Compositions and methods for modulating short-chain dehydrogenase activity

Abstract

15-PGDH inhibitors are provided. The present invention relates to a compound of the following formula (I) or (II): JPEG2022163172000219.jpg54158 In the formula, X 1 is N or CR 4 and X 2 is S, S=O, S(=O)2 or C=O, and X 3 is CR 8 or does not exist and X 4 is N, NH or CR 7 and X 5 is N, C=O or CR 16 and X 4 is CR 7 Is it X? 3 If does not exist, X 5 is N and X 5 If C=O, then X 4 is NH and X 4 is N and X 3 is CR 8 If X 5 is CR 16 is.

Description

[Technical Field]

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

[0002] Government funding This invention was made with government support under Grant Nos. 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 technology]

[0003] background Short-chain dehydrogenases (SCDs) are a family of dehydrogenases with only 15%-30% sequence identity, primarily in the coenzyme- and substrate-binding domains. In addition to their role in ethanol detoxification, SCDs are involved in the synthesis and degradation of fatty acids, steroids, and several prostaglandins and are therefore implicated in a variety of disorders, including lipid storage diseases, myopathies, SCD deficiencies, and certain genetic disorders.

[0004] The SCD 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide); 15-PGDH; enzyme number 1.1.1.141; encoded by the HPGD gene) is a key enzyme in the inactivation of several active forms of prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids (HETEs), e.g., by catalyzing the oxidation of PGE2 to 15-keto-prostaglandin E2 (15k-PGE). The human enzyme, encoded by the HPGD gene, consists of a homodimer with a subunit size of 29 kDa. This enzyme belongs to the evolutionarily conserved short-chain dehydrogenase / reductase (SDR) enzyme superfamily and has been designated SDR36C1 in accordance with 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 NADP preference of CBR1 and its high Km values ​​for most prostaglandins suggest that the majority of in vivo activity can be attributed to type I 15-PGDH encoded by the HPGD gene (hereafter and throughout the following text, simply referred to as 15-PGDH).

[0005] Recent studies suggest that inhibitors of 15-PGDH may be of therapeutic value. Recent studies link increased expression of 15-PGDH to protection from 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, including 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] overview Embodiments described herein relate to compounds and methods for modulating the activity of short-chain dehydrogenases (SCDs) (e.g., 15-PGDH), modulating tissue prostaglandin levels, and / or treating diseases, disorders, or conditions in which it is desirable to modulate SCD (e.g., 15-PGDH) activity and / or prostaglandin levels.

[0007] In some embodiments, the modulator of SCD may be an SCD inhibitor, which may be administered to the tissue or blood of a subject in an amount effective to inhibit the activity of the SCD enzyme. The SCD inhibitor may be a 15-PGDH inhibitor, which may be administered to the tissue or blood of a subject in an amount effective to increase the level of prostaglandins in the tissue or blood. 15-PGDH inhibitors include those having the following formula: [ka] wherein: X 1 is N or CR 4 and; X 2 is S, S=O, S(=O)2 or C=O; X 3 is CR 8 (compounds forming polycyclic heteroaryls with 10 ring atoms) or absent (compounds forming polycyclic heteroaryls with 9 ring atoms); X 4 is N, NH or CR 7 and; X 5 is N, C=O or CR 16 and X 4 is CR 7 Is it X? 3 If does not exist, X 5 is N and X 5 If C=O, then X 4 is NH and X 4is N and X 3 is CR 8 If X 5 is CR 16 and; R 1 , R 2 , R 3 , R 4 , R 9 , R 10 and R 16 are the same or different and independently represent hydrogen, oxygen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-S-aryl; also called "arylthio"), C1-C 24 Alkylsulfinyl (-(SO)-alkyl), C5-C 20 Arylsulfinyl (-(SO)-aryl), C1-C 24Alkylsulfonyl (-SO2-alkyl), C5-C 20 Arylsulfonyl (-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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, R 7 and R 8 are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 7 or R 8 At least one of them is not H, Compounds, and pharmaceutically acceptable salts thereof, may be included.

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

[0009] In some embodiments, the 15-PGDH inhibitor has an IC of less than 1 μM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM. 50 or preferably an IC of less than 250 nM 50 or more preferably an IC of less than 50 nM 50or more preferably an IC of less than 10 nM 50 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 in a topical composition that can be 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.

[0011] 15-PGDH inhibitors may also be administered to a subject to promote wound healing, tissue repair and / or tissue regeneration and / or tissue graft survival or regeneration.

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

[0013] In another embodiment, a 15-PGDH inhibitor may be administered to a subject in combination with a prostanoid agonist to enhance the therapeutic effect of the agonist in prostaglandin-responsive conditions.

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

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

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

[0017] In other embodiments, 15-PGDH inhibitors may be administered to recipients of tissue graft transplants, bone marrow and / or hematopoietic stem cell transplants, or umbilical cord stem cell transplants to reduce the administration of other treatments or growth factors.

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

[0019] In other embodiments, a 15-PGDH inhibitor may be administered to a subject or to the bone marrow of a subject 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 yet another embodiment, the 15-PGDH inhibitor is used to increase neutrophil counts after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; to increase neutrophil counts in subjects with neutropenia after chemotherapy or radiation therapy; to increase neutrophil counts in subjects with aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia after viral infection; to increase neutrophil counts in subjects with neutropenia; to increase platelet counts after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; to increase neutrophil counts in subjects with thrombocytopenia after chemotherapy or radiation therapy; to increase the platelet count in subjects with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow disorders, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia following a viral infection; to increase the platelet count in subjects with thrombocytopenia; to increase red blood cell count or hematocrit or hemoglobin levels after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; to increase red blood cell count or hematocrit or hemoglobin levels in subjects with anemia following chemotherapy or radiation therapy; to increase the platelet count in subjects with aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other bone marrow disorders, drug-induced anemiathe number of red blood cells or hematocrit or hemoglobin levels in a subject with anemia, immune-mediated anemia, anemia of chronic disease, anemia after a viral infection, or anemia of unknown cause; to increase the number of red blood cells or hematocrit or hemoglobin levels in a subject with anemia; to increase bone marrow stem cells after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; to increase bone marrow stem cells in a subject after chemotherapy or radiation therapy; and / or to increase bone marrow stem cells in a subject with aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced cytopenia, immune cytopenia, cytopenia after a viral infection, or cytopenia.

[0021] In other embodiments, administration of a 15-PGDH inhibitor may be used to regulate hematopoietic stem cells and hematopoiesis. A 15-PGDH inhibitor may be administered alone or in combination with cytokines 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 tissues.

[0022] In some embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF to increase neutrophils.

[0023] In other embodiments, administration of a 15-PGDH inhibitor may be combined with a hematopoietic cytokine to increase neutrophils.

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

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

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

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

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

[0031] In other embodiments, administration of a 15-PGDH inhibitor may be combined with hematopoietic cytokines in order to increase the number of hematopoietic stem cells in the blood or bone marrow.

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

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

[0034] In other embodiments, 15-PGDH inhibitors may be administered to recipients of tissue graft transplants, bone marrow and / or hematopoietic stem cell transplants, or umbilical cord stem cell transplants to reduce the administration of other treatments or growth factors.

[0035] In other embodiments, a 15-PGDH inhibitor may be administered to a subject to enhance responsiveness to cytokines in the presence of cytopenia (including any of neutropenia, thrombocytopenia, lymphopenia, and anemia), wherein the cytokines with 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, a 15-PGDH inhibitor may be administered to a subject to increase bone density, treat osteoporosis, promote healing of a fracture, or promote healing after bone surgery or joint replacement, and / or promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0037] In other embodiments, a 15-PGDH inhibitor may be administered to a subject or to the intestine of a subject to increase stem cell 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 chemotherapy treatment.

[0038] In some embodiments, a 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, 15-PGDH inhibitors may be administered to a subject after liver surgery, after living donor liver donation, after liver transplantation, or after toxin-induced liver injury to increase liver regeneration and / or to promote recovery from or resistance to hepatotoxins, including acetaminophen and related compounds.

[0040] In yet other embodiments, a 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 the growth, proliferation, or metastasis of a 15-PGDH-expressing cancer.

[0042] Still other embodiments described herein relate to methods of 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 treated with a 15-PGDH inhibitor described herein and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

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

[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's lymphoma, non-Hodgkin's 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, beta thalassemia major, sickle cell disease, Hurler syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, idiopathic myeloid metaplasia, or idiopathic myeloid leukemia. 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, comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells treated with a 15-PGDH inhibitor described herein and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

[0046] In some embodiments, ischemia is caused by 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, bone fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound wound, delayed ulcer healing, delayed wound healing, diabetes mellitus (types I and 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 diseases, 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, lacerations, left main coronary artery disease 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 artery diseaseThe condition may be associated with at least one of: pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic brain ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

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

[0048] Fibrotic diseases, disorders, and conditions characterized in whole or in part by the overproduction of fibrous material include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), scleroderma graft-versus-host disease, renal fibrosis (including glomerulosclerosis, renal tubulointerstitial fibrosis, progressive renal 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, and pulmonary fibrosis (e.g., pulmonary fibrosis ... fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fascilitis, eosinophilic fasciitis, general fibrosis syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrous tissue, retroperitoneal fibrosis, hepatic fibrosis, liver 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, organ-specific fibrosis, etc.

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

[0050] In some embodiments, 15-PGDH inhibitors may be used to treat or prevent lung fibrosis. Treatable lung 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 workers' pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of mineral dust, pulmonary fibrosis caused by infectious agents, 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.

[0051] In other embodiments, 15-PGDH inhibitors may be used to treat or prevent renal fibrosis, which may result from dialysis after renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease or renal failure, or a combination thereof.

[0052] In other embodiments, 15-PGDH inhibitors can be used to treat or prevent liver fibrosis.Liver fibrosis can be caused by chronic liver disease, virus-induced liver 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-associated liver 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.

[0053] In some embodiments, 15-PGDH inhibitors may be used to treat or prevent cardiac fibrosis (eg, cardiac fibrosis and endomyocardial fibrosis).

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

[0055] In some embodiments, 15-PGDH inhibitors may be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

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

[0057] In other embodiments, 15-PGDH inhibitors may be used to reduce or prevent scarring 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 characteristic of a fibrotic disease, disorder or condition, or other related disease, disorder or condition, is reduced in intensity, severity or frequency or delayed in onset.

[0059] In other embodiments, a 15-PGDH inhibitor may be used in a method for decreasing or reducing collagen secretion or collagen deposition in a tissue or organ (e.g., lung, liver, intestine, colon, skin, or heart) of a subject. The method may include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject may have or be at risk for excessive collagen secretion or collagen deposition in a tissue or organ (e.g., kidney, lung, liver, intestine, colon, skin, or heart). Typically, excessive collagen secretion or collagen deposition in an organ results from 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 reduce the level of collagen deposition in the tissue or organ. A sufficient period may be one week, or one week to one month, or one to two months, or more than two months. In the case of chronic conditions, the 15-PGDH inhibitor may be advantageously administered throughout life.

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

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

[0062] For example, neurological disorders may include at least one of traumatic or toxic injury to a peripheral or cranial nerve, spinal cord, or to the brain, cranial nerve, traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury, and at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, diffuse Lewy 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 Creutzfeldt-Jakob disease.

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

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

[0065] Detailed Description For convenience, certain terms employed 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 to more than one (i.e., to at least one) of the grammatical object 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, meaning that additional elements may be included. The terms "such as," "eg," and "e.g.", when used herein, are non-limiting and for descriptive purposes only. "Including" and "including but not limited to" are used interchangeably.

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

[0069] As used herein, the term "about" or "approximately" applies to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that differs by as little as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. In one embodiment, the term "about" or "approximately" covers 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.

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

[0071] The term "isomerism" refers to compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images are termed "enantiomers," or sometimes optical isomers. A carbon atom bonded to four non-identical substituents is termed a "chiral center," although sulfur bonded to three or four different substituents (e.g., sulfoxide or sulfinimide) is also termed a "chiral center."

[0072] The term "chiral isomer" refers to a compound with 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 individual enantiomeric forms of opposite chirality is called a "racemic mixture." A compound with two or more chiral centers has 2n-1 enantiomeric pairs, where n is the number of chiral centers. A compound with two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Alternatively, when more than one chiral center is present, a stereoisomer can be characterized as (+) or (-). 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 ranking 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" refers to diastereomers whose existence results from restricted rotation about a double bond. These configurations are distinguished in their names by the prefixes cis and trans or Z and E, indicating that groups are on the same or opposite sides of a double bond in a molecule according to the Cahn-Ingold-Prelog rules. Furthermore, the structures and other compounds described in this application encompass all atropic isomers thereof.

[0074] The term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers owe their existence to restricted rotation caused by hindrance of rotation about the central bond of a large group. Such atropisomers typically exist as mixtures, although recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers in certain cases.

[0075] The terms "crystalline polymorph" or "polymorph" or "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

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

[0077] The term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. The goal of a bioisosteric exchange is to create a new compound with biological properties similar to those of the parent compound. Bioisosteric exchanges can be based on physicochemical or topology. Examples of bioisosteres of carboxylic acids include sulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem.Rev. 96, 3147-3176 (1996).

[0078] The expressions "parenteral administration" and "parenterally administered" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, including, but not limited to, intravenous injection and infusion, intramuscular injection and infusion, intrapleural injection and infusion, intravascular injection and infusion, intrapericardial 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, subcuticular 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 art-recognized 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 unaffected.

[0080] The term "prevent" is art-recognized and includes stopping a disease, disorder, or condition from occurring in a subject who may be susceptible to, but has not yet been diagnosed as having, the disease, disorder, and / or condition. Preventing a disease-related condition includes stopping a 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 a preferred embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compounds or their salts) in a unit dose of the composition is an effective amount and will vary depending on the specific treatment involved. Those skilled 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. Various 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 a preferred embodiment, the active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

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

[0083] The term "immediate release" is defined as the release of a compound from a dosage form over a relatively short period of time (generally up to about 60 minutes). The term "modified release" is defined to encompass delayed release, extended release, and pulsed release. The term "pulse release" is defined as the sequential release of 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 art-recognized. In certain embodiments, this term includes compositions, polymers, and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0085] The expression "pharmaceutically acceptable carrier" is art-recognized and includes, for example, a pharmaceutically acceptable material, composition, or vehicle (such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material) involved in carrying or transporting any subject composition from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the subject composition and not harmful to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; and (9) 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) buffers, 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; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0086] The compounds of the present application can further form salts, and all of these forms are also contemplated in the present application.

[0087] A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. For example, the salt may be an acid addition salt. One embodiment of an acid addition salt is a hydrochloride salt. Pharmaceutically acceptable salts can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are 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, a carboxylic acid functional group in a compound may be converted to its corresponding ester (e.g., a methyl ester, an ethyl ester, or other ester). Also, an alcohol group in a compound may be converted to its corresponding ester (e.g., an acetate ester, a 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. Because prodrugs are known to enhance many desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), compounds may be delivered in prodrug form. Accordingly, the compounds described herein are intended to encompass prodrugs of the compounds claimed in the present application, methods of delivering them, and compositions containing them. "Prodrugs" are intended to encompass any covalently bonded carriers that release the active parent drug in vivo when such prodrug is administered to a subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs include compounds in which a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group, respectively. Prodrugs can also include precursors (precursors) of the compounds described herein that, after undergoing chemical conversion by metabolic processes, become active or more active pharmacological agents or active compounds described herein.

[0090] Examples of prodrugs include, but are not limited to, esters (e.g., acetate derivatives, dialkylaminoacetate derivatives, formates, phosphate derivatives, sulfate derivatives, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in a compound; ester groups (e.g., ethyl ester, morpholinoethanol ester) of carboxyl functional groups; N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enaminones of amino functional groups; oxime, acetal, ketal, and enol esters of ketone and aldehyde functional groups; and the like; and sulfides that are oxidized to form sulfoxides or sulfones.

[0091] The term "protecting group" refers to a group of atoms that, when attached to a reactive group in a molecule, masks, reduces, or prevents that reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, 2nd 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. Amine protecting groups are preferably easily and selectively removed in good yields 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), fluorenylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1-methyl-1-(4-biphenylyl)ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilylethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), nitroveratryloxycarbonyl (NVOC), and the like. Those skilled in the art will be able to 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 and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

[0094] Additionally, salts of the compounds described herein may exist in either 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" refers to a solvent addition form containing 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, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed 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 HO; such a combination can form one or more hydrates.

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

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

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

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

[0100] A "patient," "subject," or "host" to be treated by a subject method can refer to a human or non-human animal, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, it is intended to encompass adult and newborn animals, as well as fetuses, regardless of whether they are male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder.

[0101] The terms "prophylactic" or "therapeutic" treatment are art-recognized and include administration of one or more of the subject compositions to a host. If it is administered before the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is prophylactic, i.e., it protects the host from the onset of the undesirable condition. On the other hand, if it is administered after the manifestation of the undesirable condition, the treatment is therapeutic (i.e., it is intended to alleviate, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0102] The terms "therapeutic agent," "drug," "medicine," and "bioactive agent" are art-recognized 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, pharmaceutically acceptable salts and prodrugs thereof. 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 become biologically activated upon administration to a patient or subject.

[0103] The phrases "therapeutically effective amount" or "pharmaceutically effective amount" are art-recognized terms. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to an amount necessary or sufficient to eliminate, reduce, or maintain the target of a particular therapeutic regimen. An effective amount may 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 necessitating undue experimentation. In certain embodiments, a 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 polymer matrix (which will 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 polymer matrix in addition to the agent.

