Compositions and methods of modulating short-chain dehydrogenase activity

Abstract

To provide a compound useful for treating a disease, disorder, or condition caused by a decrease in short chain dehydrogenase (SCD) (e.g., 15-PGDH) activity and / or prostaglandin levels.SOLUTION: The present invention provides a compound for use in inhibiting the activity of a short chain dehydrogenase enzyme, the compound comprising at least one of the formulas (I) or (II), and pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority from U.S. Provisional Application No. 62 / 455,399, filed on February 6, 2017, and U.S. Provisional Application No. 62 / 510,589, filed on May 24, 2017, the contents of which are hereby incorporated by reference in their entirety.

[0002] Government Funding This invention was made with government support under grant numbers R01CA127306, R01CA127306-03S1, 1P01CA95471-10, and 5P50CA150964, awarded by the National Institutes of Health. The U.S. government may have certain rights in this invention.

Background Art

[0003] Background Short-chain dehydrogenases (SCDs) are a family of dehydrogenases with only 15% - 30% sequence identity, and are mainly similar in the coenzyme-binding domain and the substrate-binding domain. In addition to their role in ethanol detoxification, SCDs are involved in the synthesis and breakdown of fatty acids, steroids, and some prostaglandins, and are thus related to various disorders such as lipid storage diseases, myopathies, SCD deficiency, and certain hereditary disorders.

[0004] 15-Hydroxy-prostaglandin dehydrogenase (15-PGDH) (hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide); 15-PGDH; enzyme number 1.1.1.141; encoded by the HPGD gene), which is an SCD, is an important enzyme in the inactivation of several active prostaglandins, leukotrienes, and hydroxy eicosatetraenoic acids (HETEs) (for example, by catalyzing the oxidation of PGE2 to 15-keto-prostaglandin E2 (15k-PGE)). The human enzyme is encoded by the HPGD gene and consists of a homodimer with a subunit size of 29 kDa. This enzyme belongs to the evolutionarily conserved short-chain dehydrogenase / reductase enzyme (SDR) superfamily and is named SDR36C1 according to the recently approved human enzyme nomenclature. To date, two forms of 15-PGDH enzyme activity have been identified: NAD+-dependent type I 15-PGDH (encoded by the HPGD gene) and type II NADP-dependent 15-PGDH (also known as carbonyl reductase 1 (CBR1, SDR21C1)). However, the preference of CBR1 for NADP and the high Km value of CBR1 for most prostaglandins suggest that most of the in vivo activity may be due to type I 15-PGDH encoded by the HPGD gene (hereinafter, and throughout the following text, simply referred to as 15-PGDH).

[0005] Recent studies have suggested that inhibitors of 15-PGDH may have therapeutic value. Recent studies have associated increased expression of 15-PGDH with protection against thrombin-mediated cell death. 15-PGDH is well known to be responsible for the inactivation of prostaglandin E2 (PGE2), a downstream product of COX-2 metabolism. PGE2 has been shown to be beneficial in various biological processes such as hair density, skin wound healing, and bone formation. Recent studies have shown that inhibitors of 15-PGDH promote tissue regeneration and wound healing in multiple tissues. Summary of the Invention

[0006] Summary The embodiments described herein relate to compounds and methods for modulating the activity of short-chain dehydrogenase (SCD) (e.g., 15-PGDH), modulating the levels of prostaglandins in tissues, and / or treating diseases, disorders or conditions where it is desirable to modulate the activity and / or levels of SCD (e.g., 15-PGDH) and / or prostaglandins.

[0007] In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to a subject's tissue or blood in an amount effective to inhibit the activity of the SCD enzyme. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to a subject's tissue or blood in an amount effective to increase the levels of prostaglandins in the tissue or blood. The 15-PGDH inhibitor includes compounds having at least one of the following formulas:

Chemical formula

[0008] In one embodiment, at least one of R 2 or R 3 is not H, and at least one of R 9 or R 10 is not H.

[0009] In some embodiments, the 15-PGDH inhibitor has an IC 50 less than 1 μM, or preferably less than 250 nM, or more preferably less than 50 nM, at a concentration of recombinant 15-PGDH of about 5 nM to about 10 nM. 50 50 ​and, or more preferably, an IC of less than 10 nM 50 and, or more preferably, an IC of less than 5 nM 50 and can inhibit the enzymatic activity of recombinant 15-PGDH.

[0010] The 15-PGDH inhibitor may be provided as a topical composition applicable to the subject's skin to promote and / or stimulate skin pigmentation and / or hair growth and / or to inhibit hair loss and / or to treat skin damage or inflammation.

[0011] The 15-PGDH inhibitor may also be administered to a subject to promote wound healing, tissue repair and / or tissue regeneration and / or engraftment or regeneration of tissue grafts.

[0012] In one embodiment, the 15-PGDH inhibitor may be administered to a subject to treat at least one of oral ulcers, gum diseases, colitis, ulcerative colitis, gastrointestinal ulcers, inflammatory bowel disease, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary hypertension, cardiovascular diseases and kidney diseases.

[0013] In another embodiment, the 15-PGDH inhibitor may be administered to a subject in combination with a prostanoid agonist for the purpose of enhancing the therapeutic effect of the agonist in a condition responsive to prostaglandins.

[0014] In other embodiments, the 15-PGDH inhibitor may be administered to a subject and / or the subject's tissue to increase tissue stem cells. For example, the 15-PGDH inhibitor may be administered to the subject's bone marrow to increase stem cells in the subject.

[0015] In still other embodiments, the 15-PGDH inhibitor may be administered to a tissue graft donor, a bone marrow graft donor and / or a hematopoietic stem cell donor and / or to a tissue graft and / or a bone marrow graft and / or a hematopoietic stem cell graft to enhance the compatibility of the donor tissue graft, the donor bone marrow graft and / or the donor hematopoietic stem cell graft. For example, the 15-PGDH inhibitor may be administered to a subject and / or the subject's bone marrow to enhance the compatibility of the bone marrow as a donor graft, and / or to a preparation of the subject's hematopoietic stem cells to enhance the compatibility of the stem cell preparation as a donor graft, and / or to a preparation of the subject's peripheral blood hematopoietic stem cells to enhance the compatibility of the stem cell preparation as a donor graft, and / or to a preparation of cord blood stem cells to enhance the compatibility of the stem cell preparation as a donor graft, and / or to a preparation of cord blood stem cells to reduce the number of cord blood units required for transplantation.

[0016] In other embodiments, the 15-PGDH inhibitor may be administered to a subject to reduce tissue graft rejection, to improve engraftment of a tissue graft and / or a bone marrow graft (e.g., after treatment of the subject or the subject's bone marrow by radiation therapy, chemotherapy or immunosuppressive therapy), to improve engraftment of a progenitor stem cell graft, a hematopoietic stem cell graft or a cord blood stem cell graft, to improve engraftment of a hematopoietic stem cell graft or cord blood stem cells (e.g., after treatment of the subject or the subject's bone marrow by radiation therapy, chemotherapy or immunosuppressive therapy), and / or to reduce the number of cord blood units required for transplantation into the subject.

[0017] In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a tissue graft transplant, a bone marrow transplant and / or a hematopoietic stem cell transplant, or a cord blood stem cell transplant, to reduce the administration of other treatments or growth factors.

[0018] In some embodiments, the 15-PGDH inhibitor may be administered to a subject or to a tissue graft of the subject to reduce graft rejection and / or to improve engraftment of the graft (e.g., after treatment of the subject or the subject's bone marrow by radiation therapy, chemotherapy or immunosuppressive therapy).

[0019] In other embodiments, the 15-PGDH inhibitor may be administered to a subject or to the subject's bone marrow to confer resistance to the toxic or lethal effects of radiation exposure, to confer resistance to the toxic effects of Cytoxan, the toxic effects of fludarabine, the toxic effects of chemotherapy or the toxic effects of immunosuppressive therapy, to reduce radiation-induced lung toxicity, and / or to reduce infection.

[0020] In still other embodiments, the 15-PGDH inhibitor is used to increase the neutrophil count after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood, to increase the neutrophil count in a subject having neutropenia after application of chemotherapy or radiotherapy, to increase the neutrophil count in a subject having neutropenia due to aplastic anemia, myelodysplasia, myelofibrosis, other myeloid diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia after viral infection, to increase the platelet count after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood, to increase the platelet count in a subject having thrombocytopenia after application of chemotherapy or radiotherapy, to increase the platelet count in a subject having thrombocytopenia due to aplastic anemia, myelodysplasia, myelofibrosis, other myeloid diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection, to increase the red blood cell count or hematocrit or hemoglobin level after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood, to increase the red blood cell count or hematocrit or hemoglobin level in a subject having anemia after application of chemotherapy or radiotherapy, to increase the red blood cell count or hematocrit or hemoglobin level in a subject having anemia due to aplastic anemia, myelodysplasia, myelofibrosis, other myeloid disorders, drug-induced anemia (drug inducedTo increase the number of red blood cells or hematocrit or hemoglobin level in a subject having anemia, immune-mediated anemia, anemia of chronic disease, anemia after viral infection or idiopathic anemia, to increase the red blood cell count or hematocrit or hemoglobin level in a subject having anemia, to increase bone marrow stem cells after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood, to increase bone marrow stem cells in a subject after administration of chemotherapy or radiation therapy, and / or to increase bone marrow stem cells in a subject having aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug induced cytopenia, immune cytopenia, cytopenia after viral infection, or cytopenia, it may be administered to a subject.

[0021] In other embodiments, administration of a 15-PGDH inhibitor may be used to regulate hematopoietic stem cells and hematopoiesis. The 15-PGDH inhibitor may be administered alone or in combination with a cytokine to a subject in need thereof to increase and / or mobilize hematopoietic stem cells and / or neutrophils in the subject's blood, bone marrow and / or tissue.

[0022] In some embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing neutrophils.

[0023] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing neutrophils.

[0024] In yet other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells.

[0025] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hemopoietic cytokine for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells.

[0026] In some embodiments, administration of a 15-PGDH inhibitor may be combined with a second agent (including Plerixafor) for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells.

[0027] In other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0028] In still other embodiments, administration of a 15-PGDH inhibitor may be combined with a hemopoietic cytokine for the purpose of increasing the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0029] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a second agent (including Plerixafor) for the purpose of increasing the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0030] In still other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of hematopoietic stem cells in blood or bone marrow.

[0031] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hemopoietic cytokine for the purpose of increasing the number of hematopoietic stem cells in blood or bone marrow.

[0032] In other embodiments, the 15-PGDH inhibitor may be administered to a subject and / or the subject's tissue to increase tissue stem cells. For example, the 15-PGDH inhibitor may be administered to the subject's bone marrow to increase stem cells in the subject.

[0033] In yet other embodiments, the 15-PGDH inhibitor may be administered to a tissue graft donor, a bone marrow graft donor and / or a hematopoietic stem cell donor and / or a tissue graft and / or a bone marrow graft and / or a hematopoietic stem cell graft to enhance the compatibility of the donor tissue graft, the donor bone marrow graft and / or the donor hematopoietic stem cell graft. For example, the 15-PGDH inhibitor may be administered to a subject and / or the subject's bone marrow to enhance the compatibility of the bone marrow as a donor graft, and / or to a preparation of the subject's hematopoietic stem cells to enhance the compatibility of the stem cell preparation as a donor graft, and / or to a preparation of the subject's peripheral blood hematopoietic stem cells to enhance the compatibility of the stem cell preparation as a donor graft, and / or to a preparation of cord blood stem cells to enhance the compatibility of the stem cell preparation as a donor graft, and / or to a preparation of cord blood stem cells to reduce the number of cord blood units required for transplantation.

[0034] In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a tissue graft transplant, a bone marrow transplant and / or a hematopoietic stem cell transplant, or a cord blood stem cell transplant, to reduce the administration of other treatments or growth factors.

[0035] In other embodiments, the 15-PGDH inhibitor may be administered to a subject to enhance the responsiveness to cytokines in the presence of cytopenia (including any of neutropenia, thrombocytopenia, lymphocytopenia and anemia), wherein the cytokines having an increased responsiveness enhanced by the 15-PGDH inhibitor include any of G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist) and SCF.

[0036] In some embodiments, the 15-PGDH inhibitor may be administered to a subject to increase bone density, to treat osteoporosis, to promote fracture healing, or to promote healing after bone surgery or joint replacement, and / or to promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0037] In other embodiments, the 15-PGDH inhibitor may be administered to a subject, or to the intestine of a subject, to increase stem cells or cell proliferation in the intestine and / or to confer resistance to the toxic or lethal effects of radiation exposure or the toxic, lethal or mucositis effects resulting from treatment with chemotherapy.

[0038] In some embodiments, the 15-PGDH inhibitor may be administered to a subject, or to the intestine of a subject, as a treatment for colitis, ulcerative colitis or inflammatory bowel disease.

[0039] In other embodiments, the 15-PGDH inhibitor may be administered to a subject to increase liver regeneration after liver surgery, after living liver donation, after liver transplantation, or after liver injury by toxins, and / or to facilitate recovery from or resistance to hepatotoxins (including acetaminophen and related compounds).

[0040] In yet other embodiments, the 15-PGDH inhibitor may be administered to a subject to treat erectile dysfunction.

[0041] In yet other embodiments, the 15-PGDH inhibitor may be administered to inhibit at least one of growth, proliferation or metastasis of a cancer that expresses 15-PGDH.

[0042] Still other embodiments described herein relate to methods of treating a subject in need of cell therapy. The method includes administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells provided with a 15-PGDH inhibitor as described herein, and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor as described herein.

[0043] In some embodiments, the subject has been given human hematopoietic stem cells and / or has been given the above preparation and / or therapeutic composition.

[0044] In other embodiments, the subject has acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, severe aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH), pure red cell aplasia, amegakaryocytosis / congenital thrombocytopenia, severe combined immunodeficiency syndrome (SCID), Wiskott-Aldrich syndrome, severe β-thalassemia, sickle cell disease, Hurler syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia, familial erythrophagocytic lymphohistiocytosis, solid tumors, chronic granulomatous disease, mucopolysaccharidosis or Diamond-Blackfan anemia.

[0045] Another embodiment relates to a method of treating a subject having at least one symptom associated with ischemic tissue or tissue damaged by ischemia. The method comprises administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells provided with a 15-PGDH inhibitor as described herein, and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor as described herein.

[0046] In some embodiments, ischemia is acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes induced ischemia, disseminated intravascular coagulation (DIC), embolic brain ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterydisease), peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cysts, thrombosis, thrombotic brain ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vasculitic conditions, von Hippel-Lindau syndrome, and may be associated with at least one of trauma to a tissue or organ.

[0047] Other embodiments relate to methods for treating and / or preventing fibrosis and various fibrotic diseases, disorders or conditions by administration of a 15-PGDH inhibitor. In some embodiments, the 15-PGDH inhibitors described herein are administered to a subject in need thereof to reduce symptoms of fibrosis (such as collagen deposition, expression of inflammatory cytokines, and inflammatory cell infiltration), and to treat and / or prevent various fibrotic diseases, disorders or conditions characterized by overproduction of fibrous material (including overproduction of fibrous material in the extracellular matrix) or replacement of elements of normal tissue by abnormal, non-functional, and / or excessive accumulation of matrix-related components.

[0048] Fibrous diseases, disorders and conditions characterized by an overproduction of fibrous substances, either wholly or in part, include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea or linear scleroderma), sclerodermatous graft-vs-host-disease, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis of the kidney, progressive kidney disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fascilitis, eosinophilic fasciitis, a general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue to varying degrees, retroperitoneal fibrosis, hepatic fibrosis, cirrhosis, chronic renal insufficiency, myelofibrosis / bone marrow fibrosis, drug-induced ergotism, glioblastoma in Li-Fraumeni syndrome, solitary glioblastoma, myleoid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, collagenous colitis, acute fibrosis, organ-specific fibrosis, etc. may be included.

[0049] In some embodiments, a method of treating or preventing a fibrous disease, disorder or condition comprises administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof.

[0050] In some embodiments, the 15-PGDH inhibitor may be used to treat or prevent lung fibrosis. The lung fibrosis that can be treated may be selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, anthracosis, carbon pneumoconiosis, hypersensitivity pneumonitides, lung fibrosis caused by inhalation of inorganic dust, lung fibrosis caused by infectious pathogens, lung fibrosis caused by inhalation of harmful gases, aerosols, chemical dusts, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[0051] In other embodiments, the 15-PGDH inhibitor may be used to treat or prevent renal fibrosis. Renal fibrosis may be caused by dialysis after renal insufficiency, catheterization, nephrosis, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end-stage renal disease or renal failure, or combinations thereof.

[0052] In other embodiments, the 15-PGDH inhibitor may be used to treat or prevent liver fibrosis. Liver fibrosis may be caused by chronic liver disease, cirrhosis induced by virus, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-associated cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction, and exposure to toxins, or combinations thereof.

[0053] In some embodiments, the 15-PGDH inhibitor may be used to treat or prevent cardiac fibrosis (e.g., myocardial fibrosis and endomyocardial fibrosis).

[0054] In some embodiments, a 15-PGDH inhibitor may be used to treat or prevent systemic sclerosis.

[0055] In some embodiments, a 15-PGDH inhibitor may be used to treat or prevent a fibrotic disease, disorder or condition caused by postoperative adhesion formation.

[0056] In some embodiments, a 15-PGDH inhibitor may be used to reduce or prevent scar formation in a subject.

[0057] In other embodiments, a 15-PGDH inhibitor may be used to reduce or prevent scar formation or scleroderma in the skin.

[0058] In various embodiments, a 15-PGDH inhibitor may be administered in a therapeutically effective amount such that at least one symptom or feature of a fibrotic disease, disorder or condition, or another related disease, disorder or condition, is reduced in intensity, severity or frequency or its onset is delayed.

[0059] In other embodiments, the 15-PGDH inhibitor may be used in a method for reducing or decreasing collagen secretion or collagen deposition in a tissue or organ of a subject (such as the lung, liver, intestine, colon, skin or heart). The method may include administering a therapeutically effective amount of the 15-PGDH inhibitor to a subject in need thereof. The subject may have or be at risk of having excessive collagen secretion or collagen deposition in a tissue or organ (such as the kidney, lung, liver, intestine, colon, skin or heart). Typically, excessive collagen secretion or collagen deposition in an organ is due to an injury or insult. Such injuries and insults may be organ-specific. The 15-PGDH inhibitor may be administered for a period sufficient to completely or partially reduce or decrease the level of collagen deposition in the tissue or organ. The sufficient period may be one week, or one to one month, or one to two months, or two months or more. In the case of a chronic condition, the 15-PGDH inhibitor may be advantageously administered throughout life.

[0060] In other embodiments, the 15-PGDH inhibitors described herein can promote the neuroprotection of a subject from axonal degeneration, neuronal death and / or glial cell injury after injury, enhance the neuronal signaling underlying learning and memory, stimulate neuronal regeneration after injury, and / or treat nervous system diseases, disorders and / or conditions.

[0061] In some embodiments, the nervous system diseases, disorders and / or conditions that can be treated with a 15-PGDH inhibitor may include at least one of neurological disorders, psychoneurological disorders, neural injury, neural toxicity disorder, neuropathic pain and neural degenerative disorder.

[0062] For example, neurological disorders may include at least one of traumatic or toxic injury to the peripheral or cranial nerves, spinal cord, or to the brain, cranial nerves; traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury. Further, neurological disorders may include at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's, Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfieldt disease.

[0063] In some embodiments, nerve injury may be caused by or associated with at least one of epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic disorders, urinary bladder disorders, abnormal metabolic states, muscle disorders, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, nervous system diseases, sensory organ diseases, circulatory system diseases, respiratory system diseases, digestive system diseases, urogenital system diseases, skin and subcutaneous tissue diseases, musculoskeletal and connective tissue diseases, congenital anomalies, or conditions occurring during the perinatal period.

[0064] In certain embodiments, the 15-PGDH inhibitor may be administered to a subject or to the subject's neurons to promote the survival, growth, development, and / or function of neurons (particularly neurons of the CNS, brain, cerebrum, and hippocampus). In certain embodiments, the 15-PGDH inhibitor may be used to stimulate hippocampal neurogenesis for the treatment of neuropsychiatric and neurodegenerative diseases, including but not limited to schizophrenia, major depressive disorder, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neurostimulatory drugs (such as alcohol, opioids, methamphetamine, fencyclidine, and cocaine).

Mode for Carrying Out the Invention

[0065] Detailed Description For convenience, certain terms used in the specification, examples, and appended claims are collected here. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0066] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0067] The terms "comprise", "comprising", "include", "including", "have" and "having" are used in an inclusive and open sense and mean that additional elements may be included. The terms "such as" and "e.g." when used in this specification are non-limiting and are for illustrative purposes only. "Including" and "including but not limited to" are used in the same sense.

[0068] As used herein, the term "or" is to be understood to mean "and / or" unless the context clearly indicates otherwise.

[0069] As used herein, the terms "about" or "approximately" apply to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is within 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the terms "about" or "approximately" apply to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is within the range of ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1% of the reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0070] It will be noted that some of the structures of the compounds of this application contain asymmetric (chiral) carbon atoms or asymmetric (chiral) sulfur atoms. Thus, it should be understood that unless otherwise indicated, isomers resulting from such asymmetry are included in this application. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The compounds of this application may exist in stereoisomeric forms and thus may be produced as individual stereoisomers or as mixtures.

[0071] The term "isomer" means compounds having the same molecular formula but different in the nature or order of the bonds of their atoms or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are non-superimposable mirror images are called "enantiomers", or sometimes optical isomers. A carbon atom bonded to four non-identical substituents is called a "chiral center", but sulfur (e.g., sulfoxide or sulfinimide) bonded to three or four different substituents is also called a "chiral center".

[0072] The term "chiral isomer" means a compound having at least one chiral center. It has two enantiomeric forms of opposite chirality and can exist as individual enantiomers or as a mixture of enantiomers. A mixture containing equal amounts of the individual enantiomeric forms of opposite chirality is called a "racemic mixture". A compound having two or more chiral centers has 2n - 1 pairs of enantiomers, where n is the number of chiral centers. A compound having two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture". When there is one chiral center, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. Alternatively, when there is one or more chiral centers, the stereoisomers can be characterized as (+) or (-). The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn-Ingold-Prelog sequence rules (Cahn et al, Angew.Chem.Inter.Edit. 1966, 5, 385; errata 511; Cahn et al., Angew.Chem. 1966, 78, 413; Cahn and Ingold, J Chem.Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn,J., Chem.Educ. 1964, 41, 116).

[0073] The term "geometric isomer" means diastereomers whose existence is due to the rotational hindrance around a double bond. These configurations are distinguished by their names with the prefixes cis and trans or Z and E, which indicate whether the groups are on the same side or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. Further, all atropic isomers of the structures described in this application and other compounds are included.

[0074] The term "atropisomer" is a type of stereoisomer in which the atoms of two isomers are spatially differently arranged. Atropisomers result from restricted rotation due to rotation barriers around the central bond of large groups. Such atropisomers typically exist as mixtures, but as a result of recent advances in chromatography techniques, it has become possible to separate mixtures of two atropisomers in certain cases.

[0075] The term "crystalline polymorph" or "polymorph" or "crystalline form" means a crystal structure in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements having the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stabilities, and solubilities. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystal form may predominate. The crystalline polymorphs of a compound can be prepared by crystallizing under different conditions.

[0076] The term "derivative" refers to a compound having a common core structure and substituted with various groups as described herein.

[0077] The term "bioisostere" refers to a compound produced by exchanging an atom or group of atoms with another atom or group of atoms that is broadly similar. The purpose of a biologically equivalent exchange is to create a new compound having biological properties similar to the parent compound. Biologically equivalent exchanges can be based on physicochemistry or topology. Examples of bioisosteres of carboxylic acids include sulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996).

[0078] The terms "parenteral administration" and "administered parenterally" are terms recognized in the art and include modes of administration other than enteral administration and topical administration, such as by injection, and are not limited to, but include, intravenous injection and infusion, intramuscular injection and infusion, intrapleural injection and infusion, intravascular injection and infusion, intracardiac injection and infusion, intraarterial injection and infusion, intrathecal injection and infusion, intracapsular injection and infusion, intraorbital injection and infusion, intracardiac injection and infusion, intradermal injection and infusion, intraperitoneal injection and infusion, transtracheal injection and infusion, subcutaneous injection and infusion, subepidermal injection and infusion, intraarticular injection and infusion, subcapsular injection and infusion, subarachnoid injection and infusion, intraspinal injection and infusion, and intrasternal injection and infusion.

[0079] The term "treating" is recognized in the art and includes inhibiting a disease, disorder or condition in a subject (e.g., preventing its progression); and alleviating a disease, disorder or condition (e.g., causing regression of the disease, disorder and / or condition). Treating a disease or condition includes improving at least one symptom of a particular disease or condition even if the underlying pathophysiology is not affected.

[0080] The term "preventing" is recognized in the art and includes stopping a disease, disorder and / or condition from occurring in a subject who is at risk of developing the disease, disorder and / or condition but has not yet been diagnosed as having it. Preventing a condition associated with a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.

[0081] The term "pharmaceutical composition" refers to a formulation containing the disclosed compounds in a form suitable for administration to a subject. In preferred embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form can be in any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps of an aerosol inhaler, or vials. The amount of the active ingredient in a unit dose of the composition (e.g., the formulation of the disclosed compound or its salt) is an effective amount and will vary depending on the particular treatment involved. One of ordinary skill in the art will understand that it may be necessary to routinely vary the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, inhalation, etc. Dosage forms for topical or transdermal administration of the compounds described herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, spray compounds, and inhalants. In preferred embodiments, the active compound is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as required.

[0082] The term "flash dose" refers to a compound formulation that is in a dosage form that rapidly disperses.

[0083] The term "immediate release" is defined as the release of the compound from a dosage form over a relatively short period of time (generally up to about 60 minutes maximum). The term "modified release" is defined to include delayed release, extended release, and pulsed release. The term "pulsed release" is defined as the sequential release of a drug from a dosage form. The term "sustained release" or "extended release" is defined as the continuous release of a compound from a dosage form over an extended period of time.

[0084] The expression "pharmaceutically acceptable" is recognized in the art. In certain embodiments, this term includes compositions, polymers and other materials and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, while balancing a reasonable benefit / risk ratio and without undue toxicity, irritation, allergic response or other problems or complications.

[0085] The expression "pharmaceutically acceptable carrier" is recognized in the art and includes, for example, pharmaceutically acceptable materials, compositions or vehicles (such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials) involved in transporting or delivering any subject composition from one organ or part of the body to another. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the subject composition and not injurious to the patient. In certain embodiments, the pharmaceutically acceptable carrier is nonpyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0086] The compounds of the present application are further capable of forming salts. All of these forms are also contemplated in the present application.

[0087] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. For example, the salt may be an acid addition salt. One embodiment of the acid addition salt is a hydrochloride salt. Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two (generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred). A list of salts can be found in Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

[0088] The compounds described herein may also be prepared as esters (e.g., pharmaceutically acceptable esters). For example, the carboxylic acid functional group in the compound may be converted to its corresponding ester (e.g., methyl ester, ethyl ester, or other ester). Also, the alcohol group in the compound may be converted to its corresponding ester (e.g., acetate ester, propionate ester, or other ester).

[0089] The compounds described herein may also be prepared as prodrugs (e.g., pharmaceutically acceptable prodrugs). The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Prodrugs are known to improve many desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacture, etc.), and thus the compounds may be delivered in the form of prodrugs. Accordingly, the compounds described herein are intended to encompass prodrugs of the compounds claimed in this application, methods for delivering them, and compositions containing them. A "prodrug" is intended to include any covalently attached carrier that releases an active parent drug when such prodrug is administered to a subject. Prodrugs are prepared by modifying a functional group present in the compound such that the modification is cleaved either by conventional manipulation or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxy group, an amino group, a sulfhydryl group, a carboxy group, or a carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxyl group, a free amino group, a free sulfhydryl group, a free carboxy group, or a free carbonyl group, respectively. Prodrugs may also include precursors (precursors) of the compounds described herein that become an active pharmacological substance or a more active pharmacological substance or the active compounds described herein after undergoing chemical conversion by metabolic processes.

[0090] Examples of prodrugs include esters of hydroxy functional groups in a compound (e.g., acetic acid derivatives, dialkylaminoacetic acid derivatives, formic acid derivatives, phosphoric acid derivatives, sulfuric acid derivatives, and benzoic acid derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl); ester groups of carboxyl functional groups (e.g., ethyl ester, morpholinoethanol ester); N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases and enamino ketones of amino functional groups; oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups; and the like; as well as sulfides that are oxidized to form sulfoxides or sulfones, but are not limited thereto.

[0091] The term "protecting group" refers to an atomic group that, when bonded to a reactive group in a molecule, masks, reduces or prevents its reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, 2.sup.nd ed. 1991); Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8 (John Wiley and Sons, 1971-1996); and Kocienski, Protecting Groups, (Verlag, 3rd ed. 2003).

[0092] The term "amine protecting group" is intended to mean a functional group that converts an amine, amide, or other nitrogen-containing moiety into a different chemical group that is substantially inert to the conditions of a particular chemical reaction. An amine protecting group is preferably removed easily and selectively in good yield under conditions that do not affect other functional groups of the molecule. Examples of amine protecting groups include, but are not limited to, formyl, acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl (Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl (TMS), fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethyoxycarbonyl, 1-methyl-1-(4-biphenylyl)ethyoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfonyl (SES), trityl groups and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. One of ordinary skill in the art can identify other suitable amine protecting groups.

[0093] Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated (such as benzyl ethers and trityl ethers and alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers).

[0094] Furthermore, salts of the compounds described herein may exist in either the hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0095] The term "solvate" means a solvent addition form, including a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state and thus form solvates. If the solvent is water, the resulting solvate is a hydrate, and if the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as H2O, and such combinations can form one or more hydrates.

[0096] The compounds, salts and prodrugs described herein may exist in several tautomeric forms, including the enol and imine forms and the keto and enamine forms, as well as their geometric isomers and mixtures. Tautomers exist as a mixture of a set of tautomers in solution. In the solid form, usually one tautomer predominates. Even if one tautomer has been described, this application encompasses all tautomers of the compounds of the invention. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another. This reaction results in a formal transfer of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerization is referred to as tautomerism.

[0097] Of the various types of possible tautomerism, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of an electron and a hydrogen atom occurs.

