Compositions and methods for modulating short-chain dehydrogenase activity

Abstract

Compounds and methods for modulating 15-PGDH activity, modulating tissue prostaglandin levels, and treating diseases, disorders, or conditions in which modulating 15-PGDH activity and / or prostaglandin levels is desirable include the 15-PGDH inhibitors described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 027,557, filed May 20, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Short-chain dehydrogenases (SCDs) are a family of dehydrogenases that share only 15%-30% sequence identity, with similarities 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 some prostaglandins, and are therefore implicated in a variety of disorders, including lipid storage diseases, myopathies, SCD deficiencies, and certain genetic disorders.

[0003] SCD, 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), (hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide); 15-PGDH; enzyme commission number 1.1.1.141; encoded by the HPGD gene) represents a key enzyme in the inactivation of numerous active prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids (HETEs) (e.g., by catalyzing the oxidation of PGE2 to 15-keto-prostaglandin E2, 15k-PGE). This human enzyme, encoded by the HPGD gene, is composed of a homodimer with a 29 kDa subunit. This enzyme belongs to the evolutionarily conserved superfamily of short-chain dehydrogenase / reductase enzymes (SDRs) and has been designated SDR36C1 in accordance with the recently approved nomenclature for human enzymes. To date, two forms of 15-PGDH enzyme activity have been identified: the NAD+-dependent type I 15-PGDH encoded by the HPGD gene, and the NADP-dependent type II 15-PGDH, also known as carbonyl reductase 1 (CBR1, SDR21C1). However, the preference of CBR1 for NADP and its high Km values ​​for most prostaglandins suggest that the majority of in vivo activity is due to the type I 15-PGDH encoded by the HPGD gene; henceforth, type I 15-PGDH will be referred to simply as 15-PGDH throughout the following text.

[0004] Recent studies have suggested that 15-PGDH inhibitors and activators may be therapeutically valuable. 15-PGDH knockout mouse models have shown increased colon tumor incidence. More recent studies have implicated increased 15-PGDH expression in protecting against thrombin-mediated cell death. 15-PGDH is well known to be responsible for the inactivation of prostaglandin E2 (PGE2), a downstream product of COX-2 metabolism. PGE2 has been shown to be beneficial for various biological processes, such as hair density, skin wound healing, and bone formation. Summary of the Invention [Means for solving the problem]

[0005] Embodiments described herein relate to compounds and methods for modulating short-chain dehydrogenase (SCD) (e.g., 15-PGDH) activity, modulating tissue prostaglandin levels, and / or treating diseases, disorders, or conditions in which modulating SCD (e.g., 15-PGDH) activity and / or prostaglandin levels is desirable.

[0006] In embodiments, the modulator of SCD can be an SCD inhibitor, which 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 can be a 15-PGDH inhibitor, which can be administered to the tissue or blood of a subject in an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor can be represented by Formula (I): [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and each of these is one or more R 3 optionally substituted with; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R3 is -OH, -O-alkylene-OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), -N(R 5 )(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 )2, -C(O)N(R 5 )(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl or -S(O) m -alkyl, and cycloalkyl and heterocyclyl are each R 10 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with, where R4 is oxo and R7 is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl; Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 10 is —OH, halogen, C1-C6 alkyl or C1-C6 alkoxy; R11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0007] In an embodiment, the compound of formula (I) is [ka] isn't it.

[0008] In an embodiment of the compound of formula (I), R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy). 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p -cyclohexyl or -(CH2) p -OCH3; and p is 1, 2, or 3.

[0009] In an embodiment of the compound of formula (I), R 2 is NH2.

[0010] In an embodiment of the compound of formula (I), R 6 teeth, [ka] is.

[0011] In an embodiment of the compound of formula (I), R 11 is H or methyl.

[0012] In an embodiment of the compound of formula (I), R 7is phenyl, alkyl, or cycloalkyl, each of which may be one or more R 4 is optionally substituted with

[0013] In an embodiment of the compound of formula (I), R 7 is a straight or branched chain acyclic C1-C6 alkyl. 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or t-butyl. 7 is i-propyl.

[0014] In an embodiment of the compound of Formula (I), X is CH.

[0015] In an embodiment of the compounds of Formula (I), n is 1.

[0016] The present disclosure provides a compound of formula (II): [ka] (In the formula, R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy); R 6 teeth, [ka] and; R 7 is a straight or branched chain acyclic C1-C6 alkyl; R 11 is H or C1-C6 alkyl; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0017] In an embodiment of the compound of formula (I) or (II), the compound is [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0018] The present disclosure provides a compound of formula (III) [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with, where R4 is oxo and R7 is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl; Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0019] In an embodiment of the compound of formula (III), the compound is [ka] [ka] [ka] [ka] [ka] [ka] isn't it.

[0020] In an embodiment of the compound of formula (III), R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy). 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p-cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p -cyclohexyl or -(CH2) p -OCH3; and p is 1, 2, or 3.

[0021] In an embodiment of the compound of formula (III), R 2 is NH2 or -CN.

[0022] In an embodiment of the compound of formula (III), R 6 teeth, [ka] is.

[0023] In an embodiment of the compound of formula (III), R 7 is alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which may be one or more R 4 is optionally substituted with

[0024] In an embodiment of the compound of Formula (III), n is 1.

[0025] In an embodiment of the compound of formula (III), the compound is [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0026] The present disclosure provides a compound of formula (IV) [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with, where R4 is oxo and R7 is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl; Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 A compound of the formula [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0027] The present disclosure provides: [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0028] The present disclosure also relates to pharmaceutical compositions comprising any one of the compounds of Formulas (I)-(IV) or Table 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0029] In embodiments, the compound or 15-PGDH inhibitor of the present disclosure inhibits the enzymatic activity of recombinant 15-PGDH with an IC of 1 μM or less at a 15-PGDH concentration of about 1 nM to about 10 nM. 50 , IC below 250 nM 50 , IC below 50 nM 50 , IC below 10 nM 50 , IC below 5 nM 50 , IC of about 2.5 nM to about 10 nM 50 or an IC of approximately 2.5 nM or less 50 can be inhibited by

[0030] In embodiments, the compound or 15-PGDH inhibitor of the present disclosure inhibits the enzymatic activity of recombinant 15-PGDH with an IC of 1 μM or less at a 15-PGDH concentration of about 0.5 nM to about 5 nM. 50 , IC below 250 nM 50 , IC below 50 nM 50 , IC below 10 nM 50 , IC below 5 nM 50 , IC of about 2.5 nM to about 10 nM 50 or an IC of approximately 2.5 nM or less 50 can be inhibited by

[0031] In embodiments, the compound or 15-PGDH inhibitor of the present disclosure inhibits the enzymatic activity of recombinant 15-PGDH with an IC of 1 μM or less at a 15-PGDH concentration of about 1 nM to about 2 nM. 50 , IC below 250 nM 50 , IC below 50 nM 50 , IC below 10 nM 50 , IC below 5 nM 50 , IC of about 2.5 nM to about 10 nM 50 or an IC of approximately 2.5 nM or less 50 In embodiments, the compound or 15-PGDH inhibitor of the present disclosure can inhibit the enzymatic activity of recombinant 15-PGDH with an IC of less than about 2.5 nM at a 15-PGDH concentration of about 1 nM to about 2 nM. 50 can be inhibited by

[0032] The 15-PGDH inhibitors of the present disclosure can be provided in topical compositions 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.

[0033] The 15-PGDH inhibitors of the present disclosure can also be administered to a subject to promote wound healing, tissue repair and / or tissue regeneration and / or tissue graft survival or regeneration.

[0034] In embodiments, the 15-PGDH inhibitors of the present disclosure can 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, heart disease, and kidney disease.

[0035] In another embodiment, the 15-PGDH inhibitors of the present disclosure can be administered to a subject in combination with a prostanoid agonist for the purpose of enhancing the therapeutic effect of the agonist in prostaglandin-responsive conditions.

[0036] In embodiments, a 15-PGDH inhibitor of the present disclosure can be administered to a subject and / or a subject's tissue to increase stem cells in the tissue. For example, a 15-PGDH inhibitor can be administered to a subject's bone marrow to increase stem cells in the subject.