[0104] The term "ED50" is art-recognized. In certain embodiments, ED50 means the dose of a drug which produces 50% of its maximum response or effect, or the dose which produces a predetermined response in 50% of test subjects or preparations. The term "LD50" is art-recognized. In certain embodiments, LD50 means the amount of a drug that is lethal in 50% of test subjects. The term "therapeutic index" is art-recognized 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 for 50% inhibition of a biological process, or component of a process (including a protein, subunit, organelle, ribonucleoprotein, etc.).

[0106] With respect to any compound, the present application is intended to encompass all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, 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, then such substituent may be bonded to any atom in the ring. When substituents are listed without indicating the atom through which such substituent is bonded to the remainder of the compound of a given formula, then such substituent may be bonded through any atom in such substituent. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0108] When an atom or chemical moiety is followed by a range of subscript numbers (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 include 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 carbons.

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

[0110] The term "substituted alkyl" refers to an alkyl moiety having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls may be further substituted, e.g., with the substituents described above. An "alkylaryl" or "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). Unless otherwise indicated, the terms "alkyl" and "lower alkyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0111] The term "alkenyl" refers to a straight-chain, 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, eicosenyl, tetracosenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, and the like. Generally, although again not necessarily, an alkenyl group may contain from 2 to about 18 carbon atoms, and more specifically, from 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" contemplates cyclic alkenyl groups, preferably having from 5 to 8 carbon atoms. The term "substituted alkenyl" refers to an alkenyl substituted with one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to an alkenyl or heterocycloalkenyl (e.g., heterocyclohexenyl) in which at least one carbon atom has been replaced with a heteroatom. Unless otherwise indicated, the terms "alkenyl" and "lower alkenyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl, respectively.

[0112] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Generally, although not necessarily, an alkynyl group may contain from 2 to about 18 carbon atoms, more specifically from 2 to 12 carbon atoms. The term "lower alkynyl" contemplates 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 "heteroatom-containing alkynyl" and "heteroalkynyl" refer to an alkynyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the terms "alkynyl" and "lower alkynyl" encompass straight-chain, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl, respectively.

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

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

[0115] The term "aryl" refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused, directly linked, or indirectly linked (such as when different aromatic rings are bonded to a common group such as a methylene or ethylene moiety). Aryl groups may contain 5 to 20 carbon atoms, with particularly preferred aryl groups containing 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, among others. Furthermore, the term "aryl" includes polycyclic aryl groups (e.g., tricyclic, bicyclic; e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine). Aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles," "heterocycles," "heteroaryls" or "heteroaromatics."The aromatic ring may contain, at one or more ring positions, a substituent such as those 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, methyl ... Aryl groups may be substituted with aryl, arylamino, arylsulfonyl, arylisopropyl ...

[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 defined above. Exemplary aralkyl groups contain 6 to 24 carbon atoms, with particularly preferred aralkyl groups containing 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-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, 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 terms "heterocyclyl" or "heterocyclic group" include closed ring structures (e.g., 3- to 10-membered or 4- to 7-membered rings) that include one or more heteroatoms. A "heteroatom" includes an atom of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.

[0118] Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams (such as azetidinones and pyrrolidinones), sultams, and sultones. Heterocyclic groups such as pyrrole and furan can have aromatic character. Heterocyclic groups such as quinoline and isoquinoline contain fused ring structures. Other examples of heterocyclic groups include pyridine and purine. The heterocycle may be optionally substituted at one or more positions with a substituent such as those 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety). The heterocyclic group may also be substituted at one or more constituent atoms with, for example, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxyl, -CF3, or -CN.

[0119] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "Counterion" is used to represent small, negatively charged species such as fluoride, chloride, bromide, iodide, hydroxide, acetate, and sulfate. The term sulfoxide refers to sulfur bonded to two different carbon atoms and an oxygen, where the SO bond can be depicted as a double bond (S=O), an uncharged single bond (SO), or a charged single bond [S(+)-O(-)].

[0120] The term "substituted," as in "substituted alkyl," "substituted aryl," etc., as mentioned in some of the definitions above, is intended to mean that in an alkyl, aryl, or other moiety, at least one hydrogen atom bonded to a carbon (or other) atom is replaced with one or more substituents other than hydrogen. Examples of such substituents include, but are not limited to, halo, hydroxyl, silyl, sulfhydryl, C1-C6, methyl ... 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 (including -CO-aryl), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-O-(CO)-O-alkyl), C6-C 20 Arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH), mono-(C1-C 24 Alkyl)-substituted carbamoyl (-(CO)-NH(C1-C 24 di-(C1-C4 alkyl)-substituted carbamoyl (-(CO)-N(C1-C 24 alkyl)2), monosubstituted arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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 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] Additionally, the aforementioned functional groups may be further substituted with one or more additional substituents or with one or more hydrocarbyl moieties (such as those specifically listed above) if the particular group allows. 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 the term apply to all members of that group. For example, the phrase "substituted alkyl, alkenyl, and aryl" should be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl." Similarly, when the term "heteroatom-containing" appears before a list of groups that may contain heteroatoms, it is intended that the term apply to all members of that group. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" should be interpreted as "heteroatom-containing alkyl, substituted alkenyl, and substituted aryl."

[0123] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and thus the description encompasses both cases where the circumstance occurs and cases where the circumstance does not occur. For example, the phrase "optionally substituted" means that non-hydrogen substituents may or may not be present on a given atom, and thus the description encompasses structures where non-hydrogen substituents are present and structures where non-hydrogen substituents are not present.

[0124] The terms "stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation, and if necessary, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0125] The term "free compound" is used herein to describe a compound in an unbound state.

[0126] Throughout the description, when a composition is described as having, including, or comprising certain components, it is contemplated that the composition can also consist essentially of, or consist of, the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process can also consist essentially of, or consist of, the recited process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions may be performed simultaneously.

[0127] The term "small molecule" is an art-recognized term. 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 mass of cells or tissue that is the result of tumor formation (neoplasia). Neoplasms can be benign, potentially malignant (precancerous), or malignant (cancerous). An adenoma is an example of a neoplasm.

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

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

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

[0133] The term "gene expression" or "protein expression" encompasses any information regarding the amount of a gene transcript or protein present in a sample as well as information about the rate at which a gene or protein is produced, accumulated, or degraded (e.g., reporter gene data, data from nuclear runoff experiments, pulse-chase data, etc.). Certain types of data may be considered related to both gene and protein expression. For example, protein levels in a cell reflect the level of the protein as well as the level of transcription, and such data are intended to be encompassed by the phrase "gene or protein expression information." Such information may be given in the form of amount per cell, amount relative to a control gene or protein, in a unitless measure, etc. The term "information" should not be limited to any particular means of presentation, but is intended to refer to any presentation that provides relevant information. The term "expression level" refers to the amount reflected in or derivable from gene or protein expression data, regardless of whether the data covers gene transcript accumulation or protein accumulation, protein synthesis rate, etc.

[0134] The terms "healthy" and "normal" are used interchangeably herein and refer to a subject or particular cell or tissue that lacks (at least to the limits of detection) a disease state.

[0135] The term "nucleic acid" refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). This term should also be understood to encompass analogs of either 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 acids. Some categories of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such nucleic acid categories are well known in the art.

[0136] Embodiments described herein relate to compounds and methods for modulating SCD activity (e.g., 15-PGDH activity), modulating tissue prostaglandin levels, and / or treating diseases, disorders, or conditions in which modulating 15-PGDH activity and / or prostaglandin levels is desirable.

[0137] The terms "inhibitor," "activator," and "modulator" of 15-PGDH expression or activity refer to inhibitory, activating, or modulating molecules (e.g., ligands, agonists, antagonists, and their homologs and mimetics) identified using in vitro or in vivo assays for 15-PGDH expression or 15-PGDH activity, respectively. The term "modulator" encompasses inhibitors and activators. Inhibitors are, for example, agents (e.g., antagonists) that inhibit the expression of 15-PGDH or bind to and partially or completely block stimulation, reduce, prevent, delay, inactivate, desensitize, or downregulate the activity of 15-PGDH. Activators are, for example, agents (e.g., agonists) that induce or activate the expression of 15-PGDH, or bind to, stimulate, stabilize, increase, open, activate, promote, or enhance activation, sensitize, or upregulate the activity of 15-PGDH. Modulators include naturally occurring and synthetic ligands, small chemical molecules, etc.

[0138] The 15-PGDH inhibitors described herein can 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 the appearance of skin darkening or sun-tanned skin. Known activities of prostaglandins also include improving pulmonary arterial hypertension. The 15-PGDH inhibitors described herein can also be used to increase the number of tissue stem cells for purposes including increasing resistance to radiation-induced tissue damage, increasing resistance to environmental exposure to radiation, and increasing the number of stem cells to improve the compatibility of bone marrow or other types of transplants (by exposing the 15-PGDH inhibitors described herein in vivo to increase the number of stem cells before harvesting transplant tissue, or by exposing harvested tissue ex vivo before transplantation into a recipient host, or by treating the transplant recipient). The 15-PGDH inhibitors described herein may also be used for purposes including promoting liver regeneration, including liver regeneration after liver resection and toxic injury (e.g., 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 scratch wounds across keratinocyte cell cultures. 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, skin). Furthermore, the 15-PGDH inhibitors described herein may be used to treat erectile dysfunction.

[0139] The 15-PGDH inhibitors described herein can be identified using an assay in which a putative modulator compound is applied to cells expressing 15-PGDH and then the functional effect on 15-PGDH activity is determined. Samples or assays containing 15-PGDH treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to determine the degree of effect. The control sample (untreated with a modulator) is assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value compared to the control is approximately 80%, or optionally 50%, 25%, 10%, 5%, or 1%.

[0140] Agents tested as modulators of SCD (e.g., 15-PGDH) can be any small chemical molecule or compound. Typically, test compounds will be small chemical molecules, natural products, or peptides. Assays are designed to screen large compound libraries by automating the assay steps and providing compounds from any convenient source to assays that are typically run in parallel (e.g., in a microtiter format on a microtiter plate in a robotic assay). Modulators also include agents designed to increase the level of 15-PGDH mRNA or the level of translation from mRNA.

[0141] In some embodiments, the modulator of SCD may be an SCD inhibitor that can be administered to the tissue or blood of a subject in an amount effective to inhibit the activity of short-chain dehydrogenase enzymes. The SCD inhibitor may be a 15-PGDH inhibitor that can be administered to the tissue or blood of a subject in an amount effective to increase the level of prostaglandins in the tissue or blood. 15-PGDH inhibitors include those represented by formula (I) or (II): [ka] A compound having the formula: X 1 is N or CR 4 and; X 2 is S, S=O, S(=O)2 or C=O; X 3 is CR 8 (compounds forming polycyclic heteroaryls with 10 ring atoms) or absent (compounds forming polycyclic heteroaryls with 9 ring atoms); X 4 is N, NH or CR 7 and; X 5 is N, C=O or CR 16 and X 4 is CR 7 Is it X? 3 If does not exist, X 5 is N and X 5 If C=O, then X 4 is NH and X 4 is N and X 3 is CR 8 If X 5 is CR 16 and; R 1 , R 2 , R 3 , R 4 , R 9 , R 10 and R 16 are the same or different and independently represent hydrogen, oxygen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 6 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C 24Alkaryl, 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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 20Arylamide (-NH(CO)-aryl), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, R 7 and R 8are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 7 or R 8 At least one of them is not H, Compounds, and pharmaceutically acceptable salts thereof, may be included.

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

[0143] In some embodiments, the 15-PGDH inhibitor has the following formula (Ia): [ka] A compound having the formula: X 2 is S, S=O, S(=O)2 or C=O; Each R 1 , R 2 and R 3 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 6 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C 24 Alkaryl, C6-C 24Aralkyl, 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) where R is independently H, alkyl, aryl, or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C 24Alkyl, 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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, phosphoric acid ester [-OP(O)(OR)2; where R=H, methyl or other alkyl]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, wherein R 2 or R 3 At least one of them is not H, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0144] In other embodiments, the 15-PGDH inhibitor has the following formula (Ib): [ka] A compound having the formula: X 2 is S, S=O, S(=O)2 or C=O; R 2 , R 3 , R 5 and R 6 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-O-(CO)-O-alkyl), C6-C 20 Arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO - ), carbamoyl (-(CO)-NH2), C1-C 24Alkyl-carbamoyl(-(CO)-NH(C1-C 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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 20Arylsulfonyl (-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, phosphoric acid ester [-OP(O)(OR)2; where R=H, methyl or other alkyl]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, wherein R 2 or R 3 At least one of them is not H, and R 5 and R 6 may be linked to form a cyclic or polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0145] In other embodiments, the 15-PGDH inhibitor has the following formula (Ic): [ka] A compound having the formula: R 2 , R 3 and R 14 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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, phosphoric acid ester [-OP(O)(OR)2; where R=H, methyl or other alkyl]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, wherein R 2 or R 3 At least one of them is not H, and n 1 is 0 to 4, and each R 14 are the same or different, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0146] In yet other embodiments, the 15-PGDH inhibitor has the following formula (Id): [ka] A compound having the formula: 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 and R 3 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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-C24 Alkynyloxy, C5-C 20 Aryloxy, acyl (C2-C 24 Alkylcarbonyl (-CO-alkyl) and C6-C 20 arylcarbonyl (-CO-aryl), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 24aralkyl, 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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, phosphoric acid ester [-OP(O)(OR)2; where R=H, methyl or other alkyl]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, wherein R 2 or R 3 At least one of them is not H, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0147] In yet other embodiments, the 15-PGDH inhibitor has the following formula (Ie): [ka] A compound having the formula: X2 is S, S=O, S(=O)2 or C=O; R 1 and R 2 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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 20Arylsulfonyl (-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, phosphoric acid ester [-OP(O)(OR)2; where R=H, methyl or other alkyl]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, wherein R 2 or R 3 At least one of them 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: [ka] JPEG0007660087000009.jpg227158JPEG0007660087000010.jpg117158 and pharmaceutically acceptable salts thereof.

[0149] In other embodiments, the 15-PGDH inhibitor has the following formula (IIa): [ka] A compound having the formula: R 7 and R 8are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 7 or R 8 At least one of them is not H; R 9 and R 10 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-O-(CO)-O-alkyl), C6-C 20Arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO - ), carbamoyl (-(CO)-NH2), C1-C 24 Alkyl-carbamoyl(-(CO)-NH(C1-C 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-S-aryl; also called "arylthio"), C1-C 24 Alkylsulfinyl (-(SO)-alkyl), C5-C20 Arylsulfinyl (-(SO)-aryl), C1-C 24 Alkylsulfonyl (-SO2-alkyl), C5-C 20 Arylsulfonyl (-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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, optionally with R 9 or R 10 At least one of them is not H, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0150] In yet other embodiments, the 15-PGDH inhibitor has the following formula (IIb): [ka] A compound having the formula: X 7 is S, S=O, S(=O)2 or C=O; R 7 and R 8 are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 7 or R 8 At least one of them is not H; R 11is hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON +=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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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) nO] m ), phosphate, phosphate ester [-OP(O)(OR)2; where R = H, methyl or other alkyl]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof. Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0151] In some embodiments, the 15-PGDH inhibitor has the following formula (IIc): [ka] A compound having the formula: X 7 is S, S=O, S(=O)2 or C=O; R 7 and R 8 are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 7 or R 8 At least one of them is not H; R 12 and R 13 are the same or different and independently represent hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 6 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C 24 Alkaryl, C6-C24 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) where R is independently H, alkyl, aryl, or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof, wherein R 12 and R 13 may be linked to form a cyclic or polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0152] In other embodiments, the 15-PGDH inhibitor has the following formula (IId): [ka] A compound having the formula: X 7 is S, S=O, S(=O)2 or C=O; R 7 and R 8 are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 7 or R 8 At least one of them is not H; R 15 is hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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-C20 arylcarbonyl (-CO-aryl), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 24aralkyl, 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof; 2 is 0 to 4, and each R 15 are the same or different, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0153] In yet other embodiments, the 15-PGDH inhibitor has the following formula (IIe): [ka] A compound having the formula: R 8 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 15 is hydrogen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20 aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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 20Arylsulfonyl (-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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof; 2 is 0 to 4, and each R 15 are the same or different, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0154] In yet other embodiments, the 15-PGDH inhibitor has the following formula (IIf): [ka] A compound having the formula: R 8 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R 15 and R 16 are the same or different and independently represent hydrogen, oxygen, substituted or unsubstituted C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, C3-C 20aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 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 to 14 ring atoms (wherein 1 to 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), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 20 Aryloxycarbonyl (-(CO)-O-aryl), C2-C 24 Alkylcarbonate (-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 24 alkyl), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano (-CN), isocyano (-N + C - ), cyanate (-O-CN), isocyanate (-ON + =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), sulfanamide (-SON(R) 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 Alkyl sulfanyl (-S-alkyl; also called "alkylthio"), aryl sulfanyl (-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), 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]; groups incorporating an amino acid or other moiety that is expected to carry a positive or negative charge at physiological pH; and combinations thereof; 2 is 0 to 4, and each R 15 are the same or different, Compounds, and pharmaceutically acceptable salts thereof, may be included.

[0155] Examples of 15-PGDH inhibitors having formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) include the following compounds: [ka] JPEG0007660087000018.jpg204158JPEG0007660087000019.jpg214158JPEG0007660087000020.jpg86158 and pharmaceutically acceptable salts thereof.