[0098] Tautomerization can be catalyzed by: Base: 1. Deprotonation; 2. Formation of a delocalized anion (e.g., enolate); 3. Protonation at a different position of the anion; Acid: 1. Protonation; 2. Formation of delocalized cations; 3. Deprotonation at different positions adjacent to the cation.

[0099] The term "analogue" refers to a compound that is structurally similar to another but has a slightly different composition (such as replacement of one atom by an atom of a different element or the presence of a particular functional group or replacement of one functional group by another). Thus, an analogue is a compound that is similar or equivalent to a reference compound in terms of function and appearance but not in terms of structure or origin.

[0100] The "patient", "subject" or "host" to be treated by the subject method can mean a human or non-human animal, such as a mammal, fish, bird, reptile or amphibian. Thus, the subjects of the methods disclosed herein can be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cows, cats, guinea pigs or rodents. This term does not denote a particular age or sex. Thus, both male and female, adults and neonates as well as fetuses are intended to be included. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder.

[0101] The terms "preventive" treatment or "therapeutic" treatment are recognized in the art and include administering one or more of the subject compositions to a host. If it is administered before an undesirable condition (e.g., a disease or other undesirable situation in the host animal) clinically appears, the treatment is preventive, i.e., it protects the host from the onset of the undesirable condition. On the other hand, if it is administered after the appearance of an undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, improve or stabilize an existing undesirable condition or its side effects).

[0102] The terms "therapeutic agent", "drug", "medicine" and "bioactive substance" are recognized in the art and include molecules and other agents that are biologically, physiologically or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition. These terms include, but are not limited to, their pharmaceutically acceptable salts and prodrugs. Such agents may be acidic, basic or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides, etc. that are biologically activated when administered to a patient or subject.

[0103] The expressions "therapeutically effective amount" or "pharmaceutically effective amount" are terms recognized in the art. In certain embodiments, the term refers to the amount of a therapeutic agent that produces some desirable effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to the amount necessary or sufficient to eliminate, reduce or maintain the target of a particular treatment regimen. The effective amount can vary depending on factors such as the disease or condition being treated, the particular targeting construct being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation. In certain embodiments, the therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on several factors including the rate of release of the agent from the polymeric matrix (which will likely depend in part on the chemical and physical properties of the polymer); the identity of the agent; the mode and method of administration; and any other materials incorporated into the polymeric matrix in addition to the agent.

[0104] The term "ED50" is recognized in the art. In certain embodiments, ED50 means the dose of a drug that produces 50% of its maximal response or effect, or the dose that produces a given response in 50% of the test subjects or preparations. The term "LD50" is recognized in the art. In certain embodiments, LD50 means the amount of a drug that is lethal in 50% of the test subjects. The term "therapeutic index" is recognized in the art and refers to the therapeutic index of a drug, which is defined as LD50 / ED50.

[0105] The term "IC 50 " or "half maximal inhibitory concentration" is intended to refer to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process, or a component of a process (including proteins, subunits, organelles, ribonucleoproteins, etc.), by 50%.

[0106] For any compound, this application is intended to encompass all isotopes of atoms that occur in the compounds of the invention. Isotopes include atoms having the same atomic number but different mass numbers. General examples, but not limited to, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0107] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such a substituent may be attached to any atom in the ring. When a substituent is listed without indicating the atom through which such a substituent is attached to the remainder of a compound of a given formula, such a substituent may be attached through any atom in such a substituent. Combinations of substituents and / or variables are permitted, provided that such combinations result in stable compounds.

[0108] When a range of subscript numbers follows an atom or chemical moiety (e.g., C 1~6) It is intended to encompass each number within that range as well as all intermediate ranges. For example, "C 1~6 alkyl" is intended to encompass alkyl groups having 1, 2, 3, 4, 5, 6, 1 - 6, 1 - 5, 1 - 4, 1 - 3, 1 - 2, 2 - 6, 2 - 5, 2 - 4, 2 - 3, 3 - 6, 3 - 5, 3 - 4, 4 - 6, 4 - 5, and 5 - 6 carbon atoms.

[0109] The term "alkyl" is intended to encompass both branched (e.g., isopropyl, tert - butyl, isobutyl) and straight - chain (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl) ones, as well as cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), cycloalkyl groups substituted with alkyl, and alkyl groups substituted with cycloalkyl. Such aliphatic hydrocarbon groups have the specified number of carbon atoms. For example, C 1~6 alkyl is intended to encompass C1 alkyl group, C2 alkyl group, C3 alkyl group, C4 alkyl group, C5 alkyl group, and C6 alkyl group. As used herein, "lower alkyl" refers to an alkyl group having 1 - 6 carbon atoms in the carbon - chain backbone. "Alkyl" further encompasses alkyl groups having an oxygen atom, a nitrogen atom, a sulfur atom, or a phosphorus atom replaced for one or more carbon atoms of the hydrocarbon backbone. In certain embodiments, a straight - chain alkyl or a branched - chain alkyl has 6 or fewer (e.g., 4 or fewer) carbon atoms in its backbone (e.g., C 1~ C6 for straight - chain and C 3~ C6 for branched - chain). Similarly, certain cycloalkyls have 3 - 8 carbon atoms (e.g., 5 or 6 carbon atoms in the ring structure, etc.) in their ring structures.

[0110] The term "alkyl that is substituted" refers to an alkyl moiety having a substituent that has replaced hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety may be included. Cycloalkyl may be further substituted with, for example, the substituents described above. An "alkylaryl" or "aralkyl" moiety is an alkyl that is substituted with aryl (e.g., phenylmethyl (benzyl)). Unless otherwise indicated, the terms "alkyl" and "lower alkyl" each include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0111] The term "alkenyl" refers to a linear, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosanyl, tetracosanyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, etc. Although not necessarily, generally, an alkenyl group may contain 2 to about 18 carbon atoms, and more specifically may contain 2 to 12 carbon atoms. The term "lower alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" is intended to mean a cyclic alkenyl group preferably having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to an alkenyl substituted with one or more substituents, and the terms "alkenyl containing a heteroatom" and "heteroalkenyl" refer to an alkenyl or heterocycloalkenyl (e.g., heterocyclohexenyl) in which at least one carbon atom is replaced by a heteroatom. Unless otherwise indicated, the terms "alkenyl" and "lower alkenyl" each include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl.

[0112] The term "alkynyl" refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, etc. Although not necessarily, generally, an alkynyl group may contain 2 to about 18 carbon atoms, and more specifically may contain 2 to 12 carbon atoms. The term "lower alkynyl" is intended to mean an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to an alkynyl substituted with one or more substituents, and the terms "alkynyl containing a heteroatom" and "heteroalkynyl" refer to an alkynyl in which at least one carbon atom is replaced by a heteroatom. Unless otherwise indicated, the terms "alkynyl" and "lower alkynyl" each include linear, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl.

[0113] The terms "alkyl", "alkenyl", and "alkynyl" are intended to include moieties that are diradicals (i.e., have two points of attachment). Non-limiting examples of such an alkyl moiety that is a diradical are -CH2CH2- (i.e., a C2 alkyl group covalently bonded to the remainder of the molecule through each terminal carbon atom).

[0114] The term "alkoxy" refers to an alkyl group bonded through a single terminal ether bond. That is, an "alkoxy" group can be represented as -O-alkyl (where alkyl is as defined above). A "lower alkoxy" group is intended to be an alkoxy group containing from 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, and the like. Preferably, substituents specified herein as "C1-C6 alkoxy" or "lower alkoxy" contain from 1 to 3 carbon atoms, and particularly preferably, such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0115] The term "aryl" refers to an aromatic substituent that includes a single aromatic ring, or multiple aromatic rings that are fused, directly linked, or indirectly linked (such that different aromatic rings are linked to a common group such as a methylene or ethylene moiety). An aryl group may contain 5 to 20 carbon atoms, and particularly preferred aryl groups may contain 5 to 14 carbon atoms. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine. Further, the term "aryl" encompasses polycyclic aryl groups (e.g., tricyclic, bicyclic; e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine). An aryl group having a heteroatom in its ring structure may also be referred to as an "aryl heterocycle", "heterocycle", "heteroaryl", or "heteroaromatic".The aromatic ring may be substituted at one or more ring positions with substituents as described above (e.g., halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety). The aryl group may also be fused or bridged to an alicyclic or heterocyclic ring that is not aromatic so as to form a polycyclic system (e.g., tetralin, methylenedioxyphenyl). Unless otherwise indicated, the term "aryl" encompasses aromatic substituents that are unsubstituted, substituted, and / or contain heteroatoms.

[0116] The term "alkaryl" refers to an aryl group having an alkyl substituent, and the term "aralkyl" refers to an alkyl group having an aryl substituent, where "aryl" and "alkyl" are as defined above. Exemplary aralkyl groups contain from 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain from 6 to 16 carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenyl-cyclohexyl, 4-benzyl-cyclohexyl, 4-phenyl-cyclohexylmethyl, 4-benzyl-cyclohexylmethyl, and the like. Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like.

[0117] The term "heterocyclyl" or "heterocyclic group" encompasses a closed ring structure (e.g., a 3- to 10-membered ring or a 4- to 7-membered ring) containing one or more heteroatoms. "Heteroatoms" encompass atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.

[0118] The heterocyclic group may be saturated or unsaturated and may include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactone, lactam (such as azetidinone and pyrrolidinone), sultam and sultone. Heterocyclic groups such as pyrrole and furan may have aromaticity. Heterocyclic groups such as quinoline and isoquinoline contain a fused ring structure. Other examples of heterocyclic groups include pyridine and purine. The heterocycle may be substituted at one or more positions with substituents as described above (e.g., halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, or an aromatic or heteroaromatic moiety). The heterocyclic group may also be substituted at one or more of its constituent atoms with, for example, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxyl, -CF3, or -CN, etc.

[0119] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "Counterion" is used to represent a small, negatively charged chemical species such as fluoride, chloride, bromide, iodide, hydroxide, acetate, and sulfate. The term sulfoxide refers to sulfur bonded to two different carbon atoms and one oxygen, and the S - O bond may be depicted as a double bond (S=O), a single bond without charge (S - O), or a charged single bond [S(+) - O(-)].

[0120] The term "substituted", as in "substituted alkyl", "substituted aryl", etc., is intended to mean that at least one hydrogen atom bonded to a carbon (or other) atom in the alkyl, aryl or other moiety has been replaced with one or more substituents other than hydrogen, as referred to in part in the foregoing definition. Examples of such substituents include, but are not limited to, halo, hydroxyl, silyl, sulfhydryl, C1-C 24 alkoxy, C2-C 24 alkenyloxy, C2-C 24 alkynyloxy, C5-C 20 aryloxy, acyl (C2-C 24 alkylcarbonyl (-CO-alkyl) and C6-C 20 arylcarbonyl (-CO-aryl) (including), acyloxy (-O-acyl), C2-C 24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C 20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH2), mono-(C1-C 24 alkyl)-substituted carbamoyl (-(CO)-NH(C1-C 24 alkyl)), di-(C1-C4 alkyl)-substituted carbamoyl (-(CO)-N(C1-C 24 alkyl)2), mono-substituted arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamide (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanato (-O-CN), isocyanato (-ON + C - ), isothiocyanato (-S-CN), azido (-N=N + =N- ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2), mono-(C1-C 24 alkyl)-substituted amino and di-(C1-C 24 alkyl)-substituted amino, mono-(C5-C 20 aryl)-substituted amino and di-(C5-C 20 aryl)-substituted amino, C2-C 24 alkylamide (-NH-(CO)-alkyl), C6-C 20 arylamide (-NH-(CO)-aryl), imino (-CR=NH; where R = hydrogen, C1-C 24 alkyl, C5-C 20 aryl, C6-C 24 alkaryl, C6-C 24 aralkyl, etc.), alkylimino (-CR=N(alkyl); where R = hydrogen, alkyl, aryl, alkaryl, etc.), arylimino (-CR=N(aryl); where R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O - ), C1-C 24 alkylsulfanyl (-S-alkyl; also called "alkylthio"), arylsulfanyl (-S-aryl; also called "arylthio"), C1-C 24 alkylsulfinyl (-(SO)-alkyl), C5-C 20 arylsulfinyl (-(SO)-aryl), C1-C 24 alkylsulfonyl (-SO2-alkyl), C5-C 20 arylsulfonyl (-SO2-aryl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O - )2), phosphinato (-P(O)(O - )), phospho (-PO2), and phosphino (-PH2) and other functional groups; and hydrocarbyl moieties C1-C 24 alkyl, C2-C 24 alkenyl, C2-C 24 alkynyl, C5-C 20 aryl, C6-C 24Alkaryl and C6-C 24 Examples include aralkyl.

[0121] Furthermore, the aforementioned functional groups may be further substituted with one or more additional substituents or one or more hydrocarbyl moieties (such as those specifically listed above), provided that such substitution is permitted by the particular group. Similarly, the aforementioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties (such as those specifically listed above).

[0122] When the term "substituted" appears before a list of groups that may be substituted, it is intended that this term apply to all members of that group. For example, the expression "substituted alkyl, alkenyl, and aryl" should be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl". Similarly, when the term "containing a heteroatom" appears before a list of groups that may contain a heteroatom, it is intended that this term apply to all members of that group. For example, the expression "alkyl, alkenyl, and aryl containing a heteroatom" should be interpreted as "alkyl containing a heteroatom, substituted alkenyl, and substituted aryl".

[0123] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and thus this description encompasses both the case where the circumstance occurs and the case where the circumstance does not occur. For example, the expression "optionally substituted" means that a substituent other than hydrogen may or may not be present on a given atom, and thus this description encompasses both structures in which a substituent other than hydrogen is present and structures in which no substituent other than hydrogen is present.

[0124] The terms "stable compound" and "stable structure" are intended to denote compounds that are sufficiently robust to withstand isolation, and optionally purification from reaction mixtures and formulation into effective therapeutic agents.

[0125] The term "free compound" is used herein to describe a compound that is not bound.

[0126] Throughout the description, when a composition is described as having, including or comprising a particular component, it is contemplated that the composition may also consist essentially of, or consist of, the recited components. Similarly, when a method or process is described as having, including or comprising a particular process step, the process may also consist essentially of, or consist of, the recited process steps. Further, it should be understood that the order of steps or the order for performing certain actions is not critical so long as the compositions and methods described herein remain practicable. Further, two or more steps or actions may be performed simultaneously.

[0127] The term "small molecule" is a term recognized in the art. In certain embodiments, the term refers to a molecule having a molecular weight of less than about 2000 amu, or less than about 1000 amu, or even less than about 500 amu.

[0128] All percentages and ratios used herein are by weight unless otherwise indicated.

[0129] The term "neoplasm" refers to any abnormal tumor of cells or tissue as a result of neoplasia. Neoplasms can be benign, potentially malignant (precancerous), or malignant (cancerous). An adenoma is an example of a neoplasm.

[0130] The terms "adenoma", "colonic adenoma" and "polyp" are used herein to describe any precancerous neoplasm of the colon.

[0131] As used herein, the term "colon" is intended to include the right colon (including the cecum), transverse colon, left colon, and rectum.

[0132] As used herein, the terms "colorectal cancer" and "colon cancer" are used interchangeably and refer to any cancerous neoplasia of the colon (including the rectum as defined above).

[0133] As used herein, the term "gene expression" or "protein expression" includes any information regarding the amount of gene transcript or protein present in a sample, as well as information regarding the rate at which the gene or protein is produced, accumulated, or degraded (e.g., data from a reporter gene, data from a nuclear runoff experiment, pulse chase data, etc.). Certain types of data may be considered relevant to the expression of both genes and proteins. For example, the protein level within a cell reflects both the level of the protein and the level of transcription, and such data is intended to be encompassed by the expression "gene or protein expression information". Such information may be provided in terms of the amount per cell, the amount relative to a control gene or protein, or on a scale without units. The term "information" is not intended to be limited to any particular means of presentation and is meant to include any presentation that provides relevant information. The term "expression level" refers to the amount reflected in gene or protein expression data or an amount derivable from gene or protein expression data, regardless of whether the data is directed to the accumulation of gene transcripts, the accumulation of proteins, the rate of protein synthesis, etc.

[0134] As used herein, the terms "healthy" and "normal" are used interchangeably and apply to a subject, or to a particular cell or tissue, that is (at least to the limit of detection) free of a disease state.

[0135] The term "nucleic acid" refers to polynucleotides such as deoxyribonucleic acid (DNA) and, where appropriate, ribonucleic acid (RNA). This term also encompasses any analogs of RNA or DNA made from nucleotide analogs, as well as single-stranded (such as sense or antisense) and double-stranded polynucleotides where applicable to the described embodiments. In some embodiments, "nucleic acid" refers to inhibitory nucleic acid. Some categories of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such categories of nucleic acids are well known in the art.

[0136] The embodiments described herein relate to compounds and methods for modulating the activity of SCD (e.g., the activity of 15-PGDH), modulating the levels of tissue prostaglandins, and / or treating diseases, disorders or conditions where it is desirable to modulate the activity of 15-PGDH and / or the levels of prostaglandins.

[0137] The terms "inhibitor", "activator", and "modulator" of 15-PGDH expression or 15-PGDH activity are used to refer to an inhibitory molecule, an activating molecule, or a regulatory molecule (e.g., a ligand, agonist, antagonist, and homologs and mimics thereof) identified using an in vitro or in vivo assay for 15-PGDH expression or 15-PGDH activity, respectively. The term "modulator" encompasses inhibitors and activators. An inhibitor is an agent (e.g., an antagonist) that, for example, inhibits 15-PGDH expression or binds and partially or completely blocks stimulation, reduces, prevents, delays, inactivates, desensitizes, or down-regulates 15-PGDH activity. An activator is an agent (e.g., an agonist) that, for example, induces or activates 15-PGDH expression or binds and stimulates, stabilizes, increases, releases, activates, promotes, or enhances activation, sensitizes, up-regulates 15-PGDH activity. Modulators include naturally occurring and synthetic ligands, small chemical molecules, and the like.

[0138] The 15-PGDH inhibitors described herein may provide a pharmacological method for increasing the level of prostaglandins in tissues. Known activities of prostaglandins include promoting hair growth, promoting skin pigmentation, and promoting skin darkening or the appearance of a sunburn. Also included in the known activities of prostaglandins is the improvement of pulmonary arterial hypertension. The 15-PGDH inhibitors described herein may also be used for the purpose of increasing the number of tissue stem cells, including increasing resistance to tissue damage by radiation, increasing resistance to environmental exposure to radiation, increasing the number of stem cells (by exposing the 15-PGDH inhibitors described herein in vivo to increase the number of stem cells prior to harvesting of the transplanted tissue, or by ex vivo exposure of the harvested tissue prior to transplantation into the recipient host, or by treatment of the transplant recipient) to enhance the compatibility of bone marrow or other types of transplantation. The 15-PGDH inhibitors described herein may also be used for the purpose of promoting liver regeneration, including liver regeneration after hepatectomy and liver regeneration after toxic injury (which may be the toxic injury of acetaminophen overdose). Prostaglandin signaling is also known to promote wound healing, protect the stomach from ulcer formation, and promote the healing of gastric and intestinal ulcers. Furthermore, the 15-PGDH inhibitors described herein may promote the activity of human keratinocytes in the "healing" of scratches across cultures of keratinocyte cells. Thus, the 15-PGDH inhibitors described herein may also be used to heal ulcers (including but not limited to diabetic ulcers) in other tissues (including but not limited to the skin). Additionally, the 15-PGDH inhibitors described herein may be used for the treatment of erectile dysfunction.

[0139] The 15-PGDH inhibitors described herein can be identified using an assay that determines the functional effect on 15-PGDH activity after applying a compound that is presumed to be a modulator to cells expressing 15-PGDH. Samples or assays containing 15-PGDH that are treated with a prospective activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the degree of effect. A (non-modulator-treated) control sample is assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the value of 15-PGDH activity relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.

[0140] An agent tested as a modulator of SCD (e.g., 15-PGDH) can be any small chemical molecule or compound. Typically, the test compound will be a small chemical molecule, natural product, or peptide. The assay is designed to screen large compound libraries by automating the steps of the assay and providing compounds from any convenient source to the assay, typically in a microtiter format on a microtiter plate (e.g., in a robotic assay). Also included as modulators are agents designed to increase the level of 15-PGDH mRNA or the level of translation from the mRNA.

[0141] In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to a subject's tissue or blood in an amount effective to inhibit the activity of the short-chain dehydrogenase enzyme. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to a subject's tissue or blood in an amount effective to increase the level of prostaglandins in the tissue or blood. The 15-PGDH inhibitor includes a compound having the formula (I) or (II):

Chemical formula

[0142] In one embodiment, R 2 or R 3 at least one of which is not H, and R 9 or R 10 at least one of which is not H.

[0143] In some embodiments, the 15-PGDH inhibitors include the following formula (Ia):

Chemical formula

[0144] In other embodiments, the 15-PGDH inhibitors include the following formula (Ib):

Chemical formula

[0145] In other embodiments, the 15-PGDH inhibitor includes the following formula (Ic):

Chemical formula

[0146] In yet another embodiment, the 15-PGDH inhibitor includes the following formula (Id):

Chemical formula

[0147] In yet another embodiment, the 15-PGDH inhibitors include the following formula (Ie): [Chemical formula] A compound having, wherein, X2 is S, S=O, S(=O)2 or C=O; R 1 and R 2 are the same or different and independently are hydrogen, substituted or unsubstituted C1-C 24 alkyl, C2-C 24 alkenyl, C2-C 24 alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5-7 ring atoms (where 1-3 of the ring atoms are independently selected from N, NH, N(C1-C6 alkyl), NC(O)(C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (where 1-6 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C 24 alkaryl, C6-C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C 24 alkoxy, C2-C 24 alkenyloxy, C2-C 24 alkynyloxy, C5-C 20 aryloxy, acyl (C2-C 24 alkylcarbonyl (-CO-alkyl) and C6-C 20 arylcarbonyl (-CO-aryl) are included), acyloxy (-O-acyl), C2-C 24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C 20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO - ), carbamoyl (-(CO)-NH2), C1-C 24 alkyl-carbamoyl (-(CO)-NH(C1-C 24alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), urea (-(NH-(CO)-NH2)), cyano (-(CN)), isocyano (-(N + C - ), cyanato (-(O-CN)), isocyanato (-(O-N + =C - ), isothiocyanato (-(S-CN)), azido (-(N=N + =N - ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-(NH2)), C1-C 24 alkylamino, C5-C 20 arylamino, C2-C 24 alkylamide (-(NH(CO)-alkyl)), C6-C 20 arylamide (-(NH(CO)-aryl)), sulfanilamide (-(SO2N(R)2; where R is independently H, alkyl, aryl or heteroaryl)), imino (-(CR=NH; where R is hydrogen, C1-C 24 alkyl, C5-C 20 aryl, C6-C 24 alkaryl, C6-C 24 aralkyl, etc.), alkylimino (-(CR=N(alkyl); where R = hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.)), arylimino (-(CR=N(aryl); where R = hydrogen, alkyl, aryl, alkaryl, etc.)), nitro (-(NO2)), nitroso (-(NO)), sulfo (-(SO2-OH)), sulfonato (-(SO2-O - ), C1-C 24 alkylsulfanyl (-(S-alkyl; also called "alkylthio")), arylsulfanyl (-(S-aryl; also called "arylthio")), C1-C 24 alkylsulfinyl (-(SO)-alkyl), C5-C 20 arylsulfinyl (-(SO)-aryl), C1-C 24 alkylsulfonyl (-(SO2-alkyl)), C5-C 20Aryl sulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 where Y is independently H, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O - )2), phosphinato (-P(O)(O - ))), phospho (-PO2), phosphino (-PH2), polyalkyl ether (-[(CH2) n O] m ), phosphate, phosphate ester [-OP(O)(OR)2; where R = H, methyl or other alkyl]; an amino acid or other moiety expected to carry a positive or negative charge at physiological pH, incorporated groups; combinations thereof, selected from the group consisting of, R 2 or R 3 at least one of which is not H, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0148] Examples of 15-PGDH inhibitors having formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) include the following compounds:

Chemical formula

[0149] In other embodiments, the 15-PGDH inhibitor includes the following formula (IIa):

Chemical formula

[0150] In yet another embodiment, the 15-PGDH inhibitors include the following formula (IIb):

Chemical formula

[0151] In some embodiments, the 15-PGDH inhibitor includes the following formula (IIc):

Chemical formula

[0152] In other embodiments, the 15-PGDH inhibitors include the following formula (IId):

Chemical formula

[0153] In yet another embodiment, the 15-PGDH inhibitors include the following formula (IIe):

Chemical formula

[0154] In yet another embodiment, 15-PGDH inhibitors include the following formula (IIf):

Chemical formula

[0155] Examples of 15-PGDH inhibitors having formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) include the following compounds:

Chemical formula

[0156] In certain embodiments, (ia) at a concentration of 2.5 μM, the Vaco503 reporter cell line expressing the 15-PGDH luciferase fusion construct can be stimulated to a luciferase output level higher than 70 (using a scale where a value of 100 indicates a two-fold increase in reporter output relative to the baseline); (iia) at a concentration of 2.5 μM, the V9m reporter cell line expressing the 15-PGDH luciferase fusion construct can be stimulated to a luciferase output level higher than 75; (iiia) at a concentration of 7.5 μM, the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct can be stimulated to a luciferase output level higher than 70; and (iva) at a concentration of 7.5 μM, the negative control V9m cell line expressing the TK-jellyfish luciferase reporter is not activated to a level higher than 20; and (va) an IC less than 1 μM 50An inhibitor of 15-PGDH having the formula (I) and (II) may be selected that inhibits the enzymatic activity of recombinant 15-PGDH protein.

[0157] In other embodiments, the 15-PGDH inhibitor can increase the luciferase output by stimulating the Vaco503 reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of (ib) 2.5 μM; (iib) can increase the luciferase output by stimulating the V9m reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of 2.5 μM; (iiib) can increase the luciferase output by stimulating the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of 7.5 μM; (ivb) does not activate the negative control V9m cell line expressing the TK-jellyfish luciferase reporter to a luciferase level 20% higher than the background at a concentration of 7.5 μM; and (vb) IC less than 1 μM 50 inhibits the enzymatic activity of recombinant 15-PGDH protein.

[0158] In other embodiments, the 15-PGDH inhibitor has an IC of less than 1 μM, or preferably less than 250 nM, or more preferably less than 50 nM, or more preferably less than 10 nM, or more preferably less than 5 nM at a concentration of recombinant 15-PGDH of about 5 nM to about 10 nM 50 or preferably IC less than 250 nM 50 or more preferably IC less than 50 nM 50 or more preferably IC less than 10 nM 50 or more preferably IC less than 5 nM 50 and can inhibit the enzymatic activity of recombinant 15-PGDH.

[0159] In other embodiments, the 15-PGDH inhibitor can increase the cellular level of PGE-2 after stimulating A459 cells with a suitable agent (e.g., IL1-β).

[0160] The 15-PGDH inhibitors described herein may be used for the prevention or treatment of diseases associated with 15-PGDH and / or reduced prostaglandin levels and / or for which it is desirable to increase prostaglandin levels in a subject. For example, as described above, prostaglandins are known to play an important role in hair growth. Specifically, it has been shown that the intracellular stores of various types (A2, F 2a , E2) of prostaglandins in the various compartments of the hair follicle or in the skin environment adjacent thereto are essential for the maintenance and increase of hair density (Colombe L et. al, 2007, Exp.Dermatol, 16(9), 762-9). 15-PGDH, which is involved in the degradation of prostaglandins, is present in the dermal papilla of the hair follicle and has been reported to inactivate prostaglandins (especially PGF 2a and PGE2) and cause scalp damage and alopecia (Michelet J F et. al., 2008, Exp.Dermatol, 17(10), 821-8). Thus, the compounds described herein having inhibitory or inhibitory activity against 15-PGDH, which degrades prostaglandins, can improve scalp damage, prevent alopecia, and promote hair growth, and may be used in pharmaceutical compositions for the prevention of alopecia and the promotion of hair growth.

[0161] In other embodiments, the 15-PGDH inhibitors described herein are pharmaceutical compositions for promoting and / or inducing and / or stimulating pigmentation of the skin and / or skin appendages and / or as agents for preventing and / or limiting depigmentation and / or whitening of the skin and / or skin appendages (especially as agents for preventing and / or limiting gray hair) and may be used.

[0162] In some embodiments, the 15-PGDH inhibitor may be applied to the skin of a subject (e.g., by topical application) to promote and / or stimulate skin pigmentation and / or hair growth, to inhibit hair loss, and / or to treat skin damage or inflammation (such as skin damage caused by physical or chemical irritants and / or UV exposure).

[0163] In yet other embodiments, the 15-PGDH inhibitors described herein may be used in pharmaceutical compositions for the prevention or treatment of cardiovascular diseases and / or diseases of vascular insufficiency (such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary hypertension). Prostaglandins, including prostaglandin homologs produced in the body, are known to maintain proper functioning of the vascular wall, and in particular, are known to contribute to vasodilation for blood flow, prevention of platelet aggregation, and regulation of the growth of smooth muscle surrounding the vascular wall (Yan. Cheng et. al., 2006, J.Clin.,Invest). Furthermore, inhibition of prostaglandin production or loss of its activity causes endothelial degeneration in the vascular wall, platelet aggregation, and dysfunction of cellular mechanisms in smooth muscle. In particular, it has been shown that prostaglandin production in blood vessels is decreased in patients with hypertension, including pulmonary hypertension.

[0164] In other embodiments, the 15-PGDH inhibitors described herein may be used in pharmaceutical compositions for preventing or treating damage, diseases or inflammation of the oral cavity, intestinal tract and / or gastrointestinal tract, or inflammatory bowel diseases (such as oral ulcers, gum diseases, gastritis, colitis, ulcerative colitis and gastric ulcers). Gastritis and gastric ulcers, which are representative of gastrointestinal diseases, are defined as states in which the mucosa of the gastrointestinal tract is digested by gastric acid to form ulcers. Generally, in the gastric wall consisting of mucosa, submucosa, muscular layer and serosa, gastric ulcers damage even the submucosa and muscular layer, while gastritis only damages the mucosa. The morbidity rates of gastritis and gastric ulcers are relatively high, but their causes have not yet been clarified. So far, they are known to be caused by an imbalance between attack factors and defense factors, that is, an increase in attack factors (such as an increase in gastric acid or pepsin secretion) or a decrease in defense factors (such as structural or morphological defects of the gastric mucosa, a decrease in the secretion of mucus and bicarbonate ions, a decrease in prostaglandin production, etc.).

