficacy in a mouse model of metastatic hepatocellular carcinoma (Lee et al., Clin. Cancer Res., 11: 84588466, 2005).

[0019] Oral administration of FTY720 to mice was reported to effectively block VEGF-induced vascular permeability, an important process associated with angiogenesis, inflammation and pathological conditions such as sepsis, hypoxia and solid tumor growth (T Sanchez et al., J. Biol. Chem., 278(47), 47281-47290, 2003).

[0020] Cyclosporin A and FK506 (calcineurin inhibitors) are drugs used to prevent transplant organ rejection. Although they are effective in delaying or inhibiting transplant rejection, it is known that classical immunosuppressants (such as cyclosporin A and FK506) can cause a variety of adverse side effects, including nephrotoxicity, neurotoxicity, beta cell toxicity and gastrointestinal discomfort. There is an unmet need for immunosuppressants without these side effects in organ transplantation, which are effectively used as monotherapy or in combination with classical immunosuppressants to inhibit, for example, the migration of alloantigen-reactive T cells to transplanted tissues, thereby prolonging graft survival time.

[0021] FTY720 has been shown to have therapeutic efficacy in transplant rejection as a monotherapy and in synergistic combinations with classical immunosuppressants including cyclosporin A, FK506, and RAD (mTOR inhibitors). It has been shown that, unlike the classical immunosuppressants cyclosporin A, FK506, and RAD, FTY720 has the efficacy of prolonging graft survival without inducing systemic immunosuppression, and this difference in drug action is believed to be related to the observed synergistic effect of the combination (Brinkmann et al., Transplant Proc., 33:530-531, 2001; Brinkmann et al., Transplantation, 72:764-769, 2001).

[0022] Agonists of the S1P1 receptor have been reported to have therapeutic efficacy in 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 in prolonging allograft survival in a rat cardiac allograft model (Suzuki et al., Transpl. Immunol., 4:252-255, 1996). FTY720 is reported to synergize with cyclosporin A to prolong rat skin allograft survival (Yanagawa et al., J Immunol, 160:5493-5499, 1998), synergize with cyclosporin A and FK506 to prolong rat cardiac transplant survival, and synergize with cyclosporin A to prolong canine and monkey kidney transplant survival (Chiba et al., Cell Mol. Biol, 3:11-19, 2006). KRP-203, an S1P receptor agonist, is reported to have therapeutic efficacy in prolonging allograft survival in a rat skin allograft model, and as a monotherapy and in synergistic combination with cyclosporin A in a rat cardiac allograft model (Shimizu et al., Circulation, 111:222-229, 2005). It has also been reported that KRP-203 is a prodrug used in combination with mycophenolate mofetil (MMF; the active metabolite of which is mycophenolic acid, an inhibitor of purine biosynthesis) to prolong allograft survival in a rat kidney allograft model and a rat heart allograft model (Suzuki et al., J. Heart Lung Transplant, 25:302-209, 2006; Fujishiro et al., J. Heart Lung Transplant, 25:825-833, 2006). It has been reported that an agonist of the S1P1 receptor (AUY954) combined with a subtherapeutic dose of RAD001 (Certican / Everolimus, an mTOR inhibitor) can prolong rat cardiac allograft survival (Pan et al., Chemistry & Biology, 13:1227-1234, 2006).In a rat small intestinal allograft model, FTY720 was reported to synergize with cyclosporin A to prolong small intestinal allograft survival (Sakagawa et al., Transpl. Immunol, 13: 161-168, 2004). FTY720 was reported to have therapeutic efficacy in a mouse islet transplant 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 demonstrating no deleterious effects on human islet function (Truong et al., American Journal of Transplantation, 7: 2031-2038, 2007).

[0023] FTY720 was reported to reduce pain behaviors in a sparing nerve injury model of neuropathic pain that is independent of prostaglandin synthesis (O. Costu et al., Journal of Cellular and Molecular Medicine 12(3), 995-1004, 2008).

[0024] It has been reported that FTY720 attenuates the development of contact hypersensitivity (CHS) in mice. Adoptive transfer of immune lymph node cells from mice treated with FTY720 during the sensitization phase was virtually incapable of inducing CHS reactions in recipients (D. Nakashima et al., J. Investigative Dermatology, 128(12), 2833-2841, 2008).

[0025] It was reported that prophylactic oral administration of FTY720 (1 mg / kg, three times per 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).

[0026] S1P1 receptor agonists are useful in treating or preventing conditions in which suppression of the immune system or agonism of the S1P1 receptor is in order, such as diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders, and conditions with underlying defects in vascular integrity or associated with angiogenesis, such as may be pathological.

[0027] In one embodiment, the present invention encompasses compounds that are agonists of the S1P1 receptor, having good overall physical properties and biological activity and having substantially at least the effectiveness of previous compounds active at the S1P1 receptor.

[0028] Citation of any reference throughout this application shall not be construed as an admission that such reference is prior art to the present application. Summary of the invention

[0029] The present invention encompasses compounds of formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0030]

[0031] in:

[0032] R 1 is H or OH;

[0033] R 3 is H; or

[0034] R 1 and R 3 Together they form an oxo group;

[0035] as well as

[0036] R 2 is H or a group of formula (IIa):

[0037]

[0038] The condition is that if R 2 is H, then R 1 and R 3 Neither is H.

[0039] The present invention encompasses compounds that are S1P1 receptor agonists having at least immunosuppressive, anti-inflammatory and / or hemostatic activity, for example by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and / or enhancing vascular integrity.

[0040] S1P1 receptor agonists can be used to treat or prevent conditions in which suppression of the immune system or agonism of the S1P1 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 with underlying defects in vascular integrity or associated with angiogenesis, as may be pathological (e.g., as may occur in inflammation, tumor development, and atherosclerosis). Such conditions in which suppression of the immune system or agonism of the S1P1 receptor is in order include diseases and disorders mediated by lymphocytes; conditions with underlying defects in vascular integrity; autoimmune diseases and disorders; inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions); rejection of acute or chronic cells; tissue or solid organ transplants; arthritis, including psoriatic arthritis and rheumatoid arthritis; diabetes, including type I diabetes; demyelinating diseases, including multiple sclerosis; ischemia-reperfusion injury, including renal and cardiac ischemia-reperfusion injury; inflammatory skin diseases, including psoriasis, atopic dermatitis, Dermatitis and acne; hyperproliferative skin diseases, including acne; inflammatory bowel disease, including Crohn's disease and ulcerative colitis; systemic lupus erythematosus; asthma; uveitis; myocarditis; allergies; atherosclerosis; brain inflammation, including Alzheimer's disease and brain inflammatory response after traumatic brain injury; central nervous system diseases, including spinal cord injury or cerebral infarction; pathological angiogenesis, including that which may occur in primary and metastatic tumor growth; rheumatoid arthritis; diabetic retinopathy and atherosclerosis; cancer; chronic lung disease; acute lung injury; acute respiratory disease syndrome; sepsis; etc.

[0041] One aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for parenteral administration.

[0042] One aspect of the present invention relates to a pharmaceutical composition comprising a compound, salt, hydrate or solvate or crystalline form of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for parenteral administration.

[0043] One aspect of the present invention pertains to methods for treating a disorder associated with the S1P1 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.

[0044] One aspect of the present invention pertains to methods for treating an S1P1 receptor-associated 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.

[0045] One aspect of the present invention pertains to methods for treating an S1P1 receptor-associated disorder associated with the S1P1 receptor in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention, a salt, hydrate or solvate, crystalline form or pharmaceutical composition thereof.

[0046] One aspect of the present invention relates to a method for treating a disorder associated with the S1P1 receptor in an individual, the method 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 associated with the S1P1 receptor is selected from the group consisting of: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0047] One aspect of the present invention relates to a method for treating a disorder associated with an S1P1 receptor in an individual, the method 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 associated with the S1P1 receptor is selected from the group consisting of: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0048] One aspect of the present invention relates to a method for treating a disorder associated with the S1P1 receptor in an individual, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention, a salt, hydrate or solvate, a crystalline form or a pharmaceutical composition thereof, wherein the disorder associated with the S1P1 receptor is selected from the group consisting of: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] One aspect of the present invention relates to a method for treating a condition 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 condition 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.

[0054] 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.

[0055] One aspect of the present invention pertains to methods for treating atopic dermatitis 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] One aspect of the present invention relates to a method for treating a disorder associated with an S1P1 receptor in an individual, the method 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 associated with the S1P1 receptor is a microbial infection or disease, or a viral infection or disease.

[0065] One aspect of the present invention pertains to a method for treating a disorder associated with an S1P1 receptor in an individual, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention, a salt, hydrate or solvate, a crystalline form or a pharmaceutical composition thereof, wherein the disorder associated with the S1P1 receptor is a microbial infection or disease, or a viral infection or disease.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a S1P1 receptor-associated disorder.

[0073] One aspect of the present invention pertains to use of a compound, salt, hydrate or solvate, crystalline form or pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of a S1P1 receptor-associated disorder.

[0074] One aspect of the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment of an S1P1 receptor-associated disorder selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0075] One aspect of the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment of an S1P1 receptor-associated disorder selected from the group consisting of: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0076] One aspect of the present invention relates to the use of a compound, salt, hydrate or solvate, crystalline form or pharmaceutical composition of the present invention in the manufacture of a medicament for treating a S1P1 receptor-associated disorder selected from the group consisting of: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0077] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a disease or disorder mediated by lymphocytes.

[0078] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of an autoimmune disease or disorder.

[0079] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of an inflammatory disease or disorder.

[0080] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of cancer.

[0081] One aspect of the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment of an S1P1 receptor-associated disorder 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.

[0082] 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.

[0083] 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 atopic dermatitis.

[0084] 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.

[0085] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of Crohn's disease.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] One aspect of the present invention pertains to use of a compound of the present invention in the manufacture of a medicament for the treatment of a S1P1 receptor associated disorder, wherein the S1P1 receptor associated disorder is a microbial infection or disease or a viral infection or disease.

[0093] One aspect of the present invention pertains to use of a compound, salt, hydrate or solvate, crystalline form or pharmaceutical composition of the present invention in the manufacture of a medicament for treating an S1P1 receptor-associated disorder, wherein the S1P1 receptor-associated disorder is a microbial infection or disease or a viral infection or disease.

[0094] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of gastritis.

[0095] 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.

[0096] 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.

[0097] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of vitiligo.

[0098] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of hepatitis.

[0099] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of biliary cirrhosis.

[0100] One aspect of the present invention pertains to compounds of the present invention for use in a method of treatment of the human or animal body by therapy.

[0101] One aspect of the present invention pertains to a compound, salt, hydrate or solvate, crystalline form of the present invention for use in a method of treatment of the human or animal body by therapy.

[0102] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating a S1P1 receptor-associated disorder.

[0103] One aspect of the present invention pertains to a compound, salt, hydrate or solvate, crystalline form of the present invention for use in a method of treating a S1P1 receptor-associated disorder.

[0104] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating an S1P1 receptor-associated disorder selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne.

[0105] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating an S1P1 receptor-associated disorder selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne.

[0106] One aspect of the present invention pertains to a compound, salt, hydrate or solvate, crystalline form of the present invention for use in a method of treating an S1P1 receptor-associated disorder selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0107] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating a disease or disorder mediated by lymphocytes.