[0156] In certain embodiments, (ia) at a concentration of 2.5 μM, it is capable of stimulating a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70 (using a scale where 100 represents a doubling of reporter output over baseline); (iia) at a concentration of 2.5 μM, it is capable of stimulating a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 75; (iiia) at a concentration of 7.5 μM, it is capable of stimulating an LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70; and (iva) at a concentration of 7.5 μM, it does not activate a negative control V9m cell line expressing a TK-Renilla luciferase reporter to a level greater than 20; and (va) an IC of less than 1 μM. 5015-PGDH inhibitors having formulas (I) and (II) may be selected that inhibit the enzymatic activity of recombinant 15-PGDH protein at

[0157] In other embodiments, the 15-PGDH inhibitor (ib) is capable of stimulating a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 2.5 μM; (iib) is capable of stimulating a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 2.5 μM; (iiib) is capable of stimulating a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 7.5 μM; (ivb) does not activate a negative control V9m cell line expressing a TK-Renilla luciferase reporter to luciferase levels more than 20% above background at a concentration of 7.5 μM; and (vb) has an IC of 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 at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM. 50 or preferably an IC of less than 250 nM 50 or more preferably an IC of less than 50 nM 50 or more preferably an IC of less than 10 nM 50 or more preferably an IC of less than 5 nM 50 and can inhibit the enzymatic activity of recombinant 15-PGDH.

[0159] In other embodiments, 15-PGDH inhibitors can increase cellular levels of PGE-2 following stimulation of A459 cells with an appropriate agent (eg, IL1-β).

[0160] The 15-PGDH inhibitors described herein can be used to prevent or treat diseases that are associated with 15-PGDH and / or reduced prostaglandin levels, and / or that are desirable to increase the level of prostaglandins in a subject.For example, as described above, prostaglandins are known to play an important role in hair growth.Specifically, various types of prostaglandins (A2, F) in various compartments of hair follicles or in the skin environment adjacent thereto ... 2a It has been shown that the internal storage of prostaglandins (e.g., E2) is essential for maintaining and increasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9), 762-9). 15-PGDH, which is involved in the breakdown of prostaglandins, is present in the dermal papilla of the hair follicle and acts as a catalyst for the breakdown of prostaglandins (especially PGF 2a and PGE2), causing scalp damage and alopecia (Michelet JF et. al., 2008, Exp. Dermatol, 17(10), 821-8). Therefore, the compounds described herein that have suppressive or inhibitory activity against 15-PGDH, which decomposes prostaglandins, can improve scalp damage, prevent alopecia, and promote hair growth, and may be used in pharmaceutical compositions for preventing alopecia and promoting hair growth.

[0161] In other embodiments, the 15-PGDH inhibitors described herein may be used in 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 (in particular as agents for preventing and / or limiting graying of hair).

[0162] In some embodiments, a 15-PGDH inhibitor may be applied to a subject's skin (e.g., topically) 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 another embodiment, the 15-PGDH inhibitors described herein may be used in pharmaceutical compositions for the prevention or treatment of cardiovascular diseases and / or vascular insufficiency diseases (such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary arterial hypertension). Prostaglandins, including prostaglandin homologs produced in the body, are known to maintain the proper function of vascular walls, particularly by contributing to vasodilation for blood flow, preventing platelet aggregation, and regulating the proliferation 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, prostaglandin production in blood vessels has been shown to be reduced in patients with hypertension, including pulmonary arterial hypertension.

[0164] In other embodiments, the 15-PGDH inhibitors described herein may be used in pharmaceutical compositions for the prevention or treatment of oral cavity, intestinal, and / or gastrointestinal damage or disease, or inflammatory bowel disease (e.g., oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, and gastric ulcers). Gastritis and gastric ulcers, representative gastrointestinal diseases, are defined as conditions in which the gastrointestinal mucosa is digested by gastric acid, resulting in the formation of ulcers. In the stomach wall, which generally consists of the mucosa, submucosa, muscularis, and serosa, gastric ulcers damage the submucosa and muscularis as well, whereas gastritis damages only the mucosa. Although the incidence of gastritis and gastric ulcers is relatively high, their causes remain unclear. Currently, they are known to be caused by an imbalance between attacking and defensive factors, i.e., an increase in attacking factors (e.g., increased secretion of gastric acid or pepsin) or a decrease in defensive factors (e.g., structural or morphological defects in the gastric mucosa, decreased secretion of mucus and bicarbonate ions, decreased prostaglandin production, etc.).

[0165] Currently available therapeutic agents for gastritis and gastric ulcers include various drugs for strengthening defense factors (antacids that do not affect gastric acid secretion but neutralize already produced gastric acid, gastric acid secretion inhibitors, prostaglandin secretion promoters, and coating agents for the stomach 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; SJ Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). In view of the above, the 15-PGDH inhibitors described herein exhibit suppressive or inhibitory activity against 15-PGDH, which decomposes prostaglandins that protect the gastric mucosa, and therefore may be effective in preventing or treating gastrointestinal diseases (especially gastritis and gastric ulcers).

[0166] Furthermore, 15-PGDH inhibitors would also be expected to protect against other forms of intestinal damage, which may include radiation toxicity, chemotherapy toxicity, and chemotherapy-induced mucositis.

[0167] In the kidney, prostaglandins may help regulate renal blood flow and regulate 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, to prevent graft rejection and cyclosporine toxicity in kidney transplant patients, and to reduce urinary albumin excretion rates and N-acetyl-β-D-glucosaminidase levels in patients with diabetic nephropathy (see Porter, Am., 1989, J. Cardiol., 64: 22E-26E). Furthermore, U.S. Patent No. 5,807,895 discloses a method 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 therefore inhibition of prostaglandin production in the kidney leads to renal dysfunction (Hao, CM, 2008, Annu Rev Physiol, 70, 357.about.77).

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

[0169] The term "renal dysfunction," as used herein, includes symptoms such as: lower than normal creatinine clearance; lower than normal free water clearance; higher than normal blood levels of urea, nitrogen, potassium, and / or creatinine; altered activity of renal enzymes such as gamma glutamyl synthetase, alanine phosphatidase, N-acetyl-β-D-glucosaminidase, or β-w-microglobulin; and increased above normal levels of macroalbuminuria.

[0170] PGE1, PGE2 and PGF 2a Prostaglandins, including 15-PGDH, have also been shown to stimulate bone resorption and bone formation, increasing 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). Given that 15-PGDH inhibits the activity of prostaglandins, as described above, inhibition of 15-PGDH activity may result in the promotion of bone resorption and bone formation, which are inhibited by 15-PGDH. Therefore, 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 healing of fractures, or to promote healing after bone surgery or joint replacement, or to promote healing of bone-to-bone implants, bone-to-prosthesis implants, 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 can inhibit the growth, proliferation, and metastasis of cancers that express 15-PGDH.

[0172] In yet another embodiment, 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.Therefore, when the skin is damaged by a wound or burn, inhibiting 15-PGDH activity may result in the therapeutic effect of PGE2 on the wound or burn.

[0173] Furthermore, as described above, increased levels of prostaglandins have been shown to stimulate signal transduction through the Wnt signaling pathway through increased β-catenin-mediated transcriptional activity. Wnt signaling is known to be an important pathway utilized by tissue stem cells. Therefore, the 15-PGDH inhibitors described herein can be used to increase the number of tissue stem cells, including for purposes such as promoting tissue regeneration or repair in organs such as the liver, colon, and bone marrow. Furthermore, the 15-PGDH inhibitors described herein can be used 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, trauma, chronic conditions, medical interventions or other conditions that cause or are associated with tissue damage and the need for tissue repair, and are therefore suitable for treatment or amelioration using the methods described herein, include acute coronary syndromes, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune diseases, bone fractures, fractures, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns (bums), cancer, cardiovascular disease, cartilage damage, 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 wounds, delayed ulcer healing, delayed wound healing, diabetes mellitus (type I and type II), diabetes, diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic capillaries Dilation, 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 arterial disease (PAD), peripheral arterial disease, peripheral ischemia These conditions include, but are not limited to, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplant, 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, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[0175] Other illustrative examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions causing or associated with tissue damage and the need for tissue repair that are amenable to treatment or amelioration using the methods of the present invention include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue or organ transplant or graft.

[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 caused by acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns (bums), cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neurological disorders. Pathologies, chronic infections, 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 wounds, delayed ulcer healing, delayed wound healing, diabetes mellitus (types I and II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hypertension Oxygen 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 arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathies is associated with at least one of the following: pulmonary edema, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidneys, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[0178] In some embodiments, a 15-PGDH inhibitor may be provided to a preparation of hematopoietic stem cells (such as a subject's peripheral blood hematopoietic stem cells or umbilical cord stem cells) to increase the suitability 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 of an organism's blood cell types, 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 and those known in the art (see Fei, R., et al., U.S. Pat. No. 5,635,387; McGlave, et al., U.S. Pat. No. 5,460,964; Simmons, P., et al., U.S. Pat. No. 5,677,136; Tsukamoto, et al., U.S. Pat. No. 5,750,397; Schwartz, et al., U.S. Pat. No. 5,759,793; DiGuisto, et al., U.S. Pat. No. 5,681,599; Tsukamoto, et al., U.S. Pat. No. 5,716,827). Hematopoietic stem cells (HSCs) give rise to committed hematopoietic progenitor cells (HPCs) that are capable of generating the entire repertoire of mature blood cells over the lifetime of an organism.

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

[0181] The hematopoietic stem cells used in the methods described herein may be obtained from any suitable source of hematopoietic stem and progenitor cells and may be provided as a highly purified hematopoietic stem cell population or as a composition containing about 0.01% to about 100% hematopoietic stem cells. For example, hematopoietic stem cells may be provided in compositions such as unfractionated bone marrow (where hematopoietic stem cells comprise 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 can be isolated or obtained from bodily organs containing cells of hematopoietic origin. Isolated cells can 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," etc., as used herein, refer to the in vitro or ex vivo separation of one or more cells from their natural cellular environment and from association with other components of a tissue or organ, i.e., they are not significantly 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 aspirate 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, harvesting sufficient quantities of hematopoietic stem cells for therapeutic use may require mobilization of stem and progenitor cells from the donor.

[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. Increasing the number of stem cells harvested from a donor can significantly improve the number of stem cells available for therapeutic use. Hematopoietic growth factors (e.g., granulocyte colony-stimulating factor (G-CSF)) or chemotherapeutic agents are often used to stimulate mobilization. Commercially available stem cell mobilization drugs exist that can be used in combination with G-CSF to mobilize sufficient numbers of hematopoietic stem and progenitor cells for transplant into a subject. For example, G-CSF and Mozobil (Genzyme Corporation) can be administered to a donor to obtain a sufficient number of hematopoietic cells for transplantation. Other methods of hematopoietic stem cell mobilization 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, which may be collected according to techniques known in the art (see, e.g., U.S. Pat. Nos. 7,147,626 and 7,131,958, which are incorporated herein by reference for their disclosure of such methodologies).

[0186] In one embodiment, HSPCs may be obtained from a pluripotent stem cell source (e.g., induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs)). As used herein, the term "induced pluripotent stem cells" or "iPSCs" refers to non-pluripotent cells that have been reprogrammed to a pluripotent state. Once a cell of interest has been reprogrammed to 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" refers to methods of increasing the potency of a cell toward a less differentiated state. As used herein, the term "programming" refers to methods of decreasing the potency or differentiating a cell toward a more differentiated state.

[0187] In some embodiments, one or more 15-PGDH inhibitors described herein may be administered 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, a therapeutic composition comprises a population of cells, wherein the population of cells is about 95% to about 100% hematopoietic stem cells. The present invention contemplates, in part, that the use of highly purified hematopoietic stem cell therapeutic compositions (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 unfractionated cell mixtures in which hematopoietic stem cells comprise less than 1% of the total cell population.

[0189] In some embodiments, a 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 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] Hematopoietic stem cells in a therapeutic composition of the invention may be autologous ("autologous") or non-autologous ("non-autologous"; e.g., allogeneic, syngeneic, or xenogeneic) to the subject to which the therapeutic composition is administered. "Autologous," as used herein, refers to cells from the same subject. "Allogeneic," as used herein, refers to cells of the same species that are genetically different from the cells being compared. "Syngeneic," as used herein, refers to cells of a different subject that are genetically identical to the cells being compared. "Xenogeneic," as used herein, refers to cells of a different species than the cells being compared.

[0191] Hematopoietic stem cells for use in the methods of the invention can be depleted of mature hematopoietic cells (such as T cells, B cells, NK cells, dendritic cells, monocytes, granulocytes, erythroid cells, and their committed progenitors) from bone marrow aspirate, umbilical cord blood, or mobilized peripheral blood (mobilized leukapheresis product). Mature, lineage-committed cells are depleted by immunodepletion, e.g., 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). CD34 + A subsequent step of isolating primitive hematopoietic stem cells using a substrate labeled with an antibody that binds to the antigen can be performed to further purify the population of cells. Kits for purifying stem and progenitor cells from a variety of 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 x 10 5 cells, at least 0.5 x 10 5 cells, at least 1 x 10 5 Cells, at least 5 x 10 5 Cells, at least 10 x 10 5cells, at least 0.5 x 10 6 cells, at least 0.75 x 10 6 cells, at least 1 x 10 6 cells, at least 1.25 x 10 6 cells, at least 1.5 x 10 6 cells, at least 1.75 x 10 6 Cells, at least 2 x 10 6 cells, at least 2.5 x 10 6 Cells, at least 3 x 10 6 Cells, at least 4 x 10 6 Cells, at least 5 x 10 6 Cells, at least 10 x 10 6 cells, at least 15 x 10 6 Cells, at least 20 x 10 6 Cells, at least 25 x 10 6 cells, or at least 30 x 10 6 It is a cell.

[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 x 10 5 At least 0.5 × 10 cells / kg body weight 5 At least 1 x 10 cells / kg body weight 5 At least 5 x 10 cells / kg body weight 5 At least 10 x 10 cells / kg body weight 5 At least 0.5 × 10 cells / kg body weight 6 At least 0.75 x 10 cells / kg body weight 6 At least 1 x 10 cells / kg body weight 6 At least 1.25 x 10 cells / kg body weight 6 At least 1.5 x 10 cells / kg body weight 6 At least 1.75 x 10 cells / kg body weight 6 At least 2 x 10 cells / kg body weight 6 At least 2.5 x 10 cells / kg body weight 6 At least 3 x 10 cells / kg body weight 6At least 4 x 10 cells / kg body weight 6 At least 5 x 10 cells / kg body weight 6 At least 10 x 10 cells / kg body weight 6 At least 15 x 10 cells / kg body weight 6 At least 20 x 10 cells / kg body weight 6 At least 25 x 10 cells / kg body weight 6 cells / kg body weight, or at least 30 × 10 6 cells / kg body weight.

[0194] Preparations of hematopoietic stem cells treated with 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, and in the treatment of ischemia or tissues damaged by ischemia, and in reducing further damage to ischemic tissue and / or repairing damage to ischemic tissue via cell mobilization, improving angiogenesis in ischemic tissue, improving tissue regeneration at the site of ischemia, reducing necrosis or apoptosis in ischemic tissue and / or increasing 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 hematopoietic stem cells and a 15-PGDH inhibitor are useful for subjects in need of hematopoietic system reconstitution, such as subjects who have undergone or are scheduled to undergo myeloablative therapy.

[0195] Subjects who may be treated with the 15-PGDH inhibitor-treated hematopoietic stem cell preparations and / or the 15-PGDH inhibitor and hematopoietic stem cell therapeutic compositions may include subjects with or diagnosed with various types of leukemia, anemia, lymphoma, myeloma, immunodeficiency disorders, and solid tumors. Subjects may also include humans who are candidates for stem cell or bone marrow transplantation, such as those undergoing treatment for malignant disease or as a component of gene therapy. Subjects may also include individuals or animals donating stem cells or bone marrow for allogeneic transplantation. In certain embodiments, subjects may be undergoing myeloablative radiation therapy or chemotherapy or may have experienced acute radiation or chemical injury resulting in bone marrow destruction. In certain embodiments, subjects may be undergoing radiation therapy or chemotherapy, such as those undergoing various cancer treatments. Typical subjects include animals that exhibit abnormal amounts (either lower or higher than those in "normal" or "healthy" subjects) of one or more physiological activities that can be modulated by an agent or stem cell or bone marrow transplantation.

[0196] 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 a hematopoietic stem cell may also include subjects undergoing chemotherapy or radiation therapy for cancer, as well as subjects suffering from (e.g., afflicted with) a non-malignant hematologic disorder, particularly an immunodeficiency (e.g., SCID, Fanconi anemia, severe aplastic anemia, or congenital hemoglobinopathies, or metabolic storage diseases (e.g., Hurler disease, Hunter disease, mannosidosis, etc.)), or cancer, particularly a hematologic malignancy (e.g., acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's lymphoma or non-Hodgkin's lymphoma), multiple myeloma, myelodysplastic syndrome, etc.), or a non-hematologic cancer such as a solid tumor (including breast cancer, ovarian cancer, brain cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer).

[0197] Subjects 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, subjects suffer from a disorder that is the result of a side effect or complication of another primary treatment, such as radiation therapy, chemotherapy, or treatment with a myelosuppressant drug (zidovudine, chloramphenicol, or ganciclovir). Such disorders include neutropenia, anemia, thrombocytopenia, and immune dysfunction. Other subjects may have a disorder caused by an infection (e.g., a viral, bacterial, or fungal infection) that causes damage to stem or progenitor cells in the bone marrow.