[0165] Currently available therapeutic agents for gastritis and gastric ulcers include various drugs for strengthening defense factors (such as antacids that neutralize already produced gastric acid without affecting gastric acid secretion, inhibitors of gastric acid secretion, promoters of prostaglandin secretion, and coating agents for the gastric wall, etc.). In particular, prostaglandins are known to be essential for maintaining the mechanisms for protecting and defending the gastric mucosa (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65; S.J.Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). Considering the above, the 15-PGDH inhibitors described herein may be effective in preventing or treating gastrointestinal diseases (especially gastritis and gastric ulcers) because they exhibit inhibitory activity or inhibitory effect against 15-PGDH that degrades prostaglandins that protect the gastric mucosa.

[0166] Furthermore, 15-PGDH inhibitors would also be expected to provide protection from other forms of intestinal injury, which would likely include radiation toxicity, chemotherapy toxicity, and chemotherapy-induced mucositis.

[0167] In the kidney, prostaglandins may help regulate renal blood flow and play a role in regulating urine formation through both renal vascular and tubular effects. In clinical studies, PGE1 has been used to improve creatinine clearance in patients with chronic kidney disease, prevent graft rejection and cyclosporine toxicity in kidney transplant patients, and reduce urinary albumin excretion rate and N-acetyl-β-D-glucosaminidase levels in patients with diabetic nephropathy (see Porter, Am., 1989, J.Cardiol., 64: 22E-26E). Additionally, U.S. Patent No. 5,807,895 discloses methods for preventing renal dysfunction by intravenous administration of prostaglandins such as PGE1, PGE2, and PGI2. Furthermore, it has been reported that prostaglandins act as vasodilators in the kidney, and thus inhibition of prostaglandin production in the kidney results in renal dysfunction (Hao.C M, 2008, Annu Rev Physiol, 70, 357.about.77).

[0168] Accordingly, the 15-PGDH inhibitors described herein having inhibitory activity against 15-PGDH, which degrades prostaglandins, may be effective in preventing or treating kidney diseases associated with renal dysfunction.

[0169] As used herein, the term "renal dysfunction" encompasses the following signs: lower than normal creatinine clearance; lower than normal free water clearance; higher than normal blood levels of urea, nitrogen, potassium, and / or creatinine; changes in the activity of renal enzymes such as gamma glutamyl synthetase, alanine phosphatidase, N-acetyl-β-D-glucosaminidase, or β-ω-microglobulin; and an increase above normal levels of macroalbuminuria.

[0170] PGE1, PGE2 and PGF 2a Prostaglandins, including those, have also been shown to stimulate bone resorption and bone formation to increase bone volume and strength (H. Kawaguchi et. al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Considering that 15-PGDH inhibits prostaglandin activity as described above, inhibition of 15-PGDH activity may result in promotion of bone resorption and bone formation inhibited by 15-PGDH. Thus, the 15-PGDH inhibitors described herein may be effective in promoting bone resorption and bone formation by inhibiting 15-PGDH activity. 15-PGDH inhibitors may also be used to increase bone density, to treat osteoporosis, to promote fracture healing, or to promote healing after bone surgery or joint replacement, or to promote healing of implants from bone to bone, implants from bone to prosthesis, dental implants and bone grafts.

[0171] In yet other embodiments, the 15-PGDH inhibitors described herein may be effective in treating cancers that express 15-PGDH. Inhibition of 15-PGDH may inhibit the growth, proliferation and metastasis of cancers that express 15-PGDH.

[0172] In yet other embodiments, the 15-PGDH inhibitors described herein may be effective in wound healing. Among various prostaglandins, PGE2 is known to act as a mediator for wound healing. Thus, when the skin is damaged by a wound or a burn, inhibition of 15-PGDH activity may result in a therapeutic effect of the wound or burn by PGE2.

[0173] Furthermore, as described above, an increase in the level of prostaglandins has been shown to stimulate signal transduction through the Wnt signaling pathway via an increase in β-catenin-mediated transcriptional activity. Wnt signaling is known to be an important pathway utilized by tissue stem cells. Thus, the 15-PGDH inhibitors described herein may be utilized to increase the number of tissue stem cells for purposes that would include promoting tissue regeneration or repair in organs that would include the liver, colon, and bone marrow. Furthermore, the 15-PGDH inhibitors described herein may be utilized to promote tissue regeneration or repair in additional organs including, but not limited to, the brain, eye, cornea, retina, lung, heart, stomach, small intestine, pancreas, pancreatic β-cells, kidney, bone, cartilage, and peripheral nerves.

[0174] Syndromic conditions, traumas, chronic conditions, medical interventions or other conditions that cause or are associated with tissue damage and the need for tissue repair and, thus, are suitable for treatment or amelioration using the methods described herein include, but are not limited to, acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, atherosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burns, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes mellitus, diabetic neuropathy, ischemia induced by diabetes, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vasculitic conditions, von Hippel-Lindau syndrome, and trauma to tissue or organ.

[0175] Other exemplary examples of genetic disorders, symptomatic conditions, traumas, chronic conditions, medical interventions or other conditions that cause or are associated with tissue damage and the need for tissue repair suitable for treatment or improvement using the methods of the present invention include ischemia resulting from surgery, chemotherapy, radiotherapy, or transplantation or grafting of cells, tissues or organs.

[0176] In various embodiments, the methods of the present invention are suitable for treating cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

[0177] In some embodiments, ischemia is associated with at least one of acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, atherosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burns, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, ischemia induced by diabetes, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vasculitis, von Hippel-Lindau syndrome, and trauma to a tissue or organ.

[0178] In some embodiments, the 15-PGDH inhibitor may be administered to a preparation of hematopoietic stem cells (such as the subject's peripheral blood hematopoietic stem cells or cord stem cells) to enhance the compatibility of the stem cell preparation as a donor graft or to reduce the number of units of cord blood required for transplantation.

[0179] Hematopoietic stem cells are multipotent stem cells that give rise to all types of blood cells in an organism, including myeloid (e.g., monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, dendritic cells) and lymphoid (e.g., T cells, B cells, NK cells) lineages, as well as those known in the art (see Fei, R., et al, U.S. Patent No. 5,635,387; McGlave, et al, U.S. Patent No. 5,460,964; Simmons, P., et al, U.S. Patent No. 5,677,136; Tsukamoto, et al, U.S. Patent No. 5,750,397; Schwartz, et al, U.S. Patent No. 5,759,793; DiGuisto, et al, U.S. Patent No. 5,681,599; Tsukamoto, et al, U.S. Patent No. 5,716,827). Hematopoietic stem cells (HSCs) give rise to committed hematopoietic progenitor cells (HPCs) that can generate the entire repertoire of mature blood cells throughout the life of an organism.

[0180] Hematopoietic stem cells and hematopoietic progenitor cells are generally described herein as hematopoietic stem cells, unless otherwise indicated, and can refer to cells or populations identified by the presence of the antigen marker CD34 (CD34 + ). In some embodiments, hematopoietic stem cells can be identified by the presence of the antigen marker CD34 and the absence of lineage (lin) markers, and thus are characterized as CD34 + / lin - .

[0181] In the methods described herein, the hematopoietic stem cells used may be obtained from any suitable source of hematopoietic stem and progenitor cells and may be provided as a highly purified population of hematopoietic stem cells or as a composition comprising from about 0.01% to about 100% hematopoietic stem cells. For example, the hematopoietic stem cells may be provided in a composition such as unfractionated bone marrow (where the hematopoietic stem cells constitute less than about 1% of the bone marrow cell population), umbilical cord blood, placental blood, placenta, fetal blood, fetal liver, fetal spleen, Wharton's jelly, or mobilized peripheral blood.

[0182] Suitable sources of hematopoietic stem cells may be isolated or obtained from body organs containing cells of hematopoietic origin. Isolated cells may include cells removed from their original environment. For example, cells are isolated if they are separated from some or all of the components that normally accompany the cells in their native state. For example, the terms "isolated cell population," "isolated cell source," or "isolated hematopoietic stem cells," as used herein, apply to the in vitro or ex vivo separation of one or more cells from their natural cellular environment and from their association with other components of a tissue or organ, i.e., it is not highly associated with substances in vivo.

[0183] Hematopoietic stem cells may be obtained or isolated from adult bone marrow, including the femur, hip, rib, sternum, and other bones. Bone marrow aspirates containing hematopoietic stem cells may be obtained or isolated directly from the hip using a needle and syringe. Other sources of hematopoietic stem cells include umbilical cord blood, placental blood, mobilized peripheral blood, Wharton's jelly, placenta, fetal blood, fetal liver, or fetal spleen. In certain embodiments, it may be necessary to mobilize the stem and progenitor cells in the donor in order to harvest a sufficient amount of hematopoietic stem cells for therapeutic use.

[0184] "Hematopoietic stem cell mobilization" refers to the release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukapheresis prior to stem cell transplantation. By increasing the number of stem cells collected from a donor, the number of stem cells available for therapeutic use can be significantly improved. Hematopoietic growth factors (e.g., granulocyte colony-stimulating factor (G-CSF)) or chemotherapeutic agents are often used to stimulate mobilization. There are commercially available stem cell mobilizing agents that can be used in combination with G-CSF to mobilize a sufficient amount of hematopoietic stem and progenitor cells for transplantation into a subject. For example, G-CSF and Mozobil (Genzyme Corporation) may be administered to a donor to collect a sufficient number of hematopoietic cells for transplantation. Other methods of mobilizing hematopoietic stem cells will be apparent to those skilled in the art.

[0185] In some embodiments, hematopoietic stem and progenitor cells (HSPCs) are obtained from umbilical cord blood. Umbilical cord blood may be collected according to techniques known in the art (see, e.g., U.S. Patent Nos. 7,147,626 and 7,131,958; these are incorporated herein by reference with respect to such methodologies).

[0186] In one embodiment, HSPCs may be obtained from pluripotent stem cell sources (e.g., induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs)). As used herein, the term "induced pluripotent stem cell" or "iPSC" refers to non-pluripotent cells that have been reprogrammed into a pluripotent state. Once a subject's cells have been reprogrammed into a pluripotent state, the cells can then be programmed into a desired cell type (such as a hematopoietic stem cell or hematopoietic progenitor cell). As used herein, the term "reprogramming" is applied to methods that enhance the ability of a cell to a less differentiated state. As used herein, the term "programming" is applied to methods that decrease the ability of a cell or differentiate a cell into a more differentiated state.

[0187] In some embodiments, one or more of the 15-PGDH inhibitors described herein may be given to or contacted with hematopoietic stem cells ex vivo to provide a therapeutic composition. In one embodiment, the therapeutic composition may comprise a population of hematopoietic stem cells treated ex vivo with one or more 15-PGDH inhibitors. In certain embodiments, the therapeutic composition comprising enhanced HSPCs is whole bone marrow, umbilical cord blood or mobilized peripheral blood.

[0188] In certain embodiments, the therapeutic composition comprises a population of cells, wherein the population of cells is from about 95% to about 100% hematopoietic stem cells. The present invention contemplates, in part, that the use of therapeutic compositions of highly purified hematopoietic stem cells (e.g., compositions comprising a population of cells comprising about 95% hematopoietic stem cells) can improve the efficiency of stem cell therapy. Currently practiced transplantation methods typically use an unfractionated cell mixture in which hematopoietic stem cells constitute less than 1% of the total cell population.

[0189] In some embodiments, the therapeutic composition comprises a population of cells, wherein the population of cells comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25% or 30% hematopoietic stem cells. In some embodiments, the population of cells comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25% or 30% hematopoietic stem cells. In other embodiments, the population of cells is from about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 60% to 70%, about 70% to 80%, about 80% to 90%, about 90% to 95%, or about 95% to 100% hematopoietic stem cells.

[0190] The hematopoietic stem cells in the therapeutic composition of the present invention may be autologous / autogeneic ("self") or non-autologous ("non-self"; e.g., allogeneic, syngeneic or xenogeneic) with respect to the subject to which the therapeutic composition is administered. "Autologous" as used herein applies to cells from the same subject. "Allogeneic" as used herein applies to cells of the same species that are genetically different from the cells being compared. "Syngeneic" as used herein applies to cells of different subjects that are genetically identical to the cells being compared. "Xenogeneic" as used herein applies to cells of a different species from the cells being compared.

[0191] The hematopoietic stem cells for use in the method of the present invention may be depleted of mature hematopoietic cells (such as T cells, B cells, NK cells, dendritic cells, monocytes, granulocytes, erythrocyte cells, and their committed progenitor cells from bone marrow aspirates, umbilical cord blood or mobilized peripheral blood (mobilized leukapheresis products)). Mature, lineage-committed cells can be depleted by immunodepletion, for example, by labeling a solid substrate with antibodies that bind to a panel of so-called "lineage" antigens (CD2, CD3, CD11b, CD14, CD15, CD16, CD79, CD56, CD123, and CD235a). A subsequent step of isolating primitive hematopoietic stem cells using a substrate labeled with an antibody that binds to the CD34 + antigen can be performed to further purify the cell population. Kits for purifying stem and progenitor cells from various cell sources are commercially available and, in certain embodiments, these kits are suitable for use in the methods described herein.

[0192] In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is at least 0.1×10 5 cells, at least 0.5×10 5 cells, at least 1×10 5 cells, at least 5×10 5 cells, at least 10×10 5cells, at least 0.5×10 6 cells, at least 0.75×10 6 cells, at least 1×10 6 cells, at least 1.25×10 6 cells, at least 1.5×10 6 cells, at least 1.75×10 6 cells, at least 2×10 6 cells, at least 2.5×10 6 cells, at least 3×10 6 cells, at least 4×10 6 cells, at least 5×10 6 cells, at least 10×10 6 cells, at least 15×10 6 cells, at least 20×10 6 cells, at least 25×10 6 cells, or at least 30×10 6 cells.

[0193] In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is the amount of HSPCs in a partial or single cord of blood, or at least 0.1×10 5 cells / kg body weight, at least 0.5×10 5 cells / kg body weight, at least 1×10 5 cells / kg body weight, at least 5×10 5 cells / kg body weight, at least 10×10 5 cells / kg body weight, at least 0.5×10 6 cells / kg body weight, at least 0.75×10 6 cells / kg body weight, at least 1×10 6 cells / kg body weight, at least 1.25×10 6 cells / kg body weight, at least 1.5×10 6 cells / kg body weight, at least 1.75×10 6 cells / kg body weight, at least 2×10 6 cells / kg body weight, at least 2.5×10 6 cells / kg body weight, at least 3×10 6cells / kg body weight, at least 4×10 6 cells / kg body weight, at least 5×10 6 cells / kg body weight, at least 10×10 6 cells / kg body weight, at least 15×10 6 cells / kg body weight, at least 20×10 6 cells / kg body weight, at least 25×10 6 cells / kg body weight, or at least 30×10 6 cells / kg body weight.

[0194] Preparations of hematopoietic stem cells administered one or more 15-PGDH inhibitors and / or therapeutic compositions comprising hematopoietic stem cells and one or more 15-PGDH inhibitors may be used to improve hematopoietic stem cell transplantation, as well as in the treatment of ischemic or ischemic damaged tissues, and to reduce further damage to ischemic tissues and / or repair damage to ischemic tissues via cell mobilization, improve angiogenesis in ischemic tissues, improve tissue regeneration at the site of ischemia, reduce necrosis or apoptosis of ischemic tissues and / or increase cell survival at the site of ischemia. In certain embodiments, preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or therapeutic compositions of 15-PGDH inhibitors and hematopoietic stem cells are useful for subjects in need of hematopoietic system reconstitution, such as subjects who have received or are scheduled to receive myeloablative therapy.

[0195] Preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or subjects that may be treated with a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells may include subjects diagnosed with having various types of leukemia, anemia, lymphoma, myeloma, immunodeficiency disorders, and solid tumors. Also included are human subjects who are candidates for stem cell transplantation or bone marrow transplantation, such as those during the treatment process of a malignant disease or components of gene therapy. Also included may be individuals or animals that provide stem cells or bone marrow for allogeneic transplantation. In certain embodiments, the subject may have received myeloablative irradiation therapy or chemotherapy, or may have experienced acute radiation injury or chemical injury resulting in myelosuppression. In certain embodiments, the subject may have received irradiation therapy or chemotherapy, such as during various cancer treatments. Typical subjects include animals that exhibit abnormal amounts (lower or higher amounts than in a "normal" or "healthy" subject) of one or more physiological activities that can be regulated by an agent or transplantation of stem cells or bone marrow.

[0196] Also, subjects that may be treated with a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells include subjects receiving chemotherapy or radiation therapy for cancer, as well as subjects suffering from non-malignant blood disorders, particularly immunodeficiencies (e.g., SCID, Fanconi anemia, severe aplastic anemia, or congenital hemoglobinopathies, or metabolic storage diseases (especially Hurler disease, Hunter disease, mannosidosis, etc.)), or cancer, particularly hematological malignancies (acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin lymphoma or non-Hodgkin lymphoma), multiple myeloma, myelodysplastic syndromes, etc.), or non-hematological cancers such as solid tumors (breast cancer, ovarian cancer, brain cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer or pancreatic cancer).

[0197] In addition, the subject may also include those suffering from aplastic anemia, immune disorders (severe combined immunodeficiency syndrome or lupus), myelodysplasia, thalassemia, sickle cell disease or Wiskott-Aldrich syndrome. In some embodiments, the subject has a disorder that is the result of side effects or complications of another primary treatment, such as treatment with radiation therapy, chemotherapy, or myelosuppressive drugs (zidovadine, chloramphenical or gangciclovir). Such disorders include neutropenia, anemia, thrombocytopenia and immune dysfunction. Other subjects may have a disorder caused by an infection (e.g., viral, bacterial or fungal infection) that causes damage to the stem cells or progenitor cells of the bone marrow.

[0198] Furthermore, subjects suffering from the following conditions may also benefit from treatment with a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a treatment using a 15-PGDH inhibitor and a hematopoietic stem cell therapeutic composition: lymphopenia, lymphorrhea, lymph stasis, erythrocytopenia, erythrocyte degenerative disorders, erythroblastopenia, erythroleukemia; erythroclasis, thalassemia, myelodysplasia, myelofibrosis, thrombocytopenia, disseminated intravascular coagulation (DIC), immune (autoimmune) thrombocytopenic purpura (ITP), ITP induced by HIV, myelodysplasia; thrombocytotic disease, thrombocytosis, congenital neutropenia (such as Kostmann syndrome and Schwachman-Diamond syndrome), neoplastic associated neutropenias, childhood and adult cyclic neutropenia; post-infection neutropenia; myelodysplastic syndrome; neutropenia associated with chemotherapy and radiation therapy; chronic granulomatous disease; mucopolysaccharidosis; Diamond-Blackfan anemia; sickle cell disease; or severe beta-thalassemia.

[0199] In other embodiments, a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells may be used in cell therapy for treating ischemic tissue or treating or ameliorating one or more conditions associated with tissue ischemia (including, but not limited to, impairment or loss of organ function (including, but not limited to, impairment or loss of brain, kidney, or heart function), spasm, limp, numbness, tingling, weakness, pain, reduced wound healing, inflammation, skin discoloration, and gangrene).

[0200] In one embodiment, the subject exhibits at least one condition of ischemic tissue or tissue damaged by ischemia. In certain embodiments, the subject is a human having or at risk of having ischemic tissue or tissue damaged by ischemia, for example, a subject having diabetes, peripheral vascular disease, thromboangiitis obliterans, vasculitis, cardiovascular disease, coronary artery disease or heart failure, or cerebrovascular disease, cardiovascular disease, or cerebrovascular disease.

[0201] Exemplary examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions that cause ischemia, are associated with ischemia, or increase the risk of ischemia in a subject and are thus suitable for treatment or amelioration using the methods described herein include acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, atherosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burns, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, ischemia induced by diabetes, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vasculitic condition, von Hippel-Lindau syndrome, and trauma to tissue or organ, but are not limited thereto.

[0202] Other exemplary examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions that cause ischemia in the subject, are associated with ischemia, or increase the risk of ischemia, or cause the presentation of one or more symptoms of ischemia suitable for treatment or amelioration using the methods of the present invention include ischemia resulting from surgery, chemotherapy, radiation therapy, or transplantation or grafting of cells, tissues or organs.

[0203] In various embodiments, the methods of the present invention are suitable for treating cerebrovascular ischemia, myocardial ischemia, critical limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

[0204] In various embodiments, the present invention contemplates that the therapeutic cell compositions disclosed herein can be used to treat ischemic tissues where it is desirable to increase blood flow, oxygen supply, glucose supply or nutrient supply to the tissue.

[0205] In some embodiments, a 15-PGDH inhibitor may be provided to a preparation of tissue stem cells (such as neural stem cells, mesenchymal stem cells, or stem cells capable of generating other tissues) and / or a preparation of pluripotent stem cells.

[0206] In one embodiment, the tissue stem cells may be obtained from pluripotent stem cell sources (such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs)). As used herein, the term "induced pluripotent stem cell" or "iPSC" refers to a non-pluripotent cell that has been reprogrammed into a pluripotent state. Once a cell of the subject is reprogrammed into a pluripotent state, it can then be programmed into a desired cell type (such as a hematopoietic stem cell or hematopoietic progenitor cell). As used herein, the term "reprogramming" is applied to methods that enhance the ability of a cell into a less differentiated state. As used herein, the term "programming" is applied to methods that reduce the ability of a cell or differentiate a cell into a more differentiated state.

[0207] In some embodiments, one or more of the 15-PGDH inhibitors described herein may be provided to or contacted with tissue stem cells and / or pluripotent stem cells ex vivo to provide a therapeutic composition. In one embodiment, the therapeutic composition may include a population of tissue stem cells that have been treated ex vivo with one or more 15-PGDH inhibitors.

[0208] In certain embodiments, the therapeutic composition includes a population of cells, wherein the population of cells is about 95% to about 100% tissue stem cells. The present invention contemplates, in part, that the use of a therapeutic composition of highly purified tissue stem cells (e.g., a composition comprising a population of cells comprising about 95% tissue stem cells) can improve the efficiency of stem cell therapy.

[0209] In some embodiments, the therapeutic composition includes a population of cells, wherein the population of cells includes less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25% or 30% tissue stem cells. In some embodiments, the population of cells includes less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25% or 30% tissue stem cells. In other embodiments, the population of cells is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 60% to 70%, about 70% to 80%, about 80% to 90%, about 90% to 95%, or about 95% to 100% tissue stem cells.

[0210] The tissue stem cells in the therapeutic composition of the present invention may be autologous / autogeneic ("self") or non-autologous ("non-self"; e.g., allogeneic, syngeneic or xenogeneic) with respect to the subject to which the therapeutic composition is administered. "Autologous", as used herein, applies to cells from the same subject. "Allogeneic", as used herein, applies to cells of the same species that are genetically different from the cells being compared. "Syngeneic", as used herein, applies to cells of different subjects that are genetically identical to the cells being compared. "Xenogeneic", as used herein, applies to cells of a different species from the cells being compared.

[0211] Preparations of tissue stem cells provided with one or more 15-PGDH inhibitors and / or therapeutic compositions comprising tissue stem cells and one or more 15-PGDH inhibitors may be used to improve tissue stem cell transplantation, and in the treatment of damaged tissue, and in the reduction of further tissue damage and / or the enhancement of regeneration of damaged tissue via mobilization of stem cells and / or the increase of cell survival at the tissue damage site.

[0212] Symptomatic conditions, traumas, chronic conditions, medical interventions or other conditions that cause or are associated with tissue damage and the need for tissue repair and are thus suitable for treatment or amelioration using the methods described herein include, but are not limited to, acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, atherosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burns, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes mellitus, diabetic neuropathy, ischemia induced by diabetes, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vasculitic conditions, von Hippel-Lindau syndrome, and trauma to tissue or organ.

[0213] Other exemplary examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions that cause or are associated with tissue damage and the need for tissue repair and are suitable for treatment or amelioration using the methods of the present invention include ischemia due to surgery, chemotherapy, radiotherapy, or transplantation or grafting of cells, tissues or organs.

[0214] In various embodiments, the methods of the present invention are suitable for treating cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

[0215] In other embodiments, the 15-PGDH inhibitor may be administered to a bone marrow transplant donor or hematopoietic stem cell donor to enhance the compatibility of the donor bone marrow graft or donor hematopoietic stem cell graft.

[0216] In other embodiments, the 15-PGDH inhibitor may also be administered to the subject's bone marrow to increase stem cells in the subject or to enhance the compatibility of the bone marrow as a donor graft.

[0217] In yet other embodiments, the 15-PGDH inhibitor may be administered to a subject to reduce tissue transplant rejection, improve engraftment of a bone marrow graft, improve engraftment of a hematopoietic stem cell graft or umbilical cord blood stem cell graft, improve engraftment of a hematopoietic stem cell graft or umbilical cord stem cell graft, and / or reduce the number of units of umbilical cord blood required for transplantation into the subject. Administration may be, for example, after treatment of the subject or the subject's bone marrow by radiotherapy, chemotherapy or immunosuppressive therapy.

[0218] In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a bone marrow transplant, a hematopoietic stem cell transplant, or an umbilical cord blood stem cell transplant to reduce the administration of other treatments or growth factors.

[0219] In some embodiments, the 15-PGDH inhibitor may be administered to a subject to improve neutrophil recovery after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiotherapy, and in individuals having neutropenia resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, neutropenia resulting from other bone marrow diseases, drug-induced neutropenia, immune neutropenia, idiopathic neutropenia, and after infection with viruses including, but not limited to, HIV, CMV, and parvovirus.

[0220] In other embodiments, the 15-PGDH inhibitor may be administered to a subject to improve platelet recovery after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiotherapy, and in individuals having neutropenia resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia resulting from other bone marrow diseases, drug-induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and after infection with viruses including, but not limited to, HIV, CMV, and parvovirus.

[0221] In yet other embodiments, the 15-PGDH inhibitor may be administered to a subject to improve hemoglobin recovery after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiotherapy, and in individuals having anemia resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, anemia resulting from other bone marrow diseases, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, idiopathic anemia, and after infection with viruses including, but not limited to, HIV, CMV, and parvovirus.

[0222] In some embodiments, the 15-PGDH inhibitor may be administered to a subject to increase the number of bone marrow stem cells in an individual after bone marrow transplantation, after umbilical cord blood transplantation, after transplantation of hematopoietic stem cells, after conventional chemotherapy, after radiotherapy, in an individual with other bone marrow diseases, in an individual with cytopenia after viral infection, and in an individual with cytopenia.

[0223] In other embodiments, the 15-PGDH inhibitor may be administered to a subject to improve the response to cytokines administered to an individual having cytopenia, including but not limited to neutropenia, thrombocytopenia, lymphopenia, and anemia. Cytokines whose response may be improved by SW033291 include, but are not limited to, G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, SCF, and TPO-RA (thrombopoietin receptor agonist).

[0224] In further embodiments, the 15-PGDH inhibitor may be administered to a subject or to a tissue graft of a subject to reduce graft rejection, to improve graft engraftment, to improve graft engraftment after treatment of the subject or the subject's bone marrow by radiotherapy, chemotherapy, or immunosuppressive therapy, to confer resistance to the toxic or lethal effects of radiation exposure, to confer resistance to the toxic effects of cyclophosphamide, the toxic effects of fludarabine, the toxic effects of chemotherapy, or the toxic effects of immunosuppressive therapy, to reduce infection, and / or to reduce radiation-induced lung toxicity.

[0225] In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a tissue stem cell transplantation, including but not limited to transplantation of hematopoietic stem cells, neural stem cells, mesenchymal stem cells, or stem cells for other tissues, to accelerate tissue regeneration and repair after transplantation.

[0226] In some embodiments, the administration of the 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing neutrophils.

[0227] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing neutrophils.

[0228] In still other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells.

[0229] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells.

[0230] In some embodiments, administration of a 15-PGDH inhibitor may be combined with a second agent (including plerixafor) for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells.

[0231] In other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0232] In still other embodiments, administration of a 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0233] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a second agent (including plerixafor) for the purpose of increasing the number of peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation and / or for the purpose of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0234] In still other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

[0235] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

[0236] In other embodiments, a 15-PGDH inhibitor may be used to treat and / or prevent fibrosis and various fibrotic diseases, disorders or conditions, and to reduce symptoms of fibrosis (such as collagen deposition, expression of inflammatory cytokines and inflammatory cell infiltration).

[0237] In some embodiments, a method of treating or preventing a fibrotic disease, disorder or condition comprises administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof such that at least one symptom or feature of the fibrotic disease, disorder or condition or another related disease, disorder or condition is reduced in terms of intensity, severity or frequency or the onset thereof is delayed.

[0238] As used herein, the term "fibrotic" disease, disorder or condition includes diseases, disorders or conditions characterized by the overproduction of fibrous material, wholly or in part (including overproduction of fibrous material within the extracellular matrix), or replacement of elements of normal tissue by abnormal, non-functional, and / or excessive accumulation of matrix-related components. Fibrotic diseases, disorders or conditions may include acute and chronic clinical or subclinical presentations where the biology or pathology associated with fibrosis is apparent.

[0239] Examples of fibrotic diseases, disorders and conditions include systemic sclerosis, multiple sclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea or linear scleroderma), scleroderma graft-versus-host disease, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive kidney disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., glomerulosclerotic pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, triangular fibrocartilage fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, a general fibrosing syndrome characterized by replacement of normal muscle tissue by fibrous tissue to varying degrees, retroperitoneal fibrosis, hepatic fibrosis, cirrhosis, chronic renal failure, myelofibrosis (myelofibrosis / bone marrow fibrosis), drug-induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, collagenous colitis, acute fibrosis, organ-specific fibrosis, etc.

[0240] Exemplary organ-specific fibrotic disorders include, but are not limited to, pulmonary fibrosis, pulmonary hypertension, cystic fibrosis, asthma, chronic obstructive pulmonary disease, hepatic fibrosis, renal fibrosis, NASH, etc. Many fibrotic diseases, disorders or conditions have a disorganized and / or excessive deposition of extracellular matrix in the affected tissue. Fibrosis can be associated with inflammation, occur as a symptom of an underlying disease, and / or be caused by a surgical procedure or the process of wound healing. Untreated fibrosis can lead to destruction of the structure of the underlying organ or tissue (commonly called scarring).

[0241] In some embodiments, the 15-PGDH inhibitor may be used to treat or prevent pulmonary fibrosis. Pulmonary fibrosis may be selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious pathogens, pulmonary fibrosis caused by inhalation of harmful gases, aerosols, chemical dusts, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[0242] Pulmonary fibrosis is characterized by progressive scarring of lung tissue, accompanied by fibroblast proliferation, excessive accumulation of extracellular matrix proteins, and abnormal alveolar structure. The thickened and hardened tissue makes it difficult for the lungs to function properly, leading to respiratory disorders such as shortness of breath and can ultimately be fatal. Pulmonary fibrosis can be caused by acute lung injury, viral infection, toxin exposure, radiation, chronic diseases, drug treatment, or can be idiopathic (i.e., the underlying cause is unknown).