[0108] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating an autoimmune disease or disorder.

[0109] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating an inflammatory disease or disorder.

[0110] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating cancer.

[0111] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating an S1P1 receptor-associated disorder 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.

[0112] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating psoriasis.

[0113] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating atopic dermatitis.

[0114] One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of rheumatoid arthritis.

[0115] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating Crohn's disease.

[0116] One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of transplant rejection.

[0117] One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of multiple sclerosis.

[0118] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating systemic lupus erythematosus.

[0119] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating ulcerative colitis.

[0120] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating type I diabetes.

[0121] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating acne.

[0122] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating a S1P1 receptor-associated disorder, wherein said S1P1 receptor-associated disorder is a microbial infection or disease or a viral infection or disease.

[0123] One aspect of the present invention pertains to a compound, salt, hydrate or solvate, crystalline form of the present invention for use in a method of treating an S1P1 receptor associated disorder, wherein the S1P1 receptor associated disorder is a microbial infection or disease or a viral infection or disease.

[0124] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating gastritis.

[0125] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating polymyositis.

[0126] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating thyroiditis.

[0127] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating vitiligo.

[0128] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating hepatitis.

[0129] One aspect of the present invention pertains to compounds of the present invention for use in a method of treating biliary cirrhosis.

[0130] One aspect of the present invention relates to a process for preparing a composition, the process comprising compounding a compound of the present invention with a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for parenteral administration.

[0131] One aspect of the present invention relates to a process for preparing a composition, the process comprising compounding a compound, salt, hydrate or solvate, crystalline form of the present invention with a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for parenteral administration.

[0132] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent publication proceeds. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Figure 1A A representative synthetic scheme for preparing compounds of the present invention is shown, wherein PG 1 is a protecting group (e.g., an allyl group as described in Example 1.1 (Step H)). For the synthesis of (rac), (R) and (S) isomers of 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, see WO2010 / 011316 and WO2011 / 094008. It should be understood that although the (R)-acid is explicitly shown in Figure 1A However, the synthesis can be carried out starting from the (rac)-acid or the (S)-acid.

[0134] Figure 1B A representative synthetic scheme for preparing compounds of the present invention such as Compound 2 and Compound 3 is shown, wherein R a and R b are independently C1-C6 alkyl and PG 2 is a protecting group (eg, a tert-butyldimethylsilyl group as described in Example 1.2 (Step B)). b For the synthesis of ethyl), see WO2010 / 011316.

[0135] Figure 1C A representative synthetic scheme for preparing compounds of the present invention such as Compound 4 and Compound 5 is shown, wherein R b is C1-C6 alkyl (eg, ethyl) and PG 3 is a protecting group (eg, a tert-butyldimethylsilyl group as described in Example 1.4 (Step A)). b For the synthesis of ethyl), see WO2010 / 011316.

[0136] Figure 2 A representative sample of compound 1 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks.

[0137] Figure 3 Representative in vitro beta-arrestin agonist assay curves for Compound 1 are shown (n=3).

[0138] Figure 4A representative sample of compound 2-1 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks. See Example 1.2 (Step G (Fractions 4 and 5)) for details.

[0139] Figure 5 A representative sample of compound 2-2 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks. See Example 1.2 (Step G (Fractions 7 and 8)) for details.

[0140] Figure 6 A representative sample of compound 3 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks. See Example 1.3 for details.

[0141] Figure 7 A representative example of compound 4-1 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks. See Example 1.4 (Step H) for details.

[0142] Figure 8 A representative example of compound 4-2 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks. See Example 1.4 (Step I) for details.

[0143] Fig. 9 A representative sample of compound 6 is shown. 1 H NMR spectrum, where "X" refers to the NMR solvent and / or residual solvent peaks. See Example 1.5 (Step D) for details. DETAILED DESCRIPTION

[0144] definition

[0145] For clarity and consistency, the following definitions will be used throughout this patent document.

[0146] The term "C1-C6 alkyl" refers to 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. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [i.e., CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., CH2CH(CH3)CH2CH3], n-hexyl, etc.

[0147] As used herein, the term "hydrate" refers to a compound of the present invention or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0148] As used herein, the term "solvate" refers to a compound of the invention or a salt thereof that further comprises 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.

[0149] When referring to treatment, the term "in need of treatment" and the term "in need" are used interchangeably to mean a judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc. in the case of humans; a 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 within the caregiver's area of ​​expertise, but includes the knowledge that the individual or animal is ill or will become ill due to a disease, condition, or disorder that can be treated by the compounds of the invention. Thus, the compounds of the invention can be used in a protective or preventive manner; or the compounds of the invention can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0150] The term "subject" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and most preferably humans.

[0151] The term "inverse agonist" refers to an agent that binds to the endogenous form of a receptor or to the constitutively activated form of a receptor and inhibits the baseline intracellular response elicited by the active form of the receptor below the normal base level activity observed in the absence of an agonist or partial agonist, or reduces the portion of GTP binding to the membrane. In some embodiments, the baseline intracellular response is inhibited by at least 30% in the presence of an inverse agonist. In some embodiments, the baseline intracellular response is inhibited by at least 50% in the presence of an inverse agonist. In some embodiments, the baseline intracellular response is inhibited by at least 75% in the presence of an inverse agonist compared to the baseline response in the absence of an inverse agonist.

[0152] The term "modulate" or "modulating" refers to an increase or decrease in the amount, quality, response or effect of a specific activity, function or molecule.

[0153] The term "oxo" refers to a diradical =0 (ie, the oxo group bonded to the carbon is a carbonyl group, as shown in Formula (Iu) and Formula (Iz)).

[0154] The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient; including but not limited to salts, solvates and hydrates of the compounds of the invention, whereby the composition is suitable for studying a specific effective result in a mammal (such as but not limited to humans). One of ordinary skill in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired effective result according to the needs of the technician.

[0155] The term "therapeutically effective amount" refers to the amount of an active compound or agent that elicits the biological or medicinal response in a tissue, system, individual or human that is being sought by a researcher, veterinarian, physician or other clinician, caregiver, or individual, including one or more of the following:

[0156] (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who does not yet experience or exhibit the pathology or symptomology of the disease;

[0157] (2) inhibiting a disease, e.g., inhibiting the pathology or symptomology of a disease, condition or disorder in an individual who is experiencing or exhibiting the disease, condition or disorder (i.e., preventing further development of the pathology and / or symptomology); and

[0158] (3) ameliorating a disease, e.g., improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology).

[0159] The compounds of the present invention:

[0160] One aspect of the present invention relates to certain compounds of formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0161]

[0162] in:

[0163] R 1 is H or OH;

[0164] R 3 is H; or

[0165] R 1 and R 3 Together they form an oxo group;

[0166] as well as

[0167] R 2 is H or a group of formula (IIa):

[0168]

[0169] The condition is that if R 2 is H, then R 1 and R 3 Neither is H.

[0170] One aspect of the present invention relates to the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0171]

[0172] One aspect of the present invention relates to compounds of formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0173]

[0174] Where: R 1 , R 2 and R 3 Have the same definitions as described herein (above and below).

[0175] One aspect of the present invention relates to compounds of formula (Ie) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0176]

[0177] Where: R 1 , R 2 and R 3 Have the same definitions as described herein (above and below).

[0178] In some embodiments, R 1 OH; R 3 H; or R 1 and R 3 together to form an oxo group; and R 2 For H.

[0179] In some embodiments, R 1 For OH.

[0180] In some embodiments, R 1 For H.

[0181] In some embodiments, R 2 For H.

[0182] In some embodiments, R 2 It is a group of formula (IIa).

[0183] In some embodiments, R 1 and R 3 Together they form an oxo group.

[0184] In some embodiments, if R 2 is H, then R 1 and R 3 Neither is H.

[0185] In some embodiments, R 1 and R 3 Neither is H.

[0186] In some embodiments, if R 1 is H, then R 2 It is a group of formula (IIa).

[0187] In some embodiments, R 1 OH; R 3 is H; and R 2 For H.

[0188] In some embodiments, R 1 and R 3 together to form an oxo group; and R 2 For H.

[0189] In some embodiments, R 1 H; R 3 is H; and R 2 Another aspect of the present invention relates to a compound of formula (Ig) and a pharmaceutically acceptable salt, solvate and hydrate thereof:

[0190]

[0191] Some embodiments of the present invention relate to compounds of formula (Ii) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0192]

[0193] Some embodiments of the present invention relate to a compound selected from the group consisting of the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0194]

[0195] Compound 1.

[0196] Some embodiments of the present invention relate to a compound selected from (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 1) and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0197] Some embodiments of the present invention relate to Compound 1.

[0198] In some embodiments, the present invention encompasses compounds of formula (Ik) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

[0199]

[0200] in:

[0201] R 1 is OH; and

[0202] R 3 is H;

[0203] or R 1 and R 3 Together they form an oxo group.

[0204] In some embodiments, the present invention encompasses compounds of formula (Im) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

[0205]

[0206] Where: R 1 and R 3 Have the same definitions as described herein (above and below).

[0207] In some embodiments, the present invention encompasses compounds of formula (Io) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

[0208]

[0209] in:

[0210] R 1 is H or OH; and

[0211] R 3 is H;

[0212] or R 1 and R 3 Together for the oxygen generation.

[0213] In some embodiments, the present invention encompasses compounds of formula (Iq) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

[0214]

[0215] Where: R 1 and R 3 Have the same definitions as described herein (above and below).

[0216] In some embodiments, R 1 is OH and R2 is H. Another aspect of the present invention relates to compounds of formula (Is) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0217]

[0218] Some embodiments of the present invention relate to a compound selected from 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 2) and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0219] In some embodiments, R 1 and R 2 One aspect of the present invention relates to compounds of formula (Iu) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0220]

[0221] Some embodiments of the present invention relate to a compound selected from 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 3) and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0222] In some embodiments, the present invention encompasses compounds of formula (Iw) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

[0223]

[0224] in:

[0225] R 1 is H or OH; and

[0226] R 3 is H;

[0227] or R 1 and R 3 Together for the oxygen generation.

[0228] In some embodiments, the present invention encompasses compounds of formula (Ix) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

[0229]

[0230] Where: R 1 and R 3Have the same definitions as described herein (above and below).

[0231] In some embodiments, R 1 is OH and R2 is H. Another aspect of the present invention relates to compounds of formula (Iy) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0232]

[0233] Some embodiments of the present invention relate to a compound selected from 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 4) and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0234] In some embodiments, R 1 and R 2 One aspect of the present invention relates to compounds of formula (Iz) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0235]

[0236] Some embodiments of the present invention relate to a compound selected from 2-(7-((4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 5) and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0237] For any formula described herein that does not specifically show the stereochemistry of a carbon, it is understood that the carbon may be depicted to specifically show the stereochemistry as (R) or (S).

[0238] Thus, in some embodiments, the stereochemistry of the C(3) carbon of a 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group as specifically shown in any of the formulae described herein (above and below) is (R). In some embodiments, the stereochemistry of the C(3) carbon of a 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group as specifically shown in any of the formulae described herein (above and below) is (S). The C(3) carbon is specifically identified in Formulae (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy), and (Iz).