[0198] Additionally, subjects suffering from the following conditions may benefit from treatment with 15-PGDH inhibitor-treated hematopoietic stem cell preparations and / or 15-PGDH inhibitor and hematopoietic stem cell therapeutic compositions: lymphopenia, lymphorrhea, lymphostasis, erythrocytopenia, erythrodegenerative disorders, erythroblastopenia, leukoerythroblastosis; erythroclasis, thalassemia, myelodysplasia, myelofibrosis, thrombocytopenia, disseminated intravascular coagulation (DIC), immune (autoimmune) thrombocytopenic purpura (ITP), HIV-induced ITP, myelodysplasia; thrombocytotic disease, thrombocytosis, congenital neutropenia (such as Kostmann syndrome and Shwachman-Diamond syndrome), neoplastic associated neutropenia. neutropenias), childhood and adult cyclic neutropenia; post-infectious neutropenia; myelodysplastic syndromes; neutropenia associated with chemotherapy and radiation therapy; chronic granulomatous disease; mucopolysaccharidoses; Diamond-Blackfan anemia; sickle cell disease; or beta-thalassemia major.

[0199] In other embodiments, preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or therapeutic compositions of 15-PGDH inhibitors and hematopoietic stem cells may be used in cell therapy to treat ischemic tissue or to treat or ameliorate one or more symptoms associated with tissue ischemia, including, but not limited to, impaired or lost organ function (including, but not limited to, impaired or lost brain, kidney, or heart function), convulsions, claudication, numbness, tingling, weakness, pain, reduced wound healing, inflammation, skin discoloration, and gangrene.

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

[0201] Illustrative examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions, or other conditions that cause or are associated with ischemia or increase the risk of ischemia in a subject and are therefore suitable for treatment or amelioration using the methods described herein include acute coronary syndromes, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune diseases, Fractures, fractures, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns (BUMS), cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated hemorrhage 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 arterial disease These conditions include, but are not limited to, peripheral arterial disease (PAD), peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, inflammatory conditions of the blood vessels, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[0202] Other illustrative examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions, or other conditions that cause or are associated with ischemia in a subject, or that increase the risk of ischemia, or that cause a subject to exhibit one or more symptoms of ischemia that are amenable to treatment or amelioration using the methods of the invention, include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplant or graft.

[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 tissue 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 that can give rise to other tissues) and / or a preparation of pluripotent stem cells.

[0206] In one embodiment, tissue stem cells may be obtained from a pluripotent stem cell source (e.g., induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs)). As used herein, the term "induced pluripotent stem cells" or "iPSCs" refers to non-pluripotent cells that have been reprogrammed to a pluripotent state. Once a subject's cells have been reprogrammed to a pluripotent state, they 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" refers to methods of increasing the potential of a cell to a less differentiated state. As used herein, the term "programming" refers to methods of decreasing the potential of a cell or differentiating a cell to a more differentiated state.

[0207] In some embodiments, one or more 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, hi one embodiment, a therapeutic composition may comprise a population of tissue stem cells treated ex vivo with one or more 15-PGDH inhibitors.

[0208] In certain embodiments, a therapeutic composition comprises 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, a 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% tissue 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% 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 compositions of the present invention may be autologous ("autologous") or non-autologous ("non-autologous"; e.g., allogeneic, syngeneic, or xenogeneic) to the subject to which the therapeutic composition is administered. "Autologous" as used herein refers to cells from the same subject. "Allogeneic" as used herein refers to cells of the same species that are genetically different from the cells being compared. "Syngeneic" as used herein refers to cells of a different subject that are genetically identical to the cells being compared. "Xenogeneic" as used herein refers 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 reducing further tissue damage and / or enhancing regeneration of damaged tissue via stem cell mobilization and / or increasing cell survival at the site of tissue damage.

[0212] Symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions that result in 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 acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune diseases, bone fractures, fractures, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns (BUMS), cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DI) C), 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 arterial disease (P) These conditions include, but are not limited to, AD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[0213] Other illustrative examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions causing or associated with tissue damage and the need for tissue repair that are amenable to treatment or amelioration using the methods of the present invention include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue or organ transplant or graft.

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

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

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

[0218] In other embodiments, 15-PGDH inhibitors may be administered to recipients of bone marrow transplants, hematopoietic stem cell transplants, or umbilical cord blood stem cell transplants to reduce the administration of other treatments or growth factors.

[0219] In some embodiments, a 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 radiation therapy, and in individuals with 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 viral infections including, but not limited to, HIV, CMV, and parvovirus.

[0220] In other embodiments, 15-PGDH inhibitors may be administered to subjects to improve platelet recovery after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, and in individuals with 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 viral infections including, but not limited to, HIV, CMV, and parvovirus.

[0221] In still other embodiments, 15-PGDH inhibitors may be administered to subjects to improve hemoglobin recovery after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, and in individuals with 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 viral infections including, but not limited to, HIV, CMV, and parvovirus.

[0222] In some embodiments, 15-PGDH inhibitors may be administered to subjects to improve bone marrow stem cell numbers after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, in individuals with other bone marrow diseases, in individuals with cytopenias after viral infections, and in individuals with cytopenias.

[0223] In other embodiments, a 15-PGDH inhibitor may be administered to a subject with cytopenia, including but not limited to, neutropenia, thrombocytopenia, lymphopenia, and anemia, to improve response to cytokines administered to the subject. Cytokines to which SW033291 may improve response 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, a 15-PGDH inhibitor may be administered to a subject or to a tissue graft in a subject to reduce graft rejection, to improve graft survival, to improve graft survival after treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy or immunosuppressive therapy, to confer resistance to the toxic or lethal effects of radiation exposure, to confer resistance to the toxic effects of cytoxan, fludarabine, chemotherapy or immunosuppressive therapy, to reduce infection, and / or to reduce radiation-induced lung toxicity.

[0225] In other embodiments, 15-PGDH inhibitors may be administered to recipients of tissue stem cell transplants, including but not limited to, hematopoietic stem cells, neural stem cells, mesenchymal stem cells or other tissue stem cell transplants, to accelerate tissue regeneration and repair after transplantation.

[0226] In some embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF to increase neutrophils.

[0227] In other embodiments, administration of a 15-PGDH inhibitor may be combined with hematopoietic cytokines to increase neutrophils.

[0228] In yet other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF to increase the number of peripheral blood hematopoietic stem cells and / or to mobilize peripheral blood hematopoietic stem cells.

[0229] In other embodiments, administration of a 15-PGDH inhibitor may be combined with hematopoietic cytokines in order to increase the number of peripheral blood hematopoietic stem cells and / or to mobilize peripheral blood hematopoietic stem cells.

[0230] In some embodiments, administration of a 15-PGDH inhibitor may be combined with a second agent, including plerixafor, to increase the number of and / or mobilize peripheral blood hematopoietic stem cells.

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

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

[0234] In yet other embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF to increase 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 hematopoietic cytokines in order to increase the number of hematopoietic stem cells in the blood or bone marrow.

[0236] In other embodiments, 15-PGDH inhibitors 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, inflammatory cytokine expression and inflammatory cell infiltration).

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

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

[0239] Examples of fibrotic diseases, disorders, and conditions include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), scleroderma graft-versus-host disease, renal fibrosis (including glomerulosclerosis, renal tubulointerstitial fibrosis, progressive renal disease, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., glomerulosclerosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, etc.), and / or inflammatory diseases, disorders, and conditions. These include: 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 fasciitis, eosinophilic fasciitis, general fibrosis syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrous tissue, retroperitoneal fibrosis, hepatic fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis / bone marrow fibrosis, drug-induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative syndromes, gynecological cancers, Kaposi's sarcoma, leprosy, collagenous colitis, acute fibrosis, and organ-specific fibrosis.

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

[0241] In some embodiments, 15-PGDH inhibitors can be used to treat or prevent pulmonary fibrosis.Pulmonary fibrosis can 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 workers' pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of mineral dust, pulmonary fibrosis caused by infectious pathogens, pulmonary fibrosis caused by inhalation of harmful gases, aerosols, chemical dusts, smoke or vapor, 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, stiff tissue makes it difficult for the lungs to function properly, leading to respiratory problems such as shortness of breath, which can ultimately be fatal. Pulmonary fibrosis can be caused by acute lung injury, viral infection, exposure to toxins, radiation, chronic disease, drug treatment, or can be idiopathic (i.e., the underlying cause is unknown).

[0243] The classic finding in idiopathic pulmonary fibrosis is diffuse peripheral scarring of the lungs, often at the lung base, with small bubbles (known as bullae) adjacent to the outer layer of the lung surface. Idiopathic pulmonary fibrosis often shows a slow and relentless progression. Early on, patients often complain of a dry cough with no known cause. Next, shortness of breath (dyspnea) caused by increasingly inactive activities begins and worsens over time. Eventually, shortness of breath becomes disabling, limiting all activity, even while sitting quietly. In rarer cases, fibrosis can progress rapidly, with dyspnea and disability occurring within weeks to months of disease onset. This form of pulmonary fibrosis is called Hamman-Rich syndrome.

[0244] Pulmonary hypertension is characterized by elevated blood pressure in the pulmonary vasculature, including the pulmonary arteries, veins, and / or capillaries. Abnormally high pressure strains the right ventricle of the heart, causing 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 pulmonary conditions (including tumors, emphysema, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis). Pulmonary fibrosis can lead to narrowing of the pulmonary vasculature, resulting in pulmonary hypertension.

[0245] Chronic obstructive pulmonary disease (COPD) is a common lung disease that often accompanies chronic bronchitis or emphysema. Symptoms often include coughing, mucus buildup, fatigue, wheezing, and respiratory infections.

[0246] Chronic bronchitis and emphysema are lung diseases in which the airways narrow. This leads to restricted airflow 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 lead to chronic bronchitis. In the lung airways, chronic bronchitis is characterized by an increase in the number (hyperplasia) and size (hypertrophy) of airway goblet cells and mucus glands. As a result, there is more mucus than normal in the airways, which contributes to narrowing of the airways and causing a productive cough. Microscopically, there is infiltration of the airway walls by inflammatory cells. Following inflammation, there is scarring and remodeling, which thickens the walls and leads to narrowing of the airways. As chronic bronchitis progresses, squamous metaplasia (abnormal changes in the tissue lining the airways) and fibrosis (further thickening and scarring of the airway walls) occur. These changes result in airflow restriction and difficulty breathing.

[0248] Asthma is a chronic lung disease characterized by inflammation and narrowing of the airways. Asthma causes frequent recurrences of wheezing, chest tightness, shortness of breath and coughing. Swelling and excessive mucus production can cause further narrowing of the airways and worsening of symptoms. There is evidence that matrix degradation may increase in asthma, which may contribute to the mechanical changes of the airways in asthma (Roberts et al (1995) Chest 107:111 S-117S, the entire contents of which are incorporated herein by reference). Treating extracellular matrix degradation may improve asthma symptoms.

[0249] Cystic fibrosis (CF) is a recessive, multisystemic genetic disorder characterized by abnormal chloride and sodium transport across epithelia, resulting in viscous secretions in the lungs, pancreas, liver, intestine, and reproductive system. It is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Lung disease results from airway obstruction due to mucus accumulation, reduced mucociliary clearance, and resulting inflammation, which can lead to fibrotic injury and structural changes in the lungs. Fibrotic lung damage progresses over time, leading some CF patients to require lung transplantation.

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

[0251] In other embodiments, 15-PGDH inhibitors 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. Adhesion formation due to mechanical injury, ischemia, and infection can increase postoperative morbidity and mortality. While sophisticated surgical procedures can reduce the extent of adhesion formation, adhesions are rarely removed, and effective adjunctive therapy is necessary. Reducing the fibrosis associated with this process can reduce pain, obstruction, and other complications of surgery and promote healing and recovery.

[0252] Wounds (i.e., lacerations, fissures) in mammalian tissues result in tissue destruction and microvascular coagulation at the wound surface. Such tissue repair represents an orderly and regulated cellular response to injury. Soft tissue wounds, regardless of size, heal in a similar manner. 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 extensively characterized and, in some cases, quantified (see, e.g., Hunt, TK, 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 hypoxic, acidotic, and hypercapnic, with high lactic acid levels. Adjacent to the wound space is a gradient zone of ischemia where dividing fibroblasts are concentrated. Behind the leading zone is a region of active collagen synthesis characterized by mature fibroblasts and numerous 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 increasing the rate of wound repair.

[0253] In some embodiments, 15-PGDH inhibitors can be administered to a subject in need of treatment to reduce or prevent scar formation in the subject.Scar formation is a natural part of the healing process.Unregulated collagen synthesis and deposition in wounds can lead to excessive thick or raised scar formation.In general, the larger the wound, the longer it takes to heal and the greater the likelihood of scarring.

[0254] In other embodiments, 15-PGDH inhibitors 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 located within the borders of the original injury. They are often described as itchy. In some cases, hypertrophic scars shrink and disappear on their own. Keloids are raised, dark red areas that tend to cover areas much larger than the area of ​​the original injury. Even if surgically removed, keloids tend to recur. Atrophic scars are depressions in the skin (such as those that can form from severe acne). They are caused by inflammation, which destroys collagen during the remodeling process, leaving depressed areas.

[0255] In some embodiments, 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis.Systemic sclerosis is a systemic connective tissue disease characterized by changes in microvasculature, impaired immune system and massive deposition of collagen and other matrix substances in connective tissue.Systemic sclerosis is a clinically heterogeneous systemic disorder that affects the connective tissue of skin and internal organs (such as digestive tract, lung, heart and kidney).Reducing the fibrosis caused by systemic sclerosis can improve symptoms and / or prevent further complications in affected tissues.

[0256] In other embodiments, 15-PGDH inhibitor can be used to treat or prevent liver fibrosis.Liver fibrosis can be caused by chronic liver disease, virus-induced liver 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 liver cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxin.

[0257] Nonalcoholic steatohepatitis (NASH) is a common liver disease. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The main characteristics of NASH are inflammation and damage, as well as fat in the liver. Nevertheless, NASH can become severe and can lead to cirrhosis, where the liver becomes permanently damaged and scarred and can no longer function normally.

[0258] NASH is usually an asymptomatic disease with few or no symptoms. Patients generally feel well in the early stages and only begin to experience symptoms (such as fatigue, weight loss, and weakness) once the disease becomes more advanced or cirrhosis develops. NASH progression can take years or even decades. The process can be halted, and in some cases, it may even begin to reverse itself without specific treatment. Alternatively, NASH can slowly worsen, leading to the development and accumulation of scarring or fibrosis in the liver. As fibrosis worsens, cirrhosis develops, causing the liver to become severely damaged, hardened, and unable to function normally. Not everyone with NASH develops cirrhosis, but once severe scarring or cirrhosis does occur, few treatments can halt its progression. Those with cirrhosis experience fluid retention, muscle wasting, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure and is increasingly being performed in people with NASH. NASH ranks as one of the leading causes of cirrhosis in the United States, after hepatitis C and alcoholic liver disease.

[0259] In some embodiments, 15-PGDH inhibitors may be used to treat or prevent renal fibrosis, which may result from dialysis after renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease, or renal failure.

[0260] Renal fibrosis (fibrosis of the kidney) results from the excessive formation of fibrous connective tissue in the kidney. Renal fibrosis causes significant morbidity and mortality, leading to the need for dialysis or kidney transplantation. Fibrosis can occur in either the filtering or reabsorptive components of the nephron, the functional unit of the kidney. Several factors can contribute to renal scarring, particularly disturbances in the physiology involved in the autoregulation of glomerular filtration. This, in turn, leads to the replacement of normal structures by accumulated extracellular matrix. A spectrum of changes in the physiology of individual cells leads to the production of numerous peptide and non-peptide fibrogens, which stimulate a shift in the balance between extracellular matrix synthesis and degradation, promoting scarring.

[0261] In some embodiments, the symptoms of fibrosis in a tissue or organ may include inflammation. In these embodiments, the 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 a 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 assessed by demonstrating a decrease in the number of neutrophils in bronchoalveolar lavage fluid (BAL fluid) from a subject with cystic fibrosis. Excessive neutrophil recruitment to the airways of patients with cystic fibrosis (CF) is an important predictor of the severity of lung disease in CF and is therefore an important therapeutic target. Methods for measuring such cell numbers are well known in the art, including, but not limited to, FACS techniques. In some embodiments, the method may include reducing the number of neutrophil cells in BAL fluid from the subject compared to a control. Any suitable control, such as a cystic fibrosis subject not treated with a 15-PGDH inhibitor, may be used for comparison. In some embodiments, a reduction in the number of inflammatory cells (such as neutrophil counts) confers a clinical benefit to the subject, hi various embodiments, the reduction in the number of inflammatory cells is at least 5%, 10%, 15%, 20%, 25%, 50% or more compared to a control.

[0262] In another embodiment, the beneficial effects of a 15-PGDH inhibitor may be assessed by a reduction in one or more inflammatory biomarkers in a suitable sample from the subject. In various non-limiting embodiments, the inflammatory biomarkers may include or consist of one or more fibrosis-related or proinflammatory 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 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 include reducing the amount of one or more inflammatory biomarkers in a sample from the subject compared to a control.

[0263] In other embodiments, a 15-PGDH inhibitor may be used in a method for decreasing or reducing collagen secretion or collagen deposition in a tissue or organ (e.g., lung, liver, skin, or heart) of a subject. The method may include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject may have or be at risk for excessive collagen secretion or collagen deposition in a tissue or organ (e.g., kidney, lung, liver, intestine, colon, skin, or heart). Typically, excessive collagen secretion or collagen deposition in an organ results from 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 reduce the level of collagen deposition in the tissue or organ. A sufficient period may be one week, or one week to one month, or one to two months, or more than two months. In the case of chronic conditions, the 15-PGDH inhibitor may be advantageously administered lifelong.