[0037] In yet other embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to tissue graft donors, bone marrow graft donors, and / or hematopoietic stem cell donors and / or tissue grafts, and / or bone marrow grafts, and / or hematopoietic stem cell grafts to enhance the compatibility of the donor tissue grafts, donor bone marrow grafts, and / or donor hematopoietic stem cell grafts. In embodiments, the 15-PGDH inhibitors are administered ex vivo to the tissue grafts, and / or bone marrow grafts, and / or hematopoietic stem cell grafts. For example, a 15-PGDH inhibitor can be administered to a subject and / or the subject's bone marrow to increase its suitability as a donor graft, and / or to a preparation of the subject's hematopoietic stem cells to increase its suitability as a donor graft, and / or to a preparation of the subject's peripheral blood hematopoietic stem cells to increase its suitability as a donor graft, and / or to a preparation of umbilical cord blood stem cells to increase its suitability as a donor graft, and / or to a preparation of umbilical cord blood stem cells to reduce the number of units of umbilical cord blood required for transplantation.

[0038] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to a subject to reduce tissue transplant rejection, enhance engraftment of tissue and / or bone marrow transplants, enhance engraftment of bone marrow transplants after the subject or the subject's bone marrow has been treated with radiation therapy, chemotherapy, or immunosuppressive therapy, enhance engraftment of progenitor stem cell transplants, hematopoietic stem cell transplants, or umbilical cord blood stem cell transplants, enhance engraftment of hematopoietic stem cell transplants or umbilical cord stem cell transplants after the subject or the subject's bone marrow has been treated with radiation therapy, chemotherapy, or immunosuppressive therapy, and / or reduce the number of units of cord blood required for transplant into the subject.

[0039] In embodiments, the 15-PGDH inhibitors of the present disclosure can 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 therapies or growth factors.

[0040] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to a subject or a subject's tissue graft to reduce graft rejection, enhance graft survival, and / or enhance graft survival after treating the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy.

[0041] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to a subject or to the bone marrow of a subject to confer resistance to the toxic or lethal effects of exposure to radiation, 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.

[0042] In still other embodiments, the 15-PGDH inhibitors of the present disclosure increase neutrophil counts after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood; increase neutrophil counts in neutropenic subjects after chemotherapy administration or after radiation therapy; 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 following a viral infection; increase neutrophil counts in neutropenic subjects; Increasing platelet counts after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; Increasing platelet counts in subjects with thrombocytopenia after chemotherapy or radiation therapy; Increasing platelet counts in subjects with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection; Increasing platelet counts in subjects with thrombocytopenia; Increasing platelet counts in subjects with bone marrow, hematopoietic stem cells, or umbilical cord blood to increase red blood cell count, hematocrit value, or hemoglobin level after hematopoietic cell transplantation, to increase red blood cell count, hematocrit value, or hemoglobin level in subjects with anemia after chemotherapy or radiation therapy, and to increase red blood cell count, hematocrit value, or hemoglobin level in subjects with aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other bone marrow disorders, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, anemia after viral infection, or anemia of unknown cause the amount of erythropoietin in the blood of a subject with anemia, to increase red blood cell count or hematocrit or hemoglobin levels in an anemic subject, to increase bone marrow stem cells after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells or umbilical cord blood, to increase bone marrow stem cells in a subject after administration of chemotherapy or after 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 viral infection or cytopenia.

[0043] In embodiments, administration of a 15-PGDH inhibitor of the present disclosure can be used to regulate hematopoietic stem cells and hematopoiesis. A 15-PGDH inhibitor can be administered to a subject in need thereof, alone or in combination with cytokines, to increase and / or mobilize hematopoietic stem cells and / or neutrophils in the subject's blood, bone marrow, and / or tissues.

[0044] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with G-CSF to increase neutrophils.

[0045] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with hematopoietic cytokines to increase neutrophils.

[0046] In yet other embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with G-CSF to increase the number of peripheral blood hematopoietic stem cells and / or to mobilize peripheral blood hematopoietic stem cells.

[0047] In embodiments, the 15-PGDH inhibitors of the present disclosure may be administered in combination with hematopoietic cytokines to increase the number of and / or mobilize peripheral blood hematopoietic stem cells.

[0048] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with a second agent, including plerixafor, to increase the number of peripheral blood hematopoietic stem cells and / or mobilize peripheral blood hematopoietic stem cells.

[0049] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with G-CSF to increase and / or mobilize peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0050] In yet other embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with hematopoietic cytokines to increase and / or mobilize peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0051] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with a second agent, including plerixafor, for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0052] In yet other embodiments, the 15-PGDH inhibitors of the present disclosure can be administered in combination with G-CSF to increase the number of hematopoietic stem cells in the blood or bone marrow.

[0053] In embodiments, administration of a 15-PGDH inhibitor of the present disclosure can be combined with hematopoietic cytokines for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

[0054] In embodiments, a 15-PGDH inhibitor of the present disclosure can be administered to a subject and / or a subject's tissue to increase stem cells in the tissue. For example, a 15-PGDH inhibitor can be administered to a subject's bone marrow to increase stem cells in the subject.

[0055] In embodiments, the 15-PGDH inhibitors of the present disclosure can 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 therapies or growth factors.

[0056] In still other embodiments, the 15-PGDH inhibitors of the present disclosure increase neutrophil counts after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood; increase neutrophil counts in neutropenic subjects after administration of chemotherapy or radiation therapy; 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 following a viral infection; increase neutrophil counts in neutropenic subjects. , increasing platelet counts after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or umbilical cord blood; increasing platelet counts in subjects with thrombocytopenia after administration of chemotherapy or radiation therapy; increasing platelet counts in subjects with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia or thrombocytopenia following viral infection; increasing platelet counts in subjects with thrombocytopenia after administration of chemotherapy or radiation therapy using bone marrow, hematopoietic stem cells or umbilical cord blood; Increasing red blood cell counts, hematocrit values, or hemoglobin levels after hematopoietic cell transplantation using cord blood; increasing red blood cell counts, hematocrit values, or hemoglobin levels in anemic subjects after chemotherapy or radiation therapy; increasing red blood cell counts, hematocrit values, or hemoglobin levels in subjects with aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other bone marrow disorders, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, anemia after viral infection, or anemia of unknown cause and / or to increase bone marrow stem cells in subjects with aplastic anemia, to increase red blood cell count or hematocrit or hemoglobin levels in anemic subjects, to increase bone marrow stem cells after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells or umbilical cord blood, to increase bone marrow stem cells in a subject after administration of chemotherapy or radiation therapy, and / or to increase bone marrow stem cells in subjects with aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced cytopenias, immune cytopenias, cytopenias following viral infections or cytopenias.

[0057] In embodiments, a 15-PGDH inhibitor of the present disclosure can be administered to a subject to increase responsiveness to cytokines in the presence of cytopenia, where the cytopenia includes any of neutropenia, thrombocytopenia, lymphopenia, and anemia; and the cytokines having increased responsiveness potentiated 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.

[0058] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to a subject to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and / or promote healing of bone-to-bone implants, bone-to-prosthetic implants, dental implants, and bone grafts.

[0059] In embodiments, a 15-PGDH inhibitor of the present disclosure can be administered to a subject or the intestinal tract of a subject to increase stem cell or cell proliferation in the intestinal tract and / or confer resistance to the toxic or lethal effects of exposure to radiation or the toxic, lethal or mucositis effects resulting from chemotherapy treatment.

[0060] In embodiments, a 15-PGDH inhibitor of the present disclosure may be administered to a subject or to the intestinal tract of a subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

[0061] In embodiments, 15-PGDH inhibitors of the present disclosure can be administered to a subject to increase liver regeneration and / or promote recovery from or tolerance to liver toxins, including acetaminophen and related compounds, following liver surgery, living donor liver donation, liver transplantation, or liver injury due to toxins.

[0062] In yet other embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to a subject to treat erectile dysfunction.

[0063] In yet other embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to inhibit at least one of the growth, proliferation, or metastasis of a 15-PGDH-expressing cancer.

[0064] Yet another embodiment described herein relates to a method 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 administered with a 15-PGDH inhibitor described herein and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

[0065] In embodiments, the subject has received human hematopoietic stem cells and / or preparations and / or therapeutic compositions thereof.

[0066] In 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, amegakaryocytic / congenital thrombocytopenia, severe combined myeloma, leukemia ... If you have: immunodeficiency syndrome (SCID), Wiskott-Aldrich syndrome, major beta-thalassemia, sickle cell disease, Hurler syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, primary myelofibrosis, familial hemophagocytic lymphohistiocytosis, solid tumor, chronic granulomatous disease, mucopolysaccharidosis or Diamond-Blackfan anemia.

[0067] Another embodiment relates to a method of treating a subject having at least one condition 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 administered with a 15-PGDH inhibitor as described herein and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor as described herein.