[0239] For clarity, the complete numbering of the carbon atoms present in the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group of formula (Ia) is shown below:

[0240]

[0241] Some embodiments of the present invention comprise every combination of one or more compounds selected from the following group shown in Table A and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0242] Table A

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252] Some embodiments of the present invention include every combination of one or more compounds selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0253] (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0254] (2S,3S,4S,5R,6S)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0255] (2S,3S,4S,5R,6R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0256] (2S,3S,4S,5R)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0257] (2S,3S,4S,5R,6S)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0258] (2S,3S,4S,5R,6R)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0259] 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0260] 2-((R)-7-((4-((1S,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0261] 2-((R)-7-((4-((1R,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0262] 2-((R)-7-((4-((1R,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0263] 2-((R)-7-((4-((1S,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0264] 2-((S)-7-((4-((1S,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0265] 2-((S)-7-((4-((1R,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0266] 2-((S)-7-((4-((1R,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0267] 2-((S)-7-((4-((1S,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0268] 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0269] 2-((R)-7-((4-((S)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0270] 2-((R)-7-((4-((R)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0271] 2-((S)-7-((4-((S)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0272] 2-((S)-7-((4-((R)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0273] 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0274] 2-((R)-7-((4-((1R,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0275] 2-((R)-7-((4-((1S,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0276] 2-((R)-7-((4-((1S,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0277] 2-((R)-7-((4-((1R,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0278] 2-((S)-7-((4-((1R,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0279] 2-((S)-7-((4-((1S,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0280] 2-((S)-7-((4-((1S,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0281] 2-((S)-7-((4-((1R,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0282] 2-(7-((4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0283] 2-((R)-7-((4-((R)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0284] 2-((R)-7-((4-((S)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0285] 2-((S)-7-((4-((R)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0286] 2-((S)-7-((4-((S)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0287] 2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0288] (R)-2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and

[0289] (S)-2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

[0290] In addition, individual compounds and those compounds of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy) and / or (Iz) (including diastereomers and enantiomers thereof) encompass all pharmaceutically acceptable salts, solvates and hydrates.

[0291] It should be understood that the present invention includes each diastereomer, each enantiomer and mixtures thereof of each compound of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy) and / or (Iz) disclosed herein, as if they were each individually disclosed by the specific stereochemical name of each chiral carbon. Separation of the individual isomers (e.g., by chiral HPLC, recrystallization of a mixture of diastereomers, etc.) or selective synthesis of the individual isomers (e.g., by enantioselective synthesis, etc.) is achieved by applying various methods well known to practitioners in the art.

[0292] Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy) and / or (Iz) of the present invention can be prepared according to relevant open literature procedures used by those skilled in the art. Exemplary reagents and procedures for these reactions are shown in the working examples below. Protection and deprotection can be carried out by procedures generally known in the art as required (see, for example, G Greene, TW and Wuts, PGM, Protecting Groups in Organic Synthesis, 3rd edition, 1999 [Wiley]; incorporated herein by reference in its entirety).

[0293] Pharmaceutical composition

[0294] Another aspect of the present invention relates to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers.Some embodiments relate to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

[0295] Some embodiments of the present invention include methods of producing a pharmaceutical composition comprising compounding at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.

[0296] The formulations may be prepared by any suitable method, generally by uniformly admixing the active compound with liquid or finely divided solid carriers or both in the required proportions and then, if necessary, shaping the resulting mixture into the desired presentation.

[0297] Conventional excipients, such as adhesives, fillers, acceptable wetting agents, tableting lubricants and disintegrants can be used in tablets and capsules for oral administration. Orally administered liquid preparations can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations can be in the form of dry powders, which can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending agents or emulsifiers, non-aqueous vehicles (including edible oils), preservatives and flavoring agents and colorants can be added to the liquid preparation. Parenteral dosage forms can be prepared by dissolving the compound of the present invention in a suitable liquid vehicle and filtering and sterilizing the solution, then filling in a suitable vial or ampoule and sealing. These are just a few examples of many suitable methods for preparing dosage forms well known in the art.

[0298] The compounds of the invention can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers, except those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0299] Although the compounds of the invention may in alternative uses be administered as the raw material or pure chemical for either prophylactic or therapeutic use, it is preferable to present the compound or active ingredient as a pharmaceutical formulation or composition which also includes a pharmaceutically acceptable carrier.

[0300] Therefore, the present invention also provides a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or derivative thereof and one or more pharmaceutically acceptable carriers and / or prophylactic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0301] Drug formulations include those suitable for oral, rectal, nasal, local (including oral and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) use, or are in a form suitable for suction, insufflation or by transdermal patch. Transdermal patch distributes medicine at a controlled rate by presenting the medicine for absorption in an effective manner with minimum drug degradation. Usually, transdermal patch includes impermeable backing layer, single pressure-sensitive adhesive and a removable protective layer with a release liner. Those of ordinary skill in the art will understand and appreciate the technology suitable for manufacturing the effective transdermal patch of expectation based on the needs of the technician.

[0302] Therefore, the compounds of the present invention can be put into pharmaceutical formulations and unit dosage forms thereof together with conventional adjuvants, carriers or diluents, and in this form can be used as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels or capsules filled therein, 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 contain 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 active ingredients comparable to the expected daily dosage range to be used.

[0303] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions or liquids. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specific amount of the active ingredient. Examples of such 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, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered as a composition by injection, wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

[0304] The compounds of the invention or their salts, solvates, hydrates or physiologically functional derivatives can be used as active ingredients in pharmaceutical compositions, in particular as S1P1 receptor modulators. The term "active ingredient" is defined in the context of "pharmaceutical composition" and refers to the component of the pharmaceutical composition that provides the primary pharmacological effect, as opposed to "inactive ingredients" which are generally considered to provide no pharmaceutical benefit.

[0305] The dosage when using the compound of the present invention can vary in a wide range, and according to convention and known to the physician, it should be adjusted according to the individual conditions of each individual case. For example, it depends on the nature and severity of the disease being treated, the patient's condition, the compound used, or whether to treat acute or chronic disease states or prevent, or whether other active compounds are also applied in addition to the compound of the present invention. The representative dosage of the present invention includes but is not limited to about 0.001mg to about 5000mg, about 0.001mg to about 2500mg, about 0.001mg to about 1000mg, 0.001mg to about 500mg, 0.001mg to about 250mg, about 0.001mg to 100mg, about 0.001mg to about 50mg and about 0.001mg to about 25mg. Multiple dosages can be applied in one day, particularly when it is considered that a relatively large amount is needed, such as 2,3 or 4 dosages. Depending on the individual and as the patient's physician or caregiver thinks appropriate, it may be necessary to deviate upward or downward from the dosage described herein.

[0306] The amount of active ingredient or its active salt, solvate or hydrate derivative required for therapeutic use will not only vary with the salt selected, but will also vary with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be determined by the physician or clinician. Generally, those skilled in the art understand how to extrapolate in vivo data obtained in one model system (usually an animal model) to another, such as a human. In some cases, these extrapolations may be based solely on the weight of an animal model relative to another (e.g., a mammal, preferably a human), however, more commonly, these extrapolations are not simply based on weight, but also in combination with various factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient; the severity of the disease; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic and toxicological characteristics of the specific compound used; whether a drug delivery system is used; whether an acute or chronic disease state is being treated or prevented; or whether other active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating disease conditions with the compounds and / or compositions of the present invention is selected according to various factors including those described above. Thus, the actual dosage regimen employed may vary widely and, therefore, may deviate from the preferred dosage regimen, and one skilled in the art will recognize that doses and dosage regimens outside of these typical ranges can be tested and, where appropriate, employed in the methods of the invention.

[0307] The desired dosage can be conveniently presented in a single dose or in divided doses administered at appropriate intervals, for example, as 2, 3, 4 or more subdoses per day. The subdoses themselves can be further divided into, for example, multiple discrete loosely spaced administrations. The daily dose can be divided into several portions (e.g., 2, 3 or 4 portions) for administration, particularly when a relatively large amount is administered as appropriate. If appropriate, depending on individual behavior, it may be necessary to deviate from the indicated daily dose upward or downward.

[0308] For preparing pharmaceutical compositions from the compounds of the present invention, suitable pharmaceutically acceptable carriers can be solid, liquid or a mixture of the two. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent or encapsulating material.

[0309] In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active component.

[0310] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0311] Powders and tablets may contain varying percentage amounts of active compound. A representative amount in a powder or tablet may be from 0.5% to about 90% of the active compound. However, a skilled person will know when amounts outside this range are required. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. The term "preparation" is intended to encompass formulating the active compound with an encapsulating material as a carrier, providing a capsule in which the active component with or without a carrier is surrounded by a carrier and is thus associated with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0312] To prepare suppositories, a low melting wax, such as a compound of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed uniformly therein (e.g., by stirring). The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0313] 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.

[0314] Liquid form preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated into solutions in polyethylene glycol aqueous solutions. Suitable dispersing or wetting agents and suspending agents can be used to prepare injectable preparations according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution (Ringer'ssolution) and isotonic sodium chloride solution. In addition, conventional sterile fixed oils are used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, it is found that fatty acids (such as oleic acid) can be used in the preparation of injections.

[0315] Therefore, the compound according to the present invention can be formulated for parenteral administration (e.g., by injection, such as rapid injection or continuous infusion), and can be presented in unit dosage form in ampoules, prefilled syringes, small volume infusions, or in multi-dose containers with preservatives added. The pharmaceutical composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain a preparaton, such as a suspending agent, a stabilizer, and / or a dispersant. Alternatively, the active ingredient can be in powder form, obtained by aseptic separation of sterile solids or by lyophilization from a solution, for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0316] Aqueous preparations suitable for oral administration can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavoring agents, stabilizers and thickening agents as desired.

[0317] Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active component in water with viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

[0318] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration shortly before use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these preparations may also contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0319] For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0320] Ointments and creams may be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. Lotions may be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants.

[0321] Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored basis, usually sucrose and acacia or tragacanth; tablets comprising the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0322] The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or sprayer. The formulation can be provided in a single dosage form or in multiple dosage forms. In the latter case of a dropper or pipette, this can be achieved by the patient administering a solution or suspension of an appropriate predetermined volume. In the case of a spray, this can be achieved, for example, by a metered atomizing spray pump.

[0323] Administration to the respiratory tract can also be achieved by aerosol formulations, wherein the active ingredient is provided in a pressurized package with a suitable propellant. If the compound of the present invention or a pharmaceutical composition comprising it is administered as an aerosol (e.g., nasal aerosol, by inhalation), this can, for example, be performed using a sprayer, atomizer, pump atomizer, inhalation device, metered dose inhaler or dry powder inhaler. The pharmaceutical form for administering the compound of the present invention as an aerosol can be prepared by a process well known to those skilled in the art. For example, a solution or dispersion of the compound of the present invention or its pharmaceutically acceptable salt, solvate, hydrate or derivative in water, water / alcohol mixture or suitable saline solution can be used with conventional additives (e.g., benzyl alcohol or other suitable preservatives), absorption enhancers, solubilizers, dispersants, etc. for increasing bioavailability, and if appropriate, conventional propellants (e.g., carbon dioxide, CFC such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, etc.) can also be used. Aerosols can also conveniently contain surfactants, such as lecithin. The drug dosage can be controlled by providing a metering valve.