[0264] 15-PGDH inhibitors for use in treating fibrotic diseases, disorders, or conditions and / or collagen deposition can be identified using an assay in which a putative inhibitor compound is applied to cells expressing 15-PGDH and then the functional effect on 15-PGDH activity is determined. Samples or assays containing 15-PGDH treated with a potential inhibitor are compared to control samples without the inhibitor to determine the extent of the effect. The control sample (untreated with a modulator) is assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value compared to the control is approximately 80%, or 50%, 25%, 10%, 5%, or 1%, as appropriate.

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

[0266] PGE1 analogs are also used in the treatment of erectile dysfunction. Thus, in some embodiments, the 15-PGDH inhibitors described herein may be used alone or in combination with prostaglandins to treat erectile dysfunction.

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

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

[0269] In some embodiments, the 15-PGDH inhibitors described herein may be used in methods for treating (e.g., inhibiting, alleviating, ameliorating, alleviating, or slowing the progression of) or preventing (e.g., delaying the onset or reducing the risk of onset) one or more diseases, disorders, or conditions caused by or associated with insufficient (e.g., abnormal) neurogenesis or undesired neuronal cell death in a subject in need thereof. These methods include administering to the subject an effective amount of a 15-PGDH inhibitor described herein (and / or a compound of any of the other formulas described herein) or a salt thereof (e.g., a pharmaceutically acceptable salt), as defined elsewhere 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 caused by or associated with insufficient neurogenesis (e.g., abnormal hippocampal neurogenesis), as thought to occur in neuropsychiatric disorders, or abnormal neuronal 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 depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neurostimulants (such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine).

[0271] In some embodiments, the subject may be a subject in need thereof (e.g., a subject identified as being 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 the judgment of the subject or a medical professional and may be subjective (e.g., 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, 15-PGDH inhibitors may be used to treat diseases, disorders, or conditions associated with elements of the nervous system, including the central, somatic, autonomic, sympathetic, and parasympathetic components of the nervous system, neurosensory tissues of the eye, ear, nose, mouth, or other organs, and glial tissues associated with neuronal cells and structures. Neurological disorders can be caused by neuronal damage, such as mechanical injury or damage from toxic compounds, by abnormal growth or development of neurons, or by misregulation (e.g., downregulation) of neuronal activity.

[0273] Neurological disorders can adversely affect nervous system functions such as sensory function (the ability to sense changes within the body and in the external environment); integrative function (the ability to interpret those changes); and motor function (the ability to respond to those interpretations by initiating an action 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 traumatic or toxic injury to peripheral or cranial nerves, spinal cord or brain, 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 cognitive and neurodegenerative disorders such as Alzheimer's disease, Alzheimer's disease-related dementia (e.g., 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. Autonomic dysfunction includes hypertension and sleep disorders.

[0275] Neuropsychiatric disorders such as depression, schizophrenia, schizoaffective disorder, Korsakoff's psychosis, mania, anxiety or phobic disorders, learning or memory disorders (such as amnesia and age-related memory loss), attention deficit disorder, dysthymic disorder, major depressive disorder, mania, obsessive-compulsive disorder, psychoactive substance use disorders, anxiety, phobias, panic disorders, bipolar affective disorders, psychogenic pain syndromes, and eating disorders may also be treated 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 nervous system damage due to infectious diseases (such as meningitis, high fever of various etiologies, HIV, syphilis, or post-polio syndrome) and nervous system damage due to electricity (including contact with electricity or lightning and complications of electroconvulsive psychiatric therapy). Neurological disorders associated with eye conditions include retinal and optic nerve damage, glaucoma and age-related macular degeneration.

[0276] The developing brain is the target of neurotoxicity in the developing central nervous system throughout many stages of pregnancy and during infancy and early childhood, and the 15-PGDH inhibitors described herein can be used to prevent or treat neurological defects in embryos or fetuses in utero, in premature infants, or in children who require such treatment (including those with neurological birth defects).Additional neurological disorders include, for example, those listed 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 for treating medical conditions associated with nerve damage, including any movement disorder, epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic nervous system disorder, bladder disorder, abnormal metabolic condition, muscular system disorder, infectious and parasitic diseases, neoplasms, endocrine disorders, nutritional and metabolic disorders, immunological disorders, blood and blood-forming organ disorders, psychiatric disorders, nervous system disorders, sensory organ disorders, circulatory system disorders, respiratory system disorders, digestive system disorders, genitourinary system disorders, skin and subcutaneous tissue disorders, musculoskeletal and connective tissue disorders, congenital anomalies, or certain perinatal conditions, as well as symptoms, signs, and ill-defined 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 by 15-PGDH inhibitors can be caused by conditions including, but not limited to, sleep apnea and parasomnia.

[0281] Autonomic disorders treatable by 15-PGDH inhibitors 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 gastric acid hypersecretion), autonomic insufficiency, excessive epiphoresis, excessive rhinorrhea, and cardiovascular disorders (including, but not limited to, cardiac dysrythmias and arrhythmias, hypertension, and carotid sinus disease).

[0282] Bladder disorders treatable by 15-PGDH inhibitors can be caused by conditions including, but not limited to, spinal cord injury and spastic or atonic bladder.

[0283] Abnormal metabolic conditions treatable by 15-PGDH inhibitors can be caused by conditions including, but not limited to, hyperthyroidism or hypothyroidism.

[0284] Disorders of the muscular system treatable by 15-PGDH inhibitors may include, but are not limited to, muscular dystrophies and upper airway and facial spasms.

[0285] 15-PGDH inhibitors are also used to treat migraine (including migraine with aura, migraine without aura, menstrual migraine, migraine variants, atypical migraines, complex migraine, hemiplegic migraine, transformed migraines, and chronic daily migraine), episodic tension headache, chronic tension headache, analgesic rebound headache, episodic cluster headache, chronic cluster headache, cluster variants, chronic paroxysmal hemicrania, hemicrania continua. continua, post-traumatic headache, post-traumatic neck pain, post-herpetic neuralgia involving the head or face, pain from spinal fractures secondary to osteoporosis, arthritic pain in the spine, headaches related to cerebrovascular disease and stroke, vascular headaches, reflex sympathetic dystrophy, cervicalgia (which may be attributable to a variety of causes, including but not limited to muscular, disc, or degenerative, including arthritis, postural, or metastatic), glossodynia, carotidynia, cricoid pain, ear pain due to middle ear lesions, stomach pain, sciatica, maxillary neuralgia, sore throat, myalgia of the neck muscles, trigeminal neuralgia (sometimes called tic douloureux), post-lumbar puncture headache, low cerebro-spinal fluid pressure headache headache), temporomandibular joint disorders, atypical facial pain, ciliary neuralgia, paratrigeminal neuralgia (sometimes called Rader syndrome), petrosal 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)It may be used to treat neuropathic pain caused by conditions including, but not limited to, facial neuralgia syndrome, facial ulcers, facial ulcers (sometimes called facial neuralgia, facial ulcers syndrome), ...

[0286] As used herein, the term "headache" includes but is not limited 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, hemicrania continua headaches, post-traumatic headache, post-herpetic headache, vascular headache, headache associated with reflex sympathetic dystrophy, crivicalgia headaches, caroidynia headaches, sciatica headaches, trigeminal headache, occipital pain, maxillary headaches, diary headaches, paratrigeminal headaches, petrosal headache, headaches, Sluder's headache, vidian headaches, low CSF pressure headaches, TMJ headaches, causalgia headaches, myofascial headaches, all primary headaches (e.g., primary stabbing headache, primary cough headache, primary exertional headache, primary sexually-associated headache, hypnotic headache, and new-onset persistent daily headache), all trigeminal autonomic cephalagias (e.g., sudden paroxysmal hemicrania, SUNCT, all possible TACs, and SUNAs), chronic daily headaches, occipital neuralgia, atypical facial pain, neuropathic trigeminal pain, and various types of headache.

[0287] In yet another embodiment, 15-PGDH inhibitors may be used to promote the survival, plasticity, and / or growth of neural stem or progenitor cells. The 15-PGDH inhibitor may be administered to stem or progenitor cells ex vivo, in vitro, or in vivo. When administered to stem or progenitor cells ex vivo or in vitro, the stem 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 commonly used in the field of regenerative medicine to transplant neural stem / progenitor cells(s) into a desired region may be used in combination with the administration of a 15-PGDH inhibitor to the cells or the region. More specifically, for example, a method of transplanting neural stem / progenitor cells(s) into a desired region can be exemplified by suspending the neural stem / progenitor cells in phosphate-buffered saline containing a 15-PGDH inhibitor and then adding / injecting the resulting cell suspension into the desired region.

[0289] In other embodiments, the 15-PGDH inhibitors described herein may be applied to nerve grafts. Such grafts may include any tissue intended for transplantation in humans or animals. Various types of grafts, such as autografts, syngrafts, allografts, and xenografts, are encompassed by the present invention. The size (e.g., length and diameter) of the graft is not critical. For example, the length of a nerve graft may be from about 1 centimeter to about 10 centimeters, or may exceed about 10 centimeters. The diameter of the nerve graft may match the diameter of the injured nerve or portion of a nerve, as needed. A nerve graft may be a structurally intact segment of a nerve to fill a gap along the length of the recipient nerve or to replace the distal end, i.e., for end-to-end grafting. Alternatively, a nerve graft may be a partial nerve segment or an eccentric shape (e.g., a nerve flap) intended to reconstruct an injured 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 can be treated. The therapeutic agent may be applied en bloc to the entire nerve graft. This en bloc treatment may be applied to live (fresh) or previously frozen nerve grafts. 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 will be joined to the stump of the damaged nerve. When a therapeutic agent is applied to an injured nerve, the therapeutic agent may be applied to any region of the injured nerve (such as the region of the injury site or the region adjacent to the injury site) that promotes repair of the damaged nerve.

[0291] The 15-PGDH inhibitor can be included in the culture medium for application to the nerve graft. The culture medium can 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 storing the nerve graft before transplantation. The storage solution includes a culture medium and at least one 15-PGDH inhibitor. The storage solution may also include other biologically active substances, such as growth factors, as 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, such as the tetrazole compounds of formula (I) and (II), the 2-alkylideneaminooxyacetamide compounds of formula (I), the heterocyclic compounds of formula (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. thiazolidine-2,4-dione compounds; thiazolidenedione derivatives described in U.S. Patent Application Publication No. 2011 / 0269954; phenylfuran compounds, phenylthiophene compounds, or phenylpyrazole compounds described in U.S. Patent No. 7,294,641; 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acids and salts; lactones described in U.S. Patent No. 4,725,676; azo compounds described in U.S. Patent No. 4,889,846; and 15-PGDH inhibitors described in PCT / US2014 / 060761 and U.S. Patent Application Publication No. 2015 / 0072998A1, all of which are incorporated herein by reference in their entireties.

[0293] The 15-PGDH inhibitors described herein may be provided in pharmaceutical or cosmetic compositions depending on the pathological or cosmetic condition or disorder to be treated. Pharmaceutical compositions containing the 15-PGDH inhibitors described herein as an active ingredient may be prepared 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 comprise fillers, anti-cohesives, lubricants, wetting agents, flavorings, emulsifiers, preservatives, etc. The pharmaceutical composition may be formulated into a suitable formulation according to methods known to those skilled in the art so as to provide immediate, controlled, or sustained release of the 15-PGDH inhibitor after administration to a mammal.

[0294] In some embodiments, pharmaceutical compositions may be formulated into parenteral or oral dosage forms.Solid dosage forms for oral administration may be prepared by adding excipients (if necessary, binders, disintegrants, lubricants, coloring agents and / or flavoring agents) to the 15-PGDH inhibitor and molding the resulting mixture into tablets, sugar-coated pills, granules, powders, or capsules.Additives that can be added to the composition may be those commonly used 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, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate, and polypyrrolidone. Examples of disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride and lactose.In addition, purified talc, stearic acid salts, sodium borate and polyethylene glycol may be used as lubricants, and sucrose, bitter orange peel, citric acid and tartaric acid may be used as flavorings.In some embodiments, pharmaceutical compositions can be made into aerosol preparations (e.g., they can be nebulized) for administration by inhalation.

[0295] The 15-PGDH inhibitor may be combined with flavorings, buffers, stabilizers, etc., and incorporated into oral liquid dosage forms such as solutions, syrups, or elixirs 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 example, for subcutaneous, intramuscular, or intravenous administration, by adding a pH adjuster, a buffer, a stabilizer, a relaxant, or a local anesthetic. Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, 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 inhibitors may be incorporated into suppositories in a conventional manner by adding thereto a pharmaceutically acceptable carrier known in the art (e.g., polyethylene glycol, lanolin, cocoa butter, or fatty acid triglycerides), optionally together with a surfactant such as Tween.

[0298] The pharmaceutical composition may be formulated into various dosage forms as described above and then administered via various routes, including oral, inhalation, transdermal, subcutaneous, intravenous, or intramuscular routes. The dosage may be a pharmaceutically effective amount. A pharmaceutically effective amount may be an amount of a 15-PGDH inhibitor that treats or improves alopecia, cardiovascular disease, gastrointestinal disease, wound, and kidney disease. The pharmaceutically effective amount of the compound will be appropriately determined depending on the type and severity of the disease being treated, the age, sex, weight, and physical condition of the patient being treated, the route of administration, the duration of treatment, and other factors. Generally, the effective amount of the compound may range from 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 cannot be uniformly determined because it depends on the age, sex, weight, and physical condition of the patient being treated. The formulation may be administered once daily or in divided doses several times daily.

[0299] Cosmetic compositions comprising 15-PGDH inhibitors may include any substance or preparation intended to be brought into contact exclusively or primarily with the various superficial parts of the human body (epidermis, hair and hair system, nails, lips, and external genitalia), or with the teeth or buccal mucosa, for the purposes of cleansing them, perfume them, modifying their appearance and / or correcting body odor, and / or protecting them or keeping them in good condition.

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

[0301] For topical administration, cosmetic compositions may be administered in the form of aqueous, alcoholic, aqueous-alcoholic, or oily solutions or suspensions; lotion or serum-type dispersions; emulsions or multiple emulsions with a liquid or semi-liquid consistency or paste-like properties obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O); free or compressed powders to be used as is or incorporated into a physiologically acceptable medium; microcapsules or microparticles; or vesicular dispersions of ionic and / or nonionic type. Thus, the compositions may be in the form of salves, tinctures, emulsions, creams, ointments, powders, patches, impregnated pads, solutions, emulsions or vesicular dispersions, lotions, aqueous or anhydrous gels, sprays, suspensions, shampoos, aerosols, or foams. The compositions may be anhydrous or aqueous. They may also include solid preparations such as soaps or cleansing cakes.

[0302] The cosmetic composition may in particular comprise a hair care composition, in particular a shampoo, setting lotion, treatment lotion, styling cream or gel, hair restructuring lotion, mask, etc. The cosmetic composition may be a cream, hair lotion, shampoo, or conditioner. These may in particular be used in treatments with or without subsequent rinsing, 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, thus comprising a pressurized propellant. Thus, it may be in the form of a lotion, serum, emulsion, cream, gel, salve, ointment, powder, balm, patch, impregnated pad, cake, or foam.

[0303] In particular, compositions for application to the scalp or hair may be in the form of a hair care lotion for daily or twice-weekly application, in particular in the form of a shampoo or conditioner for twice-weekly or weekly application, in the form of a liquid or solid soap for daily application to cleanse the scalp, in the form of a hairstyle 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. They may also be in the form of a hair dye or mascara to be applied with a brush or comb.

[0304] Furthermore, for topical application to eyelashes or body hair, the composition may be in the form of a tinted or untinted mascara, which is applied to eyelashes using a brush, or to beards or mustaches.For compositions 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, oral syrup, or tablet.According to certain embodiments, the composition is in the form of a hair cream or hair lotion, shampoo, hair conditioner, or mascara for hair or eyelashes.

[0305] In a known manner, the cosmetic composition may also contain adjuvants common in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV filters, odor absorbers, and dyes. The amounts of these various adjuvants are those conventionally used in the cosmetic field, for example, 0.1% to 20% (particularly not more than 10%) of the total weight of the composition. Depending on their nature, these adjuvants may be incorporated 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, which involves administering the 15-PGDH inhibitor together with one or more additional active substances. The terms "combinatorial therapy" or "combination therapy" encompass the administration of a 15-PGDH inhibitor and one or more therapeutic agents as part of a specific treatment regimen intended to provide beneficial effects through the simultaneous action of these therapeutic agents. The administration of these therapeutic agents in combination is typically carried out over a defined period of time (usually minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" or "combination therapy" is intended to encompass both sequential administration of these therapeutic agents (i.e., each therapeutic agent is administered at a different time) and substantially simultaneous administration of these therapeutic agents, or at least two of these therapeutic agents. Substantially simultaneous administration may be achieved, for example, by administering to a subject individual doses of each therapeutic agent at a fixed ratio, or multiple individual doses of each therapeutic agent. The sequential or substantially simultaneous administration of each therapeutic agent may be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, 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 important.

[0307] In some embodiments, the additional active substance may be selected from lipoxygenase inhibitors, in particular as described in EP 648488, bradykinin inhibitors, in particular as described in EP 845700, prostaglandins and their derivatives (in particular as described in WO 98 / 33497, WO 95 / 11003, JP 97-100091, JP 96-134242), agonists or antagonists of prostaglandin receptors, and nonprostanoic analogues of prostaglandins, such as those described in EP 1175891 and EP 1175890, WO 01 / 74307, WO 01 / 74313, WO 01 / 74314, WO 01 / 74315 or WO 01 / 72268.