[0068] In embodiments, ischemia is defined as 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, decreased cerebral blood flow, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic encephalopathy, or the like. 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 (types I and II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic peripheral telangiectasia, ischemic vascular disease, hyperoxia Wound, 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 trunk lesion, 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 The condition may be associated with at least one of neurological disease, 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, renal vascular disease, vascular inflammatory conditions, von Hippel-Lindau syndrome, and tissue or organ wounds.

[0069] 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 embodiments, the 15-PGDH inhibitors described herein can be administered to a subject in need thereof to reduce fibrotic symptoms such as collagen deposition, inflammatory cytokine expression, and inflammatory cell infiltration, and to treat and / or prevent various fibrotic diseases, disorders, and conditions characterized, in whole or in part, by excessive production of fibrous material, e.g., excessive production 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.

[0070] Fibrotic diseases, disorders, and conditions characterized in whole or in part by the excessive production of fibrous material include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, systemic 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 nephropathy), and pulmonary fibrosis (e.g., glomerulosclerosis, pulmonary fibrosis, idiopathic nephropathy). These include: pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrosing 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, fibrosis syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrous tissue, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis (bone marrow fibrosis), drug-induced ergot, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, leprosy, collagenous colitis, acute fibrosis, and organ-specific fibrosis.

[0071] In embodiments, a method for treating or preventing a fibrotic disease, disorder, or condition comprises administering a therapeutically effective amount of a 15-PGDH inhibitor of the present disclosure to a subject in need thereof.

[0072] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used to treat or prevent pulmonary fibrosis. Treatable 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 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.

[0073] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used to treat or prevent renal fibrosis, which can result from dialysis after renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease or end-stage renal failure, or a combination thereof.

[0074] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used to treat or prevent liver fibrosis, which can result from chronic liver disease, viral cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions, exposure to toxins, or a combination thereof.

[0075] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used to treat or prevent cardiac fibrosis, for example, cardiac fibrosis and endomyocardial fibrosis.

[0076] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used to treat or prevent systemic sclerosis.

[0077] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

[0078] In embodiments, the 15-PGDH inhibitors of the present disclosure may be used to reduce or prevent scar formation in a subject.

[0079] In embodiments, the 15-PGDH inhibitors of the present disclosure may be used to reduce or prevent skin or scleroderma scarring.

[0080] In various embodiments, the 15-PGDH inhibitors of the present disclosure can 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.

[0081] In embodiments, the 15-PGDH inhibitors disclosed herein can be used in methods for reducing or alleviating collagen secretion or collagen deposition in a subject's tissue or organ, such as the lung, liver, intestine, colon, skin, or heart. The methods can include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject can have or be at risk for excessive collagen secretion or collagen deposition in a tissue or organ, such as the kidney, lung, liver, intestine, colon, skin, or heart. Typically, excessive collagen secretion or collagen deposition in an organ results from injury or damage. Such injury or damage can be organ-specific. The 15-PGDH inhibitor can be administered for a sufficient period of time to completely or partially reduce or alleviate collagen deposition levels in the tissue or organ. A sufficient period of time can 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, it can be advantageous to administer the 15-PGDH inhibitor lifelong.

[0082] Other embodiments described herein relate to the use of a 15-PGDH inhibitor of the present disclosure in combination with a corticosteroid or a TNF inhibitor to treat inflammation, reduce aberrant immune system activity, and / or promote wound healing in a subject in need thereof. It has been found that corticosteroids administered to a subject can induce 15-PGDH expression in the subject's tissues. It has been found that administering a 15-PGDH inhibitor in combination with a corticosteroid enhances the anti-inflammatory and / or immunosuppressive effects of the corticosteroid while attenuating corticosteroid-induced side effects and / or cytotoxic effects. Administration of a 15-PGDH inhibitor in combination with a corticosteroid can increase the therapeutic efficacy of inflammation, disorders, immune disorders, and / or wounds; in some instances, a lower dose of the corticosteroid can be administered to achieve similar efficacy, and in other instances, a higher dose can be administered to attenuate and / or prolong the duration of the attenuation and / or reduction of side effects or cytotoxic effects.

[0083] In embodiments, the inflammatory and / or immune-mediated diseases or disorders treated with the combination of a 15-PGDH inhibitor and a corticosteroid or a TNF inhibitor of the present disclosure may include intestinal, gastrointestinal, or intestinal disorders. As described below, it has been found that inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered to a subject in need thereof, alone or in combination with a corticosteroid and a tumor necrosis factor (TNF)-alpha antagonist, to treat intestinal, gastrointestinal, or intestinal disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0084] In embodiments, the 15-PGDH inhibitors of the present disclosure can be used as glucocorticoid sensitizers to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticoid resistance, or refractoriness or intolerance to corticosteroids. For example, the 15-PGDH inhibitors can be administered to a subject in combination with a corticosteroid to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticoid resistance, or refractoriness or intolerance to corticosteroids.

[0085] The 15-PGDH inhibitors of the present disclosure can also be administered to a subject in combination with a corticosteroid or a TNF inhibitor to promote wound healing, tissue repair and / or tissue regeneration, and / or tissue graft survival or regeneration.

[0086] In embodiments, the 15-PGDH inhibitors of the present disclosure can be administered to a subject in an amount effective to increase prostaglandin levels in the subject and attenuate corticosteroid-induced side effects and / or cytotoxic effects. DETAILED DESCRIPTION OF THE INVENTION

[0087] definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to facilitate description of the presently disclosed subject matter.

[0088] As used herein, the verb "comprise" and its conjugations as used in the specification and claims are used in an open-ended sense, meaning that the items that follow the word are included, but not to the exclusion of items not specifically mentioned. The present invention may suitably "comprise," "consist of," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0089] It is further noted that the claims may be drafted to exclude any optional element, and thus, this statement is intended to serve as a predicate for using exclusive terminology such as "solely," "only," or a "negative" limitation in connection with the recitation of claim elements.

[0090] The term "pharmaceutically acceptable" means suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and effective for its intended use within the scope of sound medical judgment.

[0091] The term "pharmaceutically acceptable salts" includes those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Additionally, one of ordinary skill in the art will recognize that acid addition salts can be prepared by reacting a compound with the appropriate inorganic or organic acid by any of a number of known methods. The term "pharmaceutically acceptable salt" also includes salts obtained by reacting an active compound that functions as an acid with an inorganic or organic base to form a salt, such as salts of ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, etc. Non-limiting examples of inorganic or metal salts include lithium salts, sodium salts, calcium salts, potassium salts, magnesium salts, etc.

[0092] Additionally, salts of the compounds described herein can exist in hydrated or unhydrated (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.

[0093] 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, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as HO, and such a combination can form one or more hydrates.

[0094] The compounds and salts described herein may exist in several tautomeric forms, such as enol-imine and keto-enamine forms, geometric isomers, and mixtures thereof. Tautomers exist as a mixture of a set of tautomers in solution. In solid form, one tautomer usually predominates. Even if one tautomer is described, this application includes all tautomers of the compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form 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, the tautomers reach chemical equilibrium. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0095] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, which involves the simultaneous transfer of an electron and a hydrogen atom.

[0096] Tautomerization can be catalyzed by: Bases: 1. Deprotonation; 2. Formation of a delocalized anion (e.g., enolate); 3. Protonation at a different position on the anion; Acids: 1. Protonation; 2. Formation of a delocalized cation; 3. Deprotonation at a different position adjacent to the cation.

[0097] The following terms, as used herein, have the following meanings unless otherwise indicated: "Amino" refers to the -NH2 radical. "Cyano" refers to the -CN radical. "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo radical. "Hydroxy" or "hydroxyl" refers to the --OH radical. "Imino" refers to the =NH substituent. "Nitro" refers to the -NO2 radical. "Oxo" refers to the =O substituent. "Thioxo" refers to the =S substituent.

[0098] "Alkyl" or "alkyl group" refers to a fully saturated, straight- or branched-chain hydrocarbon radical having from 1 to 12 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 12 is included. Alkyl containing up to 12 carbon atoms is C1-C 12 Alkyl, alkyl containing up to 10 carbon atoms is C1-C 10 An alkyl having up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl having up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties listed above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes C1-C5 alkyl and all of the moieties described above for C1-C6, but also includes C7, C8, C9 and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Including alkyl. C1~C 12Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, alkyl groups can be optionally substituted.

[0099] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched chain divalent hydrocarbon radical having 1 to 12 carbon atoms. 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0100] "Alkenyl" or "alkenyl group" refers to a straight- or branched-chain hydrocarbon radical having from 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyl, and alkenyl groups containing up to 10 carbon atoms are C2-C 10 An alkenyl group containing up to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl group containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties listed above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Alkynyl is also included. Similarly, C2-C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12 Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, and 3-nonenyl. , 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted.