[0324] In formulations intended for administration to the respiratory tract (including intranasal formulations), the compound typically has a small particle size, for example, about 10 microns or less. Such particle sizes can be obtained by means known in the art, for example, by micronization. If desired, a formulation suitable for sustained release of the active ingredient can be used.

[0325] Alternatively, the active ingredient 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 hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP)). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form (e.g. capsules, cartridges) in gelatin or blister packs from which the powder can be administered by an inhaler.

[0326] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation, the package containing discrete quantities of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be an appropriate number of any of these in packaged form.

[0327] In some embodiments, the composition is a tablet or capsule for oral administration.

[0328] In some embodiments, the composition is a liquid for intravenous administration.

[0329] Compounds according to the present invention may optionally exist as pharmaceutically acceptable salts, and the salts include pharmaceutically acceptable acid addition salts prepared by pharmaceutically acceptable nontoxic acids (including inorganic acids and organic acids). Representative acids include but are not limited to acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, etc., such as Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977) those pharmaceutically acceptable salts listed, which are incorporated herein by reference in their entirety.

[0330] Acid addition salts can be obtained as the direct product of compound synthesis. In an alternative, the free base can be dissolved in a suitable solvent containing an appropriate acid and the salt can be isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0331] The compounds of the present invention can be converted into "prodrugs". The term "prodrug" refers to a compound modified with a specific chemical group known in the art, and when administered to an individual, it undergoes a biotransformation to obtain the parent compound. Therefore, a prodrug can be considered as a compound of the present invention, which contains one or more specialized non-toxic protective groups used in a transient manner to change or eliminate the properties of the compound. In a general aspect, the "prodrug" method is used to promote oral absorption. In T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" "American Chemical Society Conference Proceedings (ACS Symposium Series)" Vol. 14; and "Bioreversible Carriers in Drug Design", Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, a thorough discussion was carried out, both of which are incorporated herein by reference in their entirety.

[0332] Some embodiments of the present invention include methods of preparing a pharmaceutical composition for "combination therapy" comprising compounding at least one compound according to any of the compound embodiments disclosed herein with at least one known agent as described herein and a pharmaceutically acceptable carrier.

[0333] It should be noted that when S1P1 receptor agonists are used as active ingredients in pharmaceutical compositions, they are not intended for use only in humans, but also in other non-human mammals. Indeed, recent advances in the field of animal health care require consideration of the use of active agents, such as S1P1 receptor agonists, for the treatment of S1P1 receptor-related diseases or disorders in companion animals (e.g., cats, dogs, etc.) and livestock animals (e.g., cattle, chickens, fish, etc.). One of ordinary skill in the art would readily appreciate the utility of such compounds in such a setting.

[0334] Hydrates and solvents

[0335] It should be understood that when the phrase "pharmaceutically acceptable salts, solvates and hydrates" is used with reference to a specific formula herein, it is intended to include solvates and / or hydrates of the compound of the specific formula, pharmaceutically acceptable salts of the compound of the specific formula, and solvates and / or hydrates of pharmaceutically acceptable salts of the compound of the specific formula. It should also be understood by those of ordinary skill in the art that hydrates are a subgenus of solvates.

[0336] The compounds of the present invention can be administered in a variety of oral and parenteral dosage forms. It is apparent to those skilled in the art that the following dosage forms may include the compounds of the present invention or its pharmaceutically acceptable salt or its solvate or hydrate as an active ingredient. In addition, various hydrates and solvates of the compounds of the present invention and their salts can be used as intermediates for manufacturing pharmaceutical compositions. Typical procedures for preparing and identifying suitable hydrates and solvates other than those mentioned herein are well known to those skilled in the art; see, for example, KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids", "Polymorphism in Solid Medicine (Polymorphism in Pharmaceutical Solids)" 202-209, Harry G.Brittan, Vol. 95, Marcel Dekker, Inc., New York, 1999, incorporated herein by reference in its entirety. Therefore, one aspect of the present invention relates to hydrates and solvates of the compounds of the present invention and / or pharmaceutically acceptable salts thereof as described herein, which can be separated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, etc. There are several commercial entities that provide fast and efficient services for routine identification of solvates and hydrates. Example companies that provide these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, CT).

[0337] Other Utilities

[0338] Another object of the present invention relates to radiolabeled compounds of the present invention which will be useful not only in radioimaging but also in in vitro and in vivo assays for localizing and quantifying S1P1 receptors in tissue samples (including humans) and for identifying S1P1 receptor ligands by inhibiting the binding of the radiolabeled compounds. A further object of the present invention is to develop novel S1P1 receptor assays comprising such radiolabeled compounds.

[0339] The present invention includes isotopically labeled compounds of the present invention. Isotopically labeled or radiolabeled compounds are compounds identical to the compounds disclosed herein, but one or more atoms are replaced or substituted by atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Suitable radionuclides that can be incorporated into the 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 O. 17 O. 18 O. 18 F. 35 S. 36 Cl, 75 Br, 76 Br, 77 Br, 82 Br, 123 I. 124 I. 125 I and 131 I. The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro S1P1 receptor labeling and competition assays, incorporation of 3 H. 14 C. 82 Br, 125 I. 131 I or 35 Compounds containing S will generally be the most useful. For radioactive imaging applications, 11 C. 18 F. 125 I. 123 I. 124 I. 131 I. 75 Br, 76 Br or 77 Br will usually be the most useful.

[0340] It is understood that a "radiolabeled" or "labeled" compound is one of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy), and / or (Iz) containing at least one radionuclide. In some embodiments, the radionuclide is selected from 3 H. 14 C. 125 I. 35 S and82 Br.

[0341] Certain isotopically labeled compounds of the invention are useful in compound and / or substrate tissue distribution assays. 3 H and / or 14 C isotopes can be used in these studies. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Figure 1A , 1B Isotopically labeled compounds of the present invention may be prepared by replacing a non-isotopically labeled reagent with an isotopically labeled reagent by procedures analogous to those disclosed in 1C and / or 1C and the Examples below. Other useful synthetic methods are discussed below. In addition, it should be understood that all atoms represented in the compounds of the present invention may be the most commonly occurring isotope or a rare radioactive isotope or non-radioactive isotope of such atom.

[0342] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the present invention and are well known in the art. Certain synthetic methods for incorporating active levels of tritium into target molecules include the following:

[0343] A. Catalytic reduction with tritium gas: This method generally produces high specific activity products and requires halogenated or unsaturated precursors.

[0344] B. Use sodium borohydride [ 3 H] Reduction: This method is fairly cheap and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc.

[0345] C. Using lithium aluminum hydride [ 3 H] Reduction: This method provides products with almost theoretical specific activity. It also requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, etc.

[0346] D. Tritium Gas Exposure Labeling: This method involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0347] Radiolabeled S1P1 receptor compounds of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy) and / or (Iz) can be used in screening assays to identify / evaluate compounds. In general, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce binding of "radiolabeled compounds" of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy) and / or (Iz) to the S1P1 receptor. Therefore, the ability of a test compound to compete with a “radiolabeled compound” of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is), (Iu), (Iw), (Ix), (Iy) and / or (Iz) for binding to the S1P receptor directly correlates to its binding affinity.

[0348] The labeled compounds of the present invention bind to the S1P1 receptor. In one embodiment, the labeled compounds have an IC of less than about 500 μM. 50 In another embodiment, the labeled compound has an IC of less than about 100 μM. 50 In yet another embodiment, the labeled compound has an IC of less than about 10 μM. 50 In yet another embodiment, the labeled compound has an IC of less than about 1 μM 50 , and in yet another embodiment, the labeled inhibitor has an IC of less than about 0.1 μM 50 .

[0349] Other uses of the disclosed receptors and methods will become apparent to those skilled in the art based on this disclosure and so forth.

[0350] As will be appreciated, the steps of the methods of the present invention need not be performed any particular number of times or in any particular order. Additional objects, advantages and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are intended to be illustrative rather than limiting.

[0351] Example

[0352] Example 1: Synthesis of compounds of the present invention

[0353] exist Figure 1A , 1B Illustrative syntheses of compounds of the invention are shown in 1A and 1C.

[0354] The compounds of the present invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the present invention, but the present invention is not limited to the details of these examples. The compounds described herein (above and below) are named using ANTIQUID® Professional (version 17.0.0.206). In some cases, common names are used, and it is understood that those skilled in the art will recognize these common names.

[0355] Chemistry: Proton NMR ( 1 H NMR) spectra. Proton NMR ( 1 H NMR) spectra. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations used are as follows: s = singlet, d = doublet, dd = doublet of a doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet. A Smith synthesizer was used. TM or Emrys Optimizer TM (Biotage) was subjected to microwave irradiation. 254 Thin layer chromatography (TLC) was performed on 100% HPLC-MS / MS (Merck), preparative TLC was performed on PK6F silica gel 60A 1 mm plates (Whatman), and column chromatography was performed on a silica gel column using Kieselgel 60 (0.063-0.200 mm) (Merck). Evaporation was performed under reduced pressure on a Büchi rotary evaporator. 545 is used for palladium filtration.

[0356] LCMS specifications: HPLC-pump: LC-10AD VP, Shimadzu Inc.; HPLC system controller: SCL-10AVP, Shimadzu Inc; UV detector: SPD-10A VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, LeapScientific; Mass spectrometer: API 150EX with turbo ion spray source, AB / MDS Sciex; Software: Analyst1.2.

[0357] Example 1.1: Preparation of (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 1).

[0358] Step A: Preparation of 1-cyclopentyl-2-(trifluoromethyl)benzene.

[0359] In the 50L three-necked round-bottom flask equipped with mechanical stirrer, thermocouple and nitrogen inlet, anhydrous THF (35L) is added, and is cooled to 0-5 ℃.In 30-60 minutes, iron chloride (III) (2.7kg, 0.15 equivalent) is added in batches in the flask and stirred for 15-30 minutes, produces clear green solution.Under nitrogen atmosphere, in the reactor of 100 gallons of dry glass, THF (87.5L) and magnesium chips (4.05kg, 1.5 equivalents) are added, and are cooled to 0-5 ℃.FeCl3 solution in THF is added to the mixture of THF and magnesium with the speed keeping internal temperature lower than 10 ℃.With the speed keeping internal temperature lower than 20 ℃, TMEDA (15.5kg, 1.2 equivalents) is added in the yellow / green mixture of gained. The resulting reaction mixture was heated to 40-45°C for 1 hour, and a mixture of 1-bromo-2-(trifluoromethyl)benzene (25 kg, 1.0 equivalent) and bromocyclopentane (19.9 kg, 1.2 equivalent) was added to the reaction mixture at a rate that maintained the internal temperature below 25°C. The resulting reaction mixture was stirred overnight at room temperature and subsequently cooled to an internal temperature of 0-5°C. 6N HCl (100 L, 1.5 h) was added to the resulting mixture at a rate that maintained the internal temperature below 15°C (note that the exotherm was very large). After quenching, MTBE (200 L) was added, and the reactor contents were stirred for 30 minutes. The phases were separated, and the aqueous layer was stripped with MTBE (75 L). The combined organic layer was washed with H2O (50 L), brine (50 L) and dried (MgSO4). The mixture was filtered through a series (1 micron) filter cartridge, and then filtered into a clean dry reactor through another series (0.45 micron) filter cartridge. The solvent was evaporated under vacuum (jacket ≤ 30 °C) and co-evaporated with heptane (2 x 25 L) to give a viscous liquid. The viscous liquid was dissolved in heptane (100 L) and passed through a plug of silica (25 kg). The residue was purified by chromatography on heptane (TLC, R f Elution from the silica gel plug was carried out using 4% paraformaldehyde (0.1447 W, 4% NaOH, 0.247 g, heptane) and evaporation of the product containing fractions gave the title compound (11.7 kg, 49.2%) as a yellow liquid with a purity of 94.1% as determined by HPLC. 1 H NMR was consistent with reference standards.