[0243] Classical findings in idiopathic pulmonary fibrosis often show diffuse peripheral scarring of the lungs, often at the base of the lungs, with small blebs (known as blisters) adjacent to the outer layer of the lung surface. Idiopathic pulmonary fibrosis often shows a slow and relentless progression. At an early stage, patients often complain of a dry cough of unknown origin. Next, shortness of breath (dyspnea) begins, caused by a progressive decrease in activity, and worsens over time. Ultimately, shortness of breath handicaps the body, limits all activities, and even occurs while sitting quietly. In rarer cases, the fibrosis can progress rapidly, with dyspnea and physical disability occurring within weeks to months from the onset of the disease. This form of pulmonary fibrosis is called Hamman-Rich syndrome.

[0244] Pulmonary hypertension is characterized by an increase in blood pressure in the pulmonary vascular system, which includes the pulmonary arteries, veins, and / or capillaries. Abnormally high pressure places a burden on the right ventricle of the heart and causes it to dilate. Over time, the right ventricle weakens and loses its ability to pump sufficient blood to the lungs, potentially leading to the development of heart failure. Pulmonary hypertension can result from other medical conditions such as chronic liver disease and cirrhosis, rheumatic disorders (such as scleroderma or systemic lupus erythematosus (lupus)), and lung conditions (including tumors, emphysema, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis). Pulmonary fibrosis can lead to narrowing of the pulmonary vascular system, which can result in pulmonary hypertension.

[0245] Chronic obstructive pulmonary disease (COPD) is a common lung disease often associated with chronic bronchitis or emphysema. Symptoms can often include cough, mucus accumulation, fatigue, wheezing, and respiratory infections.

[0246] Chronic bronchitis and emphysema are lung diseases in which the airways become narrowed. This leads to a restriction in the flow of air into and out of the lungs, causing shortness of breath (dyspnea). In clinical practice, COPD is defined by its characteristically low airflow on pulmonary function tests.

[0247] Lung damage and inflammation in the large airways result in chronic bronchitis. In the airways of the lungs, the characteristics of chronic bronchitis are an increase (hyperplasia) and an increase in size (hypertrophy) in the number of goblet cells and mucus glands in the airways. As a result, more mucus than normal is present in the airways, which contributes to airway narrowing and causes coughing with phlegm. Microscopically, there is infiltration of the airway wall by inflammatory cells. Following inflammation, scarring and remodeling occur, thickening the wall and causing airway narrowing. As chronic bronchitis progresses, squamous metaplasia (abnormal changes in the tissue lining the inside of the airways) and fibrosis (further thickening and scarring of the airway wall) occur. The result of these changes is airflow restriction and dyspnea.

[0248] Asthma is a chronic lung disease characterized by airway inflammation and narrowing. Asthma causes recurrent wheezing, chest tightness, shortness of breath and coughing. Swelling and excessive mucus production can cause further airway narrowing and worsening of symptoms. There is evidence that matrix breakdown may be increased in asthma, which may contribute to the mechanical changes in the airways in asthma (Roberts et al (1995) Chest 107:111S - 117S, which is hereby incorporated by reference in its entirety). Treatment of extracellular matrix breakdown may improve the symptoms of asthma.

[0249] Cystic fibrosis is an autosomal recessive multisystemic genetic disease characterized by abnormal transport of chloride and sodium across epithelia, resulting in thick secretions in the lungs, pancreas, liver, intestine and genital systems. Cystic fibrosis is caused by mutations in the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR). Lung disease is due to fibrous injury and structural changes in the lungs, airway blockage due to mucus accumulation, decreased mucociliary clearance, and resulting inflammation. Fibrous lung injury progresses over time and some patients with cystic fibrosis will require lung transplantation.

[0250] Common symptoms in subjects with cystic fibrosis include accumulation of thick mucus, production of large amounts of sputum, frequent chest infections, frequent coughing, frequent shortness of breath, inflammation, reduced exercise capacity, opportunistic infections of the lungs and sinuses (including but not limited to Staphylococcus aureus, Haemophilus influenzae, Mycobacterium aviium and Pseudomonas aeruginosa), pneumonia, tuberculosis, bronchiectasis, hemoptysis, pulmonary hypertension (and resulting heart failure), hypoxemia, respiratory failure, allergic bronchopulmonary aspergillosis, sinus mucus, sinus infections, facial pain, fever, excessive nasal discharge, development of nasal polyps, cardiorespiratory complications, CF - related diabetes, rectal prolapse, pancreatitis, malabsorption, intestinal obstruction, exocrine pancreatic insufficiency, biliary obstruction, and cirrhosis, but are not limited thereto.

[0251] In other embodiments, the 15-PGDH inhibitor may be used to treat or prevent fibrotic diseases, disorders or conditions caused by postoperative adhesion formation. Postoperative adhesion formation is a common surgical complication. The formation of adhesions due to mechanical injury, ischemia and infection can increase postoperative morbidity and mortality. Sophisticated surgical procedures can reduce the extent of adhesion formation, but adhesions are rarely removed and effective adjuvant therapies are needed. Reduction of fibrosis associated with this process can reduce pain, obstruction and other surgical complications and promote healing and recovery.

[0252] Wounds (i.e., lacerations, tears) in mammalian tissue result in tissue destruction and the coagulation of microvessels at the wound surface. The repair of such tissue represents an orderly and controlled cellular response to injury. Soft tissue wounds heal in a similar manner regardless of size. Tissue growth and repair are biological systems in which cell proliferation and angiogenesis occur in the presence of an oxygen gradient. The series of morphological and structural changes that occur during tissue repair have been characterized in detail and in some cases quantified (see, e.g., Hunt, T.K., et al., 「Coagulation and macrophage stimulation of angiogenesis and wound healing」 in The Surgical Wound, pp.1-18, ed. F.Dineen&G.Hildrick-Smith (Lea&Febiger, Philadelphia:1981)). Cellular morphology consists of three distinct zones. The central avascular wound space is in a state of oxygen deficiency, acidosis, and hypercarbia, with high lactate levels. Adjacent to the wound space is a gradient zone of local anemia (ischemia) where dividing fibroblasts aggregate. Behind the leading zone is an area of active collagen synthesis characterized by mature fibroblasts and a large number of newly formed capillaries (i.e., neovascularization). U.S. Patent Nos. 5,015,629 and 7,022,675 (each incorporated herein by reference) disclose methods and compositions for enhancing the rate of wound repair.

[0253] In some embodiments, the 15-PGDH inhibitor may be used to reduce or prevent scar formation in a subject by administering it to a subject in need of treatment. Scar formation is a natural part of the healing process. Disordered collagen synthesis and deposition in a wound can result in excessive, thick, or raised scarring. Generally, the larger the wound, the longer it takes to heal and the higher the likelihood of scarring.

[0254] In other embodiments, the 15-PGDH inhibitor may be used to reduce or prevent scar formation or scleroderma in the skin. There are several types of scars in the skin. Hypertrophic scars are raised, pinkish-red areas that are located within the boundaries of the original injury. They are often described as itchy. In some cases, hypertrophic scars will shrink and disappear on their own. Keloids are raised, dark red areas that tend to cover an area much wider than the original injury. Even when surgically removed, keloids tend to recur. Atrophic scars are depressions in the skin (such as those that may form from severe acne). They are caused by inflammation that destroys collagen during the remodeling process, leaving a sunken area.

[0255] In some embodiments, the 15-PGDH inhibitor may be used to treat or prevent systemic sclerosis. Systemic sclerosis is a systemic connective tissue disease characterized by changes in the microvasculature, immune system disorders, and massive deposition of collagen and other matrix substances in the connective tissue. Systemic sclerosis is a clinically heterogeneous systemic disorder that affects the connective tissue of the skin and internal organs (such as the gastrointestinal tract, lungs, heart, and kidneys). Reduction of fibrosis resulting from systemic sclerosis may improve symptoms and / or prevent further complications in the affected tissues.

[0256] In other embodiments, the 15-PGDH inhibitor may be used to treat or prevent liver fibrosis. Liver fibrosis can result from chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions, and exposure to toxins.

[0257] Non-alcoholic steatohepatitis (NASH) is a common liver disease. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The main features of NASH are fat in the liver, in addition to inflammation and damage. Nevertheless, NASH can progress and lead to cirrhosis, in which the liver is permanently damaged and scarred and can no longer function properly.

[0258] NASH is usually an asymptomatic disease with few or no symptoms. Patients generally feel well in the early stages and only start to experience symptoms (such as fatigue, weight loss, and weakness) when the disease progresses or cirrhosis develops. The progression of NASH can take years or even decades. The process can stop, and in some cases, it may even reverse on its own without specific treatment. Alternatively, NASH can slowly worsen and cause the appearance and accumulation of scarring or fibrosis in the liver. As fibrosis worsens, cirrhosis develops, and the liver becomes severely damaged, hardened, and unable to function properly. Not all people with NASH develop cirrhosis, but once severe scarring or cirrhosis appears, there are few treatments available to stop its progression. People with cirrhosis experience fluid retention, muscle wasting, bleeding from the intestine, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and it is being increasingly performed in people with NASH. NASH is ranked as one of the leading causes of cirrhosis in the United States, after hepatitis C and alcoholic liver disease.

[0259] In some embodiments, the 15-PGDH inhibitor may be used to treat or prevent renal fibrosis. Renal fibrosis can result from dialysis after renal failure, catheterization, nephrosis, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease or renal failure.

[0260] Renal fibrosis (fibrosis of the kidney) is caused by the excessive formation of fibrous connective tissue in the kidney. Renal fibrosis results in significant morbidity and mortality and leads to the need for dialysis or kidney transplantation. Fibrosis can occur in either the filtration or reabsorption components of the nephron, which are the functional units of the kidney. Several factors can contribute to scarring of the kidney, particularly disruption of physiological functions involved in the autoregulation of glomerular filtration, which in turn leads to replacement of normal structure by the accumulated extracellular matrix. The spectrum of changes in the physiological functions of individual cells stimulates changes in the balance between synthesis and degradation of the extracellular matrix, resulting in the production of numerous peptide and non-peptide fibrogens that promote scarring.

[0261] In some embodiments, the symptoms of fibrosis of a tissue or organ may include inflammation. In these embodiments, a therapeutically effective amount of a 15-PGDH inhibitor administered to a subject in need thereof may be an amount effective to reduce or decrease the number of inflammatory cells in the tissue or organ. An appropriate sample may be obtained from the subject to determine the reduction or decrease in the number of inflammatory cells. In a non-limiting embodiment, the beneficial effect may be evaluated by showing a decrease in the number of neutrophils in bronchoalveolar lavage fluid (BAL fluid) from a subject having cystic fibrosis. The excessive recruitment of neutrophils to the airways of patients with cystic fibrosis (CF) is an important predictor of the severity of lung disease in CF and is thus an important therapeutic target. Methods for measuring such cell numbers are well known in the art, including but not limited to FACS technology. In some embodiments, the method may include reducing the number of neutrophil cells in BAL fluid from the subject as compared to a control. Any suitable control, such as a subject with cystic fibrosis not treated with a 15-PGDH inhibitor, may be used for comparison. In some embodiments, the reduction in the number of inflammatory cells (such as the number of neutrophils) provides a clinical benefit to the subject. In various embodiments, the reduction in the number of inflammatory cells is at least 5%, 10%, 15%, 20%, 25%, 50% or more as compared to the control.

[0262] In another embodiment, the beneficial effects of the 15-PGDH inhibitor may be evaluated by a decrease in one or more inflammatory biomarkers in a suitable sample from the subject. In various non-limiting embodiments, the inflammatory biomarker may comprise or consist of one or more of the cytokines associated with fibrosis or inflammatory cytokines. Such cytokines may include, for example, IL1β, MIP2 (e.g., CCL3 or CCL4), IFNδ, TGFβ, TNFα, IL-6, MCP-1, IL2, and IL-10 in the BAL fluid. Methods for measuring the amount of such biomarkers are well known in the art, including, but not limited to, ELISA. Thus, in this embodiment, the method may further comprise comparing and reducing the amount of one or more inflammatory biomarkers in a sample from the subject to a control.

[0263] In other embodiments, the 15-PGDH inhibitor may be used in a method for reducing or decreasing collagen secretion or collagen deposition in a tissue or organ of a subject (such as the lung, liver, skin, or heart). The method may comprise administering a therapeutically effective amount of the 15-PGDH inhibitor to a subject in need thereof. The subject may be at risk of or have excessive collagen secretion or collagen deposition in a tissue or organ (such as the kidney, lung, liver, intestine, colon, skin, or heart). Usually, excessive collagen secretion or collagen deposition in an organ is due to injury or insult. Such injuries and insults may be organ-specific. The 15-PGDH inhibitor may be administered for a period sufficient to completely or partially reduce or decrease the level of collagen deposition in the tissue or organ. The sufficient period may be one week, or one to one month, or one to two months, or two months or more. In the case of a chronic condition, the 15-PGDH inhibitor may be advantageously administered for life.

[0264] 15-PGDH inhibitors used to treat fibrotic diseases, disorders or conditions and / or collagen deposition can be identified using an assay that determines the functional effect on 15-PGDH activity after applying a compound presumed to be an inhibitor to cells expressing 15-PGDH. Samples or assays containing 15-PGDH treated with a prospective inhibitor are compared to control samples without the inhibitor to examine the degree of effect. A (non-treated with a modulator) control sample is assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the value of 15-PGDH activity compared to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.

[0265] Furthermore, in model organisms, PGE2 signaling stimulates liver regeneration and increases survival after exposure to hepatotoxic substances (such as acetaminophen). Thus, the 15-PGDH inhibitors described herein can be used to increase liver regeneration after liver resection, after liver surgery, after living liver donation or in other settings including after liver transplantation, or to increase liver regeneration and increase survival after exposure to hepatotoxic substances (including but not limited to acetaminophen and similar compounds).

[0266] Also, PGE1 analogs have been used in the treatment of erectile dysfunction. Thus, in some embodiments, the 15-PGDH inhibitors described herein can be used alone or in combination with prostaglandins for the treatment of erectile dysfunction.

[0267] The 15-PGDH inhibitors described herein can also be used to enhance neuronal signaling underlying learning and memory, to stimulate neuronal regeneration after injury, and / or to treat diseases, disorders and / or conditions of the nervous system, in order to promote neuroprotection of a subject from axonal degeneration, neuronal death and / or glial cell damage after injury.

[0268] In some embodiments, the neurological diseases, disorders and / or conditions that can be treated with a 15-PGDH inhibitor may include at least one of neurological disorders, neuropsychiatric disorders, nerve injuries, neurotoxic disorders, neuropathic pain, and neurodegenerative disorders.

[0269] In some embodiments, the 15-PGDH inhibitors described herein are used in methods for treating (e.g., suppressing, alleviating, improving, reducing, or slowing the progression of) or preventing (e.g., delaying the onset or reducing the risk of onset of) one or more diseases, disorders or conditions caused by or associated with insufficient (e.g., abnormal) neurogenesis or unwanted neuronal cell death in a subject in need thereof. These methods include administering to the subject an effective amount of a 15-PGDH inhibitor (and / or any compound of any other formula described herein) or a salt thereof (e.g., a pharmaceutically acceptable salt) as defined anywhere herein. The one or more diseases, disorders or conditions may include neuropathy, nerve trauma, and neurodegenerative diseases.

[0270] In some embodiments, the one or more diseases, disorders or conditions may be diseases, disorders or conditions caused by or associated with insufficient neurogenesis (e.g., abnormal hippocampal neurogenesis) as thought to occur in neuropsychiatric diseases, or abnormal neuronal cell death as thought to occur in neurodegenerative diseases. Examples of the one or more diseases, disorders or conditions include, but are not limited to, schizophrenia, major depressive disorder, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neurostimulatory drugs (such as alcohol, opioids, methamphetamine, fencyclidine, and cocaine).

[0271] In some embodiments, the subject may be a subject in need thereof (e.g., a subject identified as in need of such treatment (such as a subject having or at risk of having one or more of the diseases or conditions described herein)). Identification of a subject in need of such treatment may be at the discretion of the subject or a medical professional and may be subjective (e.g., an opinion) or objective (e.g., measurable by a test or diagnostic method). In some embodiments, the subject may be a mammal. In certain embodiments, the subject may be a human.

[0272] In other embodiments, the 15-PGDH inhibitor may be used to treat diseases, disorders or conditions associated with elements of the nervous system, including components of the central, somatic, autonomic, sympathetic and parasympathetic nervous systems, the neuro-sensory tissues of the eye, ear, nose, mouth or other organs, and glial tissues associated with the cells and structures of neurons. Neurological disorders can be caused by damage to neurons, such as mechanical damage or damage by toxic compounds, by abnormal growth or development of neurons, or by dysregulation (such as down-regulation) of neuronal activity.

[0273] Neurological disorders can adversely affect functions of the nervous system, such as sensory function (the ability to sense changes in the body and the external environment); integrative function (the ability to interpret such changes); and motor function (the ability to respond to such interpretation by initiating activities such as muscle contraction or glandular secretion).

[0274] Examples of neurological disorders that may be treated by administering a 15-PGDH inhibitor to a subject in need thereof include peripheral or cranial nerves, spinal cord or brain, trauma or toxic injury to cranial nerves, traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. Other neurological disorders that may be treated by administering a 15-PGDH inhibitor to a subject in need thereof include Alzheimer's disease, dementia associated with Alzheimer's disease (such as Pick's disease), Parkinson's disease and other diffuse Lewy body diseases, senile dementia, Huntington's disease, Gilles de la Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease), diabetic neuropathy, progressive supranuclear palsy, epilepsy, and Creutzfeldt-Jakob disease, etc., including cognitive impairment and neurodegenerative disorders. Autonomic dysfunction includes hypertension and sleep disorders.

[0275] Also, neuropsychiatric disorders such as depression, schizophrenia, schizoaffective disorder, Korsakoff's psychosis, mania, anxiety disorder, or phobic disorder, learning disorder or memory disorder (such as amnesia and age-related memory loss), attention deficit disorder, mood disorder, major depressive disorder, mania, obsessive-compulsive disorder, psychoactive substance use disorders, anxiety, phobia, panic disorder, bipolar disorder, psychogenic pain syndrome, and eating disorder should also be treatable with the 15-PGDH inhibitors described herein. Other examples of neurological disorders that may be treated by administering a 15-PGDH inhibitor to a subject in need thereof include damage to the nervous system by infectious diseases (such as meningitis, high fever of various etiologies, HIV, syphilis, or post-polio syndrome, etc.), and damage to the nervous system by electricity (including contact with electricity or lightning, and complications of electro-convulsive psychiatric therapy). Neurological disorders related to eye conditions include damage to the retina and optic nerve, glaucoma, and age-related macular degeneration.

[0276] The developing brain is a target of neurotoxicity in the developing central nervous system throughout much of pregnancy and during infancy and childhood, and the 15-PGDH inhibitors described herein may be used in the prevention or treatment of neurological deficits in the embryo or fetus in utero, in premature infants, or in children in need of such treatment, including those with neurological birth defects. Further neurological disorders include, for example, those enumerated in HARRISON’S PRINCIPLES OF INTERNAL MEDICINE (Braunwald et al., McGraw-Hill, 2001) and AMERICAN PSYCHIATRIC ASSOCIATION’S DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS DSM-IV (American Psychiatric Press, 2000).

[0277] The 15-PGDH inhibitors described herein may also be used in methods of treating medical conditions associated with nerve injury. The medical conditions can refer to any movement disorder, epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic disorder, bladder disorder, abnormal metabolic state, muscle disorder, infectious and parasitic diseases, neoplasm, endocrine disease, nutritional / metabolic disease, immunological disease, blood and blood-forming organ disease, mental disorder, nervous system disease, sensory organ disease, circulatory system disease, respiratory system disease, digestive system disease, urogenital system disease, skin and subcutaneous tissue disease, musculoskeletal and connective tissue disease, congenital anomaly, or specific conditions occurring during the perinatal period, as well as symptoms, signs, and indefinite conditions.

[0278] Treatable cerebrovascular diseases can be caused by conditions including, but not limited to, aneurysm, stroke, arrhythmia, myocardial infarction, ischemia-reperfusion injury, and cerebral hemorrhage.

[0279] Treatable autoimmune diseases include, but are not limited to, multiple sclerosis.

[0280] Sleep disorders treatable with a 15-PGDH inhibitor may be caused by conditions including, but not limited to, sleep apnea and associated disorders during sleep.

[0281] Autonomic disorders treatable with a 15-PGDH inhibitor may be caused by conditions including, but not limited to, gastrointestinal disorders (including, but not limited to, gastrointestinal motility disorders, nausea, vomiting, diarrhea, chronic hiccups, gastroesophageal reflux disease, and excessive gastric acid secretion), autonomic insufficiency, excessive epiphoresis, excessive rhinorrhea, and cardiovascular disorders (including, but not limited to, cardiac dysrythmias and arrythmias, hypertension, and carotid sinus disease).

[0282] Bladder disorders treatable with a 15-PGDH inhibitor may be caused by conditions including, but not limited to, spinal cord injury and spastic or flaccid bladder.

[0283] Abnormal metabolic conditions treatable with a 15-PGDH inhibitor may be caused by conditions including, but not limited to, hyperthyroidism or hypothyroidism.

[0284] Musculoskeletal disorders treatable with a 15-PGDH inhibitor may include, but are not limited to, muscular dystrophy and upper airway and facial contractures.

[0285] 15-PGDH inhibitors also include migraines (including migraines with aura, migraines without aura, menstrual migraines, migraine variants, atypical migraines, complex migraines, hemiplegic migraines, transformed migraines, and chronic daily migraines), episodic tension-type headaches, chronic tension-type headaches, analgesic rebound headaches, episodic cluster headaches, chronic cluster headaches, cluster variants, chronic paroxysmal hemicrania, hemicrania continua, post-traumatic headaches, post-traumatic neck pain, postherpetic neuralgia involving the head or face, pain from vertebral fractures secondary to osteoporosis, arthritic pain in the spine, headaches associated with cerebrovascular disease and stroke, headaches due to vascular disorders, reflex sympathetic dystrophy, cervicalgia (which can be caused by various factors, including but not limited to muscle, disc, or degeneration, arthritis, posture-related, or metastasis), glossodynia, carotidynia, cricoidynia, ear pain due to middle ear lesions, stomach pain, sciatica, maxillary neuralgia, laryngeal pain, neck muscle myalgia, trigeminal neuralgia (also known as tic douloureux), post-lumbar puncture headache, low cerebro-spinal fluid pressure headache, temporomandibular joint disorder, atypical facial pain, ciliary neuralgia, paratrigeminal neuralgia (also known as Raeder's syndrome), pyramidal neuralgia, Eagle's syndrome, idiopathic intracranial hypertension, orofacial pain, myofascial pain syndrome involving the head, neck, and shoulders, chronic migraneous neuralgia, cervical headache, paratrigeminal paralysis, SPG neuralgia (lower-half(headache), lower facial neuralgia syndrome, Sluder's neuralgia, and sometimes called Sluder's syndrome), carotid artery pain, vidian neuralgia, causalgia and / or neuropathic pain caused by a condition including but not limited to the above combinations may be used to treat.

[0286] As used herein, the term "headache" can refer to migraine, tension headache, cluster headache, trigeminal neuralgia, secondary headache, tension-type headache, chronic and episodic headache, medication overuse / rebound headaches, chronic paroxysmal hemicrinia headaches, hemicranias continua headaches, post-traumatic headache, post-herpetic headache, vascular headache, headache associated with reflex sympathetic dystrophy, cervicalgia headache, caroidynia headache, sciatica headache, trigeminal headache, occipital headache, maxillary headache, diary headache, paratrigeminal headache, petrosal headache, Sluder's headache, vidian headache, low CSF pressure headache, TMJ headache, causalgia headache, myofascial headache, all primary headaches (e.g., primary stabbing headache, primary cough headache, primary exertional headache, primary headache associated with sexual activity, headache during sleep, and new daily persistent headache), all trigeminal autonomic cephalagias (e.g., episodic paroxysmal hemicrania, SUNCT, all possible TACs, and SUNA), chronic daily headache, occipital neuralgia, atypical facial pain, neuropathic trigeminal pain, as well as various types of headache.

[0287] In yet other embodiments, the 15-PGDH inhibitor may be used to promote the survival, plasticity, and / or growth of neural stem cells or progenitor cells. The 15-PGDH inhibitor may be administered to the stem cells or progenitor cells ex vivo, in vitro, or in vivo. When administered ex vivo or in vitro to the stem cells or progenitor cells, the stem cells or progenitor cells can then be transplanted into a subject for therapeutic use.

[0288] In the case of neural stem / progenitor cells, for example, a method of transplanting neural stem / progenitor cells (plural possible) into a desired region commonly used in the field of regenerative medicine may be utilized in combination with the administration of the 15-PGDH inhibitor to the cells or the region. More specifically, for example, a method of transplanting neural stem / progenitor cells (plural possible) into a target region can be exemplified by suspending neural stem / progenitor cells in phosphate-buffered saline containing the 15-PGDH inhibitor and adding / injecting the resulting cell suspension into the target region.

[0289] In other embodiments, the 15-PGDH inhibitors described herein may be applied to nerve grafts. The grafts can include any tissue intended for transplantation in humans or animals. Various types of grafts are encompassed by the present invention, such as autografts, syngrafts, allografts, and xenografts. The size of the graft (e.g., length and diameter) is not critical. For example, the length of the nerve graft may be about 1 centimeter to about 10 centimeters, or may exceed about 10 centimeters. The diameter of the nerve graft may, as needed, match the diameter of the damaged nerve or a portion of the nerve. The nerve graft may be a structurally complete segment of the nerve to fill a gap along the length of the recipient's nerve or to replace the distal end, i.e., for end-to-end grafting. Alternatively, the nerve graft may be a partial nerve segment or may be eccentric in shape (e.g., a nerve flap) and is intended to reconstruct a damaged nerve that has some structural disruption but retains physical continuity.

[0290] When a 15-PGDH inhibitor is applied to a nerve graft, the entire graft may be treated. The therapeutic agent may be applied to the entire nerve graft in a single application. This single application may be applied to a living (fresh) or previously frozen nerve graft. The therapeutic agent may also be applied to the nerve graft before, during, or after transplantation. The therapeutic agent may be applied to any part of the graft, such as the end(s) that are joined to the cut ends of the damaged nerve. When the therapeutic agent is applied to the damaged nerve, the therapeutic agent may be applied to any region of the damaged nerve that promotes repair of the damaged nerve, such as the region of the damage site or the region adjacent to the damage site.

[0291] The 15-PGDH inhibitor can be placed in a culture medium for application to a nerve graft. The culture medium may be, for example, an undefined medium, a defined medium, or a defined medium supplemented with serum. The embodiments described herein also include a storage solution for storage of the nerve graft prior to transplantation. The storage solution contains a culture medium and at least one 15-PGDH inhibitor. The storage solution may also contain other bioactive substances such as growth factors described below.

[0292] It will be understood that other 15-PGDH inhibitors may be used in the methods described herein. These other 15-PGDH inhibitors may include known 15-PGDH inhibitors, which include, for example, the tetrazole compounds of Formulas (I) and (II), the 2-alkylideneaminooxyacetamide compounds of Formula (I), the heterocyclic compounds of Formulas (VI) and (VII), and the pyrazole compounds of Formula (III) described in U.S. Patent Application Publication No. 2006 / 0034786 and U.S. Patent No. 7,705,041; the benzylidene-1,3-thiazolidine compounds of Formula (I) described in U.S. Patent Application Publication No. 2007 / 0071699; the phenylfurylmethylthiazolidine-2,4-dione compounds and phenylthienylmethylthiazolidine-2,4-dione compounds described in U.S. Patent Application Publication No. 2007 / 0078175; the thiazolidinedione derivatives described in U.S. Patent Application Publication No. 2011 / 0269954; the phenylfuran compounds, phenylthiophene compounds, or phenylpyrazole compounds described in U.S. Patent No. 7,294,641; 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acid and salts; the lactones described in U.S. Patent No. 4,725,676; the azo compounds described in U.S. Patent No. 4,889,846; and the 15-PGDH inhibitors described in PCT / US2014 / 060761 and U.S. Patent Application Publication No. 2015 / 0072998A1, all of which are hereby incorporated by reference in their entirety.

[0293] The 15-PGDH inhibitors described herein may be provided in a pharmaceutical composition or a cosmetic composition, depending on the pathological or cosmetic condition or disorder being treated. A pharmaceutical composition containing a 15-PGDH inhibitor described herein as an active ingredient may be produced by mixing the derivative with a pharmaceutically acceptable carrier(s) or excipient(s), or by diluting the 15-PGDH inhibitor with a diluent according to conventional methods. The pharmaceutical composition may further contain a filler, an anti-cohesive, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, etc. The pharmaceutical composition may be formulated into a suitable preparation according to methods known to those skilled in the art so as to provide immediate release, controlled release or sustained release of the 15-PGDH inhibitor after administration to a mammal.

[0294] In some embodiments, the pharmaceutical composition may be formulated into a parenteral dosage form or an oral dosage form. The solid dosage form for oral administration may be produced by adding an excipient to the 15-PGDH inhibitor (optionally together with a binder, a disintegrant, a lubricant, a coloring agent, and / or a flavoring agent), and shaping the resulting mixture into the form of tablets, dragees, granules, powders, or capsules. The additives that can be added to the composition may be conventional in the art. For example, examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicates, etc. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphonate, and polyvinylpyrrolidone. Examples of disintegrants include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Further, purified talc, stearates, sodium borate, and polyethylene glycol may be used as lubricants, and sucrose, bitter orange peel, citric acid, and tartaric acid may be used as flavoring agents. In some embodiments, the pharmaceutical composition can be made into an aerosol formulation (e.g., capable of spraying them) for administration by inhalation.

[0295] The 15-PGDH inhibitor may be combined with a flavoring agent, a buffering agent, a stabilizer, etc., and incorporated into an oral liquid dosage form such as a solution, a syrup, or an elixir according to conventional methods. An example of a buffering agent may be sodium citrate. Examples of stabilizers include tragacanth, acacia, and gelatin.