[0308] In other embodiments, 15-PGDH inhibitors may be administered in combination with active substances (single or in mixtures) such as vasodilators, prostanoid agonists, antiandrogens, cyclosporines and their analogs, antibacterial agents, triterpenes, etc. Vasodilators may include potassium channel agonists, including minoxidil and its derivatives, aminexil, and 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, and 4,973,474, cromakalin, and diazoxide. Antiandrogens may include 5α-reductase inhibitors such as finasteride and compounds described in U.S. Patent No. 5,516,779, cyprosterone acetate, azelaic acid, its salts and derivatives, and compounds described in U.S. Patent No. 5,480,913, flutamide and 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, pyridinic acid, hinokitiol, mipirocin, and compounds described in EP 680745, clinicin hydrochloride, benzoyl or benzyl peroxide, and minocycline. Anti-inflammatory agents 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 (particularly 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 and / or cosmetic compositions include aminexil 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 or COX-2 activators, glycosidase inhibitors, glycosaminoglycanase inhibitors, pyroglutamic acid esters, hexosaccharidic or acylhexosaccharidic acids. and 5,631,282); 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, vitamin B12 analogs, and pantothenol); hydroxy acids; benzophenones; esterified fatty acids; and hydantoins.

[0310] The pharmaceutical and / or cosmetic compositions comprising the 15-PGDH inhibitors described herein may further comprise at least one compound selected from, for example, prostaglandins, in particular prostaglandins PGE1, PGE2, their salts, esters, analogs and derivatives thereof, in particular those described in WO98 / 33497, WO95 / 11003, JP97-100091, JP96-134242, in particular agonists of prostaglandin receptors. In particular, the pharmaceutical compositions may further comprise at least one compound selected from prostaglandins F 2α receptor agonists (in acid form or in precursor form, especially in ester form) (e.g., latanoprost, fluprostenol, cloprostenol, bimatoprost, unoprostone, etc.), prostaglandin E2 receptor agonists (and their precursors, especially esters such as travoprost) (17-phenyl PGE2, biprostol, butaprostol, misoprostol, sulprostone, 16,16-dimethyl PGE2, 11-deoxy PGE1, 1-deoxy PGE1, etc.), prostacyclin (IP) receptor agonists and their precursors (especially esters) (cicaprost, iloprost, isocarbacycline, beraprost, eprostenol, treprostinil, etc.), prostaglandins D2 receptor agonists and their precursors (especially 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.), It may contain at least one compound such as agonists of the receptor for thromboxane A2 (TP) and their precursors (especially esters), such as 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).

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

[0312] The present invention is 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 of structural analogs of identified 15-PGDH inhibitors (Tables 1 and 2). The data provided represent the IC40 of each compound for inhibition of the enzymatic activity of recombinant 15-PGDH in an in vitro assay. 50 Recombinant 15-PGDH is human unless otherwise specified. Additionally, this example provides data for selected compounds on the induction of PGE2 in A549 cell cultures given 2.5 μM or 0.1 μM of the selected compounds.

[0314] [Table 1] JPEG0007660087000022.jpg213158JPEG0007660087000023.jpg212158JPEG0007660087000024.jpg211158JPEG0007660087000025.jpg213158JPEG0007660087000026.jpg215158JPEG0007660087000027.jpg213158JPEG0007660087000028.jpg213158JPEG0007660087000029.jpg215158JPEG0007660087000030.jpg218158JPEG0007660087000031.jpg212158JPEG0007660087000032.jpg212158JPEG0007660087000033.jpg214158JPEG0007660087000034.jpg213158JPEG0007660087000035.jpg213158JPEG0007660087000036.jpg214158JPEG0007660087000037.jpg214158JPEG0007660087000038.jpg211158JPEG0007660087000039.jpg214158JPEG0007660087000040.jpg213158

[0315]

Table 2

[0316] Example 2 The following examples describe the synthesis of at least some of the analogs listed in Tables 1 and 2, and provide mass spectrometric and NMR confirmation of their structures.

[0317] [ka]

[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 in a microwave reactor at 150 °C for 6 hours and then cooled to room temperature. The slurry solution was filtered and washed with ether to give a white solid (226 mg, 41% yield). The ester intermediate was dissolved in MeOH (2 mL) and aqueous NaOH (1 M, 2 mL), and the solution was stirred at room temperature for 12 hours. 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 (182 mg, 90% yield). MS (ES+) m / z = 248 [M+H] + .

[0319] Step 2 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) was added POCl3 (0.38 mL, 4 mmol). The mixture was heated at 100 °C for 3 h, and excess POCl3 was removed under reduced pressure. The resulting crude material was dissolved in dichloromethane (2 mL) and Et3N (0.55 mL, 4 mmol) and cooled to -20 °C. Piperidine (0.08 mL, 0.8 mmol) was then added to the 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 (47 mg, 35% yield). 1 H NMR (400 MHz, chloroform-d) δ 11.64 (s, 1H), 7.47 (s, 1H), 3.82 (t, J = 5.0 Hz, 2H), 3.29 (t, J = 5.2 Hz, 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 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)Cl (4 mg, 0.5% mmol), KPO (42 mg, 0.2 mmol), 1,4-dioxane (2 mL), and HO (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 NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the product.

[0321] [ka]

[0322] The general procedure described above gave the target compound 36a (81% yield).

[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] [ka]

[0325] The general procedure described above gave the target compound 37a (85% yield).

[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] [ka]

[0328] The general procedure described above gave the target compound 38a (65% yield).

[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=4.8Hz, 2H), 3.33(t, J=4.8Hz, 2H), 1.71(s, 4H), 1.51(s, 2H); 13C 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] [ka]

[0331] The general procedure described above gave the target compound 40a (79% yield).

[0332] 1 H NMR(400MHz, chloroform-d) δ 12.49(s, 1H), 7.97(d, J=8.3Hz, 2H), 7.85(s, 1H), 7.34(d, J=7.8Hz, 2H), 3.84(t, J=5.1Hz, 2H), 3.34(t, J=5.5Hz, 2H), 2.45(s, 3H), 1.74-1.67(m, 4H), 1.54-1.48(m, 2H); 13 C 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] [ka]

[0334] The general procedure described above gave the target compound 43a (51% yield).

[0335] 1 H NMR(400MHz, chloroform-d) δ 12.45(s, 1H), 7.82(d, J=7.8Hz, 1H), 7.68-7.58(m, 3H), 7.53(d, J=7.5Hz, 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] [ka]

[0337] The general procedure described above gave the target compound 47a (66% yield).

[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); 13C 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] [ka]

[0340] The general procedure described above gave the target compound 46a (73% yield).

[0341] 1 H 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 C 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] [ka]

[0343] The general procedure described above gave the target compound 61a (82% yield).

[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] [ka]

[0346] The general procedure described above gave the target compound 56a (53% yield).

[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); 13C 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] [ka]

[0349] The general procedure described above gave the target compound 68a (48% yield).

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

[0351] [ka]

[0352] The general procedure described above gave the target compound 69a (86% yield).

[0353] 1 H NMR(400MHz, chloroform-d) δ 12.63(s, 1H), 8.01(d, J=8.0Hz, 2H), 7.79(s, 1H), 7.01(d, J=8.0Hz, 2H), 4.10(q, J=7.0Hz, 2H), 3.83(t, J=5.1Hz, 2H), 3.33(t, J=5.4Hz, 2H), 1.73-1.65(m, 4H), 1.53-1.50(m, 2H), 1.46(t, J=7.0Hz, 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] [ka]

[0355] The general procedure described above gave the target compound 45a (50% yield).

[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); 13C 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] [ka]

[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, N Ar reaction gave the target compound 39a.

[0359] 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) was added piperidine (0.05 mL, 0.5 mmol). The mixture was heated at 90° C. for 3 hours, 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 H 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); 13C 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] [ka]

[0362] Step 1 To a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (1.55 g, 10 mmol) in AcOH (20 mL) was added ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (2.44 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 washed with ether to give a yellow solid (2.47 g, 79% yield). The ester intermediate was dissolved in MeOH (20 mL) and aqueous NaOH (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, 91% yield).

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

[0364] Step 2 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) was added POCl3 (4.69 mL, 50 mmol). The mixture was heated at 100 °C for 3 h, and excess POCl3 was removed under reduced pressure. The resulting crude material was dissolved in dichloromethane (10 mL) and Et3N (6.88 mL, 50 mmol) and cooled to -20 °C. Piperidine (1 mL, 10 mmol) was then added to the 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 H NMR(400MHz, chloroform-d) δ 8.04(d, J=8.3Hz, 2H), 7.42(s, 1H), 7.02(d, J=8.3Hz, 2H), 6.97(s, 1H), 3.89(s, 3H), 3.77(t, J=4.5Hz, 2H), 3.73(t, J=5.3Hz, 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 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)Cl (4 mg, 0.5% mmol), KPO (42 mg, 0.2 mmol), 1,4-dioxane (2 mL), and HO (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 NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the product.

[0367] [ka]

[0368] The general procedure described above gave the target compound 22a (67% yield).

[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] [ka]

[0371] The general procedure described above gave the target compound 23a (57% yield).

[0372] 1 H NMR(400MHz, chloroform-d) δ 9.21(s, 1H), 8.77(d, J=5.0Hz, 1H), 8.50(d, J=8.1Hz, 1H), 8.08(d, J=8.4Hz, 2H), 7.49(dd, J=8.0, 4.9Hz, 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); 13C 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] [ka]

[0374] The general procedure described above gave the target compound 24a (36% yield).

[0375] 1 H NMR(400MHz, chloroform-d) δ 9.13(d, J=8.0Hz, 1H), 8.83(d, J=4.0Hz, 1H), 8.28(s, 1H), 8.20(d, J=7.7Hz, 2H), 7.92(t, J=7.8Hz, 1H), 7.49-7.46(m, 1H), 7.04(d, J=7.7Hz, 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 C 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] [ka]

[0377] The general procedure described above gave the target compound 25a (53% yield).

[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] [ka]

[0380] The general procedure described above gave the target compound 26a (45% yield).

[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); 13C 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] [ka]

[0383] The general procedure described above gave the target compound 27a (65% yield).

[0384] 1 H NMR(400MHz, chloroform-d) δ 8.88(s, 1H), 8.67(t, J=8.0Hz, 1H), 8.11(d, J=8.7Hz, 2H), 7.39(s, 1H), 7.15(dt, J=8.7, 2.5Hz, 1H), 7.05(d, J=8.7Hz, 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 C 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] [ka]

[0386] The general procedure described above gave the target compound 28a (72% yield).

[0387] 1 H NMR(400MHz, chloroform-d) δ 9.48(s, 2H), 9.40(s, 1H), 8.11(d, J=8.8Hz, 2H), 7.43(s, 1H), 7.05(d, J=8.7Hz, 2H), 7.03(s, 1H), 3.90(s, 3H), 3.77(t, J=5.3Hz, 2H), 3.71(t, J=5.5Hz, 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] [ka]

[0389] The general procedure described above gave the target compound 29a (64% yield).

[0390] 1H NMR(400MHz, クロロホルム-d) δ 8.83(s, 1H), 8.27(s, 1H), 8.04(d, J=8.7Hz, 2H), 7.46(s, 1H), 6.97(d, J=8.7Hz, 2H), 6.85(s, 1H), 3.98(s, 3H), 3.83(s, 3H), 3.78(t, J=5.4Hz, 2H), 3.71(t, J=5.4Hz, 2H), 1.70(s, 4H), 1.61(s, 2H); 13 C NMR(101MHz, クロロホルム-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]

change

[0392] The target compound 30a (yield 61%) of the above-mentioned general なhandshunによっ was obtained.

[0393] 1 H NMR(400MHz, クロロホルム-d) δ 8.46-8.45(m, 1H), 8.11(d, J=8.5Hz, 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); 13C 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] [ka]

[0395] The general procedure described above gave the target compound 71a (73% yield).

[0396] 1 H NMR(400MHz, chloroform-d) δ 8.07(d, J=8.8Hz, 2H), 7.24(s, 1H), 7.03(d, J=8.8Hz, 2H), 6.95(s, 1H), 6.94-6.91(m, 2H), 6.33(dd, J=3.8, 2.7Hz, 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 C 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] [ka]

[0398] The general procedure described above gave the target compound 34a (85% yield).

[0399] 1 H NMR(400MHz, 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=5.4Hz, 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] [ka]

[0401] The general procedure described above gave the target compound 67a (35% yield).

[0402] 1 H NMR(400MHz, chloroform-d) δ 8.00(d, J=8.8Hz, 2H), 6.99(d, J=8.8Hz, 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); 13C 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] [ka]

[0404] The general procedure described above gave the target compound 35a (40% yield).

[0405] 1 H NMR(400MHz, chloroform-d) δ 8.02(d, J=8.4Hz, 2H), 7.12(s, 1H), 6.98(d, J=8.4Hz, 2H), 6.84(s, 1H), 3.85(s, 3H), 3.76(s, 2H), 3.69(t, J=5.5Hz, 2H), 2.79(s, 3H), 1.68(s, 4H), 1.58(s, 2H); 13 C 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] [ka]

[0407] In addition, the S reaction of the chloride intermediate with a nucleophile N The target compound was also obtained by Ar reaction.

[0408] To 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 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 give the product.

[0409] [ka]

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

[0411] 1 H NMR(400MHz, chloroform-d) δ 7.99(d, J=7.5Hz, 2H), 6.98(d, J=7.5Hz, 2H), 6.63(s, 1H), 6.38(q, J=5.3Hz, 1H), 6.31(s, 1H), 3.86(s, 3H), 3.75(t, J=4.6Hz, 2H), 3.64(t, J=4.6Hz, 2H), 3.14(d, J=5.0Hz, 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] [ka]

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

[0414] 1 H NMR(400MHz, chloroform-d) δ 7.97(d, J=8.8Hz, 2H), 6.97(d, J=8.8Hz, 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] [ka]

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

[0417] 1 H NMR(400MHz, chloroform-d) δ 8.01(d, J=8.8Hz, 2H), 6.99(d, J=8.8Hz, 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); 13C 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] [ka]

[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. The solid was dissolved in MeOH (20 mL) and aqueous NaOH (1 M, 20 mL), and the solution was stirred at room temperature for 5 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 pale yellow solid (1.55 g, 92% yield). 1 H NMR (400MHz, DMSO-d6) δ 13.57(s, 1H), 8.26-8.22(m, 3H), 7.39(d, J=7.9Hz, 2H), 7.32(s, 1H), 2.39(s, 3H).

[0420] Step 3 To 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 the amine (0.12 mmol). The mixture was stirred at room temperature until the reaction was complete (the reaction was monitored by LC / MS). Water was added to the solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the product.

[0421] [ka]

[0422] The general procedure described above gave the target compound 7a (81% yield).

[0423] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=8.7Hz, 2H), 7.65(s, 1H), 7.32(s, 1H), 7.18(t, J=5.9Hz, 1H), 7.05(d, J=8.7Hz, 2H), 3.90(s, 3H), 3.59-3.52(m, 2H), 1.31(t, J=7.2Hz, 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] [ka]

[0425] The general procedure described above gave the target compound 8a (85% yield).

[0426] 1 H NMR(400MHz, chloroform-d) δ 8.06(d, J=8.8Hz, 2H), 7.58(s, 1H), 7.15(s, 1H), 7.01(d, J=8.8Hz, 2H), 3.87(s, 3H), 3.68(q, J=7.0Hz, 2H), 3.58(q, J=7.1Hz, 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] [ka]

[0428] The general procedure described above gave the target compound 9a (84% yield).

[0429] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=7.3Hz, 2H), 7.62(s, 1H), 7.29(s, 1H), 7.04(d, J=7.3Hz, 2H), 4.01(t, J=6.6Hz, 2H), 3.90(s, 3H), 3.73(t, J=6.6Hz, 2H), 2.04-1.93(m, 4H); 13C 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] [ka]

[0431] The general procedure described above gave the target compound 10a (88% yield).

[0432] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=7.7Hz, 2H), 7.63(s, 1H), 7.18(s, 1H), 7.04(d, J=7.8Hz, 2H), 4.08-4.06(m, 2H), 3.90(s, 3H), 3.86-3.82(m, 4H), 3.77-3.75(m, 2H); 13 C 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] [ka]

[0434] The general procedure described above gave the target compound 11a (80% yield).

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

[0436]

change

[0437] The target compound 12a (yield 72%) of the above-mentioned general なhandshunによっ was obtained.

[0438] 1 H NMR(400MHz, DMSO-d6) δ 8.31-8.27(m, 3H), 8.19(s, 1H), 7.21(s, 1H), 7.09(d, J=8.5Hz, 2H), 4.82(t, J=5.0Hz, 1H), 3.84(s, 3H), 3.56-3.52(m, 2H), 3.41-3.37(m, 2H); 13C NMR(101MHz, DMSO-d6) δ 162.5, 161.0, 155.9, 151.9, 149.9, 133.4(q, J=37.0Hz), 129.9, 128.2, 119.9(q, J=274.6Hz), 114.9, 106.6(q, J=4.1Hz), 97.9, 60.0, 55.9, 42.1. MS(ES+) m / z=381 [M+H] + .

[0439] [ka]

[0440] The general procedure described above gave the target compound 13a (89% yield).