[0101] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. 12Non-limiting examples of alkenyls include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0102] "Alkynyl" or "alkynyl group" refers to a straight- or branched-chain hydrocarbon radical having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynyl, and alkynyl groups containing up to 10 carbon atoms are C2-C 10 Alkynyl is an alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl group containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkyl includes all of the moieties listed above for C2-C5 alkyl, but also includes C6 alkyl. C2-C 10 Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Alkynyl is also included. Similarly, C2-C 12 Alkynyl includes all of the above moieties, but C 11 and C 12 Alkynyl is included. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted.

[0103] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon radical having 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. 12 Non-limiting examples of alkynylene include ethynylene, propargylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0104] "Alkoxy" means a group of the formula -OR a refers to the radical of R a is an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0105] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a Each R refers to a radical. a is independently an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0106] "Alkylcarbonyl" is -C(=O)R a R refers to the part a is an alkyl, alkenyl, or alkynyl radical as defined above. A non-limiting example of an alkylcarbonyl is a methylcarbonyl ("acetal") moiety. An alkylcarbonyl group is defined as "C w ~C z acyl, where w and z are R as defined above. a It represents the range of carbon numbers in the molecule. For example, "C1~C 10"Acyl" refers to an alkylcarbonyl group as defined above, a is C1~C as defined above 10 Alkyl, C2-C 10 Alkenyl or C2-C 10 Unless stated otherwise specifically in the specification, an alkylcarbonyl group may be optionally substituted.

[0107] "Aryl" refers to a hydrocarbon ring system radical containing a hydrogen atom, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this invention, an aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, the term "aryl" is meant to include aryl radicals that are optionally substituted.

[0108] An "aralkyl" or "arylalkyl" is an alkyl group of the formula -R b -R c refers to the radical of R b is an alkylene group as defined above, and R c is one or more aryl radicals as defined above. Aralkyl radicals include, but are not limited to, benzyl, diphenylmethyl, and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0109] "Aralkenyl" or "arylalkenyl" refers to a group of the formula -R b -R c refers to the radical of R bis an alkenylene group as defined above, and R c is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group may be optionally substituted.

[0110] "Aralkynyl" or "arylalkynyl" refers to an aralkynyl group of the formula -R b -R c refers to the radical of R b is an alkynylene group as defined above, and R c is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group may be optionally substituted.

[0111] "Carbocyclyl," "carbocyclic," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl and cycloalkyl. Cycloalkenyl and cycloalkynyl are as defined herein. Unless otherwise specifically stated herein, a carbocyclyl group can be optionally substituted.

[0112] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, which may include fused, bridged, or spiral ring systems, and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, cycloalkyl groups can be optionally substituted.

[0113] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, and having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, which may include fused, bridged, or spiral ring systems, and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specifically stated in the specification, cycloalkenyl groups can be optionally substituted.

[0114] "Cycloalkynyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, which may include fused, bridged, or spiral ring systems, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specifically stated in the specification, cycloalkynyl groups can be optionally substituted.

[0115] "Cycloalkylalkyl" refers to a group of the formula -R b -R d refers to the radical of R b is an alkylene, alkenylene, or alkynylene group as defined above, and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl radical, as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

[0116] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0117] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted with one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0118] "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted with one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[0119] "Heterocyclyl," "heterocyclyl ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical, which consists of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl or heterocyclyl ring includes heteroaryl, as defined below. Unless otherwise specifically stated herein, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused, bridged, or spiral ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, aziridinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyridin-one, and the like. The point of attachment of a heterocyclyl, heterocyclyl ring, or heterocycle to the rest of the molecule by a single bond is through a ring atom, which may be carbon or nitrogen. Unless stated otherwise specifically in the specification, heterocyclyl groups may be optionally substituted.

[0120] "Heterocyclylalkyl" refers to a group of the formula -R b -R e refers to the radical of R b is an alkylene group as defined above, and R eis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

[0121] "Heterocyclylalkenyl" refers to a group of the formula -R b -R e refers to the radical of R b is an alkenylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group may be optionally substituted.

[0122] "Heterocyclylalkynyl" refers to a group of the formula -R b -R e refers to the radical of R b is an alkynylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group may be optionally substituted.

[0123] "N-heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless otherwise specifically stated in the specification, an N-heterocyclyl group can be optionally substituted.

[0124] "Heteroaryl" refers to a 5- to 20-membered ring system radical having 1 to 13 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members. For purposes of this invention, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, in which at least one ring containing a heteroatom ring member is aromatic. The nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoi Examples include, but are not limited to, indolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

[0125] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless otherwise specifically stated in the specification, an N-heteroaryl group can be optionally substituted.

[0126] "Heteroarylalkyl" refers to a group of the formula -R b -R f refers to the radical of R b is an alkylene chain as defined above, and R f is a heteroaryl radical, as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

[0127] "Heteroarylalkenyl" refers to a group of the formula -R b -R f refers to the radical of R b is an alkenylene chain as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyl group may be optionally substituted.

[0128] "Heteroarylalkynyl" refers to a group of the formula -R b -R f refers to the radical of R b is an alkynylene chain as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group may be optionally substituted.

[0129] A "thioalkyl" is a group of the formula -SR a refers to the radical of R ais an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

[0130] As used herein, the term "substituted" means that at least one hydrogen atom has been replaced with a non-hydrogen atom, for example, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as a hydroxyl group, an alkoxy group, and an ester group; a sulfur atom in groups such as a thiol group, a thioalkyl group, a sulfone group, a sulfonyl group, and a sulfoxide group; a nitrogen atom in groups such as an amine, an amide, an alkylamine, a dialkylamine, an arylamine, an alkylarylamine, a diarylamine, an N-oxide, an imide, and an enamine; a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, and a triarylsilyl group; "Substituted" refers to any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.) replaced by a bond to a silicon atom in the group; and to other heteroatoms in various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom (e.g., oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). For example, "substituted" refers to any of the above groups in which one or more hydrogen atoms have been replaced by a bond to a heteroatom (e.g., oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR gC(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g and -SO2NR g R h "Substituted" refers to any of the above groups in which one or more hydrogen atoms have been replaced by -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above description, R g and R hare the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms have been replaced with a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the above substituents can also be optionally substituted with one or more of the above substituents.

[0131] As used herein, the symbols [ka] (Hereinafter, this may be referred to as "bonding at the bonding point") means a point of attachment between two chemical entities, one of which is shown as being attached to the bond at the point of attachment and the other of which is not shown as being attached to the bond at the point of attachment. For example, [ka] indicates that chemical "A" is attached to another chemical via a bond at the point of attachment. Additionally, specific points of attachment to chemicals not shown can be identified by inference. For example, the compound [ka] (Wherein X is [ka] is) is assumed that the bond at this point of attachment is the bond shown where X is attached to the phenyl ring ortho to the fluorine.

[0132] The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, including, but not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0133] The term "treating" is art-recognized and includes arresting, e.g., preventing the progression of, and alleviating, e.g., palliating, the disease, disorder, or condition in a subject. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if it does not affect the underlying pathophysiology.

[0134] The term "preventing" is art-recognized and includes stopping a disease, disorder, and / or condition from occurring in a subject who may be susceptible to, but has not yet been diagnosed with, such a disease, disorder, and / or condition. Preventing a disease-associated condition includes stopping the condition from occurring after the disease has been diagnosed, but before the condition is diagnosed.

[0135] A "patient," "subject," or "host" to be treated by the present methods can mean 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, adult subjects and newborn subjects, as well as fetuses, whether male or female, are intended to be encompassed. In one aspect, the subject is an animal. A patient refers to a subject suffering from a disease or disorder.

[0136] The terms "prophylactic" or "therapeutic" treatment are art-recognized and include administration of one or more of the present compositions to a host. If it is administered prior to clinical symptoms of an undesired condition (e.g., a disease or other undesired condition in a host animal), the treatment is prophylactic, i.e., it protects the host from developing the undesired condition, while if it is administered after the undesired condition, the treatment is therapeutic (i.e., intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects).

[0137] The terms "therapeutic agent," "drug," "medication," and "bioactive substance" are art-recognized and include molecules and other pharmaceutical 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 acids, bases, or salts; may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; or may be prodrugs in the form of ethers, esters, amides, etc., that become biologically activated upon administration to a patient or subject.

[0138] 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 targeted 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 is likely to depend on many factors, including: the rate of release of the agent from the polymer matrix, which depends in part on the chemical and physical properties of the polymer; the properties of the agent; the mode and method of administration; and any other materials incorporated into the polymer matrix in addition to the agent.