[0296] In some embodiments, the 15-PGDH inhibitor may be incorporated into an injectable dosage form for, e.g., subcutaneous, intramuscular or intravenous routes, by adding thereto a pH adjuster, a buffer, a stabilizer, a relaxant, a local anesthetic. Examples of pH adjusters and buffers include sodium citrate, sodium acetate and sodium phosphate. Examples of stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. The local anesthetic may be procaine HCl, lidocaine HCl, etc. The relaxant may be sodium chloride, glucose, etc.

[0297] In other embodiments, the 15-PGDH inhibitor may be incorporated into a suppository according to conventional methods by adding thereto a pharmaceutically acceptable carrier known in the art (e.g., polyethylene glycol, lanolin, cocoa butter or fatty acid triglyceride), together with a surfactant such as Tween if necessary.

[0298] The pharmaceutical composition may be formulated into various dosage forms as described above and then administered by various routes including oral, inhalation, transdermal, subcutaneous, intravenous or intramuscular routes. The dosage may be a pharmaceutically effective amount. The pharmaceutically effective amount may be the amount of the 15-PGDH inhibitor that treats or ameliorates alopecia, cardiovascular diseases, gastrointestinal diseases, wounds and kidney diseases. The pharmaceutically effective amount of the compound will be appropriately determined according to the type and severity of the disease to be treated, the age, sex, weight and physical condition of the patient to be treated, the administration route, the treatment period, etc. Generally, the effective amount of the compound may be in the range of about 1 to 1,000 mg for oral administration, about 0.1 to 500 mg for intravenous administration, and about 5 to 1,000 mg for rectal administration. Generally, the daily dosage for an adult is in the range of about 0.1 to 5,000 mg (preferably about 1,000 mg), but it cannot be uniformly determined as it depends on the age, sex, weight and physical condition of the patient to be treated. The formulation may be administered once a day or several times a day in divided doses.

[0299] A beauty composition containing a 15-PGDH inhibitor may be any substance or preparation intended to come into contact with various superficial parts of the human body (epidermis, hair and hair systems, nails, lips, and external genitalia), or teeth or buccal mucosa, exclusively or mainly for the purpose of washing them, perfuming them, modifying their appearance, and / or correcting body odor, and / or protecting them, or maintaining them in good condition.

[0300] The beauty composition can contain a cosmetically acceptable medium, which may be water or a mixture of water and at least one solvent selected from hydrophilic organic solvents, lipophilic organic solvents, amphiphilic organic solvents, and mixtures thereof.

[0301] In the case of topical administration, the beauty composition may be in the form of an aqueous, alcoholic, aqueous-alcoholic or oily solution or suspension; or in the form of a dispersion system of the lotion or serum type; an emulsion or multiple emulsion having a liquid or semi-liquid consistency or in paste form, obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O); in the form of free powder or compressed powder used as such or incorporated into a physiologically acceptable medium; or in the form of microcapsules or microparticles; or in the form of a vesicular dispersion system of the ionic and / or non-ionic type. Thus, the composition may be in the form of a salve, tincture, emulsion, cream, ointment, powder, patch, impregnated pad, solution, emulsion or vesicular dispersion, lotion, aqueous gel or anhydrous gel, spray, suspension, shampoo, aerosol or foam. The composition may be anhydrous or aqueous. The composition may also include solid preparations constituting soap or cleansing cakes.

[0302] The beauty composition may in particular include a hair care composition, in particular a shampoo, a setting lotion, a treatment lotion, a styling cream or gel, a restructuring lotion for hair, a mask, etc. The beauty composition may be a cream, a hair lotion, a shampoo or a conditioner. These may be used in particular in treatments using applications that may or may not be rinsed afterwards, or in the form of a shampoo. Also contemplated are compositions in the form of a foam, or in the form of a spray or aerosol and thus containing a pressurized propellant. Thus, it may be in the form of a lotion, a serum, an emulsion, a cream, a gel, a salve, an ointment, a powder, a balm, a patch, an impregnated pad, a cake or a foam.

[0303] In particular, compositions for application to the scalp or hair may be in the form of, for example, a hair care lotion for daily or twice-weekly application, in particular a shampoo or conditioner for twice-weekly or weekly application, in the form of a liquid or solid soap for washing the scalp for daily application, in the form of a hair styling shaping product (lacquer, hair setting product or styling gel), in the form of a treatment mask, or in the form of a foaming gel or cream for washing the hair. These may also be in the form of a hair dye or mascara applied using a brush or a comb.

[0304] Furthermore, in the case of topical application to the eyelashes or body hair, the composition may be in the form of a colored or uncolored mascara applied to the eyelashes using a brush, or to the beard or mustache. In the case of a composition administered by injection, the composition may be in the form of an aqueous lotion or an oily suspension. For oral use, the composition may be in the form of a capsule, granules, an oral syrup or a tablet. According to certain embodiments, the composition is in the form of a hair cream or hair lotion, a shampoo, a hair conditioner or a mascara for hair or eyelashes.

[0305] In a known manner, the cosmetic composition may also contain auxiliaries common in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV blockers, odor absorbers and dyes. The amounts of these various auxiliaries are those conventionally used in the cosmetics field, for example, 0.1% to 20% (especially 10% or less) of the total weight of the composition. Depending on their nature, these auxiliaries may be introduced into the fatty phase, the aqueous phase and / or the lipid globules.

[0306] In some embodiments, the 15-PGDH inhibitor may be administered in a combination therapy or co-therapy that involves administering the 15-PGDH inhibitor together with one or more additional active substances. The phrases "combinatorial therapy" or "combination therapy" encompass administering the 15-PGDH inhibitor and one or more therapeutic agents as part of a specific treatment regimen intended to produce a beneficial effect by the concurrent action of these therapeutic agents. Administration of these therapeutic agents in combination is typically carried out over a defined period (usually minutes, hours, days or weeks depending on the selected combination). "Combinatorial therapy" or "combination therapy" is intended to encompass administering these therapeutic agents sequentially (i.e., each therapeutic agent is administered at a different time), as well as administering these therapeutic agents, or at least two of these therapeutic agents, substantially simultaneously. Substantially simultaneous administration may be achieved, for example, by administering individual doses in which the ratio of each therapeutic agent is fixed, or multiple individual doses for each of the therapeutic agents, to the subject. Administering each therapeutic agent sequentially or substantially simultaneously may be done by any suitable route (including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue). The therapeutic agents may be administered by the same route or by different routes. The order in which the therapeutic agents are administered is not strictly critical.

[0307] In some embodiments, the additional active substances may in particular be lipoxygenase inhibitors as described in EP648488, in particular bradykinin inhibitors as described in EP845700, prostaglandins and their derivatives (in particular those described in WO98 / 33497, WO95 / 11003, JP97-100091, JP96-134242), agonists or antagonists of prostaglandin receptors, and nonprostanoic analogues of prostaglandins as described in EP1175891 and EP1175890, WO01 / 74307, WO01 / 74313, WO01 / 74314, WO01 / 74315 or WO01 / 72268.

[0308] In other embodiments, the 15-PGDH inhibitor may be administered in combination with an active substance (alone or as a mixture), such as a vasodilator, a prostaglandin agonist, an anti-androgen drug, cyclosporine and its analogs, an antibacterial agent, a triterpene, etc. Vasodilators may include potassium channel agonists, including minoxidil and its derivatives, aminexil, and the compounds described in U.S. Patent Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694, 5,438,058, 4,973,474, chromakalin, and diazoxide. Anti-androgen drugs may include finasteride and the compounds described in U.S. Patent No. 5,516,779, cyprosterone acetate, azelaic acid, its salts and its derivatives, and the compounds described in U.S. Patent No. 5,480,913, flutamide, and 5α-reductase inhibitors such as the compounds described in U.S. Patent Nos. 5,411,981, 5,565,467, and 4,910,226. Antibacterial compounds may include selenium derivatives, ketoconazole, triclocarban, triclosan, zinc pyrithione, itraconazole, picolinic acid, hinokitiol, mipirocine, and the compounds described in EP680745, clinycine hydrochloride, benzoyl peroxide or benzyl peroxide, and minocycline. Anti-inflammatory drugs may include inhibitors specific for Cox-2, such as NS-398 and DuP-697 (B. Batistini et al., DN&P 1994;7(8):501-511), and / or inhibitors of lipoxygenase (especially 5-lipoxygenase), such as zileuton (F.J. Alvarez & R.T. Slade, Pharmaceutical Res. 1992;9(11):1465-1473).

[0309] Other active compounds that may be present in the pharmaceutical composition and / or the cosmetic composition include aminoxyl and its derivatives, 60-[(9Z,12Z)octadeca-9,12-dienoyl]hexapyranose, benzalkonium chloride, benzethonium chloride, phenol, estradiol, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, cysteine, methionine, benzyl nicotinate, menthol, peppermint oil, calcium pantothenate, panthenol, resorcinol, protein kinase C inhibitors, prostaglandin H synthase 1, COX-1 activators or COX-2 activators, glycosidase inhibitors, glycosaminoglycanase inhibitors, pyroglutamic acid esters, hexosaccharidic or acylhexosaccharidic acids, substituted ethylene aryls, N-acylated amino acids, flavonoids, derivatives and analogs of ascomycin, histamine antagonists, triterpenes (such as ursolic acid and the compounds described in U.S. Patent No. 5,529,769, U.S. Patent No. 5,468,888, U.S. Patent No. 5,631,282, etc.), saponins, proteoglycanase inhibitors, estrogen agonists and antagonists, pseudopterins, cytokine and growth factor promoters, inhibitors of IL-1 or IL-6, IL-10 promoters, TNF inhibitors, vitamins (such as vitamin D, analogs of vitamin B12 and panthenol), hydroxy acids, benzophenones, ester-type fatty acids, and hydantoins may be included.

[0310] The pharmaceutical composition and / or cosmetic composition containing a 15-PGDH inhibitor described in this specification may further contain at least one compound selected from, for example, prostaglandins, particularly prostaglandin PGE1, PGE2, their salts, their esters, their analogs and their derivatives, particularly those described in WO98 / 33497, WO95 / 11003, JP97-100091, JP96-134242, particularly agonists of prostaglandin receptors. In particular, the pharmaceutical composition is prostaglandin F 2α agonists of receptors (in acid form, or in precursor form, particularly in ester form) (for example, latanoprost, fluprostenol, cloprostenol, bimatoprost, unoprostone, etc.), agonists of prostaglandin E2 receptors (and their precursors, particularly esters such as travoprost) (17-phenyl PGE2, biprostol, butaprost, misoprostol, sulprostone, 16,16-dimethyl PGE2, 11-deoxy PGE1, 1-deoxy PGE1, etc.), agonists of prostacyclin (IP) receptors and their precursors (particularly esters) (cicaprost, iloprost, isocarbacyclin, beraprost, epoprostenol, treprostinil, etc.), agonists of prostaglandin D2 receptors and their precursors (particularly esters) (BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), BW246C ((4R)-(3-[(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), etc.), agonists of receptors of thromboxane A2 (TP) and their precursors (particularly esters) (I-BOP ([1S-[1a,2a(Z),3b(1E,3S),4a]]-7-[3-[3-hydroxy-4-[4-(iodophenoxy)-1-butenyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid), etc.) and may contain at least one compound such as that.

[0311] Advantageously, the composition comprises at least one 15-PGDH inhibitor as defined above and a series 2 prostaglandin in the form of, for example, physiological saline or a precursor form (especially in the form of an ester (e.g., isopropyl ester)), in particular PGF 2α and PGE2), their derivatives (16,16-dimethyl PGE2, 17-phenyl PGE2 and 16,16-dimethyl PGF 2α , 17-phenyl PGF 2α etc.), a series 1 prostaglandin in the form of physiological saline or an ester (11-deoxyprostaglandin E1, 1-deoxyprostaglandin E1 etc.), their analogs (especially latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, biprostol, butaprost, misoprostol, their salts or their esters), etc., and at least one prostaglandin or one prostaglandin derivative.

[0312] The present invention will be further illustrated by the following examples, which are not intended to limit the scope of the claims.

[0313] Example 1 Analysis of the activity of 15-PGDH inhibitors This example provides data for two groups (Table 1 and Table 2) of structural analogs of a specified 15-PGDH inhibitor. The data provided are the IC 50 of each compound for the inhibition of the enzyme activity of recombinant 15-PGDH in an in vitro assay. Recombinant 15-PGDH is of human origin unless otherwise specified. Further, this example provides data for selected compounds on the induction of PGE2 in an A549 cell culture given the selected compound at 2.5 μM or 0.1 μM.

[0314] [Table 1] TIFF2025102891000022.tif215160TIFF2025102891000023.tif215160TIFF2025102891000024.tif215160TIFF2025102891000025.tif215160TIFF2025102891000026.tif218160TIFF2025102891000027.tif215159TIFF2025102891000028.tif216160TIFF2025102891000029.tif218160TIFF2025102891000030.tif220160TIFF2025102891000031.tif215160TIFF2025102891000032.tif215160TIFF2025102891000033.tif218160TIFF2025102891000034.tif216160TIFF2025102891000035.tif216160TIFF2025102891000036.tif217160TIFF2025102891000037.tif217160TIFF2025102891000038.tif215160TIFF2025102891000039.tif217160TIFF2025102891000040.tif216160

[0315]

Table 2

[0316] Example 2 The following examples illustrate the synthesis of at least some of the analogs described in Tables 1 and 2 and present the mass spectrometry and NMR confirmation of their structures.

[0317]

Chemical formula

[0318] Step 1 3-Ethyl 1-methyl 5-amino-1H-pyrazole-1,3-dicarboxylate (426 mg, 2 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (1.84 g, 10 mmol) were placed in a microwave tube. The mixture was heated at 150 °C for 6 h in a microwave reactor and then cooled to room temperature. The slurry solution was filtered and washed with ether to obtain a white solid (226 mg, yield 41%). This ester intermediate was dissolved in MeOH (2 mL) + aqueous NaOH solution (1 M, 2 mL), and the solution was stirred at room temperature for 12 h. Then the solvent was removed, and the residue was acidified to pH 2 with 1 M HCl. The precipitate was collected by filtration and washed with cold water. The obtained solid was dried to give the pure product as a white solid (182 mg, yield 90%). MS(ES+) m / z = 248 [M+H] + 。

[0319] Step 2 POCl3 (0.38 mL, 4 mmol) was added to a 25 mL vial containing 5-oxo-7-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (99 mg, 0.4 mmol). The mixture was heated at 100 °C for 3 h, and the excess POCl3 was removed under reduced pressure. The obtained crude product was dissolved in dichloromethane (2 mL) + Et3N (0.55 mL, 4 mmol) and cooled to -20 °C. Then piperidine (0.08 mL, 0.8 mmol) was added to this solution, and stirring was continued at -20 °C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, the residue was loaded onto a silica gel column, and eluted with hexane / ethyl acetate = 10 / 1 to obtain a yellow solid (47 mg, yield 35%). 1 H NMR(400MHz, chloroform-d) δ 11.64(s, 1H), 7.47(s, 1H), 3.82(t, J = 5.0Hz, 2H), 3.29(t, J = 5.2Hz, 2H), 1.71 - 1.69(m, 4H), 1.53 - 1.47(m, 2H). m / z(ES+):333 [M+H] + 。

[0320] Step 3 Under a nitrogen atmosphere, a boronic acid or boronic acid ester (0.11 mmol) was added to a dry tube containing (5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone (33 mg, 0.1 mmol), Pd(dppf)Cl2 (4 mg, 0.5% mmol), K3PO4 (42 mg, 0.2 mmol), 1,4-dioxane (2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C until the reaction was complete (the reaction was monitored by LC / MS). The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to obtain the product.

[0321]

Chemical Structure

[0322] The target compound 36a (yield 81%) was obtained by the above general procedure.

[0323] 1 H NMR (400 MHz, chloroform-d) δ 12.51 (s, 1H), 8.05 - 8.01 (m, 2H), 7.77 (s, 1H), 7.20 (t, J = 8.3 Hz, 2H), 3.84 (s, 2H), 3.33 (s, 2H), 1.72 - 1.66 (m, 4H), 1.51 - 1.49 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 164.3 (d, J = 251.4 Hz), 162.5, 157.0, 153.0, 139.4, 133.6 (d, J = 3.1 Hz), 132.5 (q, J = 35.5 Hz), 129.7 (d, J = 8.5 Hz), 122.5 (q, J = 273.8 Hz), 116.2 (d, J = 21.8 Hz), 112.1 (q, J = 4.8 Hz), 106.4, 48.2, 43.0, 26.2, 25.4, 24.5. MS(ES+) m / z = 393 [M + H]+ .

[0324] [Chemical formula]

[0325] The target compound 37a (yield 85%) was obtained by the above general procedure.

[0326] 1 H NMR (400 MHz, chloroform-d) δ 13.68 (s, 1H), 9.77 (s, 2H), 9.49 (s, 1H), 7.97 (s, 1H), 3.85 (t, J = 4.9 Hz, 2H), 3.39 - 3.35 (m, 2H), 1.73 - 1.72 (m, 4H), 1.57 - 1.52 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.1, 158.9, 155.6, 153.4, 151.7, 139.8, 133.4 (q, J = 35.8 Hz), 131.4, 122.3 (q, J = 274.1 Hz), 111.2 (q, J = 5.0 Hz), 107.6, 48.2, 43.0, 26.2, 25.4, 24.5. MS (ES+) m / z = 377 [M + H] + .

[0327] [Chemical formula]

[0328] The target compound 38a (yield 65%) was obtained by the above general procedure.

[0329] 1 H NMR (400 MHz, chloroform-d) δ 12.55 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 4.02 (s, 3H), 3.83 (t, J = 4.8 Hz, 2H), 3.33 (t, J = 4.8 Hz, 2H), 1.71 (s, 4H), 1.51 (s, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.4, 153.1, 152.6, 139.7, 138.8, 132.4 (q, J = 35.6 Hz), 130.2, 122.5 (q, J = 273.7 Hz), 122.0, 118.4, 111.9 (q, J = 5.0 Hz), 105.7, 48.2, 42.9, 39.4, 26.2, 25.4, 24.5. MS (ES+) m / z = 379 [M+H] + 。

[0330]

Chem.

[0331] The target compound 40a (yield 79%) was obtained by the above general procedure.

[0332] 1 1H NMR (400 MHz, chloroform-d) δ 12.49 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.85 (s, 1H), 7.34 (d, J = 7.8 Hz, 2H), 3.84 (t, J = 5.1 Hz, 2H), 3.34 (t, J = 5.5 Hz, 2H), 2.45 (s, 3H), 1.74 - 1.67 (m, 4H), 1.54 - 1.48 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 162.5, 158.3, 153.2, 140.9, 139.4, 134.7, 132.3 (q, J = 35.2 Hz), 129.9, 127.6, 122.6 (q, J = 273.7 Hz), 112.4 (q, J = 4.8 Hz), 106.3, 106.2, 48.2, 43.0, 26.2, 25.4, 24.5, 21.4. MS (ES+) m / z = 389 [M+H] + 。

[0333]

Chem.

[0334] The target compound 43a (yield 51%) was obtained by the above general procedure.

[0335] 1 H NMR (400 MHz, chloroform-d) δ 12.45 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.68 - 7.58 (m, 3H), 7.53 (d, J = 7.5 Hz, 1H), 3.84 - 3.81 (m, 2H), 3.37 - 3.34 (m, 2H), 1.71 - 1.65 (m, 4H), 1.55 - 1.49 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.2, 158.4, 152.3, 139.5, 137.8 (q, J = 2.1 Hz), 132.0 (q, J = 35.6 Hz), 131.9, 131.5, 129.5, 128.5 (q, J = 31.0 Hz), 126.7 (q, J = 5.1 Hz), 123.8 (q, J = 275.4 Hz), 122.4 (q, J = 275.2 Hz), 115.6 (q, J = 2.1 Hz), 106.8 (q, J = 1.9 Hz), 48.2, 43.0, 26.2, 25.4, 24.5. MS (ES+) m / z = 443 [M + H] + 。

[0336]

Chem.

[0337] The target compound 47a (yield 66%) was obtained by the above general procedure.

[0338] 1 H NMR (400 MHz, chloroform-d) δ 11.69 (s, 1H), 8.17 (d, J = 8.1 Hz, 2H), 7.88 (s, 1H), 7.78 (d, J = 8.1 Hz, 2H), 3.84 (t, J = 5.0 Hz, 2H), 3.34 (t, J = 5.0 Hz, 2H), 1.75 - 1.71 (m, 4H), 1.55 - 1.50 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.2, 156.5, 153.0, 140.7, 139.7, 132.7 (q, J = 60.5 Hz), 132.3 (q, J = 60.3 Hz), 127.9, 126.0 (q, J = 3.8 Hz), 123.9 (q, J = 274.1 Hz), 122.4 (q, J = 273.7 Hz), 112.5 (q, J = 4.8 Hz), 106.9, 48.2, 43.0, 26.2, 25.4, 24.5. MS (ES+) m / z = 443 [M+H] + 。

[0339]

Chem.

[0340] The target compound 46a (yield 73%) was obtained by the above general procedure.

[0341] 1 1H NMR (400 MHz, chloroform-d) δ 12.27 (s, 1H), 7.77 (s, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.53 (d, J = 5.0 Hz, 1H), 7.17 (t, J = 4.2 Hz, 1H), 3.83 (t, J = 5.1 Hz, 2H), 3.32 (t, J = 5.5 Hz, 2H), 1.74 - 1.65 (m, 4H), 1.53 - 1.48 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 162.4, 153.0, 152.7, 142.9, 139.5, 132.4 (q, J = 35.4 Hz), 130.0, 128.6, 127.7, 122.4 (q, J = 273.8 Hz), 111.3 (q, J = 4.9 Hz), 106.2, 48.2, 43.0, 26.1, 25.4, 24.5. MS (ES+) m / z = 381 [M+H] + 。

[0342]

Chem.

[0343] The target compound 61a (yield 82%) was obtained by the above general procedure.

[0344] 1 H NMR (400 MHz, chloroform-d) δ 12.25 (s, 1H), 8.07 - 8.05 (m, 2H), 7.87 (s, 1H), 7.55 - 7.52 (m, 3H), 3.84 (t, J = 5.1 Hz, 2H), 3.34 (t, J = 5.4 Hz, 2H), 1.75 - 1.66 (m, 4H), 1.54 - 1.49 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.4, 158.3, 153.1, 139.5, 137.5, 132.5 (q, J = 35.3 Hz), 130.5, 129.1, 127.7, 122.6 (q, J = 273.8 Hz), 112.6 (q, J = 4.8 Hz), 106.4, 48.2, 43.0, 26.2, 25.4, 24.5. MS(ES+) m / z = 375 [M + H] + 。

[0345]

Chemical formula

[0346] The target compound 56a (yield 53%) was obtained by the above general procedure.

[0347] 1 H NMR (400 MHz, chloroform-d) δ 11.01 (s, 1H), 8.05 (d, J = 7.1 Hz, 2H), 7.88 (s, 1H), 7.52 (d, J = 7.1 Hz, 2H), 3.84 - 3.82 (m, 2H), 3.35 - 3.32 (m, 2H), 1.72 - 1.68 (m, 4H), 1.54 - 1.50 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.0, 157.1, 153.1, 140.0, 136.9, 135.9, 132.7 (q, J = 35.3 Hz), 129.4, 128.8, 122.8 (q, J = 273.8 Hz), 112.2, (q, J = 4.8 Hz), 106.5, 48.2, 42.9, 26.2, 25.4, 24.5. MS (ES+) m / z = 409 [M+H] + 。

[0348]

Chem.

[0349] The target compound 68a (yield 48%) was obtained by the above general procedure.

[0350] 1 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 2H), 8.11 (d, J = 8.3 Hz, 2H), 8.03 (s, 1H), 6.91 (d, J = 8.3 Hz, 2H), 3.63 (d, J = 5.1 Hz, 2H), 3.20 (t, J = 5.5 Hz, 2H), 1.61 - 1.52 (m, 4H), 1.38 - 1.35 (m, 2H); 13 13C NMR (101 MHz, DMSO-d6) δ 162.3, 160.3, 157.4, 153.5, 138.8, 130.9 (q, J = 34.8 Hz), 129.6, 128.4, 123.2 (q, J = 273.6 Hz), 116.3, 111.5 (q, J = 5.2 Hz), 104.9, 47.8, 42.4, 26.3, 25.7, 24.4. MS (ES+) m / z = 391 [M+H] + 。

[0351]

Chem.

[0352] The target compound 69a (yield 86%) was obtained by the above general procedure.

[0353] 1 H NMR (400 MHz, chloroform-d) δ 12.63 (s, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.79 (s, 1H), 7.01 (d, J = 8.0 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.83 (t, J = 5.1 Hz, 2H), 3.33 (t, J = 5.4 Hz, 2H), 1.73 - 1.65 (m, 4H), 1.53 - 1.50 (m, 2H), 1.46 (t, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 162.6, 161.0, 157.9, 153.2, 139.3, 132.2 (q, J = 35.2 Hz), 129.8, 129.2, 122.7 (q, J = 273.7 Hz), 115.0, 112.0 (q, J = 4.7 Hz), 105.9, 63.7, 48.2, 43.0, 26.2, 25.4, 24.5, 14.8. MS (ES+) m / z = 419 [M + H] + 。

[0354]

Chem.

[0355] The target compound 45a (yield 50%) was obtained by the above general procedure.

[0356] 1 H NMR (400 MHz, chloroform-d) δ 8.16 (s, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.18 (s, 1H), 3.78 - 3.76 (m, 4H), 1.70 - 1.62 (m, 6H); 1313C NMR (101 MHz, chloroform-d) δ 165.4, 161.6, 153.2, 150.2, 148.7, 144.8, 134.6 (q, J = 38.5 Hz), 124.3, 119.2 (q, J = 274.8 Hz), 104.5 (q, J = 4.1 Hz), 100.4, 48.4, 43.8, 26.5, 25.7, 24.6. MS (ES+) m / z = 382 [M+H] + 。

[0357]

Chem.

[0358] Piperidine and the chloride intermediate in the above general procedure, which is (5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone, underwent an S N Ar reaction to obtain the target compound 39a.

[0359] Piperidine (0.05 mL, 0.5 mmol) was added to a solution of (5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone (33 mg, 0.1 mmol) in 1,4-dioxane (2 mL). The mixture was heated at 90 °C for 3 h, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give the product as a pale yellow solid (31 mg, 81% yield).

[0360] 1 1H NMR (400 MHz, chloroform-d) δ 11.38 (s, 1H), 6.90 (s, 1H), 3.77 (t, J = 5.4 Hz, 2H), 3.73 - 3.71 (t, J = 5.1 Hz, 4H), 3.30 (t, J = 5.4 Hz, 2H), 1.74 - 1.65 (m, 10H), 1.50 - 1.45 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 163.1, 158.3, 153.3, 139.6, 132.76 (q, J = 34.7 Hz), 122.70 (q, J = 273.5 Hz), 102.42 (q, J = 5.4 Hz), 99.6, 48.0, 46.8, 42.8, 26.1, 25.6, 25.4, 24.6, 24.5. MS (ES+) m / z = 382 [M+H] + 。

[0361]

Chem.

[0362] Step 1 Ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (2.44 g, 11 mmol) was added to a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (1.55 g, 10 mmol) in AcOH (20 mL). The mixture was refluxed for 5 h and then cooled to 0 °C in an ice bath. The precipitate was collected by filtration and washed with ether to give a yellow solid (2.47 g, yield 79%). This ester intermediate was dissolved in MeOH (20 mL) + aqueous NaOH solution (1 M, 20 mL), and the solution was stirred at room temperature for 8 h. The solvent was then removed, and the residue was acidified to pH 2 with 1 M HCl. The precipitate was collected by filtration and washed with cold water. The resulting solid was dried to give the pure product as a yellow solid (2.05 g, yield 91%).

[0363] 1 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 12.55 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 6.12 (s, 1H), 3.84 (s, 3H).

[0364] Step 2 POCl3 (4.69 mL, 50 mmol) was added to a 25 mL vial containing 5-(4-methoxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.43 g, 5 mmol). The mixture was heated at 100 °C for 3 h, and the excess POCl3 was removed under reduced pressure. The resulting crude product was dissolved in dichloromethane (10 mL) + Et3N (6.88 mL, 50 mmol) and cooled to -20 °C. Then, piperidine (1 mL, 10 mmol) was added to this solution, and stirring was continued at -20 °C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was loaded onto a silica gel column and eluted with hexane / ethyl acetate = 10 / 1 to give a yellow solid (705 mg, 38% yield).

[0365] 1 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 8.3 Hz, 2H), 7.42 (s, 1H), 7.02 (d, J = 8.3 Hz, 2H), 6.97 (s, 1H), 3.89 (s, 3H), 3.77 (t, J = 4.5 Hz, 2H), 3.73 (t, J = 5.3 Hz, 2H), 1.72 - 1.69 (m, 4H), 1.63 - 1.59 (m, 2H).

[0366] Step 3 Under a nitrogen atmosphere, a boronic acid or boronic acid ester (0.11 mmol) was added to a dry tube containing (7-chloro-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone (37 mg, 0.1 mmol), Pd(dppf)Cl2 (4 mg, 0.5% mmol), K3PO4 (42 mg, 0.2 mmol), 1,4-dioxane (2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C until the reaction was complete (monitored by LC / MS). The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to give the product.

[0367] [Chemistry]

[0368] The target compound 22a (yield 67%) was obtained by the above general procedure.

[0369] 1 H NMR (400 MHz, chloroform-d) δ 8.87 - 8.84 (m, 2H), 8.13 - 8.08 (m, 2H), 8.01 - 7.98 (m, 2H), 7.44 - 7.42 (m, 1H), 7.06 - 7.00 (m, 3H), 3.90 (s, 3H), 3.78 - 3.68 (m, 4H), 1.71 - 1.59 (m, 6H); 13 C NMR (101 MHz, chloroform-d) δ 162.8, 161.9, 156.2, 151.8, 150.3, 149.6, 143.6, 138.5, 129.1, 128.8, 123.2, 114.4, 105.9, 98.2, 55.5, 48.4, 43.5, 26.6, 25.6, 24.6. MS (ES+) m / z = 414 [M + H] + 。

[0370] [Chemistry]

[0371] The target compound 23a (yield 57%) was obtained by the above general procedure.

[0372] 1 H NMR (400 MHz, chloroform-d) δ 9.21 (s, 1H), 8.77 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.49 (dd, J = 8.0, 4.9 Hz, 1H), 7.38 (s, 1H), 7.02 - 6.98 (m, 3H), 3.86 (s, 3H), 3.75 - 3.68 (m, 4H), 1.68 - 1.57 (m, 6H); 1313C NMR (400 MHz, chloroform-d) δ 162.9, 161.9, 156.3, 151.7, 149.6, 143.5, 136.9, 129.3, 128.9, 127.4, 123.2, 114.4, 105.6, 98.1, 55.5, 48.4, 43.5, 26.6, 25.6, 24.6. MS (ES+) m / z = 414 [M+H] + 。

[0373]

Chem.