[0360] Step B: Preparation of 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene.

[0361] Concentrated sulfuric acid (48.6 L) was added to a 100-gallon glass-lined reactor equipped with a stirrer and cooled to an internal temperature between about -5 and -10 ° C under an atmosphere of N2. Thionyl chloride (26.99 kg, 2 equivalents) was added to the sulfuric acid at a rate to keep the internal temperature below -5 ° C. 1,3,5-trioxane (15.3 kg, 1.5 equivalents) was added to the resulting mixture in batches at a rate to keep the internal temperature below -5 ° C. After the addition of 1,3,5-trioxane, 1-cyclopentyl-2-(trifluoromethyl)benzene (24.0 kg) was added dropwise over a period of about 2-3 hours. The reaction mixture was stirred at 0 ° C for about 3-4 hours, allowed to warm to room temperature overnight, and then cooled to an internal temperature of 0-5 ° C. Water (316 L) was added dropwise to the resulting mixture over a period of about 5-6 hours (note: the exotherm is very large). After quenching with water, the aqueous mixture obtained is extracted with MTBE (243L and 123L). The combined organic matter is washed with saturated NaHCO (100L), brine (100L), water (100L), brine (100L), and dried (MgSO ). The mixture is filtered through a series (1 micron) filter cartridge, and then filtered into a clean dry reactor through another series (0.45 micron) filter cartridge. The solvent is evaporated under vacuum (jacket≤30°C), and further evaporated under vacuum at 35-40°C. The obtained oil is distilled under high vacuum to obtain the title compound (24.8kg, 83%) in the form of a yellow liquid, with a purity of 99.47% determined by HPLC. 1 H NMR was consistent with reference standards.

[0362] Step C: Preparation of ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate.

[0363] Cyclopentanone (22.00 kg), morpholine (22.88 kg) and cyclohexane (43.78 kg) were charged into a 400 L glass-lined reactor equipped with an overhead stirrer, jacket temperature control, nitrogen inlet and Dean-Stark trap. The reactor contents were heated to about 85° C. to 95° C. for about 26 hours while removing water using the Dean-Stark trap. The reaction to form the enamine (i.e., 4-(cyclopent-1-ene-1-yl)morpholine) was considered complete when the amount of morpholine was ≤3% as confirmed by GC peak area.

[0364] The reactor contents were cooled to about 60°C and ethyl glyoxylate (58.74 kg, 50% solution in toluene) was slowly added to the mixture to maintain the internal temperature< The reaction mixture was stirred at 80 ° C. The reactor contents were heated to about 85 ° C to 95 ° C for at least 25 hours while removing water using a Dean-Stark water trap. The reaction was considered complete when the amount of enamine (i.e., 4-cyclopentenylmorpholine) by GC was confirmed to be less than 0.5% by GC peak area. The cyclohexane / toluene mixture was distilled under vacuum, ethanol (261.80 kg) was charged to the reactor, and the resulting solution was distilled under vacuum again. Ethanol (34.76 kg) and water (44.00 kg) were charged to the reactor, and the reactor contents were stirred at 25 ° C. The mixture was further stirred for 6 hours at about 0-5 ° C.

[0365] The resulting product slurry was collected by filtration and washed with aqueous ethanol (34.76 kg ethanol dissolved in 176.00 kg water). The filter cake was further washed with water (110.00 kg), initially dried under vacuum at about 36 ° C for 1 hour, and then dried under vacuum at about 50 ° C for 17 hours. The title compound (23.48 kg, 37.8% yield) was obtained as a tan solid.

[0366] Step D: Preparation of E / Z ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate.

[0367] To a 400 L glass-lined reactor equipped with an overhead stirrer, jacket temperature control, and nitrogen inlet, (4-(benzyloxy)phenyl)hydrazine hydrochloride (21.08 kg, 1.000 molar equivalent), ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate (22.02 kg, 1.104 molar equivalent), ethanol (51.2 kg, 2.429 mass equivalent), and acetic acid (36.8 kg, 1.746 mass equivalent) were added. After allowing the reactor contents to stand for 10 minutes, stirring was initiated and then heated to 60° C. to 65° C. (target 60° C.). While stirring at this temperature, samples of the reaction mixture were removed at approximately 30 minute intervals and analyzed by HPLC for (4-(benzyloxy)phenyl)hydrazine, ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate, and hydrazone content. When the (4-(benzyloxy)phenyl)hydrazine HPLC% area was <1, TFA (11.6 kg, 101.7 mol, 1.200 molar equivalents, 0.550 mass equivalents) was charged over approximately 1 hour while the stirred reaction mixture was maintained at 60°C ± 5°C with reactor jacket cooling. As stirring continued at 60°C to 65°C, the reaction mixture was monitored by HPLC for hydrazone and imine content. After stirring at 60°C to 65°C for at least 12 hours, the imine content of the reaction mixture as determined by HPLC was <5% area, and the stirred reaction mixture was cooled to 20°C to 25°C over approximately 3 hours. Stirring was maintained at this temperature to isomerize the Z isomer to the desired E isomer. The E isomer was crystallized from the reaction mixture. During this period of stirring at 20°C to 25°C, the reaction mixture was monitored by HPLC for Z and E isomer % area content, which was continued until the Z isomer content of the reaction mixture was determined by HPLC to be <15% area.

[0368] The stirred reaction mixture was cooled (0°C to 5°C) over at least 2 hours and then filtered. Ethanol (27.4 kg, 1.300 mass equivalents) was charged to the reactor, stirred and cooled to 0°C to 5°C, and then used in approximately two equal portions to slurry wash the product cake twice. Ethanol (13.8 kg, 0.655 mass equivalents) was charged to the reactor, stirred and cooled to 0°C to 5°C, and then used to wash the product cake by displacement. USP purified water (100 kg, 4.744 mass equivalents) was charged to the reactor, and the temperature was adjusted to 20°C to 25°C. USP purified water was then used to wash the product cake three times in approximately three equal portions, the first two times by re-slurrying and the third time by displacement. Ethanol (16.4 kg, 0.778 mass equivalents) was charged to the reactor, stirred and cooled to 0°C to 5°C, and then used to wash the product cake by displacement. The washed product cake was first dried at a jacket temperature of 35° C. for 1 hour under full vacuum, and then dried at a jacket temperature of 50° C. While continuing to dry at a jacket temperature of 50° C., the product solids were turned over every 1 to 3 hours, and the product samples were analyzed for loss on drying (LOD) every ≥4 hours. When the LOD was <1%, the product was cooled to <30° C. The yield of the title compound was 13.06 kg (37.59 mol, 44.7%).

[0369] Step E: Preparation of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate.

[0370] To a 200-liter Hastelloy reactor was added ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (E / Z mixture, 12 kg), 10% Pd / C (50% wet with H2O; 1.80 kg), and ethyl acetate (108 kg). The suspension was degassed 3 times with N2, and triethylamine (1.76 kg) was added. To the resulting mixture was added formic acid (3.34 kg) while maintaining the internal temperature below 35°C. The progress of the reaction was followed by HPLC to monitor the complete consumption of the starting material (i.e., E / Z mixture of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and the debenzylated intermediate. After approximately 30 minutes, an additional amount of formic acid (0.50 kg) was added, and the combined peak area of ​​ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate and the related debenzylation intermediate was determined by HPLC to be <1%. The reactor contents were filtered through a 1.2 μm cartridge filter, followed by a 0.2 μm inline polishing filter. Water (60 kg) was added to the filtrate, and the two-phase mixture was partitioned. The organics were separated and concentrated under vacuum at approximately 60°C ± 5°C to a minimum stirring volume, ethyl acetate (21.6 kg) was added, and the mixture was further concentrated under vacuum to a minimum stirring volume. Ethyl acetate (16.8 kg) was again charged to the crude mixture, and the resulting solution was heated to approximately 60°C. Heptane (37.2 kg) was charged, maintaining the internal temperature at 60°C. The solution was slowly cooled to approximately 0 to 5°C for approximately 2-3 hours to promote crystallization. The slurry was filtered and the filter cake was reslurried in heptane (27.12 kg) and ethyl acetate (7.08 kg). The resulting suspension was filtered and the solid was dried under vacuum at approximately 40 ± 5 °C (until loss on drying (LOD) was < 1%) to give the title compound (6.23 kg, 70.3% yield) as a solid.

[0371] Step F: Preparation of ethyl (R / S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate.

[0372] To a 50 liter glass reactor containing ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (2.000 kg, 1.000 equiv) was added cesium carbonate (3.266 kg, 1.300 equiv) and acetonitrile (15.720 kg) under nitrogen. To the resulting mixture was added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (2.228 kg, 1.100 equiv) over approximately one hour while maintaining the stirred reactor contents at 40°C ± 5°C. After the addition of 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene, the reactor contents were heated to 65°C ± 5°C with stirring until the concentration of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate in the reaction mixture was less than 2.0% area as determined by HPLC. The reaction mixture was cooled to 50°C ± 5°C and filtered under nitrogen through a fine filter cloth with suction to remove cesium salts (Note: ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate may precipitate below 30°C). The filter cake was washed with fresh hot (50°C ± 5°C) acetonitrile (5.658 kg divided into approximately three equal portions). The filtrate was returned to the reactor. The combined filtrates were concentrated by vacuum distillation at a jacket temperature of 60°C ± 10°C. Ethanol (3.156 kg) was added to the reactor and concentrated again by vacuum distillation at a jacket temperature of 60°C ± 10°C with stirring. Again, ethanol (3.156 kg) was added to the reactor and the contents were concentrated by vacuum distillation at a jacket temperature of 60°C ± 10°C to a reactor volume of approximately 14 L. The stirred reactor contents were cooled to 0°C ± 5°C, and the temperature was maintained for 4 hours to promote product crystallization. The resulting slurry was filtered. The filter cake was washed with cold 0°C ± 5°C ethanol (2x 3.156kg). The filter cake was dried under vacuum at 35°C ± 5°C until the weight loss in ≥ 1 hour was ≤ 2%, to obtain the title compound (3.0943kg, 81.0% yield) as a solid.