[0139] The term "ED50" is art-recognized. In certain embodiments, ED50 refers to the dose of a drug which produces 50% of the drug's 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 refers to the dose of a drug which 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.

[0140] 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 process component (including a protein, subunit, organelle, ribonucleoprotein, etc.).

[0141] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and the description thereby includes cases where the circumstance occurs and cases where it does not occur. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and thus the description includes structures where the non-hydrogen substituent is present and structures where the non-hydrogen substituent is not present.

[0142] Throughout this specification, when a composition is described as having, including, or comprising certain components, it is also intended that the composition 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 consists essentially of or also consists of the recited process steps. Furthermore, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Furthermore, two or more steps or actions can be performed simultaneously.

[0143] All percentages and ratios used herein are by weight unless otherwise specified.

[0144] The term "neoplasm" refers to any abnormal mass of cells or tissue that results from neoplastic formation. Neoplasms can be benign, potentially malignant (precancerous), or malignant (cancerous). An adenoma is an example of a neoplasm.

[0145] The terms "adenoma," "colon adenoma," and "polyp" are used herein to describe any precancerous neoplasia of the colon.

[0146] As used herein, the term "colon" is intended to encompass the right colon (including the cecum), transverse colon, left colon, and rectum.

[0147] The terms "colorectal cancer" and "colon cancer" are used interchangeably herein to refer to a cancerous neoplasia of the colon (including the rectum as defined above).

[0148] The terms "gene expression" or "protein expression" include information about the amount of gene transcript or protein present in a sample, as well as any information about the rate of gene or protein production, accumulation, or degradation (e.g., reporter gene data, data from nuclear flux experiments, pulse-chase data, etc.). Certain types of data may be examined as relating to both gene expression and protein expression. For example, intracellular protein levels reflect levels of transcription as well as levels of protein, and such data are intended to be included in the phrase "gene expression or protein expression information." Such information may be given in the form of amounts per cell, amounts relative to a control gene or protein, unitless measurements, etc., and the term "information" should not be limited to any particular means of expression but is intended to refer to any representation that provides the relevant information. The term "expression level" refers to the amount reflected in or derived from gene or protein expression data, regardless of whether the data concern gene transcript accumulation, protein accumulation, or protein synthesis rate.

[0149] The terms "healthy" and "normal" are used interchangeably herein and refer to a subject or particular cell or tissue that is free from a disease state (at least to the limits of detection).

[0150] The term "nucleic acid" refers to polynucleotides such as deoxyribonucleic acid (DNA) and, where appropriate, ribonucleic acid (RNA). This term should be understood to include analogs of RNA or DNA made from nucleotide analogs, as well as single-stranded (such as sense or antisense) and double-stranded polynucleotides, where applicable to the described embodiments. In some embodiments, "nucleic acid" refers to inhibitory nucleic acids. Some categories of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such categories of nucleic acids are well known in the art.

[0151] 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 it is desirable to modulate 15-PGDH activity and / or prostaglandin levels.

[0152] The terms "inhibitor," "activator," and "modulator" of 15-PGDH expression or activity are used to refer to molecules, such as ligands, agonists, antagonists, and their homologs and mimetics, that inhibit, activate, or modulate 15-PGDH expression or 15-PGDH activity, respectively, identified using in vitro and in vivo assays for 15-PGDH expression or 15-PGDH activity. The term "modulator" includes inhibitors and activators. Inhibitors are, for example, agents that inhibit or bind to 15-PGDH expression, partially or fully block stimulation by 15-PGDH activity, reduce, suppress, delay activation, inactivate, desensitize, or downregulate 15-PGDH activity, e.g., antagonists. Activators are, for example, agents that induce or activate the expression of 15-PGDH, or bind to it to stimulate, stabilize, increase, release, activate, promote, enhance, sensitize, or upregulate the activity of 15-PGDH, such as agonists. Modulators include natural or synthetic ligands and small chemical molecules.

[0153] Compounds of the Disclosure The 15-PGDH inhibitors described herein can provide a pharmacological method for increasing prostaglandin levels in tissues. Known activities of prostaglandins include promoting hair growth, promoting skin pigmentation, and promoting the appearance of skin darkening or tanning. Also known activities of prostaglandins include ameliorating pulmonary arterial hypertension. The 15-PGDH inhibitors described herein can be used to increase tissue stem cell numbers (by exposing transplant tissue in vivo to a 15-PGDH inhibitor described herein to increase stem cell numbers before harvesting, exposing harvested tissue ex vivo before transplantation into a recipient host, or treating transplant recipients) for purposes including increasing resistance to radiation-induced tissue damage, increasing resistance to environmental radiation exposure, and increasing stem cell numbers to improve compatibility for bone marrow or other types of transplants. The 15-PGDH inhibitors described herein can also be used for purposes including promoting liver regeneration, including liver regeneration after liver resection and liver regeneration after toxic injury, which may be, for example, 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 can promote the activity of human keratinocytes in the "healing" of scratched keratinocyte cell cultures. Therefore, the 15-PGDH inhibitors described herein can also be used to heal ulcers in other tissues, including, but not limited to, skin and diabetic ulcers. Furthermore, the 15-PGDH inhibitors described herein can be used to treat erectile dysfunction.

[0154] 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 measured. To determine the extent of the effect, a sample or assay containing 15-PGDH treated with a potential activator, inhibitor, or modulator is compared to a control sample that does not contain the inhibitor, activator, or modulator. 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 is about 80%, optionally 50%, 25%, 10%, 5%, or 1% compared to the control.

[0155] Agents tested as modulators of SCD (e.g., 15-PGDH) can be any small chemical molecule or compound. Typically, test compounds are small chemical molecules, natural products, or peptides. Assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to the assay, and are generally 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.

[0156] In embodiments, the SCD modulator can be an SCD inhibitor that can be administered to a subject's tissue or blood in an amount effective to inhibit the activity of short-chain dehydrogenase enzymes. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to a subject's tissue or blood in an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor can include a compound having the structure of Formula (I).

[0157] The 15-PGDH inhibitor is represented by the formula (I): [ka] (In the formula, R 1is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and each of these is one or more R 3 optionally substituted with; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 3 is -OH, -O-alkylene-OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), -N(R 5 )(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 )2, -C(O)N(R 5 )(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl or -S(O) m -alkyl, and cycloalkyl and heterocyclyl are each R 10 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8-alkylene-aryl optionally substituted with Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 10 is —OH, halogen, C1-C6 alkyl or C1-C6 alkoxy; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0158] In an embodiment, the compound of formula (I) is [ka] isn't it.

[0159] In an embodiment of the compound of formula (I), R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy). 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p-cyclohexyl or -(CH2) p -OCH3; and p is 1, 2, or 3.

[0160] In an embodiment of the compound of formula (I), R 2 is NH2.

[0161] In an embodiment of the compound of formula (I), R 3 is halogen, —OH, —NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy.

[0162] In an embodiment of the compound of formula (I), R 4 is oxo, and R 7 When R is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl. 7 When R is aryl or heteroaryl, 4 is not oxo. In embodiments, R 4 is halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with

[0163] In an embodiment of the compound of formula (I), R 6 teeth, [ka] is.

[0164] In an embodiment of the compound of formula (I), R 11 is H or methyl.

[0165] In an embodiment of the compound of formula (I), R 7is phenyl, alkyl, or cycloalkyl, each of which may be one or more R 4 is optionally substituted with

[0166] In an embodiment of the compound of formula (I), R 7 is a straight or branched chain acyclic C1-C6 alkyl. 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or t-butyl. 7 is i-propyl.

[0167] In an embodiment of the compound of Formula (I), X is CH.

[0168] In an embodiment of the compounds of Formula (I), n is 1.

[0169] The present disclosure provides a compound of formula (II) [ka] (In the formula, R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy); R 6 teeth, [ka] and; R 7 is a straight or branched chain acyclic C1-C6 alkyl (e.g., i-propyl); R 11 is H or C1-C6 alkyl; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0170] In an embodiment of the compound of formula (I) or (II), the compound is [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0171] In embodiments, without being limited by theory, Applicants have unexpectedly and surprisingly found that R 7 It has been discovered that a straight or branched chain acyclic alkyl group at position 1 improves the solubility and metabolic stability of the compound.

[0172] In embodiments, R 7 is isopropyl.

[0173] The present disclosure provides a compound of formula (III) [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m-alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0174] In an embodiment of the compound of formula (III), the compound is [ka] [ka] [ka] [ka] [ka] [ka] isn't it.