[0441] 1 H NMR(400MHz, chloroform-d) δ 8.11(d, J=8.7Hz, 2H), 7.66(s, 1H), 7.23(s, 1H), 7.06(d, J=8.7Hz, 2H), 4.27(t, J=5.7Hz, 2H), 4.10(t, J=5.7Hz, 2H), 3.91(s, 3H), 2.66-2.62(m, 4H); 13 C 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] [ka]

[0443] The general procedure described above gave the target compound 14a (87% yield).

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

[0445]

change

[0446] The target compound 15a (yield 85%) was obtained using the above-mentioned general Nashuite.

[0447] 1 H NMR(400MHz, クロロホルム-d) δ 8.10(d, J=8.4Hz, 2H), 7.63(s, 1H), 7.15(s, 1H), 7.05(d, J=8.4Hz, 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); 13C NMR (101MHz, クロロホルム-d) δ 162.4, 162.1, 155.7, 152.2, 149.5, 134.2(q, J=37.5Hz), 129.0, 128.2, 119.4(q, J=274.5Hz), 114.6, 104.6(q, J=4.1Hz), 99.6, 87.8(d, J=171.0Hz), 55.5, 43.1(d, J=4.8Hz), 38.8(d, J=4.7Hz), 31.9(d, J=20.1Hz), 31.0(d, J=20.2Hz). MS(ES+) m / z=423 [M+H] + .

[0448]

change

[0449] The target compound 16a (yield 71%) of the above-mentioned general なhandshunによっ was obtained.

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

[0451] [ka]

[0452] The general procedure described above gave the target compound 17a (55% yield).

[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] [ka]

[0455] The general procedure described above gave the target compound 18a (85% yield).

[0456] 1H NMR(400MHz, chloroform-d) δ 8.09(d, J=8.7Hz, 2H), 7.61(s, 1H), 7.10-7.03(m, 3H), 4.73(d, J=12.9Hz, 1H), 4.47(d, J=13.4Hz, 1H), 3.90(s, 3H), 3.12(t, J=12.8Hz, 1H), 2.83(t, J=12.7Hz, 1H), 1.77-1.65(m, 3H), 1.35-1.22(m, 2H), 0.99(d, J=5.9Hz, 3H); 13 C 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] [ka]

[0458] The general procedure described above gave the target compound 19a (88% yield).

[0459] Mixture of rotamers

[0460] 1H 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 C 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] [ka]

[0462] The general procedure described above gave the target compound 20a (61% yield).

[0463] 1H 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 C 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] [ka]

[0465] The general procedure described above gave the target compound 21a (87% yield).

[0466] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=8.6Hz, 2H), 7.62(s, 1H), 7.12(s, 1H), 7.05(d, J=8.5Hz, 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); 13C 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] [ka]

[0468] The general procedure described above gave the target compound 57a (86% yield).

[0469] A mixture of cis and trans

[0470] 1 H 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 (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); 13C NMR(101MHz, クロロホルム-d) δ 162.68, 162.35, 161.66, 155.53, 155.50, 152.93, 152.87, 149.48, 134.22(q, J=37.4Hz), 128.99, 128.41, 119.41(q, J=274.6Hz), 114.57, 104.38(q, J=4.2Hz), 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]

change

[0472] The target compound 59a (yield 89%) of the above-mentioned general なhandshunによっ was obtained.

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

[0474] [ka]

[0475] The general procedure described above gave the target compound 60a (89% yield).

[0476] 1 H NMR(400MHz, chloroform-d) δ 8.07(d, J=7.3Hz, 2H), 7.62(s, 1H), 7.14(s, 1H), 7.02(d, J=7.3Hz, 2H), 4.86(t, J=15.4Hz, 2H), 3.88(s, 3H), 3.14(t, J=12.8Hz, 1H), 2.81(t, J=12.6Hz, 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] [ka]

[0478] The general procedure described above gave the target compound 62a (81% yield).

[0479] Mixture of rotamers

[0480] 1 H 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 C 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] [ka]

[0482] The general procedure described above gave the target compound 63a (86% yield).

[0483] Mixture of rotamers

[0484] 1 H 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); 13C 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] [ka]

[0486] The general procedure described above gave the target compound 64a (88% yield).

[0487] Mixture of rotamers

[0488] 1 H 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); 13C 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=3.9Hz), 41.2(q, J=26.4Hz), 40.3(q, J=26.8Hz), 24.6, 23.8, 23.7, 23.6. MS(ES+) m / z=473 [M+H] + .

[0489] [ka]

[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 general procedure described above.

[0491] 1 H 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] DAST (16 mg, 0.1 mmol) was slowly added to 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) at −10° C. The mixture was stirred at the same temperature for 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 NaSO, and concentrated by rotary evaporation. The crude was purified by flash chromatography on silica gel to give the target product 58a as a pale yellow solid (12 mg, 56% yield).

[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=18.4Hz), 37.0(d, J=18.7Hz), 26.3(d, J=5.4Hz), 26.2(d, J=6.0Hz), 25.2, 24.3. MS(ES+) m / z=437 [M+H] + .

[0494] [ka]

[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 hours. 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 gave the desired product, which was used in the next step without purification. This crude material 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 allowed to warm to room temperature and continued stirring for an additional 3 hours. The reaction was quenched by the addition of water, 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 material 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] Mixture of rotamers

[0497] 1H NMR(400MHz, クロロホルム-d) δ 8.09(d, J=8.8Hz, 2H), 7.63(s, 1H), 7.17および7.13(2 s, 1H), 7.05(d, J=8.8Hz, 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 C NMR(101MHz, クロロホルム-d) δ 162.43, 162.37, 162.02, 155.74, 155.70, 152.27, 149.52, 134.26(q, J=36.8Hz), 129.05, 128.33, 118.67(q, J=274.4Hz), 118.15(d, J=242.2Hz), 114.61, 104.63(q, J=4.2Hz), 100.08, 99.71, 47.86, 46.63(t, J=6.3Hz), 43.49, 42.17(t, J=6.4Hz), 40.82(t, J=19.7Hz), 39.94(t, J=19.9Hz), 24.81, 24.02, 23.70(t, J=4.4Hz), 23.38(t, J=4.2Hz). MS(ES+) m / z=455 [M+H] + .

[0498]

change

[0499] DAST (64 mg, 0.4 mmol) was slowly added to 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. After the addition of DAST, the mixture was warmed to room temperature and continued stirring 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 NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the target product 65a as a pale yellow solid (22 mg, 51% yield).

[0500] A mixture of rotamers. 1 H NMR(400MHz, chloroform-d) δ 8.10(d, J=8.9Hz, 2H), 7.64(s, 1H), 7.20(s, 1H), 7.05(d, J=8.9Hz, 2H), 4.27(t, J=11.3Hz, 1H), 4.06(t, J=11.7Hz, 1H), 4.01(t, J=5.4Hz, 1H), 3.91(s, 3H), 3.81(t, J=5.6Hz, 1H), 2.17-2.05(m, 2H), 1.93-1.87(m, 2H); 13C 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=32.9Hz), 46.50, 42.23, 32.92(t, J=22.6Hz), 32.70(t, J=22.6Hz), 22.76(t, J=4.2Hz), 21.51(t, J=4.1Hz). MS(ES+) m / z=441 [M+H] + .

[0501] [ka]

[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) and aqueous NaOH (1 M, 20 mL), and the solution was stirred at room temperature for 8 hours. 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 H NMR (400MHz, DMSO-d6) δ 13.10(s, 1H), 10.58(s, 1H), 8.54(d, J=2.6Hz, 1H), 8.47(d, J=2.6Hz, 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 hours. Water was added to the solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude product was dissolved in dichloromethane (14 mL). The mixture was placed in an ice bath, and EtN (1.96 mL, 14 mmol) and TfO (1.77 mL, 10.5 mmol) were slowly added to the solution. After the addition of TfO, the reaction was stirred at 0 °C for 2 hours, and then the ice bath was removed. The mixture was continued to stir at room temperature for an additional 2 hours. 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 H 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)Cl (4 mg, 0.5% mmol), KPO (42 mg, 0.2 mmol), 1,4-dioxane (2 mL), and HO (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 NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the product.

[0505] [ka]

[0506] The general procedure described above gave the target compound 41a (88% yield).

[0507] 1 H NMR(400MHz, chloroform-d) δ 8.80(d, J=2.3Hz, 2H), 7.59(d, J=7.4Hz, 2H), 7.53(t, J=7.5Hz, 2H), 7.46(t, J=7.2Hz, 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] [ka]

[0509] The general procedure described above gave the target compound 46a (88% yield).

[0510] 1 H NMR(400MHz, chloroform-d) δ 8.81(d, J=2.3Hz, 1H), 8.78(d, J=2.3Hz, 1H), 7.41(d, J=5.1Hz, 1H), 7.37(d, J=3.5Hz, 1H), 7.16(dd, J=5.1, 3.7Hz, 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] [ka]

[0512] Step 1 [ka]

[0513] To a solution of 5-(butylthio)-1H-pyrazol-3-amine (1.71 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 product 2a as a yellow solid (2.4 g, 63% yield).

[0514] 1 H NMR(400MHz, chloroform-d) δ 8.04(d, J=8.2Hz, 2H), 7.42(s, 1H), 7.02(d, J=8.5Hz, 2H), 6.63(s, 1H), 3.89(s, 3H), 3.18(t, J=7.3Hz, 2H), 1.82-1.74(m, 2H), 1.54-1.44(m, 2H), 0.95(t, J=7.3Hz, 3H); 13 C 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 [ka]

[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) was added HO (3.7 μL, 0.12 mmol) and AcOH (0.5 mL). The reaction was monitored by LC / MS. After completion of the reaction, the reaction was quenched by adding aqueous NaHCO. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give product 3a as a yellow solid (35 mg, 90% yield).

[0517] 1H 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 C 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] [ka]

[0519] The target compound 4a was obtained by the general procedure described above by using 5 equivalents of H2O2 instead.

[0520] 1 H NMR(400MHz, chloroform-d) δ 8.10(d, J=8.3Hz, 2H), 7.75(s, 1H), 7.26(s, 1H), 7.04(d, J=7.4Hz, 2H), 3.90(s, 3H), 3.41(t, J=7.3Hz, 2H), 1.88-1.80(m, 2H), 1.51-1.41(m, 2H), 0.92(t, J=7.2Hz, 3H); 13C 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] [ka]

[0522] The target compound 48a was prepared similarly to 3a by using 4,4,4-trifluoro-1-(thiazol-2-yl)butane-1,3-dione instead.

[0523] 1 H 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] [ka]

[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(400MHz, chloroform-d) δ 8.19(d, J=9.1Hz, 2H), 7.68(s, 1H), 7.04(d, J=9.1Hz, 2H), 3.91(s, 3H), 3.33(t, J=7.4Hz, 2H), 1.85-1.78(m, 2H), 1.56-1.47(m, 2H), 0.96(t, J=7.4Hz, 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) was added HO (3.7 μL, 0.12 mmol) and AcOH (0.5 mL). The reaction was stirred overnight and quenched by the addition of aqueous NaHCO. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give product 49a as a yellow solid (34 mg, 85% yield).

[0527] 1 H NMR(400MHz, chloroform-d) δ 8.15(d, J=8.5Hz, 2H), 7.87(s, 1H), 6.98(d, J=8.5Hz, 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=7.4Hz, 3H); 13C 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] [ka]

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

[0530] 1 H 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] [ka]

[0532] Step 1 To a solution of 5-(butylthio)-1H-pyrazol-3-amine (1.71 g, 10 mmol) in AcOH (20 mL) was added ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (2.44 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 a yellow solid (2.11 g, 64% yield). 1H NMR(400MHz, DMSO-d6) δ 12.30(s, 1H), 7.78(d, J=8.6Hz, 2H), 7.10(d, J=8.7Hz, 2H), 6.10(s, 1H), 5.97(s, 1H), 3.83(s, 3H), 3.08(t, J=7.2Hz, 2H), 1.67-1.59(m, 2H), 1.45-1.36(m, 2H), 0.89(t, J=7.3Hz, 3H). MS(ES+) m / z=330 [M+H] + .

[0533] Step 2 To a 25 mL vial containing 2-(butylthio)-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.98 g, 6 mmol) was added POCl (5.63 mL, 60 mmol). The mixture was heated at 90 °C for 4 h, and excess POCl was removed under reduced pressure. To the crude material cooled in an ice bath, cold aqueous NaHCO was slowly added, and the resulting solution was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the product as a yellow solid (1.73 mg, 83% yield). 1 H NMR(400MHz, chloroform-d) δ 8.14(d, J=9.1Hz, 2H), 7.48(s, 1H), 7.02(d, J=9.1Hz, 2H), 3.90(s, 3H), 3.34(t, J=7.4Hz, 2H), 1.83-1.77(m, 2H), 1.56-1.47(m, 2H), 0.96(t, J=7.4Hz, 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)Cl (4 mg, 0.5 mmol), KPO (42 mg, 0.2 mmol), 1,4-dioxane (2 mL), and HO (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 NaSO, and concentrated by rotary evaporation. The crude product was dissolved in chloroform (2 mL), and HO (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, aqueous NaHCO was added to quench the reaction. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude product was purified by flash chromatography on silica gel to give the product.

[0535] [ka]

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

[0537] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=8.6Hz, 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=8.7Hz, 2H), 3.86(s, 3H), 3.12(t, J=7.6Hz, 2H), 1.90-1.79(m, 1H), 1.77-1.66(m, 1H), 1.55-1.40(m, 2H), 0.93(t, J=7.3Hz, 3H); 13C 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] [ka]

[0539] The general procedure described above gave the target compound 6a (86% yield).

[0540] 1 H NMR(400MHz, 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=8.7Hz, 2H), 3.87(s, 3H), 3.11(t, J=7.7Hz, 2H), 1.90-1.78(m, 1H), 1.77-1.66(m, 1H), 1.55-1.40(m, 2H), 0.93(t, J=7.2Hz, 3H); 13 C 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] [ka]

[0542] The general procedure described above gave the target compound 51a (54% yield).

[0543] 1 H NMR(400MHz, chloroform-d) δ 9.20(s, 1H), 8.81(d, J=3.3Hz, 1H), 8.47(dt, J=8.1, 1.9Hz, 1H), 8.11(d, J=8.9Hz, 2H), 7.53(dd, J=8.2, 5.0Hz, 1H), 7.43(s, 1H), 7.19(s, 1H), 7.04(d, J=8.9Hz, 2H), 3.89(s, 3H), 3.12(t, J=7.8Hz, 2H), 1.93-1.79(m, 1H), 1.76-1.65(m, 1H), 1.53-1.42(m, 2H), 0.93(t, J=7.3Hz, 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] [ka]

[0545] The general procedure described above gave the target compound 52a (81% yield).

[0546] 1H NMR(400MHz, クロロホルム-d) δ 9.44(s, 2H), 9.40(s, 1H), 8.10(d, J=7.9Hz, 2H), 7.46(s, 1H), 7.21(s, 1H), 7.03(d, J=7.9Hz, 2H), 3.89(s, 3H), 3.12(t, J=7.7Hz, 2H), 1.90-1.79(m, 1H), 1.75-1.64(m, 1H), 1.53-1.42(m, 2H), 0.93(t, J=7.3Hz, 3H); 13 C NMR(101MHz, クロロホルム-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]

change

[0548] The target compound 53a (yield 75%) of the above-mentioned general なhandshunによっ was obtained.

[0549] 1 H NMR(400MHz, クロロホルム-d) δ 8.81(s, 1H), 8.28(s, 1H), 8.07(d, J=8.8Hz, 2H), 7.52(s, 1H), 7.07(s, 1H), 7.01(d, J=8.8Hz, 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=7.3Hz, 3H); 13C 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] [ka]

[0551] The general procedure described above gave the target compound 54a (69% yield).

[0552] 1 H NMR(400MHz, chloroform-d) δ 8.08(d, J=8.9Hz, 2H), 7.29(s, 1H), 7.16(s, 1H), 7.03(d, J=8.9Hz, 2H), 6.96-6.95(m, 1H), 6.92-6.90(m, 1H), 6.35(t, J=3.1Hz, 1H), 3.89(s, 3H), 3.75(s, 3H), 3.12(t, J=7.3Hz, 2H), 1.89-1.65(m, 2H), 1.55-1.42(m, 2H), 0.93(t, J=7.3Hz, 3H); 13 C 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] [ka]

[0554] The general procedure described above gave the target compound 73a (62% yield).

[0555] 1 H NMR(400MHz, chloroform-d) δ 8.78(s, 1H), 8.07(d, J=8.4Hz, 2H), 7.47(s, 1H), 7.10(s, 1H), 7.04(d, J=8.4Hz, 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=7.2Hz, 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] [ka]

[0557] The general procedure described above gave the target compound 72a (65% yield).

[0558] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=8.9Hz, 2H), 7.66(d, J=2.0Hz, 1H), 7.37(s, 1H), 7.21(s, 1H), 7.03(d, J=8.9Hz, 2H), 6.79(d, J=1.9Hz, 1H), 3.94(s, 3H), 3.89(s, 3H), 3.10(t, J=7.8Hz, 2H), 1.90-1.79(m, 1H), 1.73-1.62(m, 1H), 1.54-1.41(m, 2H), 0.92(t, J=7.3Hz, 3H);13 C 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] [ka]

[0560] The general procedure described above gave the target compound 74a (45% yield).