[0374] The target compound 24a (yield 36%) was obtained by the above general procedure.

[0375] 1 1H NMR (400 MHz, chloroform-d) δ 9.13 (d, J = 8.0 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.28 (s, 1H), 8.20 (d, J = 7.7 Hz, 2H), 7.92 (t, J = 7.8 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.04 (d, J = 7.7 Hz, 2H), 7.00 (s, 1H), 3.90 (s, 3H), 3.81 - 3.78 (m, 2H), 3.75 - 3.72 (m, 2H), 1.72 (s, 4H), 1.63 (s, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 163.3, 161.7, 156.4, 151.2, 150.3, 149.9, 148.3, 143.9, 136.6, 129.7, 129.0, 126.2, 125.4, 114.3, 106.2, 97.5, 55.4, 48.4, 43.5, 26.7, 25.7, 24.7. MS (ES+) m / z = 414 [M+H] + 。

[0376]

Chem.

[0377] The target compound 25a (yield 53%) was obtained by the above general procedure.

[0378] 1 H NMR (400 MHz, chloroform-d) δ 8.63 - 8.61 (m, 1H), 8.12 - 8.08 (m, 3H), 7.94 - 7.92 (m, 1H), 7.43 (s, 1H), 7.06 - 7.03 (m, 3H), 3.90 (s, 3H), 3.78 - 3.71 (m, 4H), 1.72 - 1.70 (m, 4H), 1.65 - 1.63 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.6, 162.1, 156.2, 152.2, 152.0, 150.2, 149.6, 142.2, 141.3, 128.9, 128.9, 124.0, 121.9, 114.5, 106.1, 98.6, 55.5, 48.4, 43.6, 26.6, 25.7, 24.6. MS(ES+) m / z = 448 [M + H] + 。

[0379]

Chem.

[0380] The target compound 26a (yield 45%) was obtained by the above general procedure.

[0381] 1 H NMR (400 MHz, chloroform-d) δ 8.80 (s, 1H), 8.69 - 8.67 (m, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.56 - 7.54 (m, 1H), 7.32 (s, 1H), 7.02 - 6.98 (m, 3H), 3.86 (s, 3H), 3.70 - 3.61 (m, 4H), 1.64 (s, 4H), 1.50 (s, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.8, 162.0, 155.9, 152.0, 150.2, 149.0, 148.1, 141.6, 140.9, 137.9, 131.1, 131.0, 129.0, 128.9, 125.0, 114.4, 113.1, 107.1, 98.2, 55.5, 48.4, 43.5, 26.5, 25.6, 24.6. MS (ES+) m / z = 448 [M+H] + 。

[0382]

Chem.

[0383] The target compound 27a (yield 65%) was obtained by the above general procedure.

[0384] 1 1H NMR (400 MHz, chloroform-d) δ 8.88 (s, 1H), 8.67 (t, J = 8.0 Hz, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.39 (s, 1H), 7.15 (dt, J = 8.7, 2.5 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.99 (s, 1H), 3.90 (s, 3H), 3.76 (s, 2H), 3.68 (s, 2H), 1.70 (s, 4H), 1.59 (s, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 164.5 (d, J = 244.8 Hz), 162.9, 161.9, 156.3, 151.7, 149.6, 148.5 (d, J = 15.8 Hz), 142.4 (d, J = 6.4 Hz), 142.3, 129.1, 128.8, 125.4 (d, J = 4.7 Hz), 114.4, 109.5 (d, J = 37.5 Hz), 105.4, 98.1, 55.5, 48.4, 43.5, 26.6, 25.6, 24.6. MS (ES+) m / z = 432 [M+H] + 。

[0385] [Chemical formula]

[0386] The target compound 28a (yield 72%) was obtained by the above general procedure.

[0387] 1 H NMR (400 MHz, chloroform-d) δ 9.48 (s, 2H), 9.40 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 3.90 (s, 3H), 3.77 (t, J = 5.3 Hz, 2H), 3.71 (t, J = 5.5 Hz, 2H), 1.71 - 1.70 (m, 4H), 1.62 - 1.60 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.6, 162.0, 159.9, 156.8, 156.2, 152.0, 149.4, 140.5, 128.9, 128.9, 125.8, 114.4, 105.6, 98.5, 55.5, 48.4, 43.6, 26.6, 25.6, 24.6. MS (ES+) m / z = 415 [M + H] + .

[0388] [Chemical formula]

[0389] The target compound 29a (yield 64%) was obtained by the above general procedure.

[0390] 11H NMR (400 MHz, chloroform-d) δ 8.83 (s, 1H), 8.27 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.46 (s, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.85 (s, 1H), 3.98 (s, 3H), 3.83 (s, 3H), 3.78 (t, J = 5.4 Hz, 2H), 3.71 (t, J = 5.4 Hz, 2H), 1.70 (s, 4H), 1.61 (s, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 163.6, 161.5, 156.0, 151.1, 149.6, 139.2, 139.1, 136.8, 133.6, 129.8, 128.7, 126.5, 114.2, 112.7, 101.0, 96.9, 55.4, 48.4, 43.4, 39.4, 26.8, 25.7, 24.7. MS (ES+) m / z = 417 [M + H] + 。

[0391]

Chem.

[0392] The target compound 30a (yield 61%) was obtained by the above general procedure.

[0393] 1 1H NMR (400 MHz, chloroform-d) δ 8.46 - 8.45 (m, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.89 - 7.87 (m, 1H), 7.74 (s, 1H), 7.45 (s, 1H), 7.06 - 7.02 (m, 3H), 3.90 (s, 3H), 3.77 (s, 2H), 3.71 (s, 2H), 1.71 (s, 4H), 1.62 (s, 2H); 1313C NMR (101 MHz, chloroform-d) δ 163.9 (d, J = 239.5 Hz), 162.7, 162.0, 156.2, 151.9, 149.6, 148.3 (d, J = 15.1 Hz), 143.6, 143.5, 142.2 (d, J = 3.6 Hz), 128.9, 121.0 (d, J = 4.5 Hz), 114.4, 109.9 (d, J = 40.1 Hz), 106.1, 98.4, 55.5, 48.4, 43.6, 26.6, 25.6, 24.6. MS (ES+) m / z = 432 [M+H] + 。

[0394]

Chem.

[0395] The target compound 71a (yield 73%) was obtained by the above general procedure.

[0396] 1 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 6.94 - 6.91 (m, 2H), 6.33 (dd, J = 3.8, 2.7 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.76 - 3.71 (m, 4H), 1.70 - 1.68 (m, 4H), 1.61 - 1.56 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 163.3, 161.6, 155.9, 151.6, 149.7, 139.4, 129.8, 128.8, 127.7, 123.8, 115.8, 114.3, 109.1, 106.0, 97.7, 55.5, 48.3, 43.4, 36.4, 26.6, 25.6, 24.7. MS (ES+) m / z = 416 [M+H] + 。

[0397]

Chem.

[0398] The target compound 34a (yield 85%) was obtained by the above general procedure.

[0399] 1 H NMR (400 MHz, chloroform-d) δ 8.10 - 8.06 (m, 4H), 7.57 - 7.53 (m, 3H), 7.35 (s, 1H), 7.02 - 6.99 (m, 3H), 3.87 (s, 3H), 3.74 (t, J = 5.4 Hz, 4H), 1.69 - 1.68 (m, 4H), 1.63 - 1.59 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 163.2, 161.7, 156.3, 151.5, 149.8, 146.5, 131.0, 129.6, 129.3, 128.8, 128.6, 114.3, 105.6, 97.8, 55.4, 48.4, 43.5, 26.6, 25.7, 24.7. MS(ES+) m / z = 413 [M + H] + 。

[0400]

Chem.

[0401] The target compound 67a (yield 35%) was obtained by the above general procedure.

[0402] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.78 - 3.71 (m, 4H), 2.91 - 2.84 (m, 1H), 1.71 - 1.69 (m, 4H), 1.62 - 1.60 (m, 2H), 1.36 - 1.31 (m, 2H), 1.17 - 1.13 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 163.6, 161.5, 156.3, 152.0, 151.2, 148.8, 129.9, 128.8, 114.2, 99.5, 97.1, 55.4, 48.4, 43.4, 26.7, 25.6, 24.7, 10.7, 9.5. MS (ES+) m / z = 377 [M+H] + 。

[0403]

Chem.

[0404] The target compound 35a (yield 40%) was obtained by the above general procedure.

[0405] 1 1H NMR (400 MHz, chloroform-d) δ 8.02 (d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.84 (s, 1H), 3.85 (s, 3H), 3.76 (s, 2H), 3.69 (t, J = 5.5 Hz, 2H), 2.79 (s, 3H), 1.68 (s, 4H), 1.58 (s, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 163.5, 161.6, 156.0, 151.2, 148.7, 145.9, 129.6, 128.8, 114.2, 105.5, 97.2, 55.4, 48.4, 43.4, 26.6, 25.6, 24.6, 17.4. MS (ES+) m / z = 351 [M+H] + 。

[0406]

Chem.

[0407] Also, the target compound was obtained by the SNAr reaction of the chloride intermediate with the nucleophile. N Ar reaction.

[0408] A solution of (7-chloro-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-2-yl)(piperidin-1-yl)methanone (37 mg, 0.1 mmol) in 1,4-dioxane (2 mL) was added with an amine or NaOMe (0.2 mmol). The mixture was heated at 90 °C until the reaction was complete (the reaction was monitored by LC / MS), and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to obtain the product.

[0409]

Chemical formula

[0410] The above-mentioned S N The target compound 31a (yield 81%) was obtained by the above-mentioned Ar reaction.

[0411] 1 H NMR (400 MHz, chloroform-d) δ 7.99 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 7.5 Hz, 2H), 6.63 (s, 1H), 6.38 (q, J = 5.3 Hz, 1H), 6.31 (s, 1H), 3.86 (s, 3H), 3.75 (t, J = 4.6 Hz, 2H), 3.64 (t, J = 4.6 Hz, 2H), 3.14 (d, J = 5.0 Hz, 3H), 1.68 (s, 4H), 1.57 (s, 2H); 13 C NMR (101 MHz, chloroform-d) δ 163.8, 161.1, 157.9, 150.3, 148.9, 147.5, 131.1, 128.7, 114.0, 95.8, 82.2, 55.4, 48.4, 43.3, 28.6, 26.7, 25.6, 24.6. MS (ES+) m / z = 366 [M + H] + .

[0412]

Chemical formula

[0413] The above-mentioned SN The target compound 32a (yield 82%) was obtained by the Ar reaction.

[0414] 1 H NMR (400 MHz, chloroform-d) δ 7.97 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.74 (s, 1H), 6.36 (s, 1H), 3.85 (s, 3H), 3.76 - 3.71 (m, 4H), 3.36 (s, 6H), 1.69 - 1.68 (m, 4H), 1.63 - 1.59 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 163.5, 161.2, 157.2, 151.3, 150.8, 150.2, 130.8, 128.7, 114.0, 96.1, 89.1, 55.4, 48.3, 43.4, 41.2, 26.7, 25.7, 24.7. MS(ES+) m / z = 380 [M + H] + 。

[0415]

Chemical formula

[0416] The above S N The target compound 33a (yield 68%) was obtained by the Ar reaction.

[0417] 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.77 (s, 1H), 6.58 (s, 1H), 4.24 (s, 3H), 3.86 (s, 3H), 3.74 - 3.72 (m, 2H), 3.64 - 3.61 (m, 2H), 1.68 - 1.65 (m, 4H), 1.58 - 1.52 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 163.4, 161.6, 158.5, 155.8, 152.1, 150.5, 130.0, 128.8, 114.2, 96.7, 84.1, 57.0, 55.4, 48.3, 43.2, 26.6, 25.5, 24.6. MS (ES+) m / z = 367 [M+H] + .

[0418] [Chemical formula]

[0419] Step 1 To a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (1.55 g, 10 mmol) in AcOH (20 mL) was added 4,4,4-trifluoro-1-(4-methoxyphenyl)butane-1,3-dione (2.71 g, 11 mmol). The mixture was refluxed for 5 h and then cooled to 0 °C in an ice bath. The precipitate was collected by filtration and recrystallized from hexane / ethyl acetate to give a yellow solid. This solid was dissolved in MeOH (20 mL) + aqueous NaOH solution (1 M, 20 mL), and the solution was stirred at room temperature for 5 h. Then the solvent was removed, and the residue was acidified to pH 2 with 1 M HCl. The precipitate was collected by filtration and washed with cold water. The obtained solid was dried to give the pure product as a pale yellow solid (1.55 g, yield 92%). 1 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.26 - 8.22 (m, 3H), 7.39 (d, J = 7.9 Hz, 2H), 7.32 (s, 1H), 2.39 (s, 3H).

[0420] Step 3 A solution of 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (34 mg, 0.1 mmol), HATU (42 mg, 0.11 mmol), and DIPEA (0.035 mL, 0.2 mmol) in DMF (2 mL) was added to the amine (0.12 mmol). The mixture was stirred at room temperature until the reaction was complete (monitored by LC / MS). Water was added to the solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to obtain the product.

[0421]

Chemical Structure

[0422] The target compound 7a (81% yield) was obtained by the above general procedure.

[0423] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.7 Hz, 2H), 7.65 (s, 1H), 7.32 (s, 1H), 7.18 (t, J = 5.9 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 3.59 - 3.52 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 162.4, 160.9, 155.4, 151.6, 150.3, 134.0 (q, J = 37.4 Hz), 128.9, 128.1, 119.3 (q, J = 274.7 Hz), 114.5, 104.9 (q, J = 4.1 Hz), 98.4, 55.5, 34.3, 14.9. MS (ES+) m / z = 365 [M + H] + 。

[0424]

Chemical Structure

[0425] The target compound 8a (yield 85%) was obtained by the above general procedure.

[0426] 1 H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 8.8 Hz, 2H), 7.58 (s, 1H), 7.15 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.68 (q, J = 7.0 Hz, 2H), 3.58 (q, J = 7.1 Hz, 2H), 1.32 - 1.26 (m, 6H); 13 C NMR (101 MHz, chloroform-d) δ 162.8, 162.3, 155.5, 153.1, 149.3, 134.2 (q, J = 37.3 Hz), 129.0, 128.4, 119.4 (q, J = 274.5 Hz), 114.5, 104.4 (q, J = 4.1 Hz), 99.7, 55.5, 43.6, 41.2, 14.5, 12.8. MS (ES+) m / z = 393 [M + H] + 。

[0427]

Chemical formula

[0428] The target compound 9a (yield 84%) was obtained by the above general procedure.

[0429] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 7.3 Hz, 2H), 7.62 (s, 1H), 7.29 (s, 1H), 7.04 (d, J = 7.3 Hz, 2H), 4.01 (t, J = 6.6 Hz, 2H), 3.90 (s, 3H), 3.73 (t, J = 6.6 Hz, 2H), 2.04 - 1.93 (m, 4H); 1313C NMR (101 MHz, chloroform-d) δ 162.3, 161.0, 155.4, 153.2, 149.2, 134.2 (q, J = 37.3 Hz), 128.9, 128.3, 119.4 (q, J = 274.5 Hz), 114.5, 104.5 (q, J = 4.1 Hz), 99.9, 55.5, 48.9, 47.2, 26.6, 23.9. MS (ES+) m / z = 391 [M+H] + 。

[0430]

Chem.

[0431] The target compound 10a (yield 88%) was obtained by the above general procedure.

[0432] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 7.7 Hz, 2H), 7.63 (s, 1H), 7.18 (s, 1H), 7.04 (d, J = 7.8 Hz, 2H), 4.08 - 4.06 (m, 2H), 3.90 (s, 3H), 3.86 - 3.82 (m, 4H), 3.77 - 3.75 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 162.4, 161.9, 155.7, 152.0, 149.4, 134.1 (q, J = 37.5 Hz), 129.0, 128.2, 119.3 (q, J = 274.9 Hz), 114.5, 104.7 (q, J = 4.0 Hz), 100.1, 67.1, 66.8, 55.5, 47.8, 43.1. MS (ES+) m / z = 407 [M+H] + 。

[0433]

Chem.

[0434] The target compound 11a (yield 80%) was obtained by the above general procedure.

[0435] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 7.4 Hz, 2H), 7.61 (s, 1H), 7.15 (s, 1H), 7.05 (d, J = 7.4 Hz, 2H), 3.90 (s, 3H), 3.80 (t, J = 5.5 Hz, 2H), 3.75 (t, J = 5.5 Hz, 2H), 1.90 - 1.81 (m, 4H), 1.69 - 1.65 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 163.4, 162.3, 155.5, 153.1, 149.4, 134.2 (q, J = 37.2 Hz), 129.0, 128.3, 119.4 (q, J = 274.5 Hz), 114.5, 104.3 (q, J = 4.1 Hz), 99.4, 55.5, 49.4, 47.5, 29.7, 27.2, 27.0, 26.8. MS (ES+) m / z = 419 [M + H] + 。

[0436]

Chem.

[0437] The target compound 12a (yield 72%) was obtained by the above general procedure.

[0438] 1 1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.27 (m, 3H), 8.19 (s, 1H), 7.21 (s, 1H), 7.09 (d, J = 8.5 Hz, 2H), 4.82 (t, J = 5.0 Hz, 1H), 3.84 (s, 3H), 3.56 - 3.52 (m, 2H), 3.41 - 3.37 (m, 2H); 1313C NMR (101 MHz, DMSO-d6) δ 162.5, 161.0, 155.9, 151.9, 149.9, 133.4 (q, J = 37.0 Hz), 129.9, 128.2, 119.9 (q, J = 274.6 Hz), 114.9, 106.6 (q, J = 4.1 Hz), 97.9, 60.0, 55.9, 42.1. MS (ES+) m / z = 381 [M+H] + 。

[0439]

Chem.

[0440] The target compound 13a (yield 89%) was obtained by the above general procedure.

[0441] 1 1H NMR (400 MHz, chloroform-d) δ 8.11 (d, J = 8.7 Hz, 2H), 7.66 (s, 1H), 7.23 (s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.27 (t, J = 5.7 Hz, 2H), 4.10 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 2.66 - 2.62 (m, 4H); 13 13C NMR (101 MHz, chloroform-d) δ 207.1, 162.5, 162.2, 155.9, 151.7, 149.5, 134.13 (q, J = 37.7 Hz), 129.0, 128.1, 119.33 (q, J = 274.6 Hz), 114.6, 104.89 (q, J = 4.0 Hz), 100.1, 55.5, 45.8, 42.1, 41.7, 40.9. MS (ES+) m / z = 419 [M+H] + 。

[0442]

Chem.

[0443] The target compound 14a (yield 87%) was obtained by the above general procedure.

[0444] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 7.26 (d, J = 3.1 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.69 - 4.50 (m, 2H), 3.91 (s, 3H), 3.78 - 3.69 (m, 1H), 3.28 (t, J = 12.5 Hz, 1H), 3.04 - 2.96 (m, 1H), 2.11 - 2.01 (m, 2H), 1.66 - 1.61 (m, 2H), 1.46 (s, 9H); 13 13C NMR (101 MHz, chloroform-d) δ 162.4, 162.1, 155.7, 155.1, 152.3, 149.5, 134.1 (q, J = 37.4 Hz), 129.0, 128.2, 119.3 (q, J = 274.8 Hz), 114.6, 104.6 (q, J = 4.1 Hz), 99.5, 55.5, 54.8, 47.9, 46.1, 41.7, 33.1, 32.2, 28.4。

[0445]

Chemical Structure

[0446] The target compound 15a (yield 85%) was obtained by the above general procedure.

[0447] 1 1H NMR (400 MHz, chloroform-d) δ 8.10 (d, J = 8.4 Hz, 2H), 7.63 (s, 1H), 7.15 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 5.04 - 4.89 (m, 1H), 4.17 - 4.08 (m, 2H), 3.91 (s, 3H), 3.90 - 3.85 (m, 1H), 3.72 - 3.65 (m, 1H), 2.05 - 1.95 (m, 4H); 1313C NMR (101 MHz, chloroform-d) δ 162.4, 162.1, 155.7, 152.2, 149.5, 134.2 (q, J = 37.5 Hz), 129.0, 128.2, 119.4 (q, J = 274.5 Hz), 114.6, 104.6 (q, J = 4.1 Hz), 99.6, 87.8 (d, J = 171.0 Hz), 55.5, 43.1 (d, J = 4.8 Hz), 38.8 (d, J = 4.7 Hz), 31.9 (d, J = 20.1 Hz), 31.0 (d, J = 20.2 Hz). MS (ES+) m / z = 423 [M+H] + 。

[0448]

Chem.

[0449] The target compound 16a (yield 71%) was obtained by the above general procedure.

[0450] 1 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 8.6 Hz, 2H), 7.58 (s, 1H), 7.07 (s, 1H), 7.00 (d, J = 8.9 Hz, 2H), 4.77 (d, J = 13.1 Hz, 1H), 4.55 (d, J = 13.3 Hz, 1H), 3.86 (s, 3H), 3.55 - 3.48 (m, 2H), 3.12 (t, J = 12.3 Hz, 1H), 2.81 (t, J = 11.9 Hz, 1H), 2.27 (s, 1H), 1.89 - 1.77 (m, 3H), 1.37 - 1.28 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 162.4, 162.2, 155.6, 152.6, 149.5, 134.2 (q, J = 37.4 Hz), 129.0, 128.3, 119.4 (q, J = 274.6 Hz), 114.5, 104.5 (q, J = 4.1 Hz), 99.3, 67.2, 55.5, 47.3, 42.7, 38.9, 29.4, 28.5. MS (ES+) m / z = 435 [M+H] +。

[0451]

Chem.

[0452] The target compound 17a (yield 55%) was obtained by the above general procedure.

[0453] 1 H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 7.9 Hz, 2H), 7.62 (s, 1H), 7.17 (s, 1H), 7.02 (d, J = 7.9 Hz, 2H), 4.76 - 4.72 (m, 1H), 4.62 - 4.59 (m, 1H), 4.11 - 4.01 (m, 1H), 3.88 (s, 3H), 3.69 - 3.64 (m, 1H), 2.98 - 2.91 (m, 1H), 1.81 - 1.60 (m, 6H); 13 C NMR (101 MHz, chloroform-d) δ 162.8, 162.5, 156.0, 152.7, 149.6, 133.9 (q, J = 37.6 Hz), 129.1, 129.0, 128.1, 119.3 (q, J = 274.7 Hz), 114.6, 104.7, 100.3, 60.7, 55.5, 38.6, 37.6, 26.4, 25.2, 19.8. MS (ES+) m / z = 435 [M + H] + 。

[0454]

Chem.

[0455] The target compound 18a (yield 85%) was obtained by the above general procedure.

[0456] 11H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 7.10 - 7.03 (m, 3H), 4.73 (d, J = 12.9 Hz, 1H), 4.47 (d, J = 13.4 Hz, 1H), 3.90 (s, 3H), 3.12 (t, J = 12.8 Hz, 1H), 2.83 (t, J = 12.7 Hz, 1H), 1.77 - 1.65 (m, 3H), 1.35 - 1.22 (m, 2H), 0.99 (d, J = 5.9 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 162.3, 162.1, 155.5, 152.8, 149.5, 134.2 (q, J = 37.4 Hz), 129.0, 128.3, 119.4 (d, J = 274.6 Hz), 114.5, 104.4 (q, J = 4.3 Hz), 99.2, 55.5, 47.6, 43.1, 34.7, 33.8, 31.2, 21.7. MS (ES+) m / z = 419 [M+H] + 。

[0457]

Chemical formula

[0458] The target compound 19a (yield 88%) was obtained by the above general procedure.

[0459] Mixture of rotational isomers

[0460] 11H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 8.6 Hz, 2H), 7.60 (s, 1H), 7.11 and 7.08 (2 s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 4.62 - 4.58 (m, 1H), 4.43 - 4.37 (m, 1H), 3.88 (s, 3H), 3.13 - 3.06 (m, 1H), 2.89 - 2.75 (m, 1H), 2.52 - 2.47 (m, 1H), 1.91 - 1.57 (m, 4H), 1.27 - 1.15 (m, 1H), 0.97 and 0.87 (2 d, J = 6.5 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 162.35, 162.05, 161.87, 155.52, 152.88, 152.84, 149.51, 149.46, 134.21 (q, J = 37.6 Hz), 128.98, 128.38, 128.37, 119.40 (q, J = 274.9 Hz), 114.56, 104.39, 104.34, 104.30, 99.55, 99.26, 55.49, 54.62, 50.02, 47.88, 43.40, 33.22, 32.09, 31.22, 26.03, 25.03, 19.15, 18.58. MS (ES+) m / z = 419 [M+H] + 。

[0461]

Chemical Structure

[0462] The target compound 20a (yield 61%) was obtained by the above general procedure.

[0463] 11H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 8.6 Hz, 2H), 7.57 (s, 1H), 7.03 - 6.97 (m, 3H), 5.05 and 4.58 (2 s, 1H), 4.65 and 4.24 (2 d, J = 13.8 Hz, 1H), 3.86 (s, 3H), 3.23 - 2.89 (m, 1H), 1.77 - 1.51 (m, 6H), 1.35 - 1.30 (m, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 162.6, 162.3, 155.5, 153.1, 149.5, 134.2 (q, J = 37.2 Hz), 128.9, 128.3, 119.4 (q, J = 274.5 Hz), 114.5, 104.2 (q, J = 4.6 Hz), 99.0, 98.7, 55.5, 50.2, 44.9, 42.3, 37.1, 30.9, 30.0, 26.2, 25.6, 19.0, 16.9, 15.6. MS (ES+) m / z = 419 [M+H] + 。

[0464]

Chemical Structure

[0465] The target compound 21a (yield 87%) was obtained by the above general procedure.

[0466] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.6 Hz, 2H), 7.62 (s, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 4.16 - 4.05 (m, 2H), 3.90 (s, 3H), 3.70 - 3.50 (m, 3H), 3.39 (s, 3H), 2.04 - 1.92 (m, 2H), 1.78 - 1.64 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.4, 162.1, 155.6, 152.5, 149.5, 134.2 (q, J = 37.4 Hz), 129.0, 128.3, 119.4 (q, J = 274.5 Hz), 114.5, 104.5 (q, J = 4.1 Hz), 99.4, 75.4, 55.8, 55.5, 44.3, 39.9, 31.3, 30.3. MS (ES+) m / z = 435 [M+H] + 。

[0467]

Chem.

[0468] The target compound 57a (yield 86%) was obtained by the above general procedure.

[0469] A mixture of cis and trans

[0470] 1 1H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.8 Hz, 2H), 7.61 (s, 1H), 7.11 (s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.76 - 4.50 (m, 2H), 3.92 - 3.88 and 3.82 - 3.78 (2 m, 1H), 3.89 (s, 3H), 3.59 - 3.29 (m, 1H), 2.58 - 2.52 (m, 1H), 2.28 - 2.22 (m, 2H), 2.07 - 1.76 (m, 2H), 0.97 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); 1313C NMR (101 MHz, chloroform-d) δ 162.68, 162.35, 161.66, 155.53, 155.50, 152.93, 152.87, 149.48, 134.22 (q, J = 37.4 Hz), 128.99, 128.41, 119.41 (q, J = 274.6 Hz), 114.57, 104.38 (q, J = 4.2 Hz), 99.63, 99.56, 55.51, 54.34, 53.39, 49.85, 49.38, 42.57, 39.61, 32.31, 31.31, 28.05, 27.09, 19.20, 18.67, 18.35, 17.60. MS (ES+) m / z = 433 [M+H] + 。

[0471]

Chem.

[0472] The target compound 59a (yield 89%) was obtained by the above general procedure.

[0473] 1 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 7.7 Hz, 2H), 7.63 (s, 1H), 7.16 (s, 1H), 7.02 (d, J = 7.7 Hz, 2H), 4.09 (t, J = 5.1 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H), 3.89 (s, 3H), 2.17 - 2.06 (m, 4H); 13 13C NMR (101 MHz, chloroform-d) δ 162.5, 162.0, 155.8, 151.8, 149.5, 134.2 (q, J = 37.5 Hz), 129.0, 128.2, 122.9 (t, J = 242.2 Hz), 119.3 (q, J = 274.6 Hz), 114.6, 104.8 (q, J = 4.1 Hz), 100.1, 55.5, 44.0 (t, J = 5.5 Hz), 39.8 (t, J = 5.3 Hz), 34.8 (t, J = 23.3 Hz), 34.0 (t, J = 23.4 Hz). MS (ES+) m / z = 441 [M+H]+ .

[0474]

Chem.

[0475] The target compound 60a (yield 89%) was obtained by the above general procedure.

[0476] 1 H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 7.3 Hz, 2H), 7.62 (s, 1H), 7.14 (s, 1H), 7.02 (d, J = 7.3 Hz, 2H), 4.86 (t, J = 15.4 Hz, 2H), 3.88 (s, 3H), 3.14 (t, J = 12.8 Hz, 1H), 2.81 (t, J = 12.6 Hz, 1H), 2.41 - 2.31 (m, 1H), 2.04 - 1.86 (m, 2H), 1.76 - 1.63 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.4, 162.0, 155.7, 152.1, 149.5, 134.20 (d, J = 37.4 Hz), 129.0, 128.2, 127.0 (q, J = 278.4 Hz), 119.3 (q, J = 274.5 Hz), 114.6, 104.65 (q, J = 4.2 Hz), 99.9, 55.5, 46.1, 41.7, 40.6 (q, J = 27.5 Hz), 38.6, 25.2 (q, J = 1.6 Hz), 24.4 (q, J = 1.8 Hz). MS (ES+) m / z = 473 [M + H] + .

[0477]

Chem.

[0478] The target compound 62a (yield 81%) was obtained by the above general procedure.

[0479] Mixture of rotational isomers

[0480] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.20 and 7.17 (2 s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 4.63 and 4.60 (2 s, 2H), 4.15 and 3.98 (2 t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 2.63 - 2.56 (m, 2H), 2.18 - 2.13 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 205.0, 204.9, 162.5, 162.4, 155.8, 151.9, 151.7, 149.5, 129.1, 128.2, 119.4 (q, J = 274.6 Hz), 114.6, 104.9 (q, J = 4.2 Hz), 100.3, 57.1, 55.5, 54.0, 45.8, 41.8, 38.4, 38.2, 23.0, 21.5. MS (ES+) m / z = 419 [M + H] + 。

[0481]

Chem.