[0175] In an embodiment of the compound of formula (III), R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy). 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p -cyclohexyl or -(CH2) p -OCH3; and p is 1, 2, or 3.

[0176] In an embodiment of the compound of formula (III), R 2 is NH2 or -CN.

[0177] In an embodiment of the compound of formula (III), R 4 is oxo, and R 7 When R is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl. 7 When R is aryl or heteroaryl, 4 is not oxo. In embodiments, R 4 is halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with

[0178] In an embodiment of the compound of formula (III), R 6 teeth, [ka] is.

[0179] In an embodiment of the compound of formula (III), R 6 teeth, [ka] is.

[0180] In an embodiment of the compound of formula (III), R 7 is alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which may be one or more R 4 is optionally substituted with

[0181] In an embodiment of the compound of Formula (III), n is 1.

[0182] In an embodiment of the compound of formula (III), the compound is [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0183] The present disclosure provides a compound of formula (IV) [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6teeth, [ka] and; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 A compound of the formula [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0184] The present disclosure provides: [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0185] In an embodiment of the compound of formula (IV), R 4 is oxo, and R 7 When R is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl. 7 When R is aryl or heteroaryl, 4 is not oxo. In embodiments, R 4 is halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with

[0186] In embodiments of formulas (I)-(IV), R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy). 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p -cyclohexyl or -(CH2) p -OCH3; and p is 1, 2, or 3. In embodiments, R 1is a 3- to 5-membered cycloalkyl or -(C1-C6 alkylene)-(3- to 5-membered cycloalkyl). In an embodiment, R 1 is cyclobutyl. In embodiments, R 1 is —(CH2)2OMe or —(CH2)3OMe.

[0187] In embodiments of formulas (I)-(IV), R 2 is —NH or CN. In embodiments, R 2 is -NH2.

[0188] In embodiments of formulas (I)-(IV), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(O)(C1-C6 alkyl), —C(O)O(C1-C6 alkyl), or —C(O)NR 5 (C1-C6 alkyl), each of which is one or more R 4 In embodiments, R 7 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which may be selected from the group consisting of one or more R 4 In embodiments, R 7 is C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl, each of which may be one or more R 4 In embodiments, R 7 is a straight or branched chain acyclic C1-C6 alkyl. 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or t-butyl. 7 is i-propyl, n-butyl, s-butyl, t-butyl, cyclobutyl, phenyl, pyrazolyl, or 2-oxaspiro[3.3]heptane. 7is i-propyl, n-butyl, s-butyl, t-butyl, cyclobutyl, phenyl, [ka] is.

[0189] In embodiments of formulas (I)-(IV), R 4 is halogen, alkyl, -CN, -N(R 5 )2, -OH, -O-(C1-C6 alkylene)-OH, -S(O) m (C1-C6 alkyl), —C(O)(C1-C6 alkyl), —C(O)-(3- to 6-membered cycloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl. 4 is independently selected from methyl or ethyl. In embodiments, R 4 is methyl.

[0190] In embodiments of Formulas (I)-(IV), X is CH.

[0191] In embodiments of Formulas (I)-(IV), n is 1.

[0192] In embodiments, the 15-PGDH inhibitors of the present disclosure relate to compounds in Table 1 or pharmaceutically acceptable salts, tautomers, or solvates thereof.

[0193] Colonic 15-PGDH inhibition can be measured using an appropriate dose of a compound of the present disclosure at 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 15 hours, 20 hours, 24 hours, 48 ​​hours, 72 hours, or more after administration. In embodiments, colonic 15-PGDH inhibition is measured 30 minutes after administration. In embodiments, colonic 15-PGDH inhibition is measured at 4 hours. In embodiments, suitable doses are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 mg / kg or more (including all values ​​and ranges therebetween). In embodiments, the 15-PGDH inhibitors of the present disclosure inhibit colonic 15-PGDH activity in the range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges thereof. See PCT U.S. Patent Application Publication No. 2019 / 062686.

[0194] In embodiments, 15-PGDH inhibition in the lungs, liver, intestine, skin, heart (or any other organ disclosed herein) can be measured at 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 15 hours, 20 hours, 24 hours, 48 ​​hours, 72 hours, or more (including all times and ranges therebetween) using an appropriate dose of a compound of the present disclosure. In embodiments, pulmonary 15-PGDH inhibition is measured at 30 minutes. In certain embodiments, pulmonary 15-PGDH inhibition is measured at 4 hours. In embodiments, suitable doses are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 mg / kg or more (including all values ​​and ranges therebetween). In embodiments, the 15-PGDH inhibitors of the present disclosure inhibit pulmonary 15-PGDH activity in the range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges thereof.

[0195] In embodiments, a 15-PGDH inhibitor of the present disclosure (e.g., having Formulas I-IV) inhibits colonic 15-PGDH activity by about 25% to 100% at 30 minutes when administered to a mammal at 10 mg / kg, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges thereof. In embodiments, a compound of the present disclosure inhibits colonic 15-PGDH activity by about 65% to 100% at 30 minutes when administered to a mammal at 10 mg / kg (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, can inhibit colonic 15-PGDH activity by about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 30 minutes. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, inhibit colonic 15-PGDH activity by about 80% to 100% and any subranges thereof at 30 minutes. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, inhibit colonic 15-PGDH activity by about 90% to 100% and any subranges thereof at 30 minutes.

[0196] In embodiments, a 15-PGDH inhibitor of the present disclosure (e.g., having Formulas I-IV) when administered at 10 mg / kg to a mammal inhibits colonic 15-PGDH activity by about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges thereof, at 4 hours. In embodiments, a compound of the present disclosure, when administered at 10 mg / kg to a mammal, inhibits colonic 15-PGDH activity by about 65% to 100% (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 4 hours. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, can inhibit colonic 15-PGDH activity by about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 4 hours. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, inhibit colonic 15-PGDH activity by about 80% to 100% and any subranges thereof at 4 hours. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, inhibit colonic 15-PGDH activity by about 80% to 98% and any subranges thereof at 4 hours.

[0197] In embodiments, a 15-PGDH inhibitor of the present disclosure (e.g., having Formulas I-IV) administered to a mammal at 10 mg / kg inhibits 15-PGDH activity in the lung, liver, intestinal tract, skin, or heart (or any other organ disclosed herein) in a range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges thereof, in 30 minutes. In embodiments, compounds of the present invention inhibit pulmonary 15-PGDH activity in the range of about 65% to 100% (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 30 minutes when administered to a mammal at 10 mg / kg. In embodiments, compounds of the present invention can inhibit pulmonary 15-PGDH activity in the range of about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 30 minutes when administered to a mammal at 10 mg / kg. In embodiments, compounds of the present invention inhibit pulmonary 15-PGDH activity in the range of about 80% to 100% (e.g., about 80%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 30 minutes when administered to a mammal at 10 mg / kg.

[0198] In embodiments, a 15-PGDH inhibitor of the present disclosure (e.g., having Formulas I-IV) administered to a mammal at 10 mg / kg inhibits 15-PGDH activity in the lung, liver, intestinal tract, skin, or heart (or any other organ disclosed herein) by about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges thereof, within 4 hours. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, inhibit pulmonary 15-PGDH activity by about 65% to 100% (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 4 hours. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, can inhibit pulmonary 15-PGDH activity by about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 4 hours. In embodiments, compounds of the present invention, when administered to a mammal at 10 mg / kg, inhibit pulmonary 15-PGDH activity by about 80% to 100% (e.g., about 80%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges thereof, at 4 hours.

[0199] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) have a human or mouse microsomal stability T of greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, or greater than 100 minutes (including all values ​​and ranges therebetween). 1 / 2 In embodiments, compounds of the invention have a human or mouse microsomal stability T of greater than 110 minutes, greater than 120 minutes, greater than 130 minutes, or greater than 145 minutes (including all values ​​and ranges therebetween). 1 / 2 In embodiments, the 15-PGDH inhibitors of the present invention have a human or mouse microsomal stability T in the range of 65 to at least 145 (e.g., 65, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more, including all values ​​and ranges therebetween). 1 / 2In embodiments, compounds of the invention have a human or mouse microsomal stability T 1 / 2 It has.