[0373] Step G: Preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

[0374] A 1.0 M buffer solution was prepared containing potassium dihydrogen phosphate (29.1 g, 0.0335 equiv) in USP purified water (213 g) and potassium dihydrogen phosphate (368.2 g, 0.331 equiv) in USP purified water (2.107 g). To a 50 liter glass reactor was added ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (3.094 kg, 1.000 equiv), immobilized Candida antarctica lipase B (88.18 g, 293250 units / kg of ethyl ester starting material), and acetonitrile (22.32 kg). To the stirred contents of the reactor was added the previously prepared 1.0 M potassium phosphate buffer. The resulting mixture was stirred at a temperature of 40°C ± 5°C under nitrogen until the concentration of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid was ≥ 35% area as determined by HPLC (Note: Although the reaction is typically complete after about 10 hours, the reaction mixture can be kept at 40°C ± 5°C overnight). The stirred reactor contents were cooled to 25°C ± 5°C and the pH was adjusted to between 4 and 5 by adding a solution of citric acid (278.5 g, 0.228 equiv) dissolved in USP purified water (1.454 kg). The reactor contents were filtered to remove the immobilized lipase as well as phosphate and citrate. The reactor and solids were washed with acetonitrile (4.827 kg) and the combined filtrate was added back to the reactor. The stirred reactor contents were concentrated to a volume of 1.0 L to 2.0 L by vacuum distillation at a jacket temperature of 55 ° C ± 5 ° C. Ethyl acetate (5.582 kg) and USP purified water (6.188 kg) were added to the reactor. The contents were stirred for at least 10 minutes at 20 ° C ± 5 ° C, and a solution of sodium chloride (1 kg) in USP purified water (1 kg) was added to promote phase separation. After phase separation was complete, the lower aqueous layer was drained. The solution of sodium chloride (5.569 kg) in USP purified water (12.38 kg) was divided into approximately two equal parts, and the ethyl acetate phase was washed (2x). The ethyl acetate phase was transferred to a glass bottle, and the reactor was rinsed with ethyl acetate (838.5 g), and added to the glass bottle containing the ethyl acetate phase. The reactor was washed sequentially with USP purified water (12.38 kg), acetone (4.907 kg) and ethyl acetate (838.5 g), and the ethyl acetate mixture from the glass bottle was transferred back to the reactor and concentrated to a volume of 1 L to 2 L by vacuum distillation at a jacket temperature of 55°C ± 5°C with stirring.2-Propanol (14.67 kg) was added to the reactor and after stirring, the resulting mixture was concentrated to a volume of 1 L to 2 L by vacuum distillation at a jacket temperature of 55°C ± 5°C. 2-Propanol (7.333 kg) was added to the reactor and heated at 60°C ± 5°C with stirring until the contents dissolved. The stirred reactor contents were cooled to 20°C ± 5°C and filtered through a medium porosity sintered glass filter to remove any inorganic solids to obtain a 2-propanol solution containing 1.3188 kg of the title compound.

[0375] Step H: Preparation of (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid allyl ester.

[0376] Allyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (0.183 g, 0.783 mmol) and (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (0.358 g, 0.783 mmol) were weighed into an oven-dried round-bottom flask equipped with a septum and a stir bar. MeCN (7.825 mL) was added followed by 4-methylmorpholine (0.172 mL, 1.565 mmol) and reactant 2 (0.298 g, 0.783 mmol). The solution exhibited a light amber appearance. The reaction was stirred at room temperature under nitrogen for 3 hours. LCMS was complete. The reaction was concentrated to dryness and purified by column chromatography (silica gel, 5-10% EtOH in DCM) to give 257 mg of the desired compound (clear, colorless film that eventually solidified upon standing). 1 H NMR is consistent with the β isomer; LCMS m / z = 674.4 [M+H] + The α isomer is the less polar eluting reaction product.

[0377] Step I: Preparation of (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 1).

[0378] At room temperature, tetrakis(triphenylphosphine)palladium(1.0g, Aldrich, batch number 0001371338, loading of about 0.06mmol / g) bound to a polymer was stirred in THF(5mL) for 16 hours. Tetrahydrofuran was decanted, and a solution of morpholine (33.37 μL, 0.381mmol) and (2S, 3S, 4S, 5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid allyl ester (0.257g, 0.381mmol) in THF(5mL) was added. The reaction was stirred at room temperature under nitrogen for 1 hour. LCMS showed complete conversion to the desired compound. The resin was removed by filtration and washed with THF, EtOAc, DCM and DCM / EtOH (1: 1 ratio). The washings were concentrated to a semisolid and absorbed in DCM and EtOH. Concentration of the mixture resulted in the formation of a precipitate (batch 1). The supernatant was removed and ppt 1 was dried under high vacuum to give 49.6 mg of an off-white solid. The supernatant was further concentrated to provide a second batch (batch 2), which was recovered in the same manner to give 16 mg of the desired compound. The total amount of isolated compound 1 was 65.6 mg. LCMS m / z=634.4[M+H] + ; 1 H NMR can be Figure 2 Found in.

[0379] Example 1.2: Preparation of 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 2-1 and Compound 2-2).

[0380] Step A: Preparation of (4-bromo-3-(trifluoromethyl)phenyl)methanol.

[0381] To a solution of 4-bromo-3-(trifluoromethyl)benzoic acid methyl ester (10g, 35.33mmol) in THF (100mL) under nitrogen, a solution of 2M lithium borohydride in THF (2.309g, 106.0mmol) was added. The mixture was heated under reflux. The mixture was cooled to 0°C and quenched carefully with 6N HCl (aqueous solution) (about 20mL or less) (violent in the initial 3-5mL) until pH 3. The mixture was diluted with water (25mL) and extracted with EtOAc (2X). The combined organic matter was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness under vacuum to obtain crude (4-bromo-3-(trifluoromethyl)phenyl)methanol as a brown solid.

[0382] Step B: Preparation of ((4-bromo-3-(trifluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane.

[0383] To a solution of (4-bromo-3-(trifluoromethyl)phenyl)methanol (from step A) in DCM (100.00 mL) under nitrogen was added 1H-imidazole (2.886 g, 42.40 mmol) and the mixture was cooled to 0°C. To this was added tert-butylchlorodimethylsilane (5.858 g, 38.86 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was not complete and therefore more 1H-imidazole (2.886 g, 42.40 mmol) and tert-butylchlorodimethylsilane (5.858 g, 38.86 mmol) were added at 0°C and the reaction continued to stir at room temperature overnight. The mixture was quenched with water and the organic layer was separated. The organic layer was concentrated to dryness under vacuum, and the residue was purified by silica gel column chromatography to give ((4-bromo-3-(trifluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane (12.2359 g, 33.13 mmol, 93.8%) as a pale yellow oil.

[0384] Step C: Preparation of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanone.

[0385] To a solution of ((4-bromo-3-(trifluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane (1 g, 2.708 mmol) in THF (5 mL) was added isopropylmagnesium chloride (4.062 mL, 8.124 mmol) at -78°C under nitrogen. The mixture was stirred at room temperature overnight. To the resulting mixture was added copper (I) iodide (0.258 g, 1.354 mmol). After stirring at room temperature for 1 minute, cyclopent-2-enone (0.272 mL, 3.249 mmol) was added. The mixture was stirred at room temperature for 10 minutes. The mixture was quenched with saturated NH4Cl (aq.) and extracted with EtOAc (2X). The combined organics were concentrated to dryness under vacuum and the residue was purified by silica gel column chromatography to give 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanone (0.4851 g, 1.302 mmol, 48.1%) as a pale yellow oil; LCMS m / z = 282.4 [M+H] + .

[0386] Step D: Preparation of 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)cyclopentanone.

[0387] To a solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanone (0.4617 g, 1.239 mmol) in THF (5 mL) at room temperature under a nitrogen atmosphere was added 1 M tetrabutylammonium fluoride in THF (1.859 mL, 1.859 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness under vacuum, and the residue was purified by silica gel column chromatography to give 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)cyclopentanone (0.2894 g, 1.121 mmol, 90.4%) as an off-white oil.

[0388] Step E: Preparation of ethyl 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate.

[0389] Method A

[0390] To a solution of 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)cyclopentanone (100 mg, 0.387 mmol), ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.100 g, 0.387 mmol) and triphenylphosphine (0.122 g, 0.465 mmol) in THF (5 mL) at 0°C under nitrogen was added triethylamine (64.77 μl, 0.465 mmol) followed by the slow addition of (E)-diisopropyldiazene-1,2-dicarboxylate (91.76 μl, 0.465 mmol). The mixture was stirred at room temperature overnight (16 h). The mixture was concentrated to dryness under vacuum and purified by preparative HPLC. The pure fractions were combined, neutralized with saturated NaHCO3 (aq.) and concentrated under vacuum to remove MeCN. The aqueous residue was extracted with DCM (2X) and the combined organics were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness under vacuum to give ethyl 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (39 mg, 78.07 μmol, 20.2%) as a colorless gum; LCMS m / z = 500.2 [M+H] + .

[0391] Method B

[0392] To a solution of 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)cyclopentanone (134 mg, 0.519 mmol) in DCM (5 mL) under nitrogen at 0 ° C was added N-ethyl-N-isopropylpropane-2-amine (0.108 mL, 0.623 mmol) and methanesulfonyl chloride (48.20 μl, 0.623 mmol). The mixture was stirred at 0 ° C for 30 minutes. The reaction was quenched with water, and the organic layer was separated and concentrated to dryness under vacuum. The residue was purified by silica gel column chromatography to obtain 4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl methanesulfonate (162.8 mg, 0.484 mmol, 93.3%) as an off-white oil.

[0393] To a mixture of 4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl methanesulfonate (161.8 mg, 0.481 mmol), ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.187 g, 0.722 mmol) and cesium carbonate (0.313 g, 0.962 mmol) at room temperature under nitrogen, DMF (5 mL) was added. The mixture was stirred at room temperature overnight. The mixture was filtered and purified by preparative HPLC. Pure fractions were combined, neutralized with saturated NaHCO (aqueous solution), and concentrated under vacuum to remove MeCN. The aqueous residue was extracted with DCM (2X), and the combined organic matter was dried over anhydrous Na SO and filtered. The filtrate was concentrated to dryness under vacuum to give ethyl 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (181.4 mg, 0.363 mmol, 75.5%) as an off-white gum; LCMS m / z = 500.2 [M+H] + .

[0394] Step F: Preparation of ethyl 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate.

[0395] To a solution of ethyl 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (250.5 mg, 0.501 mmol) in MeOH (50 mL) at 0°C was added sodium borohydride (37.94 mg, 1.003 mmol). The mixture was stirred at 0°C for 40 minutes. The mixture was quenched with saturated ammonium chloride (aq) (30 mL) and extracted with DCM (2X). The combined organics were concentrated in vacuo and purified by silica gel column chromatography to give ethyl 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (224.7 mg, 0.448 mmol, 89.3%) as an off-white gum; LCMS m / z = 502.2 [M+H] + .

[0396] Step G: Preparation of 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 2-1 and Compound 2-2).

[0397] To a solution of ethyl 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (222.4 mg, 0.443 mmol) in a mixed solvent of MeOH (9 mL), THF (3.0 mL) and H2O (3.0 mL) at room temperature was added lithium hydroxide hydrate (65.13 mg, 1.552 mmol). The mixture was stirred at room temperature over the weekend. The mixture was quenched with 1 M citric acid (1.6 mL), diluted with brine, and extracted with EtOAc (1X). The organic layer was concentrated to dryness under vacuum. The residue was purified by preparative HPLC to give two groups of isomers (Group 1: fractions 4 and 5; and Group 2: fractions 7 and 8). Each fraction was lyophilized separately.

[0398] Fraction 4 (34.3 mg) and fraction 5 (51.1 mg), each fraction showed similar NMR spectra (compound 2-1; 85.4 mg, 0.180 mmol, 40.7%); EC 50 (See Example 2)); LCMS m / z=474.2[M+H] + ; 1 H NMR can be Figure 4 Found in.