[0482] The target compound 63a (yield 86%) was obtained by the above general procedure.

[0483] A mixture of rotational isomers

[0484] 1 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 8.9 Hz, 2H), 7.60 (s, 1H), 7.10 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H), 3.75 - 3.71 (m, 2H), 3.56 and 3.48 (2 s, 2H), 1.74 - 1.67 (m, 2H), 1.50 - 1.44 (m, 2H), 1.02 (s, 3H), 0.93 (s, 3H); 1313C NMR (101 MHz, chloroform-d) δ 162.6, 162.4, 162.3, 155.5, 155.5, 152.9, 152.9, 149.5, 149.4, 134.2 (q, J = 37.4 Hz), 129.0, 128.4, 119.4 (q, J = 274.7 Hz), 114.6, 104.3 (q, J = 4.2 Hz), 99.7, 99.3, 58.0, 55.5, 54.1, 48.0, 43.3, 38.1, 31.9, 31.7, 26.0, 25.7, 22.7, 21.6. MS (ES+) m / z = 433 [M+H] + 。

[0485]

Chem.

[0486] The target compound 64a (yield 88%) was obtained by the above general procedure.

[0487] A mixture of rotational isomers

[0488] 1 1H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.6 Hz, 2H), 7.63 (s, 1H), 7.19 and 7.13 (2 s, 1H), 7.03 (d, J = 8.6 Hz, 2H), 5.09 - 4.96 (m, 1H), 4.80 - 4.65 (m, 1H), 3.89 (s, 3H), 3.10 (t, J = 12.2 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.60 - 2.39 (m, 1H), 2.17 - 2.12 (m, 1H), 1.94 - 1.83 (m, 1H), 1.69 - 1.62 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.4, 162.4, 161.9, 155.8, 155.7, 152.1, 149.5, 134.3 (q, J = 37.1 Hz), 134.2 (q, J = 37.1 Hz), 129.0, 126.3 (q, J = 278.3 Hz), 126.4 (q, J = 278.3 Hz), 119.2 (q, J = 274.6 Hz), 119.3 (q, J = 274.6 Hz), 114.6, 104.7 (q, J = 4.2 Hz), 100.3, 99.8, 55.5, 47.5, 46.3 (q, J = 3.9 Hz), 43.2, 41.8 (q, J = 3.9 Hz), 41.2 (q, J = 26.4 Hz), 40.3 (q, J = 26.8 Hz), 24.6, 23.8, 23.7, 23.6. MS (ES+) m / z = 473 [M+H] + 。

[0489]

Chem.

[0490] The compound (3-(hydroxymethyl)piperidin-1-yl)(5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone was obtained by the above general procedure.

[0491] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.5 Hz, 2H), 7.63 (s, 1H), 7.15 and 7.13 (2 s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 4.17 - 3.99 (m, 2H), 3.90 (s, 3H), 3.79 - 3.45 (m, 5H), 2.36 - 2.18 (m, 1H), 2.00 - 1.78 (m, 3H), 1.52 - 1.46 (m, 1H).

[0492] A solution of (3-(hydroxymethyl)piperidin-1-yl)(5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone (22 mg, 0.05 mmol) in -10 °C was slowly added with DAST (16 mg, 0.1 mmol). The mixture was stirred at the same temperature for 3 hours. Water was added to quench the reaction, and the solution was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to obtain the target product 58a as a pale yellow solid (12 mg, yield 56%).

[0493] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.6 Hz, 2H), 7.62 (s, 1H), 7.15 and 7.12 (s, 1H), 7.05 (d, J = 8.6 Hz, 2H), 4.70 - 4.24 (m, 4H), 3.90 (s, 3H), 3.21 and 3.13 (t, J = 12.4 Hz, 1H), 2.97 and 2.86 (t, J = 12.0 Hz, 1H), 2.17 - 2.03 (m, 1H), 1.94 - 1.68 (m, 3H), 1.55 - 1.45 (m, 1H); 13 C NMR (101 MHz, chloroform-d) δ 162.4, 162.3, 162.1, 155.6, 152.5, 152.5, 149.5, 134.2 (q, J = 37.1 Hz), 129.0, 128.4, 119.4 (q, J = 274.6 Hz), 114.6, 104.5 (q, J = 3.1 Hz), 99.8, 99.5, 85.5 (d, J = 169.0 Hz), 85.3 (d, J = 169.0 Hz), 55.5, 49.7 (d, J = 6.3 Hz), 47.9, 44.9 (d, J = 6.7 Hz), 43.5, 37.8 (d, J = 18.4 Hz), 37.0 (d, J = 18.7 Hz), 26.3 (d, J = 5.4 Hz), 26.2 (d, J = 6.0 Hz), 25.2, 24.3. MS(ES+) m / z = 437 [M + H] + 。

[0494] [Chem.]

[0495] To a solution of (3-(hydroxymethyl)piperidin-1-yl)(5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone (43 mg, 0.1 mmol) in anhydrous methylene chloride (2 mL) was added Dess-Martin periodinane (64 mg, 0.15 mmol). The reaction was stirred at room temperature for 2 h. After removal of the solvent, the residue was diluted with ethyl acetate and washed with a solution of sodium thiosulfate (1.0 M in saturated sodium bicarbonate), saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded the desired product, which was used in the next step without purification. This crude product was dissolved in dichloromethane (2 mL) in an ice bath and DAST (64 mg, 0.4 mmol) was added slowly. After the addition of DAST, the mixture was warmed to room temperature and stirred for an additional 3 h. Water was added to quench the reaction and the solution was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated by rotary evaporation. This crude product was purified by flash chromatography on silica gel to give the target product 66 as a pale yellow solid (19 mg, 42% yield over two steps).

[0496] A mixture of rotational isomers

[0497] 11H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.8 Hz, 2H), 7.63 (s, 1H), 7.17 and 7.13 (2 s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 5.90 - 5.53 (m, 1H), 4.83 - 4.51 (m, 2H), 3.90 (s, 3H), 3.23 - 3.10 (m, 1H), 2.91 - 2.85 (m, 1H), 2.31 - 2.14 (m, 1H), 2.05 - 2.1 (m, 1H), 1.93 - 1.80 (m, 1H), 1.72 - 1.54 (m, 2H); 13 13C NMR (101 MHz, chloroform-d) δ 162.43, 162.37, 162.02, 155.74, 155.70, 152.27, 149.52, 134.26 (q, J = 36.8 Hz), 129.05, 128.33, 118.67 (q, J = 274.4 Hz), 118.15 (d, J = 242.2 Hz), 114.61, 104.63 (q, J = 4.2 Hz), 100.08, 99.71, 47.86, 46.63 (t, J = 6.3 Hz), 43.49, 42.17 (t, J = 6.4 Hz), 40.82 (t, J = 19.7 Hz), 39.94 (t, J = 19.9 Hz), 24.81, 24.02, 23.70 (t, J = 4.4 Hz), 23.38 (t, J = 4.2 Hz). MS (ES+) m / z = 455 [M + H] + .

[0498] [Chemical Structure]

[0499] A solution of 1-(5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl)piperidin-3-one (42 mg, 0.1 mmol) at 0 °C was slowly added to DAST (64 mg, 0.4 mmol). After the addition of DAST, the mixture was warmed to room temperature and stirred for an additional 3 hours. Water was added to quench the reaction and the solution was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to afford the target product 65a as a pale yellow solid (22 mg, 51% yield).

[0500] A mixture of rotational isomers. 1 H NMR (400 MHz, chloroform-d) δ 8.10 (d, J = 8.9 Hz, 2H), 7.64 (s, 1H), 7.20 (s, 1H), 7.05 (d, J = 8.9 Hz, 2H), 4.27 (t, J = 11.3 Hz, 1H), 4.06 (t, J = 11.7 Hz, 1H), 4.01 (t, J = 5.4 Hz, 1H), 3.91 (s, 3H), 3.81 (t, J = 5.6 Hz, 1H), 2.17 - 2.05 (m, 2H), 1.93 - 1.87 (m, 2H); 1313C NMR (101 MHz, chloroform-d) δ 162.72, 162.47, 155.84, 155.76, 151.85, 151.67, 149.54, 149.46, 134.27 (q, J = 30.6 Hz), 120.38 (q, J = 217.4 Hz), 119.34 (q, J = 274.5 Hz), 117.95 (t, J = 243.5 Hz), 129.07, 128.29, 128.26, 114.62, 104.80 (q, J = 3.5 Hz), 100.43, 100.40, 55.52, 52.40 (t, J = 32.8 Hz), 48.25 (t, J = 32.9 Hz), 46.50, 42.23, 32.92 (t, J = 22.6 Hz), 32.70 (t, J = 22.6 Hz), 22.76 (t, J = 4.2 Hz), 21.51 (t, J = 4.1 Hz). MS (ES+) m / z = 441 [M+H] + 。

[0501]

Chem.

[0502] Step 1 To a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (1.55 g, 10 mmol) in AcOH (20 mL) was added 2-bromomalonaldehyde (1.66 g, 11 mmol). The mixture was refluxed overnight and the solvent was removed under reduced pressure. The crude ester was dissolved in MeOH (20 mL) + aqueous NaOH solution (1 M, 20 mL) and the solution was stirred at room temperature for 8 h. The solvent was then removed and the residue was acidified to pH 2 with 1 M HCl. The precipitate was collected by filtration and washed with cold water. The resulting solid was dried to give the pure product as a white solid (1.27 g, 71% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 10.58 (s, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 7.04 (s, 1H).

[0503] Step 2 To a solution of 7-(piperidine-1-carbonyl)quinoxalin-2(1H)-one (1.25 g, 7 mmol), HATU (3.05 g, 8 mmol), and DIPEA (2.45 mL, 14 mmol) in DMF (14 mL) was added piperidine (0.79 mL, 8 mmol). The mixture was stirred at room temperature for 3 h. Water was added to this solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was dissolved in dichloromethane (14 mL). The mixture was placed in an ice bath, and Et3N (1.96 mL, 14 mmol) and Tf2O (1.77 mL, 10.5 mmol) were slowly added to the solution. After the addition of Tf2O, the reaction was stirred at 0 °C for 2 h, then the ice bath was removed. The mixture was stirred at room temperature for an additional 2 h. The solvent was removed, and the resulting residue was purified by flash chromatography on silica gel to give the product as a pale yellow oil (2.17 g, 82% yield). 1 1H NMR (400 MHz, chloroform-d) δ 8.78 (d, J = 2.6 Hz, 1H), 8.53 (d, J = 2.6 Hz, 1H), 7.09 (s, 1H), 3.77 (d, J = 5.2 Hz, 2H), 3.70 (t, J = 5.5 Hz, 2H), 1.72 - 1.70 (m, 4H), 1.62 - 1.60 (m, 2H).

[0504] Step 3 Under a nitrogen atmosphere, boronic acid (0.11 mmol) was added to a dry tube containing 2-(piperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-6-yl trifluoromethanesulfonate (38 mg, 0.1 mmol), Pd(dppf)Cl2 (4 mg, 0.5% mmol), K3PO4 (42 mg, 0.2 mmol), 1,4-dioxane (2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C until the reaction was complete (the reaction was monitored by LC / MS). The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to obtain the product.

[0505]

Chemical formula

[0506] The target compound 41a (yield 88%) was obtained by the above general procedure.

[0507] 1 H NMR (400 MHz, chloroform-d) δ 8.80 (d, J = 2.3 Hz, 2H), 7.59 (d, J = 7.4 Hz, 2H), 7.53 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H), 6.97 (s, 1H), 3.78 - 3.72 (m, 4H), 1.7 - 1.70 (m, 4H), 1.63 - 1.60 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.8, 152.1, 150.1, 147.4, 133.6, 131.8, 129.5, 128.8, 126.9, 123.5, 97.9, 48.3, 43.5, 26.7, 25.6, 24.6. MS(ES+) m / z = 307 [M+H] + .

[0508]

Chemical formula

[0509] The target compound 46a (yield 88%) was obtained by the above general procedure.

[0510] 1 H NMR (400 MHz, chloroform-d) δ 8.81 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 5.1 Hz, 1H), 7.37 (d, J = 3.5 Hz, 1H), 7.16 (dd, J = 5.1, 3.7 Hz, 1H), 6.97 (s, 1H), 3.78 - 3.72 (m, 4H), 1.71 - 1.70 (m, 4H), 1.62 - 1.59 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 162.7, 152.1, 149.0, 147.2, 135.8, 130.4, 128.6, 128.5, 126.5, 125.1, 117.9, 98.5, 48.3, 43.5, 26.7, 25.6, 24.6. MS (ES+) m / z = 313 [M + H] + 。

[0511]

Chemical formula

[0512] Step 1

Chemical formula

[0513] 4,4,4-Trifluoro-1-(4-methoxyphenyl)butane-1,3-dione (2.71 g, 11 mmol) was added to a solution of 5-(butylthio)-1H-pyrazol-3-amine (1.71 g, 10 mmol) in AcOH (20 mL). The mixture was refluxed overnight and then cooled to 0 °C in an ice bath. The precipitate was collected by filtration and recrystallized from hexane / ethyl acetate to give the product 2a as a yellow solid (2.4 g, yield 63%).

[0514] 1 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 8.2 Hz, 2H), 7.42 (s, 1H), 7.02 (d, J = 8.5 Hz, 2H), 6.63 (s, 1H), 3.89 (s, 3H), 3.18 (t, J = 7.3 Hz, 2H), 1.82 - 1.74 (m, 2H), 1.54 - 1.44 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 162.07, 156.67, 154.97, 150.40, 133.09 (q, J = 37.0 Hz), 128.72, 128.57, 120.86 (q, J = 274.7 Hz), 114.37, 101.74 (q, J = 4.2 Hz), 96.29, 55.40, 31.65, 31.52, 21.95, 13.59. MS (ES+) m / z = 382 [M + H] + 。

[0515] Step 2

Chem.

[0516] To a solution of 2-(butylthio)-5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (38 mg, 0.1 mmol) in chloroform (2 mL) were added H2O2 (3.7 μL, 0.12 mmol) and AcOH (0.5 mL). The reaction was monitored by LC / MS. After completion of the reaction, an aqueous NaHCO3 solution was added to quench the reaction. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to give the product 3a as a yellow solid (35 mg, yield 90%).

[0517] 11H NMR (400 MHz, chloroform-d) δ 8.11 (d, J = 7.4 Hz, 2H), 7.66 (s, 1H), 7.27 (s, 1H), 7.05 (d, J = 7.4 Hz, 2H), 3.91 (s, 3H), 3.23 - 3.11 (m, 2H), 1.94 - 1.83 (m, 1H), 1.77 - 1.65 (m, 1H), 1.57 - 1.44 (m, 2H), 0.95 (t, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 162.68, 162.57, 155.97, 150.12, 134.20 (q, J = 37.7 Hz), 129.07, 127.92, 119.22 (q, J = 274.7 Hz), 114.58, 104.66 (q, J = 3.8 Hz), 97.19, 55.49, 55.10, 23.88, 21.86, 13.63. MS (ES+) m / z = 398 [M+H] + 。

[0518]

Chem.

[0519] Instead, 5 equivalents of H2O2 were used to obtain the target compound 4a according to the above general procedure.

[0520] 1 1H NMR (400 MHz, chloroform-d) δ 8.10 (d, J = 8.3 Hz, 2H), 7.75 (s, 1H), 7.26 (s, 1H), 7.04 (d, J = 7.4 Hz, 2H), 3.90 (s, 3H), 3.41 (t, J = 7.3 Hz, 2H), 1.88 - 1.80 (m, 2H), 1.51 - 1.41 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 1313C NMR (101 MHz, chloroform-d) δ 162.88, 156.82, 156.20, 149.71, 134.73 (q, J = 37.9 Hz), 129.26, 127.66, 118.82 (q, J = 274.4 Hz), 114.74, 106.18 (q, J = 4.0 Hz), 98.80, 55.57, 54.56, 24.25, 21.51, 13.46. MS (ES+) m / z = 414 [M+H] + 。

[0521]

Chem.

[0522] By using 4,4,4-trifluoro-1-(thiazol-2-yl)butane-1,3-dione instead, the target compound 48a was prepared in the same manner as 3a.

[0523] 1 1H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 8.11 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 3.44 - 3.32 (m, 2H), 1.98 - 1.87 (m, 1H), 1.80 - 1.69 (m, 1H), 1.60 - 1.48 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). MS (ES+) m / z = 375 [M+H] + 。

[0524]

Chem.

[0525] Step 1 To a solution of 5-(butylthio)-4H-1,2,4-triazol-3-amine (1.72 g, 10 mmol) in AcOH (20 mL) was added 4,4,4-trifluoro-1-(4-methoxyphenyl)butane-1,3-dione (2.71 g, 11 mmol). The mixture was refluxed overnight and then cooled to 0 °C in an ice bath. The precipitate was collected by filtration and recrystallized from hexane / ethyl acetate to give the product as a yellow solid (2.33 g, 61% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.19 (d, J = 9.1 Hz, 2H), 7.68 (s, 1H), 7.04 (d, J = 9.1 Hz, 2H), 3.91 (s, 3H), 3.33 (t, J = 7.4 Hz, 2H), 1.85 - 1.78 (m, 2H), 1.56 - 1.47 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0526] Step 2 To a solution of 2-(butylthio)-5-(4-methoxyphenyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (38 mg, 0.1 mmol) in chloroform (2 mL) were added H2O2 (3.7 μL, 0.12 mmol) and AcOH (0.5 mL). The reaction was stirred overnight and quenched by adding aqueous NaHCO3. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to give product 49a as a yellow solid (34 mg, 85% yield).

[0527] 1 H NMR (400 MHz, chloroform-d) δ 8.15 (d, J = 8.5 Hz, 2H), 7.87 (s, 1H), 6.98 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H), 3.39 - 3.26 (m, 2H), 1.92 - 1.81 (m, 1H), 1.76 - 1.65 (m, 1H), 1.56 - 1.42 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 1313C NMR (101 MHz, chloroform-d) δ 171.5, 163.7, 162.5, 156.6, 135.64 (q, J = 39.1 Hz), 130.0, 126.8, 118.51 (q, J = 275.3 Hz), 114.8, 106.11 (q, J = 3.8 Hz), 55.6, 53.4, 24.0, 21.8, 13.6.

[0528]

Chem.

[0529] The target compound 51a was prepared in the same manner as 50a by using 4,4,4-trifluoro-1-(thiazol-2-yl)butane-1,3-dione instead.

[0530] 1 1H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 8.11 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 3.44 - 3.32 (m, 2H), 1.98 - 1.87 (m, 1H), 1.80 - 1.69 (m, 1H), 1.60 - 1.48 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

[0531]

Chem.

[0532] Step 1 Ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (2.44 g, 11 mmol) was added to a solution of 5-(butylthio)-1H-pyrazol-3-amine (1.71 g, 10 mmol) in AcOH (20 mL). The mixture was refluxed overnight and then cooled to 0 °C in an ice bath. The precipitate was collected by filtration and recrystallized from hexane / ethyl acetate to give a yellow solid (2.11 g, yield 64%). 11H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 6.10 (s, 1H), 5.97 (s, 1H), 3.83 (s, 3H), 3.08 (t, J = 7.2 Hz, 2H), 1.67 - 1.59 (m, 2H), 1.45 - 1.36 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). MS (ES+) m / z = 330 [M+H] + 。

[0533] Step 2 POCl3 (5.63 mL, 60 mmol) was added to a 25 mL vial containing 2-(butylthio)-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.98 g, 6 mmol). The mixture was heated at 90 °C for 4 h, and the excess POCl3 was removed under reduced pressure. Cold aqueous NaHCO3 solution was slowly added to the crude product cooled in an ice bath, and the resulting solution was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to give the product as a yellow solid (1.73 mg, yield 83%). 1 1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J = 9.1 Hz, 2H), 7.48 (s, 1H), 7.02 (d, J = 9.1 Hz, 2H), 3.90 (s, 3H), 3.34 (t, J = 7.4 Hz, 2H), 1.83 - 1.77 (m, 2H), 1.56 - 1.47 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). MS (ES+) m / z = 349 [M+H] + 。

[0534] Step 3 Under a nitrogen atmosphere, a boronic acid or boronic ester (0.11 mmol) was added to a dry tube containing 2-(butylthio)-7-chloro-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine (35 mg, 0.1 mmol), Pd(dppf)Cl2 (4 mg, 0.5% mmol), K3PO4 (42 mg, 0.2 mmol), 1,4-dioxane (2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C until the reaction was complete (the reaction was monitored by LC / MS). The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was dissolved in chloroform (2 mL), and H2O2 (3.7 μL, 0.12 mmol) and AcOH (0.5 mL) were added. The reaction was monitored by LC / MS. After completion of the reaction, an aqueous NaHCO3 solution was added to quench the reaction. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to obtain the product.

[0535]

Chemical formula

[0536] The target compound 5a (yield 89%) was obtained by the above general procedure.

[0537] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.6 Hz, 2H), 8.03 - 8.01 (m, 2H), 7.57 - 7.55 (m, 3H), 7.37 (s, 1H), 7.17 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.12 (t, J = 7.6 Hz, 2H), 1.90 - 1.79 (m, 1H), 1.77 - 1.66 (m, 1H), 1.55 - 1.40 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 1313C NMR (101 MHz, chloroform-d) δ 161.9, 160.7, 156.8, 150.4, 146.7, 131.3, 130.7, 129.3, 129.2, 128.9, 128.7, 114.4, 106.0, 95.9, 55.5, 55.0, 24.1, 21.9, 13.7. MS (ES+) m / z = 406 [M+H] + 。

[0538]

Chem.

[0539] The target compound 6a (yield 86%) was obtained by the above general procedure.

[0540] 1 1H NMR (400 MHz, chloroform-d) δ 8.09 - 8.04 (m, 4H), 7.35 (s, 1H), 7.27 - 7.22 (m, 2H), 7.16 (s, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.11 (t, J = 7.7 Hz, 2H), 1.90 - 1.78 (m, 1H), 1.77 - 1.66 (m, 1H), 1.55 - 1.40 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 164.29 (d, J = 253.1 Hz), 161.95, 160.74, 156.76, 150.43, 145.62, 131.58 (d, J = 8.6 Hz), 129.13, 128.92, 126.75 (d, J = 3.4 Hz), 115.94 (d, J = 21.9 Hz), 114.38, 105.83, 95.99, 55.45, 54.97, 24.10, 21.92, 13.71. MS (ES+) m / z = 424 [M+H] + 。

[0541]

Chem.

[0542] The target compound 51a (yield 54%) was obtained by the above general procedure.

[0543] 1 H NMR (400 MHz, chloroform-d) δ 9.20 (s, 1H), 8.81 (d, J = 3.3 Hz, 1H), 8.47 (dt, J = 8.1, 1.9 Hz, 1H), 8.11 (d, J = 8.9 Hz, 2H), 7.53 (dd, J = 8.2, 5.0 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.04 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.12 (t, J = 7.8 Hz, 2H), 1.93 - 1.79 (m, 1H), 1.76 - 1.65 (m, 1H), 1.53 - 1.42 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 162.1, 161.0, 156.8, 151.9, 150.3, 149.6, 143.7, 136.9, 129.0, 128.9, 123.3, 114.5, 106.1, 96.4, 55.5, 55.0, 24.1, 21.9, 13.7. MS (ES+) m / z = 407 [M + H] + 。

[0544]

Chem.

[0545] The target compound 52a (yield 81%) was obtained by the above general procedure.

[0546] 11H NMR (400 MHz, chloroform-d) δ 9.44 (s, 2H), 9.40 (s, 1H), 8.10 (d, J = 7.9 Hz, 2H), 7.46 (s, 1H), 7.21 (s, 1H), 7.03 (d, J = 7.9 Hz, 2H), 3.89 (s, 3H), 3.12 (t, J = 7.7 Hz, 2H), 1.90 - 1.79 (m, 1H), 1.75 - 1.64 (m, 1H), 1.53 - 1.42 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 162.3, 161.4, 160.1, 156.8, 156.7, 150.1, 140.7, 129.0, 128.6, 125.6, 114.6, 106.1, 96.9, 55.5, 55.0, 24.0, 21.9, 13.7. MS (ES+) m / z = 408 [M + H] + 。

[0547]

Chem.

[0548] The target compound 53a (yield 75%) was obtained by the above general procedure.

[0549] 1 1H NMR (400 MHz, chloroform-d) δ 8.81 (s, 1H), 8.28 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.52 (s, 1H), 7.07 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 4.04 (s, 3H), 3.87 (s, 3H), 3.23 - 3.10 (m, 2H), 1.89 - 1.81 (m, 1H), 1.78 - 1.70 (m, 1H), 1.55 - 1.44 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 1313C NMR (101 MHz, chloroform-d) δ 161.7, 160.0, 156.5, 150.3, 139.5, 139.1, 133.6, 129.5, 128.9, 114.3, 112.4, 101.4, 95.4, 55.4, 55.1, 39.5, 24.2, 22.0, 13.7. MS (ES+) m / z = 410 [M+H] + 。

[0550]

Chem.

[0551] The target compound 54a (yield 69%) was obtained by the above general procedure.

[0552] 1 1H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.9 Hz, 2H), 7.29 (s, 1H), 7.16 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.96 - 6.95 (m, 1H), 6.92 - 6.90 (m, 1H), 6.35 (t, J = 3.1 Hz, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.12 (t, J = 7.3 Hz, 2H), 1.89 - 1.65 (m, 2H), 1.55 - 1.42 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 161.9, 160.7, 156.4, 150.3, 139.5, 129.4, 128.9, 128.0, 123.4, 116.0, 114.4, 109.3, 106.4, 96.0, 55.5, 55.0, 36.4, 24.1, 21.9, 13.7. MS (ES+) m / z = 409 [M+H] + 。

[0553]

Chem.

[0554] The target compound 73a (yield 62%) was obtained by the above general procedure.

[0555] 1 H NMR (400 MHz, chloroform-d) δ 8.78 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.10 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 3.98 (s, 3H), 3.89 (s, 3H), 3.21 - 3.09 (m, 2H), 2.64 (s, 3H), 1.90 - 1.75 (m, 2H), 1.56 - 1.44 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 161.8, 159.7, 156.4, 150.4, 148.3, 140.5, 135.1, 129.7, 128.8, 114.4, 109.6, 103.2, 95.6, 55.5, 55.1, 39.2, 24.2, 22.0, 15.2, 13.7. MS (ES+) m / z = 424 [M + H] + .

[0556]

Chemical formula

[0557] The target compound 72a (yield 65%) was obtained by the above general procedure.

[0558] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 1.9 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.10 (t, J = 7.8 Hz, 2H), 1.90 - 1.79 (m, 1H), 1.73 - 1.62 (m, 1H), 1.54 - 1.41 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H);13 13C NMR (101 MHz, chloroform-d) δ 162.2, 161.5, 156.3, 150.0, 139.1, 137.1, 133.0, 129.0, 128.7, 114.5, 110.4, 107.8, 96.7, 55.5, 55.0, 39.0, 24.0, 21.9, 13.7. MS (ES+) m / z = 410 [M+H] + 。

[0559]

Chem.

[0560] The target compound 74a (yield 45%) was obtained by the above general procedure.

[0561] 1 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 8.0 Hz, 2H), 7.16 (s, 1H), 7.15 (s, 1H), 7.03 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.11 (t, J = 7.8 Hz, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.87 - 1.78 (m, 1H), 1.74 - 1.63 (m, 1H), 1.54 - 1.39 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 161.9, 160.5, 156.4, 150.1, 146.8, 141.7, 140.1, 129.4, 128.9, 114.4, 109.5, 107.5, 96.0, 55.5, 55.0, 36.3, 24.0, 21.9, 13.7, 13.2, 11.6. MS (ES+) m / z = 438 [M+H] + 。

[0562]

Chem.

[0563] The target compound 70a (yield 46%) was obtained by the above general procedure.

[0564] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 3.11 (t, J = 7.8 Hz, 2H), 2.54 (s, 3H), 1.87 - 1.80 (m, 1H), 1.73 - 1.65 (m, 1H), 1.53 - 1.42 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 162.1, 160.9, 156.6, 150.1, 149.6, 137.3, 132.6, 129.1, 129.0, 123.8, 114.5, 106.9, 96.3, 55.5, 55.1, 33.1, 24.1, 21.9, 13.7, 13.7. MS (ES+) m / z = 424 [M + H] + 。

[0565]

Chemical formula

[0566] The target compound 55a was obtained in the same manner as SW218511 by using 5-(butylthio)-4H-1,2,4-triazol-3-amine.

[0567] 11H NMR (400 MHz, chloroform-d) δ 8.24 (d, J = 8.8 Hz, 2H), 8.14 - 8.12 (m, 2H), 7.67 (s, 1H), 7.63 - 7.58 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.44 - 3.34 (m, 2H), 1.95 - 1.87 (m, 1H), 1.79 - 1.69 (m, 1H), 1.59 - 1.47 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13 13C NMR (101 MHz, chloroform-d) δ 170.1, 162.8, 162.2, 156.9, 148.4, 132.1, 129.7, 129.5, 129.4, 129.1, 128.2, 114.5, 106.8, 55.5, 53.2, 24.0, 21.9, 13.7. MS (ES+) m / z = 407 [M+H] + .

[0568]

Chemical Structure

[0569] Step 1 3,4-Diaminobenzoic acid (1.52 g, 10 mmol) was added to a solution of benzyl (2.1 g, 10 mmol) in MeOH (20 mL). The slurry was stirred at room temperature for 8 h. The solid in the solution was collected by filtration and recrystallized from MeOH / EtOAc to give the product as a pale yellow solid (2.93 g, 90% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.30 (dd, J = 8.8, 1.8 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.50 - 7.47 (m, 4H), 7.42 - 7.34 (m, 6H).

[0570] Step 2 To a solution of 2,3-diphenylquinoxaline-6-carboxylic acid (33 mg, 0.1 mmol), HATU (42 mg, 0.11 mmol), and DIPEA (0.035 mL, 0.2 mmol) in DMF (2 mL) was added amine (0.12 mmol). The mixture was stirred at room temperature until the reaction was complete (monitored by LC / MS). Water was added to the solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to obtain the product.

[0571]

Chemical formula

[0572] The target compound 5b (yield 57%) was obtained by the above general procedure.

[0573] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.37 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 7.48 (d, J = 7.2 Hz, 4H), 7.41 - 7.33 (m, 6H); 13 C NMR (101 MHz, DMSO-d6) δ 167.3, 154.7, 154.3, 142.0, 140.3, 138.99, 138.96, 135.8, 130.2, 130.1, 129.5, 129.4, 129.2, 128.6, 128.54, 128.52, (one signal is missing due to overlap). MS (ES+) m / z = 326 [M + H] + 。

[0574]

Chemical formula

[0575] The target compound 6b (yield 67%) was obtained by the above general procedure.