[0200] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) have better human or mouse microsomal stability than previously disclosed 15-PGDH inhibitors. See, e.g., WO 2013 / 158649, WO 2015 / 065716, WO 2016 / 144958, WO 2016 / 168472, WO 2018 / 017582, WO 2018 / 102552, WO 2018 / 145080, WO 2018 / 187810, WO 2018 / 218251, and / or PCT U.S. Patent Application Publication No. 2019 / 062686, the disclosures of each of which are incorporated herein by reference in their entirety for all purposes. In embodiments, the 15-PGDH inhibitors of the present invention have a human or mouse microsomal stability T that is at least 15 minutes longer, at least 25 minutes longer, at least 35 minutes longer, at least 45 minutes longer, at least 55 minutes longer, at least 65 minutes longer, at least 75 minutes longer, at least 85 minutes longer, at least 95 minutes longer, at least 100 minutes longer, at least 110 minutes longer, or at least 120 minutes longer (including all values ​​and ranges therebetween) than previously disclosed 15-PGDH inhibitors. 1 / 2 In embodiments, the 15-PGDH inhibitors of the present invention have the microsomal stability T of previously disclosed 15-PGDH inhibitors. 1 / 2 Human or mouse microsomal stability T ranges from 15 minutes to approximately 120 minutes longer than 1 / 2 It has.

[0201] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) have a kinetic aqueous solubility of greater than about 150 μM in citrate buffer solution at pH 7 or pH 4. In embodiments, the 15-PGDH inhibitors of the present invention have a kinetic aqueous solubility of greater than about 160 μM in citrate buffer solution at pH 7 or pH 4. In embodiments, the 15-PGDH inhibitors of the present invention have a kinetic aqueous solubility of greater than about 170 μM in citrate buffer solution at pH 7 or pH 4. In embodiments, the 15-PGDH inhibitors of the present invention have a kinetic aqueous solubility of greater than about 180 μM in citrate buffer solution at pH 7 or pH 4. In embodiments, the 15-PGDH inhibitors of the present invention have a kinetic aqueous solubility of greater than about 190 μM in citrate buffer solution at pH 7 or pH 4. In embodiments, the 15-PGDH inhibitors of the present invention have a kinetic aqueous solubility of greater than about 200 μM in citrate buffer solution at pH 7 or pH 4.

[0202] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) have a kinetic aqueous solubility that is greater than previously disclosed 15-PGDH inhibitors in citrate buffer solutions at pH 7 or pH 4. In embodiments, the kinetic aqueous solubility of the 15-PGDH inhibitors of the present invention in citrate buffer solutions at pH 7 or pH 4 is at least about 5% greater, about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, or about 95% greater (including all values ​​and ranges therebetween) than previously disclosed 15-PGDH inhibitors.

[0203] In embodiments, 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) have high permeability by Caco-2 permeability assay. In embodiments, 15-PGDH inhibitors of the present invention have an efflux ratio (ER) of less than about 15, less than about 14, less than about 13, less than about 12, less than about 11, less than about 10, less than about 9, less than about 8, less than about 7, or less than about 6 (including all values ​​and ranges therebetween). In embodiments, 15-PGDH inhibitors of the present invention have an efflux ratio (ER) of less than about 10. In embodiments, a 15-PGDH inhibitor of the present invention has an efflux ratio (ER) of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6.0. In embodiments, the 15-PGDH inhibitors of the present invention have an efflux ratio (ER) in the range of about 1 to 6, including all values ​​and ranges therebetween.

[0204] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) provide a Cmax in the range of about 7,000 ng / mL to about 16,000 ng / mL (including all values ​​and ranges therebetween) when a single dose of the 15-PGDH inhibitor is administered at 20 mg / kg. In embodiments, the 15-PGDH inhibitors of the present invention provide a Cmax in the range of about 7,000 ng / mL to about 16,000 ng / mL (including all values ​​and ranges therebetween). In embodiments, the 15-PGDH inhibitors of the present invention provide a Cmax in the range of about 8,000 ng / mL to about 15,000 ng / mL (including all values ​​and ranges therebetween). In embodiments, the 15-PGDH inhibitors of the present invention provide a Cmax in the range of about 9,000 ng / mL to about 14,000 ng / mL (including all values ​​and ranges therebetween). In embodiments, the 15-PGDH inhibitors of the present invention provide a Cmax in the range of about 9,500 ng / mL to about 13,500 ng / mL, including all values ​​and ranges therebetween. In embodiments, the Cmax as disclosed herein relates to a single oral dose of 20 mg / kg of the 15-PGDH inhibitor administered to mice.

[0205] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) provide an AUC in the range of about 10,000 ng*h / mL to about 60,000 ng*h / mL (including all values ​​and ranges therebetween) when a single dose of the 15-PGDH inhibitor is administered at 20 mg / kg. In embodiments, the 15-PGDH inhibitors of the present invention provide an AUC in the range of about 20,000 ng*h / mL to about 50,000 ng*h / mL (including all values ​​and ranges therebetween). In embodiments, the 15-PGDH inhibitors of the present invention provide an AUC in the range of about 22,000 ng*h / mL to about 45,000 ng*h / mL (including all values ​​and ranges therebetween). In embodiments, the AUC as disclosed herein relates to a single oral dose of 20 mg / kg of a 15-PGDH inhibitor administered to mice.

[0206] In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) provide a clearance (Cl) in the range of about 5 ml / min / kg to about 20 ml / min / kg, including all values ​​and ranges therebetween. In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) provide a clearance (Cl) in the range of about 5 ml / min / kg to about 20 ml / min / kg, including all values ​​and ranges therebetween, when a single dose of the 15-PGDH inhibitor is administered at 5 mg / kg. In embodiments, the 15-PGDH inhibitors of the present invention provide a clearance (Cl) in the range of about 6 ml / min / kg to about 19 ml / min / kg, including all values ​​and ranges therebetween. In embodiments, the 15-PGDH inhibitors of the present invention provide a clearance (Cl) in the range of about 6 ml / min / kg to about 18 ml / min / kg, including all values ​​and ranges therebetween. In embodiments, the 15-PGDH inhibitors of the present invention provide a clearance (Cl) of about 5 ml / min / kg, about 6 ml / min / kg, about 7 ml / min / kg, about 8 ml / min / kg, about 9 ml / min / kg, about 10 ml / min / kg, about 11 ml / min / kg, about 12 ml / min / kg, about 13 ml / min / kg, about 14 ml / min / kg, about 15 ml / min / kg, about 16 ml / min / kg, about 17 ml / min / kg, about 18 ml / min / kg, about 19 ml / min / kg, or about 20 ml / min / kg (including all values ​​and ranges therebetween). In embodiments, the Cl values ​​as disclosed herein relate to a single IV dose of 5 mg / kg of the 15-PGDH inhibitor administered to mice.

[0207] EC for PGE2 induction 50 is measured using A549 cells treated with IL1-β for 24 hours. In embodiments, the 15-PGDH inhibitors of the present invention (e.g., Formulas I-IV) inhibit PGE2-induced EC 50 In an embodiment, the EC 50 In embodiments, the EC 50 In embodiments, the EC 50 In embodiments, the EC 50 In embodiments, the EC 50In embodiments, the EC 50 is from 10 nM to about 0.01 nM, including all values ​​and subranges therebetween. 50 is at least four times lower than previously disclosed 15-PGDH inhibitors, such as those disclosed in the publications cited above. 50 is at least eight times lower than previously disclosed 15-PGDH inhibitors. 50 is at least 10-fold lower than previously disclosed 15-PGDH inhibitors. 50 is at least 15-fold lower than previously disclosed 15-PGDH inhibitors. 50 is at least 20-fold lower than previously disclosed 15-PGDH inhibitors. 50 is at least 30-fold lower than previously disclosed 15-PGDH inhibitors. 50 is at least 40-fold lower than previously disclosed 15-PGDH inhibitors. 50 is at least 50-fold lower than previously disclosed 15-PGDH inhibitors. 50 is at least 10 to 50 times lower than previously disclosed 15-PGDH inhibitors.

[0208] In certain embodiments, a 15-PGDH inhibitor having Formula (I)-(IV) is capable of ia) 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 a value of 100 indicates a fold increase in reporter output over baseline) at a concentration of 2.5 μM, and iia) stimulating a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70 (using a scale where a value of 100 indicates a fold increase in reporter output over baseline) at a concentration of 2.5 μM. iiia) at a concentration of 7.5 μM, it is capable of stimulating the LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70; iva) at a concentration of 7.5 μM, it does not activate the negative control V9m cell line expressing a TK-Renilla luciferase reporter to a level greater than 20; and va) it inhibits the enzymatic activity of the recombinant 15-PGDH protein with an IC of less than 1 μM. 50 You can select what to inhibit.

[0209] In embodiments, the 15-PGDH inhibitor is capable of ib) 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) 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) 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) at a concentration of 7.5 μM, does not activate a negative control V9m cell line expressing a TK-Renilla luciferase reporter to luciferase levels greater than 20% of background; and vb) inhibits the enzymatic activity of recombinant 15-PGDH protein with an IC of less than 1 μM. 50 and inhibits.