[0561] 1 H NMR(400MHz, chloroform-d) δ 8.07(d, J=8.0Hz, 2H), 7.16(s, 1H), 7.15(s, 1H), 7.03(d, J=8.2Hz, 2H), 3.89(s, 3H), 3.84(s, 3H), 3.11(t, J=7.8Hz, 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=7.2Hz, 3H); 13 C 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] [ka]

[0563] The general procedure described above gave the target compound 70a (46% yield).

[0564] 1 H NMR(400MHz, chloroform-d) δ 8.09(d, J=8.8Hz, 2H), 7.55(s, 1H), 7.32(s, 1H), 7.17(s, 1H), 7.04(d, J=8.8Hz, 2H), 3.90(s, 3H), 3.61(s, 3H), 3.11(t, J=7.8Hz, 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=7.3Hz, 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] [ka]

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

[0567] 1H NMR(400MHz, chloroform-d) δ 8.24(d, J=8.8Hz, 2H), 8.14-8.12(m, 2H), 7.67(s, 1H), 7.63-7.58(m, 3H), 7.04(d, J=8.8Hz, 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=7.3Hz, 3H); 13 C 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] [ka]

[0569] Step 1 To a solution of benzil (2.1 g, 10 mmol) in MeOH (20 mL) was added 3,4-diaminobenzoic acid (1.52 g, 10 mmol). The slurry was stirred at room temperature for 8 hours. 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 H NMR(400MHz, DMSO-d6) δ 13.31(s, 1H), 8.64(d, J=1.8Hz, 1H), 8.30(dd, J=8.8, 1.8Hz, 1H), 8.22(d, J=8.7Hz, 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 the amine (0.12 mmol). The mixture was stirred at room temperature until the reaction was complete (the reaction was monitored by LC / MS). Water was added to the solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated by rotary evaporation. The crude material was purified by flash chromatography on silica gel to give the product.

[0571] [ka]

[0572] The general procedure described above gave the target compound 5b (57% yield).

[0573] 1 H NMR(400MHz, DMSO-d6) δ 8.70(s, 1H), 8.37(s, 1H), 8.29(d, J=8.7Hz, 1H), 8.18(d, J=8.7Hz, 1H), 7.70(s, 1H), 7.48(d, J=7.2Hz, 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 missing due to overlap). MS (ES+) m / z = 326 [M+H] + .

[0574] [ka]

[0575] The general procedure described above gave the target compound 6b (67% yield).

[0576] 1 H NMR(400MHz, DMSO-d6) δ 8.87-8.84(m, 1H), 8.63(s, 1H), 8.26(d, J=8.7Hz, 1H), 8.20(d, J=8.7Hz, 1H), 7.48(d, J=7.6Hz, 4H), 7.42-7.33(m, 6H), 2.86(d, J=3.8Hz, 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 missing due to overlap). MS (ES+) m / z = 340 [M+H] + .

[0577] [ka]

[0578] The general procedure described above gave the target compound 7b (66% yield).

[0579] 1 H NMR(400MHz, DMSO-d6) δ 8.88(t, J=5.5Hz, 1H), 8.66(s, 1H), 8.27(d, J=8.6Hz, 1H), 8.20(d, J=8.8Hz, 1H), 7.48(d, J=7.3Hz, 4H), 7.42-7.33(m, 6H), 3.40-3.34(m, 2H), 1.18(t, J=7.2Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 165.3, 154.6, 154.3, 141.9, 140.3, 139.0, 136.2, 130.2, 130.1, 129.5, 129.4, 129.3, 129.2, 128.54, 128.51, 128.1, 34.8, 15.1 (one signal missing due to overlap). MS (ES+) m / z = 354 [M+H] + .

[0580] [ka]

[0581] The general procedure described above gave the target compound 8b (73% yield).

[0582] 1 H NMR(400 MHz, DMSO-d6) δ 8.86(d, J=5.7Hz, 1H), 8.66(s, 1H), 8.27(d, J=8.6Hz, 1H), 8.20(d, J=8.4Hz, 1H), 7.48(d, J=7.3Hz, 4H), 7.42-7.34(m, 6H), 3.32-3.27(m, 2H), 1.64-1.54(m, 2H), 0.92(t, J=7.1Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 165.5, 154.6, 154.3, 141.9, 140.2, 138.98, 138.96, 136.2, 130.2, 130.1, 129.5, 129.4, 129.3, 128.5, 128.1, 41.7, 22.8, 12.0 (two signals missing due to overlap). MS (ES+) m / z = 368 [M+H] + .

[0583] [ka]

[0584] The general procedure described above gave the target compound 10b (76% yield).

[0585] 1 H NMR(400MHz, DMSO-d6) δ 8.85(t, J=5.5Hz, 1H), 8.66(s, 1H), 8.26(d, J=8.9Hz, 1H), 8.19(d, J=8.7Hz, 1H), 7.48(d, J=7.3Hz, 4H), 7.42-7.33(m, 6H), 3.35-3.31(m, 2H), 1.59-1.52(m, 2H), 1.41-1.31(m, 2H), 0.91(t, J=7.3Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 165.4, 154.6, 154.3, 141.9, 140.2, 138.97, 138.95, 136.2, 130.2, 130.1, 129.5, 129.4, 129.2, 128.5, 128.1, 39.6, 31.6, 20.2, 14.2 (two signals missing due to overlap). MS (ES+) m / z = 382 [M+H] + .

[0586] [ka]

[0587] The general procedure described above gave the target compound 11b (78% yield).

[0588] 1 H NMR(400MHz, DMSO-d6) δ 8.86(t, J=5.4Hz, 1H), 8.66(s, 1H), 8.27(d, J=8.8Hz, 1H), 8.20(d, J=8.7Hz, 1H), 7.48(d, J=7.2Hz, 4H), 7.42-7.34(m, 6H), 3.33-3.30(m, 2H), 1.61-1.54(m, 2H), 1.34-1.26(m, 4H), 0.87(t, J=6.4Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 165.4, 154.6, 154.3, 141.9, 140.2, 138.97, 138.95, 136.2, 130.2, 130.1, 129.5, 129.4, 129.3, 128.5, 128.1, 29.2, 29.1, 22.4, 14.4 (two signals missing due to overlap). MS (ES+) m / z = 396 [M+H] + .

[0589] [ka]

[0590] The general procedure described above gave the target compound 12b (86% yield).

[0591] 1 H NMR(400MHz, DMSO-d6) δ 8.21(d, J=8.5Hz, 1H), 8.15(s, 1H), 7.86(d, J=8.5Hz, 1H), 7.47(d, J=7.0Hz, 4H), 7.42-7.33(m, 6H), 3.69-3.58(m, 6H), 3.42(s, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 168.3, 154.4, 141.0, 140.2, 138.9, 137.6, 130.2, 130.1, 129.8, 129.5, 129.43, 129.40, 128.5, 127.5, 66.5, 48.2, 42.6 (three signals missing due to overlap). MS (ES+) m / z = 396 [M+H] + .

[0592] [ka]

[0593] The general procedure described above gave the target compound 13b (83% yield).

[0594] 1 H NMR(400MHz, DMSO-d6) δ 8.21(d, J=8.5Hz, 1H), 8.15(s, 1H), 7.86(d, J=8.5Hz, 1H), 7.47(d, J=5.7Hz, 4H), 7.42-7.33(m, 6H), 3.66(s, 2H), 3.47-3.36(m, 6H), 1.40(s, 9H); 13 C NMR (101 MHz, DMSO-d6) δ 168.4, 154.41, 154.39, 154.2, 141.0, 140.3, 139.0, 137.8, 130.2, 130.1, 129.8, 129.4, 128.5, 127.4, 79.7, 47.4, 42.0, 28.5 (three signals missing due to overlap).

[0595] [ka]

[0596] The general procedure described above gave the target compound 14b (53% yield).

[0597] 1 H NMR(400MHz, DMSO-d6) δ 10.62(s, 1H), 8.84(s, 1H), 8.36(d, J=8.6Hz, 1H), 8.25(d, J=8.7Hz, 1H), 7.86(d, J=8.1Hz, 2H), 7.50(d, J=7.3Hz, 4H), 7.42-7.34(m, 8H), 7.13(t, J=7.4Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 164.8, 154.9, 154.5, 142.2, 140.2, 139.4, 138.94, 138.91, 136.3, 130.2, 130.1, 129.54, 129.47, 129.1, 128.8, 128.57, 128.55, 124.4, 120.9 (three signals missing due to overlap). MS (ES+) m / z = 402 [M+H] + .

[0598] [ka]

[0599] The general procedure described above gave the target compound 15b (74% yield).

[0600] 1 H NMR(400MHz, DMSO-d6) δ 9.47(t, J=6.0Hz, 1H), 8.72(s, 1H), 8.31(d, J=8.7Hz, 1H), 8.21(d, J=8.7Hz, 1H), 7.48(d, J=7.2Hz, 4H), 7.41-7.32(m, 10H), 7.26-7.22(m, 1H), 4.56(d, J=6.0Hz, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 165.6, 154.7, 154.3, 142.0, 140.3, 139.9, 139.0, 138.9, 135.9, 130.2, 130.1, 129.5, 129.43, 129.39, 129.3, 128.8, 128.5, 128.3, 127.8, 127.3, 43.4 (one signal missing due to overlap). MS (ES+) m / z = 416 [M+H] + .

[0601] [ka]

[0602] The general procedure described above gave the target compound 17b (86% yield).

[0603] 1H NMR(400MHz, DMSO-d6) δ 8.85(t, J=5.3Hz, 1H), 8.68(s, 1H), 8.28(d, J=8.6Hz, 1H), 8.20(d, J=8.5Hz, 1H), 7.49(d, J=7.2Hz, 4H), 7.42-7.33(m, 6H), 4.80-4.77(m, 1H), 3.59-3.54(m, 2H), 3.43-3.38(m, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 165.7, 154.6, 154.3, 141.9, 140.2, 139.0, 136.1, 130.2, 130.1, 129.5, 129.4, 129.3, 128.5, 128.3, 60.1, 42.9 (three signals missing due to overlap). MS (ES+) m / z = 370 [M+H] + .

[0604] [ka]

[0605] The general procedure described above gave the target compound 18b (86% yield).

[0606] 1 H NMR(400MHz, DMSO-d6) δ 8.72-8.69(m, 2H), 8.27(dd, J=8.9, 1.9Hz, 1H), 8.18(d, J=8.7Hz, 1H), 7.49-7.47(m, 4H), 7.41-7.33(m, 6H), 4.32-4.25(m, 1H), 1.97-1.87(m, 2H), 1.75-1.68(m, 2H), 1.64-1.50(m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 165.2, 154.5, 154.2, 141.9, 140.2, 139.0, 136.2, 130.2, 130.1, 129.5, 129.43, 129.40, 129.1, 128.5, 128.2, 51.7, 32.6, 24.2 (two signals missing due to overlap). MS (ES+) m / z = 394 [M+H] + .

[0607] [ka]

[0608] The general procedure described above gave the target compound 19b (86% yield).

[0609] 1 H NMR(400MHz, DMSO-d6) δ 9.08(s, 1H), 8.69(s, 1H), 8.28(d, J=8.8Hz, 1H), 8.20(d, J=8.8Hz, 1H), 7.48(d, J=7.3Hz, 4H), 7.42-7.33(m, 6H), 5.99-5.89(m, 1H), 5.22(d, J=17.2Hz, 1H), 5.12(d, J=10.3Hz, 1H), 3.99-3.97(m, 2H); 13 C NMR(101MHz, DMSO-d6) δ 165.4, 154.7, 154.3, 142.0, 140.3, 138.97, 138.95, 135.9, 135.6, 130.2, 130.1, 129.5, 129.4, 129.3, 129.2, 128.6, 128.5, 128.3, 115.9, 42.2. MS(...

Claims

1. A composition for use in inhibiting the activity of a short-chain dehydrogenase enzyme, said composition comprising a compound or a pharma- ceutical acceptable salt thereof, said compound being: 【Chemistry 3】 【change】 【change】 【change】 A composition represented by a formula selected from the group consisting of:

2. The composition of claim 1 for use in inhibiting the activity of the 15-PGDH enzyme.

3. 10. The composition of claim 1 for use in promoting skin pigmentation and / or hair growth, and / or inhibiting hair loss, and / or treating skin damage or inflammation.

4. 10. The composition of claim 1 for use in wound healing, tissue repair and / or tissue regeneration.

5. 10. The composition of claim 1 for use in treating oral ulcers, gum disease, colitis, ulcerative colitis, gastrointestinal ulcers, inflammatory bowel disease, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary arterial hypertension, cardiovascular disease or renal disease.

6. 10. The composition of claim 1, further comprising a prostanoid agonist for the purpose of enhancing the therapeutic effect of said prostanoid agonist in prostaglandin-responsive conditions.

7. The composition of claim 1 for use in increasing tissue stem cells.

8. 10. The composition of claim 1 for use in increasing the compatibility of donor tissue grafts, donor bone marrow grafts and / or donor hematopoietic stem cell grafts.

9. 10. The composition of claim 1 for use in reducing tissue transplant rejection in a subject.

10. 10. The composition of claim 1 for use in enhancing survival of tissue and / or bone marrow transplants in a subject.

11. 10. The composition of claim 1 for use in treating bone marrow of a subject to confer resistance to the toxic or lethal effects of radiation exposure.

12. 10. The composition of claim 1 for use in increasing red blood cell count or hematocrit or hemoglobin levels in a subject with anemia following chemotherapy administration or radiation therapy.

13. 10. The composition of claim 1 for use in treating colitis, ulcerative colitis or inflammatory bowel disease.

14. 10. The composition of claim 1 for use in increasing liver regeneration after liver surgery, after living donor liver donation, after liver transplantation, or after toxin-induced liver injury.

15. 10. The composition of claim 1 for use in treating a subject in need of cell therapy.

16. The subject may be a patient with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, severe aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH), pure red cell aplasia, amegakaryocytic / congenital thrombocytopenia, severe combined immune deficiency syndrome (SCID), or a combination of these disorders.

16. The composition of claim 15, wherein the patient has a medical condition that causes idiopathic myeloid leukemia, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, idiopathic myeloid metaplasia, familial erythrophagocytic lymphohistiocytosis, solid tumors, chronic granulomatous disease, mucopolysaccharidosis, or Diamond-Blackfan anemia.

17. 10. The composition of claim 1 for use in treating a subject having at least one symptom associated with ischemic tissue or tissue damaged by ischemia.

18. The ischemia includes acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, 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 Wounds, Delayed Ulcer Healing, Delayed Wound Healing, Diabetes (Types I and II), Diabetic Neuropathy, Diabetes-Induced Ischemia, 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 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, Limb ischemia, Myocardial infarction, Myocardial ischemia, Organ ischemia, Osteoarthritis, Osteoporosis, Osteosarcoma, Parkinson's disease, Peripheral arterial disease (PAD), Peripheral arterial disease, Peripheral ischemia, Peripheral neuropathy, Peripheral vascular disease, Precancer 18. The composition of claim 17, wherein the condition is associated with at least one of the following: pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplants, 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, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

19. 10. The composition of claim 1 for use in increasing neutrophils in a subject in need thereof.

20. 10. The composition of claim 1 for use in increasing the number of and / or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof.

21. 10. The composition of claim 1 for use in increasing the number of hematopoietic stem cells in blood or bone marrow.

22. 10. The composition of claim 1 for use in treating a fibrotic disease, disorder or condition in a subject in need thereof.

23. The composition of claim 22, wherein the fibrotic disease, disorder or condition is characterized, in whole or in part, by overproduction of fibrous material, including overproduction of fibrous material in the extracellular matrix, or replacement of normal tissue elements by abnormal, non-functional, and / or excessive accumulation of matrix-associated components.

24. The fibrotic disease, disorder or condition may be systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma, scleroderma graft versus host disease, renal fibrosis, glomerulosclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy, cardiac fibrosis, pulmonary fibrosis, glomerulosclerosis 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, common fibrotic syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrotic tissue, retroperitoneal fibrosis, hepatic fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis / bone marrow fibrosis, 23. The composition of claim 22, wherein the fibrosis is selected from the group consisting of glioblastoma in Li-Fraumeni syndrome, glioblastoma in myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, leprosy, collagenous colitis, acute fibrosis and organ specific fibrosis.

25. 23. The composition of claim 22, wherein the fibrotic disease, disorder or condition comprises pulmonary fibrosis.

26. 26. The composition of claim 25, wherein 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, coal workers' pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of mineral dusts, pulmonary fibrosis caused by infectious agents, 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.

27. 26. The composition of claim 25, wherein the pulmonary fibrosis is cystic fibrosis.

28. 23. The composition of claim 22, wherein the fibrotic disease, disorder or condition comprises renal fibrosis.

29. 23. The composition of claim 22, wherein the fibrotic disease, disorder or condition comprises liver fibrosis.

30. 30. The composition of claim 29, wherein the liver fibrosis is due to chronic liver disease, virally induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or nonalcoholic steatohepatitis (NASH), NASH-associated cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha 1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions, and exposure to toxins, or a combination thereof.

31. 23. The composition of claim 22, wherein the fibrotic disease, disorder or condition comprises cardiac fibrosis.

32. 23. The composition of claim 22, wherein the fibrotic disease, disorder or condition is systemic sclerosis.

33. 23. The composition of claim 22, wherein the fibrotic disease, disorder or condition is caused by post-surgical adhesion formation.

34. The composition of claim 1 for use in promoting neuroprotection of a subject from axonal degeneration, neuronal death and / or glial cell damage following injury in a subject in need thereof, enhancing neuronal signaling underlying learning and memory, stimulating neuronal regeneration following injury, and / or treating diseases, disorders and / or conditions of the nervous system.

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