[0399] Fraction 7 (68.6 mg) and fraction 8 (9.4 mg), each fraction showed similar NMR spectra (compound 2-2; 78 mg, 0.165 mmol, 37.1%); EC 50 (See Example 2)); LCMS m / z=474.2[M+H] + ; 1 H NMR can be Figure 5 Found in.

[0400] Example 1.3: Preparation of 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 3).

[0401] To a 50 mL round bottom flask was added ethyl 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.120 g, 0.240 mmol, prepared in a similar manner as described above in Example 1.2 Step E Method B), MeOH (10 mL) and H2O (1 mL) at room temperature under N2. To the mixture was added lithium hydroxide (0.161 g, 6.726 mmol) and stirred overnight. An aliquot was sampled for LC / MS and the mixture was concentrated to almost dryness. To the resulting mixture was added charged H2O (10 mL) and acidified with 2N HCl (3.25 mL, ~pH=2-3). The slurry was filtered and the filter cake was washed with H2O (5 mL). The filter cake was collected and dried under vacuum at 45°C overnight. The crude product was purified by HPLC (20-95% MeCN / water, 0.1% TFA) to give the title compound in six fractions. Each fraction was frozen and lyophilized to give the title compound (27.9 mg). LCMS m / z=472.6 [M+H] + ; 1 H NMR can be Figure 6 Found in.

[0402] Example 1.4: Preparation of 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 4).

[0403] Step A: Preparation of ((4-bromo-3-(trifluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane.

[0404] To a mixture of (4-bromo-3-(trifluoromethyl)phenyl)methanol (7.969 g, 31.25 mmol) and 1H-imidazole (2.553 g, 37.50 mmol) in dichloromethane (DCM, 39.9 mL, 31.25 mmol) at room temperature under nitrogen was added tert-butylchlorodimethylsilane (5.181 g, 34.37 mmol). The resulting mixture was stirred for 1 hour and quenched with saturated aqueous NaHCO3 (20 mL) (pH 7) added dropwise. The layers were separated and the aqueous layer was extracted with DCM (2x10 mL). The DCM layers were combined, dried over Na2SO4, filtered and concentrated. The resulting liquid was dried overnight under vacuum at room temperature to give a light orange liquid (11.74 g); 1 H NMR (CDCl3) δ ppm 1.11 (s, 6H), 0.95 (s, 9H), 4.72 (s, 2H), 7.34 (bd, 1H), 7.64-7.68 (m, 2H).

[0405] Step B: Preparation of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanol.

[0406] To a solution of ((4-bromo-3-(trifluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane (5.637 g, 15.26 mmol) in tetrahydrofuran (50 mL, 15.26 mmol) in a 100 mL round bottom flask at -78°C under N2 was added isopropylmagnesium chloride (7.632 mL, 15.26 mmol) dropwise. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added copper (I) iodide (0.291 g, 1.526 mmol) followed by 6-oxabicyclo[3.1.0]hexane (2.645 mL, 30.53 mmol). The mixture was kept stirring at room temperature overnight under nitrogen. Copper (I) iodide (0.291 g, 1.526 mmol) and 6-oxabicyclo[3.1.0]hexane (1.322 mL, 15.26 mmol) were added to the mixture at room temperature and maintained for about 4 hours.

[0407] The mixture is quenched with saturated NH4Cl (11.5mL) to obtain a brown suspension. Add EtOAc (28mL) and water (5mL), and separate the layers obtained. Use EtOAc (2x 28mL) to extract the aqueous layer. Organic matter is merged, through Na2SO4 drying, filtered, and concentrated under vacuum. The liquid gained is dried at room temperature under high vacuum to obtain a liquid. Purification liquid (silica gel, hexane / EtOAc) obtains an orange oil (4.019g).

[0408] Step C: Preparation of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanone.

[0409] To a 500 mL round bottom flask was added 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanol (3.745 g, 10.000 mmol), Dess-Martin periodinane (6.357 g, 14.99 mmol) and dichloromethane (61 mL). To the stirred mixture was slowly added a mixture of water (0.198 mL, 10.99 mmol) in dichloromethane (198 mL) at room temperature over 50 minutes. The resulting suspension was diluted with MTBE (100 mL) and concentrated to give a wet white residue. MTBE (600 mL) was added to the residue and washed sequentially with 10% NaS2O3 / saturated NaHCO3 aqueous solution (1:1, 300 mL), H2O (300 mL) and brine (300 mL). The resulting organic layer was dried over anhydrous Na2SO4, filtered and evaporated.The resulting oil was dried under high vacuum at room temperature to give a thick orange oil (3.71 g).

[0410] Step D: Preparation of 2-(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)cyclopentanone.

[0411] To a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)phenyl)cyclopentanone (3.570 g, 9.584 mmol) in tetrahydrofuran (THF, 36 mL, 9.584 mmol) in a 200 mL round bottom flask under nitrogen was added tetrabutylammonium fluoride in THF (14.38 mL, 14.38 mmol). The resulting solution was stirred for 30 minutes. The resulting mixture was quenched with water (5 mL) and concentrated to give about 10 mL of a dark orange solution. The solution was diluted with EtOAc (200 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL), and the organics were combined. The organics were washed with brine (2 x 200 mL), dried over Na2SO4, and filtered. The solution was concentrated and dried under high vacuum to give a liquid (3.91 g). The resulting orange liquid was purified using a Biotage system (silica gel, hexane / EtOAc). The purified fractions were combined, concentrated, and dried under high vacuum to give a thick light orange oil (2.07 g); 1H NMR(CD2Cl2)δppm 1.90-2.04(m,2H),2.12-2.22(m,1H),2.26-2.37(m,1H),2.46-2.60(m,2H),3.65(dd,J1=1 1.0,J2=8.0,1H),4.71(s,2H),7.12(brd,J=8.0,1H),7.53(brd,J=8.0,1H),7.66(brs,1H).

[0412] Step E: Preparation of 4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl methanesulfonate.

[0413] To a solution of 2-(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)cyclopentanone (1.000 g, 3.872 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.809 mL, 4.647 mmol) in dichloromethane (20 mL, 3.872 mmol) at 0°C under nitrogen was slowly added methanesulfonyl chloride (0.360 mL, 4.647 mmol). The internal temperature was maintained at about 0°C to 1.5°C during the addition (about 20 minutes). The mixture was stirred at 0°C for 1 hour and quenched with H2O (4 mL) while maintaining the internal temperature at about 0°C. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 5 mL). The organics were combined, washed with saturated NaCl solution (2 x 15 mL) and dried over Na2SO4 overnight. The mixture was filtered, concentrated and dried under vacuum to give a brown residue (1.26 g); 1 H NMR(CD2Cl2)δppm 1.95-2.05(m,2H),2.15-2.25(m,1H),2.26-2.38(m,1H),2.46-2.62(m,2H),3.00(s,3H)3.66-3.7 3(brdd,1H),5.24(s,2H),7.20(d,J=8.0,1H),7.60(dd,J1=8.0,J2=2.0,1H),7.71(d,J=2.0,1H).

[0414] Step F: Preparation of ethyl 2-(7-((4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate.

[0415] To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.705 g, 2.721 mmol) and cesium carbonate (1.182 g, 3.627 mmol) in acetonitrile (ACN, 27 mL) in a 100 mL round bottom flask at room temperature under nitrogen was added dropwise a solution of 4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl methanesulfonate (0.610 g, 1.814 mmol) in acetonitrile (12 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered through a celite pad under nitrogen. The celite pad was washed with ACN (3 x 20 mL) and the pH of the organics was adjusted to pH 6-7 with 1N HCl (700 μl). The mixture was concentrated and dried overnight under vacuum at room temperature. The mixture was purified by preparative HPLC, and the fractions were lyophilized to give the title compound as an orange-red solid (227.0 mg); LCMS m / z=500.4 [M+H] + .

[0416] Step G: Preparation of ethyl 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate.

[0417] To a solution of ethyl 2-(7-((4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.227 g, 0.454 mmol) in methanol (45 mL, 0.454 mmol) at 0°C was added sodium borohydride (34.38 mg, 0.909 mmol). After 40 minutes at 0°C, the mixture was quenched with saturated ammonium chloride (40 mL) followed by water (10 mL) and concentrated. The resulting aqueous mixture (approximately 50 mL) was extracted with EtOAc (3 x 50 mL) and the combined organics were dried (anhydrous Na2SO4), filtered, and concentrated under vacuum. The resulting residue was further dried under vacuum overnight and purified by preparative HPLC to afford two sets of diastereomers. The pure fractions were combined and lyophilized to give a fluffy orange powder (102 mg, major diastereomer; LCMS m / z = 502.2 [M+H] + ) and a loose orange powder (60 mg, minor diastereomer; LCMS m / z = 502.6 [M+H] + ).

[0418] Step H: Preparation of 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 4-1)

[0419] To a solution of ethyl 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.100 g, 0.199 mmol, major diastereomer from Step G) in tetrahydrofuran (3.5 mL) and water (3.5 mL) in a 20 mL scintillation vial under nitrogen at room temperature was added lithium hydroxide hydrate (29.28 mg, 0.698 mmol). The resulting mixture was stirred at room temperature for about 5.5 hours, quenched with HCl (1.0 N, 0.72 mL) to adjust the pH to pH 3-4, and concentrated under vacuum to remove most of the THF. The aqueous mixture was extracted with EtOAc (3×10 mL), and the combined organics were dried over anhydrous Na2SO4 and filtered. The resulting solution was filtered and dried under vacuum overnight. The residue was purified by semi-preparative HPLC and the product was purified to have the expected [M+H] + The fractions were lyophilized. The fractions were combined to obtain the title compound as a solid; 67.6 mg, compound 4-1 (diastereomer); LCMS m / z=474.4 [M+H] + ; 1 HNMR can be used Figure 7 Found in.

[0420] Step I: Preparation of 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 4-2).

[0421] To a solution of ethyl 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.060 mg, 0.120 mmol, minor diastereomer from Step G) in tetrahydrofuran (2.1 mL) and water (2.1 mL) in a 20 mL scintillation vial under nitrogen at room temperature was added lithium hydroxide hydrate (17.57 mg, 0.419 mmol). The resulting mixture was stirred at room temperature for about 3 hours, quenched with HCl (1.0 N, 0.42 mL) to adjust the pH to pH 3-4, and concentrated under vacuum to remove most of the THF. The aqueous mixture was extracted with EtOAc (3×10 mL), and the combined organics were dried over anhydrous Na2SO4 and filtered. The resulting solution was filtered and dried under vacuum overnight. The residue was purified by semi-preparative HPLC and the product was purified to have the expected [M+H] +The fractions were lyophilized. The fractions were combined to obtain the title compound as a solid; 34.9 mg, compound 4-2 (diastereomer); LCMS m / z=474.4 [M+H] + ; 1 HNMR can be used Figure 8 Found in.

[0422] Example 1.5: Preparation of 2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 6).

[0423] Step A: Preparation of isopropyl 4-isopropoxy-3-(trifluoromethyl)benzoate.