[0576] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 - 8.84 (m, 1H), 8.63 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.6 Hz, 4H), 7.42 - 7.33 (m, 6H), 2.86 (d, J = 3.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 166.0, 154.6, 154.3, 141.9, 140.3, 139.0, 136.0, 130.2, 130.1, 129.5, 129.4, 129.3, 129.1, 128.54, 128.52, 128.1, 27.0, (one signal is missing due to overlap). MS (ES+) m / z = 340 [M + H] + 。

[0577]

Chem.

[0578] The target compound 7b (yield 66%) was obtained by the above general procedure.

[0579] 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 5.5 Hz, 1H), 8.66 (s, 1H), 8.27 (d...

Claims

1. A compound for use in the inhibition of the activity of short-chain dehydrogenase enzymes, comprising at least one of formula (I) or (II): 【Chemical 1】 wherein, X １ is N or CR ４ ; X ２ is S, S=O, S(=O) ２ or C=O; X ３ is either CR ８ or absent (a compound forming a polycyclic heteroaryl having 9 ring atoms); X ４ is N, NH or CR ７ ; X ５ is N, C=O or CR １６ ; when X ４ is CR ７ or X ３ is absent, X ５ is N; when X ５ is C=O, X ４ is NH; when X ４ is N and X ３ is CR ８ , X ５ is CR １６ ; R １ 、R ２ 、R ３ 、R ４ 、R ９ 、R １０ and R １６ are the same or different and independently are hydrogen, oxygen, substituted or unsubstituted C １ -C ２４ -alkyl, C ２ -C ２４ -alkenyl, C ２ -C ２４ -alkynyl, C ３ -C ２０ -aryl, heterocycloalkenyl containing 5 to 7 ring atoms (where 1 to 3 of the ring atoms are independently selected from N, NH, N(C １ -C ６ -alkyl), NC(O)(C １ -C ６ -alkyl), O, and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (where 1 to 6 of the ring atoms are independently selected from N, NH, N(C １ -C ３ -alkyl), O, and S), C ６ -C ２４ -alkaryl, C ６ -C ２４ -aralkyl, halo, silyl, hydroxyl, sulfhydryl, C １ -C ２４ -alkoxy, C ２ -C ２４ -alkenyloxy, C ２ -C ２４ -alkynyloxy, C ５ -C ２０ -aryloxy, acyl (C ２ -C ２４ -alkylcarbonyl (-CO-alkyl) and C ６ -C ２０ -arylcarbonyl (-CO-aryl) are included), acyloxy (-O-acyl), C ２ -C ２４ -alkoxycarbonyl (-(CO)-O-alkyl), C ６ -C ２０ Aryloxycarbonyl (-(CO)-O-aryl), C ２ ~C ２４ Alkyl carbonate (-(O)-(CO)-O-alkyl), C ６ ~C ２０ Aryl carbonate (-(O)-(CO)-O-aryl), carboxy (-(COOH)), carboxylato (-(COO － )), carbamoyl (-(CO)-NH ２ ), C １ ~C ２４ Alkyl-carbamoyl (-(CO)-NH(C １ ~C ２４ alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH ２ ), carbamide (-(NH)-(CO)-NH ２ ), cyano (-(CN)), isocyano (-(N ＋ C － ), cyanato (-(O)-CN), isocyanato (-(O)-N ＋ =C － ), isothiocyanato (-(S)-CN), azido (-(N=N ＋ =N － ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-(NH ２ ), C １ ~C ２４ alkylamino, C ５ ~C ２０ arylamino, C ２ ~C ２４ alkylamide (-(NH(CO)-alkyl)), C ６ ~C ２０ arylamide (-(NH(CO)-aryl)), sulfanamide (-(SO ２ N(R) ２ ; where R is independently H, alkyl, aryl or heteroaryl), imino (-(CR=NH; where R is hydrogen, C １ ~C ２４ alkyl, C ５ ~C ２０ aryl, C ６ ~C ２４ alkaryl, C ６ ~C ２４ an alkylimino (—CR═N(alkyl); where R═hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), an arylimino (—CR═N(aryl); where R═hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ２ ), nitroso (—NO), sulfo (—SO ２ —OH), sulfonato (—SO ２ —O － ), C １ to C ２４ alkylsulfanyl (—S-alkyl; also referred to as "alkylthio"), arylsulfanyl (—S-aryl; also referred to as "arylthio"), C １ to C ２４ alkylsulfinyl (—(SO)-alkyl), C ５ to C ２０ arylsulfinyl (—(SO)-aryl), C １ to C ２４ alkylsulfonyl (—SO ２ —alkyl), C ５ to C ２０ arylsulfonyl (—SO ２ —aryl), sulfonamide (—SO ２ —NH ２ , —SO ２ NY ２ (where Y is, independently, H, aryl or alkyl)), phosphono (—P(O)(OH) ２ ), phosphonato (—P(O)(O － )( ２ ), phosphinato (—P(O)(O － )( ２ ), phospho (—PO ２ ), phosphino (—PH ２ )( ｎ O] ｍ ), phosphate, phosphate ester [—OP(O)(OR) ２ ; where R═H, methyl or other alkyl]; a group incorporated with an amino acid or another moiety expected to carry a positive or negative charge at physiological pH; and combinations thereof, selected from the group consisting of, R ７ and R ８ are the same or different and each independently is selected from the group consisting of H, aryl which may or may not be substituted, heteroaryl which may or may not be substituted, cycloalkyl which may or may not be substituted, and heterocyclyl which may or may not be substituted, provided that at least one of R ７ or R ８ is not H. compounds, and their pharmaceutically acceptable salts.

2. The compound according to claim 1, comprising at least one of the following formulas: 【Chemical 2】 【Chem.】 wherein, X ２ is S, S=O, S(=O) ２ or C=O; X ６ is Cl, Br or F, and y + z = 3; R １ 、R ２ 、R ３ 、R ５ 、R ６ and R １４ are the same or different and independently are hydrogen, substituted or unsubstituted C １ -C ２４ -alkyl, C ２ -C ２４ -alkenyl, C ２ -C ２４ -alkynyl, C ３ -C ２０ -aryl, heterocycloalkenyl containing 5 to 7 ring atoms (where 1 to 3 of the ring atoms are independently N, NH, N(C １ -C ６ -alkyl), NC(O)(C １ -C ６ -alkyl), O, and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (where 1 to 6 of the ring atoms are independently N, NH, N(C １ -C ３ -alkyl), O, and S), C ６ -C ２４ -alkaryl, C ６ -C ２４ -aralkyl, halo, silyl, hydroxyl, sulfhydryl, C １ -C ２４ -alkoxy, C ２ -C ２４ -alkenyloxy, C ２ -C ２４ -alkynyloxy, C ５ -C ２０ -aryloxy, acyl (C ２ -C ２４ -alkylcarbonyl (-CO-alkyl) and C ６ -C ２０ -arylcarbonyl (-CO-aryl) are included), acyloxy (-O-acyl), C ２ -C ２４ -alkoxycarbonyl (-(CO)-O-alkyl), C ６ -C ２０ -aryloxycarbonyl (-(CO)-O-aryl), C ２ to C ２４ alkyl carbonate (—O—(CO)—O—alkyl), C ６ to C ２０ aryl carbonate (—O—(CO)—O—aryl), carboxy (—COOH), carboxylato (—COO － ), carbamoyl (—(CO)—NH ２ ), C １ to C ２４ alkyl-carbamoyl (—(CO)—NH(C １ to C ２４ alkyl)), arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH ２ ), carbamide (—NH—(CO)—NH ２ ), cyano (—CN), isocyano (—N ＋ C － ), cyanato (—O—CN), isocyanato (—O—N ＋ =C － ), isothiocyanato (—S—CN), azido (—N=N ＋ =N － ), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH ２ ), C １ to C ２４ alkylamino, C ５ to C ２０ arylamino, C ２ to C ２４ alkylamide (—NH(CO)—alkyl), C ６ to C ２０ arylamide (—NH(CO)—aryl), sulfanamide (—SO ２ N(R) ２ ; where R is independently H, alkyl, aryl or heteroaryl), imino (—CR=NH; where R is hydrogen, C １ to C ２４ alkyl, C ５ to C ２０ aryl, C ６ to C ２４ alkaryl, C ６ to C ２４ Alkylimino (—CR═N(alkyl); where R═hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl); where R═hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ２ ), nitroso (—NO), sulfo (—SO ２ —OH), sulfonato (—SO ２ —O － ), C １ ~C ２４ Alkylsulfanyl (—S-alkyl; also referred to as “alkylthio”), arylsulfanyl (—S-aryl; also referred to as “arylthio”), C １ ~C ２４ Alkylsulfinyl (—(SO)-alkyl), C ５ ~C ２０ Arylsulfinyl (—(SO)-aryl), C １ ~C ２４ Alkylsulfonyl (—SO ２ —alkyl), C ５ ~C ２０ Arylsulfonyl (—SO ２ —aryl), sulfonamide (—SO ２ —NH ２ , —SO ２ NY ２ (where Y is, independently, H, aryl or alkyl)), phosphono (—P(O)(OH) ２ ), phosphonato (—P(O)(O － )([[]] ２ ), phosphinato (—P(O)(O － )([[]] ２ ), phospho (—PO ２ ), phosphino (—PH ２ ), polyalkyl ether (—[(CH ２ )([[]] ｎ O][[[]] ｍ ), phosphate, phosphoric acid ester [—OP(O)(OR) ２ ; where R═H, methyl or other alkyl]; a group in which an amino acid or another moiety expected to carry a positive or negative charge at physiological pH is incorporated; and combinations thereof, R ５ and R ５ and R ６ may be linked to form a cyclic or polycyclic ring, where the ring is aryl, substituted or unsubstituted, heteroaryl, substituted or unsubstituted, cycloalkyl, substituted or unsubstituted, and heterocyclyl, substituted or unsubstituted, and n １ is from 0 to 4, and each R １４ is the same or different, compounds, and their pharmaceutically acceptable salts.

3. 【Fig. 3】 [Chemical] 【Chem.】 The compound according to any one of claims 1 to 2, having a formula selected from the group consisting of, and their pharmaceutically acceptable salts.

4. The compound according to claim 1, comprising at least one of the following formulas: 【Chemical Formula 4】 [Chemical] wherein, X ７ is S, S=O, S(=O) ２ or C=O; R ７ and R ８ are the same or different and each independently is selected from the group consisting of H, aryl which may or may not be substituted, heteroaryl which may or may not be substituted, cycloalkyl which may or may not be substituted, and heterocyclyl which may or may not be substituted, provided that R ７ or R ８ at least one of which is not H; R ９ 、 R １０ 、 R １１ 、 R １２ 、 R １３ and R １５ are the same or different and independently are hydrogen, oxygen, substituted or unsubstituted C １ -C ２４ alkyl, C ２ -C ２４ alkenyl, C ２ -C ２４ alkynyl, C ３ -C ２０ aryl, heterocycloalkenyl containing 5 to 7 ring atoms (where 1 to 3 of the ring atoms are independently N, NH, N(C １ -C ６ alkyl), NC(O)(C １ -C ６ alkyl), O, and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (where 1 to 6 of the ring atoms are independently N, NH, N(C １ -C ３ alkyl), O, and S), C ６ -C ２４ alkaryl, C ６ -C ２４ aralkyl, halo, silyl, hydroxyl, sulfhydryl, C １ -C ２４ alkoxy, C ２ -C ２４ alkenyloxy, C ２ -C ２４ alkynyloxy, C ５ -C ２０ aryloxy, acyl (C ２ -C ２４ alkylcarbonyl (-CO-alkyl) and C ６ -C ２０ arylcarbonyl (-CO-aryl) is included), acyloxy (-O-acyl), C ２ -C ２４ alkoxycarbonyl (-(CO)-O-alkyl), C ６ -C ２０ Aryloxycarbonyl (-(CO)-O-aryl), C ２ ~C ２４ Alkyl carbonate (-(O)-(CO)-O-alkyl), C ６ ~C ２０ Aryl carbonate (-(O)-(CO)-O-aryl), carboxy (-(COOH)), carboxylato (-(COO － ), carbamoyl (-(CO)-NH ２ ), C １ ~C ２４ Alkyl-carbamoyl (-(CO)-NH(C １ ~C ２４ alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH ２ ), urea (-(NH)-(CO)-NH ２ ), cyano (-(CN)), isocyano (-(N ＋ C － ), cyanato (-(O)-CN), isocyanato (-(O)-N ＋ =C － ), isothiocyanato (-(S)-CN), azido (-(N=N ＋ =N － ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-(NH ２ ), C １ ~C ２４ alkylamino, C ５ ~C ２０ arylamino, C ２ ~C ２４ alkylamide (-(NH)(CO)-alkyl), C ６ ~C ２０ arylamide (-(NH)(CO)-aryl), sulfanamide (-(SO ２ N(R) ２ ; where R is independently H, alkyl, aryl or heteroaryl), imino (-(CR=NH; where R is hydrogen, C １ ~C ２４ alkyl, C ５ ~C ２０ aryl, C ６ ~C ２４ alkaryl, C ６ ~C ２４ alkylimino (—CR═N(alkyl); where R═hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl); where R═hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO ２ ), nitroso (—NO), sulfo (—SO ２ —OH), sulfonato (—SO ２ —O － ), C １ —C ２４ alkylsulfanyl (—S-alkyl; also called "alkylthio"), arylsulfanyl (—S-aryl; also called "arylthio"), C １ —C ２４ alkylsulfinyl (—(SO)-alkyl), C ５ —C ２０ arylsulfinyl (—(SO)-aryl), C １ —C ２４ alkylsulfonyl (—SO ２ —alkyl), C ５ —C ２０ arylsulfonyl (—SO ２ —aryl), sulfonamide (—SO ２ —NH ２ , —SO ２ NY ２ (where Y is, independently, H, aryl or alkyl)), phosphono (—P(O)(OH) ２ ), phosphonato (—P(O)(O － ), ２ ), phosphinato (—P(O)(O － ), phospho (—PO ２ ), phosphino (—PH ２ ), polyalkylether (—[(CH ２ ), ｎ O] ｍ ), phosphate, phosphate ester [—OP(O)(OR) ２ ; where R═H, methyl or other alkyl]; an amino acid or other moiety expected to be positively or negatively charged at physiological pH; and groups incorporated from the group consisting of combinations thereof; and R １２ and R １３ may be linked to form a cyclic or polycyclic ring, where the ring is aryl, substituted or unsubstituted heteroaryl, cycloalkyl, substituted or unsubstituted, and substituted or unsubstituted heterocyclyl, and n ２ is from 0 to 4, and each R １５ is the same or different, compounds, and their pharmaceutically acceptable salts.

5. 【Fig. 5】 【Chem.】 【Chem.】 【Chem.】 The compound according to claim 1 or 4, having a formula selected from the group consisting of, and their pharmaceutically acceptable salts.

6. The compound according to any one of claims 1 to 5 for use in the inhibition of the activity of 15-PGDH enzyme.

7. At a concentration of recombinant 15-PGDH of about 5 nM to about 10 nM, an IC ５０ less than 1 μM, or preferably an IC ５０ less than 250 nM, or more preferably an IC ５０ less than 50 nM, or more preferably an IC ５０ less than 10 nM, or more preferably an IC ５０ less than 5 nM, that inhibits the enzymatic activity of recombinant 15-PGDH, a compound according to any of claims 1 to 5.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7.

9. The composition according to claim 8, administered in an amount effective to increase the level of prostaglandins in a tissue of a subject.

10. The composition according to claim 8, which is a topical composition.

11. The composition according to claim 8, applied to the skin of a subject to promote and / or stimulate skin pigmentation and / or hair growth and / or inhibit hair loss and / or treat skin damage or inflammation.

12. The composition according to claim 8, administered to a subject to promote wound healing, tissue repair and / or tissue regeneration.

13. The composition according to claim 8, administered to a subject to treat at least one of oral ulcers, gum diseases, colitis, ulcerative colitis, gastrointestinal ulcers, inflammatory bowel diseases, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary hypertension, cardiovascular diseases and kidney diseases.

14. The composition according to claim 8, administered to a subject in combination with a prostaglandin agonist for the purpose of enhancing the therapeutic effect of the prostaglandin agonist in a state responsive to prostaglandins.

15. The composition according to claim 8, administered to a tissue of a subject to increase tissue stem cells.

16. The composition according to claim 8, which is administered to a tissue graft donor, a bone marrow graft donor and / or a hematopoietic stem cell donor to enhance the compatibility of the donor tissue graft, the donor bone marrow graft and / or the donor hematopoietic stem cell graft.

17. The composition according to claim 8, which is administered to the bone marrow of the subject to increase stem cells in the subject.

18. The composition according to claim 8, which is administered to the bone marrow of the subject to enhance the compatibility of the bone marrow as a donor graft.

19. The composition according to claim 8, which is provided to a preparation of hematopoietic stem cells of the subject to enhance the compatibility of the stem cell preparation as a donor graft.

20. The composition according to claim 8, which is provided to a preparation of peripheral blood hematopoietic stem cells of the subject to enhance the compatibility of the stem cell preparation as a donor graft.

21. The composition according to claim 8, which is provided to a preparation of umbilical cord blood stem cells to enhance the compatibility of the stem cell preparation as a donor graft.

22. The composition according to claim 8, which is provided to a preparation of umbilical cord blood stem cells to reduce the number of units of umbilical cord blood required for transplantation.

23. The composition according to claim 8, which is administered to the subject to reduce tissue graft rejection.

24. The composition according to claim 8, which is administered to the subject to improve the engraftment of the tissue graft and / or the bone marrow graft.

25. The composition according to claim 8, which is administered to the subject to improve the engraftment of the bone marrow graft after treatment of the subject or the bone marrow of the subject by radiotherapy, chemotherapy or immunosuppressive therapy.

26. The composition according to claim 8, which is administered to the subject to improve the engraftment of the progenitor stem cell graft, the hematopoietic stem cell graft or the umbilical cord blood stem cell graft.

27. The composition according to claim 8, which is administered to the subject to improve the engraftment of the hematopoietic stem cell graft or the umbilical cord stem cell graft after treatment of the subject or the bone marrow of the subject by radiotherapy, chemotherapy or immunosuppressive therapy.

28. The composition according to claim 8, which is administered to the subject to reduce the number of units of umbilical cord blood required for transplantation into the subject.

29. The composition according to claim 8, which is administered to the recipient of a tissue graft transplantation, a bone marrow transplantation and / or a hematopoietic stem cell transplantation, or a umbilical cord stem cell transplantation, to reduce other treatments or the administration of growth factors.

30. The composition according to claim 8, which is administered to a subject or to a tissue graft of the subject in order to reduce graft rejection.

31. The composition according to claim 8, which is administered to a subject or to a tissue graft of the subject in order to improve graft engraftment.

32. The composition according to claim 8, which is administered to the subject or to a tissue graft of the subject in order to improve graft engraftment after treatment of the subject or the subject's bone marrow by radiotherapy, chemotherapy or immunosuppressive therapy.

33. The composition according to claim 8, which is administered to a subject or to the bone marrow of the subject in order to confer resistance to the toxic or lethal effects of radiation exposure.

34. The composition according to claim 8, which is administered to a subject or to the bone marrow of the subject in order to confer resistance to the toxic effects of cyclophosphamide, the toxic effects of fludarabine, the toxic effects of chemotherapy or the toxic effects of immunosuppressive therapy.

35. The composition according to claim 8, which is administered to a subject or to the bone marrow of the subject in order to reduce infection.

36. The composition according to claim 8, which is administered to a subject in order to increase the neutrophil count after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood.

37. The composition according to claim 8, which is administered to a subject in order to increase the neutrophil count in a subject having neutropenia after application of chemotherapy or radiotherapy.

38. The composition according to claim 8, which is administered to a subject having neutropenia resulting from aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia after viral infection in order to increase the neutrophil count.

39. The composition according to claim 8, which is administered to a subject having neutropenia in order to increase the neutrophil count.

40. The composition according to claim 8, which is administered to a subject in order to increase the platelet count after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood.

41. The composition according to claim 8, which is administered to a subject having thrombocytopenia after application of chemotherapy or radiotherapy in order to increase the platelet count.

42. The composition according to claim 8, which is administered to a subject having thrombocytopenia caused by aplastic anemia, myelodysplasia, myelofibrosis, other myeloid diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection, for increasing the platelet count in the subject.

43. The composition according to claim 8, which is administered to a subject having thrombocytopenia for increasing the platelet count in the subject.

44. The composition according to claim 8, which is administered to a subject for increasing the red blood cell count or hematocrit or hemoglobin level after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood.

45. The composition according to claim 8, which is administered to a subject having anemia after application of chemotherapy or radiotherapy for increasing the red blood cell count or hematocrit or hemoglobin level in the subject.

46. The composition according to claim 8, which is administered to a subject having aplastic anemia, myelodysplasia, myelofibrosis, anemia caused by other myeloid disorders, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, anemia after viral infection or anemia of unknown cause, for increasing the number of red blood cells or hematocrit or hemoglobin level in the subject.

47. The composition according to claim 8, which is administered to a subject having anemia for increasing the red blood cell count or hematocrit or hemoglobin level in the subject.

48. The composition according to claim 8, which is administered to a subject for increasing bone marrow stem cells after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or cord blood.

49. The composition according to claim 8, which is administered to a subject for increasing bone marrow stem cells in the subject after application of chemotherapy or radiotherapy.

50. The composition according to claim 8, which is administered to a subject having aplastic anemia, myelodysplasia, myelofibrosis, other myeloid disorders, drug-induced cytopenia, immune cytopenia, cytopenia after viral infection, or cytopenia, for increasing bone marrow stem cells in the subject.

51. The composition according to claim 8, which is administered to a subject to enhance the reactivity to cytokines in the presence of cytopenia, wherein the cytopenia includes any one of neutropenia, thrombocytopenia, lymphocytopenia, and anemia, and the cytokine having increased reactivity enhanced by a 15-PGDH inhibitor includes any one of G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist), and SCF.

52. The composition according to claim 8, which is administered to a subject or to the bone marrow of a subject to reduce radiation-induced lung toxicity.

53. The composition according to claim 8, which is administered to a subject to increase bone density, to treat osteoporosis, to promote the healing of fractures, or to promote the healing after bone surgery or joint replacement surgery.

54. The composition according to claim 8, which is administered to a subject to promote the healing of bone-to-bone implants, bone-to-artifact implants, dental implants, and bone grafts.

55. The composition according to claim 8, which is administered to a subject or to the intestine of a subject to increase stem cells in the intestine.

56. The composition according to claim 8, which is administered to a subject or to the intestine of a subject to increase stem cells in the intestine and to confer resistance to the toxic or lethal effects of radiation exposure or the toxic, lethal, or mucositis effects resulting from treatment with chemotherapy.

57. The composition according to claim 8, which is administered to a subject or to the intestine of a subject to confer resistance to the toxic or lethal effects of radiation exposure or the toxic, lethal, or mucositis effects resulting from treatment with chemotherapy.

58. The composition according to claim 8, which is administered to a subject or to the intestine of a subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

59. The composition according to claim 8, which is administered to increase liver regeneration after liver surgery, after living liver donation, after liver transplantation, or after liver injury by toxins.

60. The composition according to claim 8, which is administered to a subject to promote recovery from or resistance to hepatotoxins (including acetaminophen and related compounds).

61. The composition according to claim 8, which is administered to a subject for treating erectile dysfunction.

62. The composition according to claim 8, which is administered for inhibiting at least one of growth, proliferation or metastasis of cancer expressing 15-PGDH.

63. A method for treating a subject in need of cell therapy, comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells provided with the 15-PGDH inhibitor according to claims 1 to 5 and / or a therapeutic composition comprising human hematopoietic stem cells and the 15-PGDH inhibitor according to claims 1 to 5.

64. The method according to claim 63, further comprising administering to the subject the 15-PGDH inhibitor according to claims 1 to 5, wherein the subject has been given human hematopoietic stem cells and / or has been given the preparation and / or the therapeutic composition.

65. The subject has acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, severe aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH), erythroleukemia, amegakaryocytic / congenital thrombocytopenia, severe combined immunodeficiency syndrome (SCID), Wiskott-Aldrich syndrome, severe beta-thalassemia, sickle cell disease, Hurler syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, essential myelofibrosis, familial erythrophagocytic lymphohistiocytosis, solid tumors, chronic granulomatous disease, mucopolysaccharidosis or Diamond-Blackfan anemia. The method according to claim 64.

66. A method for treating a subject having at least one symptom associated with ischemic tissue or tissue damaged by ischemia, comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells provided with the 15-PGDH inhibitor according to claims 1 to 5 and / or a therapeutic composition comprising human hematopoietic stem cells and the 15-PGDH inhibitor according to claims 1 to 5.

67. The ischemia is associated with at least one of acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, ischemia induced by diabetes, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vasculitis, von Hippel-Lindau syndrome, and a method according to claim 66 associated with at least one of a trauma to a tissue or organ.

68. A method of increasing neutrophils in a subject in need thereof, comprising administering to the subject a 15-PGDH inhibitor according to claims 1-5.

69. The method according to claim 68, further comprising administering a hematopoietic cytokine in combination with the 15-PGDH inhibitor.

70. A method of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, comprising administering to the subject a 15-PGDH inhibitor according to claims 1-5.

71. The method according to claim 70, further comprising administering G-CSF in combination with the 15-PGDH inhibitor.

72. The method according to claim 70, further comprising administering a hematopoietic cytokine in combination with the 15-PGDH inhibitor.

73. The method according to claim 70, further comprising administering plerixafor in combination with the 15-PGDH inhibitor.

74. The method according to any one of claims 70 to 73, wherein an increase in the number of peripheral blood hematopoietic stem cells and / or mobilization of peripheral blood hematopoietic stem cells is used in hematopoietic stem cell transplantation.

75. A method for increasing the number of hematopoietic stem cells in blood or bone marrow, the method comprising administering the 15-PGDH inhibitor of claims 1 to 5 to the subject's blood or bone marrow.

76. The method according to claim 75, further comprising administering G-CSF in combination with the 15-PGDH inhibitor.

77. The method according to claim 75, further comprising administering a hematopoietic cytokine in combination with the 15-PGDH inhibitor.

78. The method according to claim 75, further comprising administering plerixafor in combination with the 15-PGDH inhibitor.

79. A method for treating or preventing a fibrotic disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the 15-PGDH inhibitor of claims 1 to 5.

80. The fibrotic disease, disorder or condition is characterized by an overall or partial overproduction of fibrous substances (including overproduction of fibrous substances in the extracellular matrix) or replacement of elements of normal tissue by abnormal, non-functional, and / or excessive accumulation of matrix-related components. The method according to claim 79.

81. The fibrotic disease, disorder or condition is selected from the group consisting of systemic sclerosis, multiple sclerosis, renal systemic fibrosis, scleroderma, scleroderma graft-versus-host disease, renal fibrosis, glomerulosclerosis, tubulointerstitial fibrosis of the kidney, progressive renal disease or diabetic nephropathy, cardiac fibrosis, pulmonary fibrosis, glomerulosclerotic pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, chemotherapy / radiation-induced pulmonary fibrosis, oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, a general fibrosing syndrome characterized by replacement of normal muscle tissue by fibrous tissue to various degrees, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure, myelofibrosis / bone marrow fibrosis, drug-induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, leprosy, collagenous colitis, acute fibrosis and organ-specific fibrosis, the method according to claim 79.

82. The fibrotic disease, disorder or condition includes pulmonary fibrosis, the method according to claim 79.

83. The pulmonary fibrosis is selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, anthracosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious pathogens, pulmonary fibrosis caused by inhalation of harmful gases, aerosols, chemical dusts, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof, the method according to claim 82.

84. The pulmonary fibrosis is cystic fibrosis, the method according to claim 82.

85. The fibrotic disease, disorder or condition includes renal fibrosis, the method according to claim 79.

86. The fibrotic disease, disorder or condition includes liver fibrosis, the method according to claim 79.

87. The liver fibrosis is caused by the method according to claim 86, which is caused by chronic liver disease, cirrhosis induced by a virus, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction, and exposure to toxins, or a combination thereof.

88. The method according to claim 79, wherein the fibrotic disease, disorder or condition includes cardiac fibrosis.

89. The method according to claim 79, wherein the fibrotic disease, disorder or condition is systemic sclerosis.

90. The method according to claim 79, wherein the fibrotic disease, disorder or condition is caused by postoperative adhesion formation.

91. The method according to claim 79, wherein the 15-PGDH inhibitor is administered in an amount effective to reduce or inhibit collagen deposition, expression of inflammatory cytokines and / or inflammatory cell infiltration in the tissue or organ of the subject to be treated.

92. A method for promoting neuroprotection of a subject from axonal degeneration, neuronal death and / or damage to glial cells after injury, enhancing neuronal signaling underlying learning and memory, stimulating neuronal regeneration after injury, and / or treating a disease, disorder and / or condition of the nervous system in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the 15-PGDH inhibitor of claims 1-5.

93. The method according to claim 92, wherein the disease, disorder and / or condition of the nervous system includes at least one of neurological disorders, psychoneurological disorders, nerve injuries, neurotoxic disorders, neuropathic pain and neurodegenerative disorders.

94. The method according to claim 92, wherein the neurological disorder includes at least one of traumatic or toxic injury to peripheral nerves or cranial nerves, spinal cord, or to the brain, cranial nerves; traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. Further, the neurological disorder may include at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, diffuse Lewy body disease, senile dementia, Huntington's disease, Gilles de la Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Creutzfeldt-Jakob disease.

95. The method according to claim 92, wherein the nerve injury may be caused by or associated with at least one of epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic nerve disorder, bladder disorder, abnormal metabolic state, muscle disorder, infectious disease and parasitosis, neoplasm, endocrine disease, nutritional / metabolic disease, immunological disease, disease of blood and blood-forming organs, mental disorder, nervous system disease, sensory organ disease, circulatory system disease, respiratory system disease, digestive system disease, urogenital system disease, skin and subcutaneous tissue disease, musculoskeletal system and connective tissue disease, congenital anomaly, or condition occurring during the perinatal period.

96. The method according to claim 92, wherein the 15-PGDH inhibitor may be administered in an amount effective to stimulate neurogenesis in the hippocampus for the treatment of neuropsychiatric diseases and neurodegenerative diseases, including schizophrenia, major depressive disorder, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neurostimulatory drugs (such as alcohol, opioids, methamphetamine, fencicline, and cocaine).

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