[0424] To a mixture of 4-hydroxy-3-(trifluoromethyl)benzoic acid (14.55 mmol) and cesium carbonate (43.7 mmol) in DMA (60 mL) was added 2-bromopropane (36.4 mmol). The reaction was stirred at 80 °C for 16 hours. The mixture was filtered through celite and concentrated under vacuum. The residue was dissolved in EtOAc and washed with water, then with brine, then dried over MgSO4 and filtered. The solvent was removed under vacuum to give the title compound (13.1 mmol) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δppm 1.36(d,J=6.32Hz,6H),1.39(d,J=6.06Hz,6H),4.72(septet,J=6.06Hz,1H),5.24(septet,J=6.25 Hz, 1H), 7.00 (d, J = 8.84Hz, 1H), 7.26 (s, 0H), 8.15 (dd, J = 8.72, 2.15Hz, 1H), 8.23 ​​(d, J = 2.15Hz, 1H).

[0425] Step B: Preparation of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol.

[0426] To a cooled (-78°C) solution of 4-isopropoxy-3-(trifluoromethyl)benzoate (13.1 mmol) in DCM (85 mL) under nitrogen was added a 2.0 M solution of LAH (19.0 mmol) via syringe. The reaction was allowed to return to room temperature and stirred for 16 hours. The reaction was cooled to 0°C and quenched with water (0.95 mL) and 10% NaOH (aq) (1.90 mL). The mixture was stirred by Filter. Concentrate the filtrate in vacuo to give the title compound (11.27 mmol) as an oil. 1H NMR(400MHz,DMSO-d6)δppm 1.27(d,J=6.06Hz,6H),4.46(d,J=5.81Hz,2H),4.75(septet,J=6.02Hz,1H),5.20(t,J=5.75Hz,1H),7.23(d,J=8.46Hz,1H),7.47-7.56(m,2H).

[0427] Step C: Preparation of 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene.

[0428] To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 hours. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO 3 , dried over MgSO 4 and filtered. The solvent was removed under vacuum to give the title compound (10.4 mmol) as an oil. 1 H NMR (400MHz, DMSO-d6) δppm 1.29 (d, J = 6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J = 8.46 Hz, 1H), 7.63-7.70 (m, 2H).

[0429] Step D: Preparation of 2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 6).

[0430] Cesium carbonate (0.302g, 0.926mmol) and 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.214g, 0.848mmol) are added to a solution of 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta [b] indol-3-yl) ethyl acetate (0.2g, 0.771mmol, see WO2010 / 011316) and DMA (2ml). The mixture is stirred at room temperature for 24 hours, and then diluted with water to form a precipitate. DMA / water is decanted, and the remaining solid is absorbed in dioxane (6mL) and 1M LiOH aqueous solution (2.0mL) is added. The reaction is stirred at room temperature for 24 hours, and then acidified with 0.5M citric acid aqueous solution. The crude product is extracted twice with EtOAc, and the combined extract is dried with sodium sulfate, filtered and concentrated. The concentrate is recrystallized from EtOAc / hexane. The solid was filtered and dried to give compound 6 (0.345 g); LCMS m / z=448.3 [M+H] + ; 1H NMR can be Fig. 9 Found in.

[0431] Example 2: β-arrestin assay.

[0432] In vitro S1P1 activity was determined in a beta arrestin assay. The EC values ​​for certain compounds of the invention are shown in the following table: 50 value.

[0433] Compound No. <![CDATA[EC 50 S1P1 (β-arrestin)]]> <![CDATA[1 A ]]> 3.9nM (n=3) 2-1 52.1nM (n=7) 2-2 85.6nM (n=7) <![CDATA[4 B ]]> 3.66nM (n=7) 4-1 16.7nM (n=7)

[0434] A The determination curve of compound 1 is shown in Figure 3 middle.

[0435] B Compound 4 is a mixture of all stereoisomers.

[0436] Those skilled in the art will recognize that various modifications, additions, substitutions and variations may be made to the illustrative examples described herein without departing from the spirit of the present invention and are therefore considered to be within the scope of the present invention. All documents cited above, including but not limited to printed publications and provisional and conventional patent applications, are incorporated herein by reference in their entirety.

[0437] This application also includes the following specific implementation schemes:

[0438] 1. A compound selected from the group consisting of a compound of formula (Ia) and a pharmaceutically acceptable salt, solvate and hydrate thereof:

[0439]

[0440] in:

[0441] R 1 is H or OH;

[0442] R 3 is H; or

[0443] R 1 and R 3 Together they form an oxo group;

[0444] as well as

[0445] R 2 is H or a group of formula (IIa):

[0446]

[0447] The condition is that if R 2 is H, then R 1 and R 3 Neither is H.

[0448] 2. The compound according to embodiment 1, wherein R1 is OH; R 3 is H; and R 2 For H.

[0449] 3. The compound according to embodiment 1, wherein R1 and R 3 together to form an oxo group; and R 2 For H.

[0450] 4. The compound according to embodiment 1, wherein R1 is H; R 3 is H; and R 2 It is a group of formula (IIa).

[0451] 5. The compound according to embodiment 1, which is selected from the compound of formula (Ig) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0452]

[0453] 6. The compound according to embodiment 1, wherein the compound is selected from the compound of formula (Io) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0454]

[0455] in:

[0456] R 1 is OH; and

[0457] R 3 is H;

[0458] or R 1 and R 3 Together they form an oxo group.

[0459] 7. The compound according to embodiment 1, wherein the compound is selected from the compound of formula (Iw) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0460]

[0461] in:

[0462] R 1 is OH; and

[0463] R 3 is H;

[0464] or R 1 and R 3 Together they form an oxo group.

[0465] 8. The compound according to embodiment 6 or 7, wherein R 1 is OH; and R 3 For H.

[0466] 9. The compound according to embodiment 6 or 7, wherein R 1 and R 3 Together they form an oxo group.

[0467] 10. A compound according to any one of embodiments 1 to 9, wherein the stereochemistry of the C(3) carbon of the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group is (R).

[0468] 11. A compound according to any one of embodiments 1 to 9, wherein the stereochemistry of the C(3) carbon of the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group is (S).

[0469] 12. A compound selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0470] (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0471] (2S,3S,4S,5R,6S)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0472] (2S,3S,4S,5R,6R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0473] (2S,3S,4S,5R)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0474] (2S,3S,4S,5R,6S)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0475] (2S,3S,4S,5R,6R)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0476] 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0477] 2-((R)-7-((4-((1S,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0478] 2-((R)-7-((4-((1R,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0479] 2-((R)-7-((4-((1R,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0480] 2-((R)-7-((4-((1S,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0481] 2-((S)-7-((4-((1S,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0482] 2-((S)-7-((4-((1R,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0483] 2-((S)-7-((4-((1R,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0484] 2-((S)-7-((4-((1S,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0485] 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0486] 2-((R)-7-((4-((S)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0487] 2-((R)-7-((4-((R)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0488] 2-((S)-7-((4-((S)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0489] 2-((S)-7-((4-((R)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0490] 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0491] 2-((R)-7-((4-((1R,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0492] 2-((R)-7-((4-((1S,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0493] 2-((R)-7-((4-((1S,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0494] 2-((R)-7-((4-((1R,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0495] 2-((S)-7-((4-((1R,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0496] 2-((S)-7-((4-((1S,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0497] 2-((S)-7-((4-((1S,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0498] 2-((S)-7-((4-((1R,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0499] 2-(7-((4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0500] 2-((R)-7-((4-((R)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0501] 2-((R)-7-((4-((S)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0502] 2-((S)-7-((4-((R)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0503] 2-((S)-7-((4-((S)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0504] 2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

[0505] (R)-2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and

[0506] (S)-2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

[0507] 13. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 12 and a pharmaceutically acceptable carrier.

[0508] 14. A method for treating an S1P1 receptor-associated disorder in an individual, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1 to 12.

[0509] 15. A method for treating a disorder associated with the S1P1 receptor in an individual, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 12, wherein the disorder associated with the S1P1 receptor is selected from: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0510] 16. Use of a compound according to any one of embodiments 1 to 12 for the manufacture of a medicament for the treatment of a S1P1 receptor-associated disorder.

[0511] 17. Use of a compound according to any one of embodiments 1 to 12 in the manufacture of a medicament for treating a S1P1 receptor-associated disorder, wherein the S1P1 receptor-associated disorder is selected from: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0512] 18. A compound according to any one of embodiments 1 to 12 for use in a method of treatment of the human or animal body by therapy.

[0513] 19. A compound according to any one of embodiments 1 to 12 for use in a method of treating a S1P1 receptor-associated disorder.

[0514] 20. A compound according to any one of embodiments 1 to 12 for use in a method of treating a S1P1 receptor-associated disorder, wherein the S1P1 receptor-associated disorder is selected from: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, an inflammatory skin disease, cancer, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes and acne.

[0515] 21. A method for preparing a composition, the method comprising compounding a compound according to any one of embodiments 1 to 12 and a pharmaceutically acceptable carrier.

Claims

1. A compound selected from the group consisting of compounds of formula (Ia) and pharmaceutically acceptable salts thereof: in: R 1 is H or OH; R 3 is H; or R 1 and R 3 Together they form an oxo group; as well as R 2 is a group of formula (IIa):

2. The compound according to claim 1, wherein R 1 is OH; and R 3 For H.

3. The compound according to claim 1, wherein R 1 and R 3 Together they form an oxo group.

4. The compound according to claim 1, wherein R 1 is H; and R 3 For H.

5. The compound according to claim 1, wherein the compound is selected from the compound of formula (Ig) and a pharmaceutically acceptable salt thereof:

6. A compound selected from the group consisting of compounds of formula (Iw) and pharmaceutically acceptable salts thereof: in: R 1 is OH; and R 3 is H; or R 1 and R 3 Together they form an oxo group.

7. The compound according to claim 6, wherein R 1 is OH; and R 3 For H.

8. The compound according to claim 6, wherein R 1 and R 3 Together they form an oxo group.

9. A compound according to any one of claims 1 to 8, wherein the stereochemistry of the C(3) carbon of the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group is (R).

10. A compound according to any one of claims 1 to 8, wherein the stereochemistry of the C(3) carbon of the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl group is (S).

11. A compound selected from the following compounds and pharmaceutically acceptable salts thereof: (2S,3S,4S,5R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6R)-6-(2-((R)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6S)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (2S,3S,4S,5R,6R)-6-(2-((S)-7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; 2-(7-((4-(3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1S,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1R,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1R,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1S,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1S,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1R,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1R,3S)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1S,3R)-3-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-(7-((4-(3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((S)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((R)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((S)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((R)-3-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-(7-((4-(2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1R,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1S,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1S,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((1R,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1R,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1S,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1S,2S)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((1R,2R)-2-hydroxycyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-(7-((4-(2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((R)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((R)-7-((4-((S)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((R)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-((S)-7-((4-((S)-2-oxocyclopentyl)-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; (R)-2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and (S)-2-(7-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a S1P1 receptor-associated disorder in a subject.

14. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a disorder associated with the S1P1 receptor in an individual, wherein the disorder associated with the S1P1 receptor is selected from: a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, cancer, transplant rejection and type I diabetes.

15. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a S1P1 receptor-associated disorder in an individual, wherein the S1P1 receptor-associated disorder is an inflammatory skin disease.

16. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a condition associated with the S1P1 receptor in an individual, wherein the condition associated with the S1P1 receptor is selected from the group consisting of psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis and acne.

17. A method for preparing a composition, the method comprising compounding a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

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