[0210] In embodiments, the compound or 15-PGDH inhibitor inhibits the enzymatic activity of recombinant 15-PGDH with an IC of less than 1 μM at a 15-PGDH concentration of about 5 nM to about 10 nM. 50 , IC<250nM 50 , IC<50nM 50 , IC<10 nM 50 , IC<5nM 50 , about 2.5 nM to about 10 nM or an IC of less than about 2.5 nM 50 can be inhibited by

[0211] In embodiments, 15-PGDH inhibitors are capable of increasing cellular levels of PGE-2 after stimulation of A459 cells with an appropriate agent, for example IL1β.

[0212] therapeutic use The 15-PGDH inhibitors described herein can be used for the prevention or treatment of diseases associated with decreased 15-PGDH and / or prostaglandin levels, and / or when it is desirable to increase prostaglandin levels in a subject. For example, as described above, prostaglandins are known to play an important role in hair growth. Specifically, various types of prostaglandins (A2, F) in the various compartments of the hair follicle or their adjacent skin environment are known to play important roles in hair growth. 2a It has been shown that the internal storage of prostaglandins (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 is involved in the breakdown of prostaglandins, especially PGF. 2a It has been reported that inactivation of 15-PGDH and PGE2 causes 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 can be used in pharmaceutical compositions for preventing alopecia and promoting hair growth.

[0213] In embodiments, the 15-PGDH inhibitors described herein can 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 whitening of hair.

[0214] In embodiments, a 15-PGDH inhibitor can be applied, e.g., topically, to the skin of a subject to promote and / or stimulate skin pigmentation and / or hair growth, inhibit hair loss, and / or treat skin damage or inflammation (e.g., skin damage caused by physical or chemical irritants and / or UV exposure).

[0215] In yet another embodiment, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of cardiovascular diseases and / or vascular insufficiency, 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 blood vessel walls, particularly by contributing to vasodilation for blood flow, preventing platelet aggregation, and regulating the proliferation of smooth muscle surrounding the blood vessel wall (Yan, Cheng et al., 2006, J. Clin., Invest). Furthermore, inhibition of prostaglandin production or loss of its activity can lead to degeneration of the endothelium of blood vessel walls, platelet aggregation, and dysfunction of smooth muscle cellular mechanisms. In particular, it has been shown that patients with hypertension, including pulmonary arterial hypertension, have reduced intravascular prostaglandin production.

[0216] In embodiments, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of oral cavity, intestinal, and / or gastrointestinal damage or disease, or inflammatory bowel diseases such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, and gastric ulcers. Gastritis and gastric ulcers, representative gastrointestinal diseases, are defined as pathological conditions in which the gastrointestinal mucosa is digested by gastric acid, resulting in the formation of ulcers. The gastric wall generally consists of the mucosa, submucosa, muscularis, and serosa. While gastric ulcers can even damage the submucosa and muscularis, gastritis only damages the mucosa. The prevalence of gastritis and gastric ulcers is relatively high, but their causes remain unclear. Previously, they have been known to result from an imbalance between aggressive and defensive factors, i.e., increased aggressive factors such as increased secretion of gastric acid or pepsin, or decreased defensive factors such as structural or morphological defects in the gastric mucosa, decreased secretion of mucus or bicarbonate ions, and decreased prostaglandin production.

[0217] Currently available therapeutic agents for gastritis and gastric ulcers include various drugs for enhancing defense factors, such as antacids that neutralize already produced gastric acid without affecting gastric acid secretion, gastric acid secretion inhibitors, prostaglandin secretagogues, and gastric wall coating agents. In particular, prostaglandins are known to be essential for maintaining 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, particularly gastritis and gastric ulcers.

[0218] Furthermore, 15-PGDH inhibitors are expected to protect against other forms of intestinal damage, such as radiation toxicity, chemotherapy toxicity, and chemotherapy-induced mucositis.

[0219] In the kidney, prostaglandins may play a role in regulating renal blood flow and urine production through both renal vascular and tubular actions. In clinical trials, PGE1 has been used to improve creatinine clearance in patients with chronic kidney disease, prevent graft rejection and cyclosporine toxicity in renal transplant patients, and 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 intravenously administering prostaglandins such as PGE1, PGE2, and PGI2. Furthermore, prostaglandins act as vasodilators in the kidney, and therefore, inhibiting prostaglandin production in the kidney has been reported to cause renal dysfunction (Hao, CM, 2008, Annu Rev Physiol, 70, 357.about.77).

[0220] Therefore, the 15-PGDH inhibitors described herein, which have suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins, may be effective in preventing or treating kidney diseases associated with renal dysfunction.

[0221] As used herein, the term "renal dysfunction" includes manifestations 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, alterations in the activity of renal enzymes such as gamma glutamyl synthetase, alanine phosphatidase, N-acetyl-β-D-glucosaminidase or β-w-microglobulin, and increased macroalbuminuria above normal levels.

[0222] In other embodiments, 15-PGDH inhibitors can be used to prevent, treat or reduce severe kidney damage, kidney disease and / or kidney injury. Examples of treatable kidney disorders, kidney diseases and / or kidney damage include acute kidney injury; hypotensive damage to the kidney; hypertensive kidney disease; diabetic kidney disease and diabetic nephropathy; vasculitic kidney disease and autoimmune diseases including, but not limited to, lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, ischemic kidney damage; acute renal failure; chronic renal failure; glomerulonephritis; nephrotic syndrome; acute tubular necrosis; nephrosclerosis; glomerulosclerosis; minimal change disease; idiopathic membranous nephropathy; membranoproliferative glomerulonephritis; Berger's disease; mesangial proliferative glomerulonephritis; chronic glomerulonephritis; focal glomerulosclerosis; renal effects of Sjogren's syndrome; renal effects of scleroderma; interstitial nephritis; and post-renal transplant kidney damage to kidney donors, transplant recipients and / or transplanted kidneys.

[0223] In certain embodiments, the subject has been identified as having acute kidney injury (AKI) based on the Acute Kidney Injury Network (AKIN) criteria or the Risk / Injury / Failure / Loss / ESRD (RIFLE) criteria.

[0224] In some embodiments, the renal impairment, renal disease, and / or renal damage is acute kidney injury. In other embodiments, the renal impairment, renal disease, and / or renal damage is ischemic acute kidney injury. In one embodiment, the subject is a human identified as having reduced effective arterial volume. In one embodiment, the subject is identified as having vascular volume deficiency (e.g., due to hemorrhage, gastrointestinal loss, renal loss, skin and mucous membrane loss, nephrotic syndrome, cirrhosis, or capillary leak). In one embodiment, the subject is identified as having reduced cardiac output (e.g., due to cardiogenic shock, pericardial disease, congestive heart failure, valvular heart disease, pulmonary disease, or sepsis). In one embodiment, the subject is identified as having systemic vasodilation (e.g., caused by cirrhosis, anaphylaxis, or sepsis). In one embodiment, the subject is identified as having renal vasoconstriction (e.g., caused by early sepsis, hepatorenal syndrome, acute hypercalcemia, drugs, or radiocontrast agents).

[0225] In some embodiments, the kidney disorder, kidney disease, and / or kidney damage is nephrotoxic kidney damage. In one embodiment, the human subject has been exposed to a nephrotoxin. For example, the nephrotoxin can be a nephrotoxic agent selected from the group consisting of an antibiotic (e.g., an aminoglycoside), a chemotherapeutic agent (e.g., cisplatin), a calcineurin inhibitor, amphotericin B, and an x-ray contrast agent. In another example, the nephrotoxin can be an illicit drug or a heavy metal.

[0226] In certain embodiments, the subject has experienced a traumatic injury or a crush injury.

[0227] In certain embodiments, the subject is about to undergo or has undergone organ transplant surgery (eg, kidney transplant surgery or heart transplant surgery).

[0228] In certain embodiments, the subject is undergoing or has undergone surgery complicated by reduced blood flow.

[0229] In certain embodiments, the subject is undergoing or has undergone cardiothoracic or vascular surgery.

[0230] In certain embodiments, the subject will be taking or is taking a medication that interferes with normal bladder emptiness (eg, an anticholinergic).

[0231] In certain embodiments, the subject has benign prostatic hyperplasia or cancer (eg, prostate cancer, ovarian cancer, or colorectal cancer).

[0232] In certain embodiments, the subject has a kidney stone.

[0233] In certain embodiments, the subject has an obstructive urinary catheter.

[0234] In certain embodiments, the subject is taking a drug that causes or leads to crystalluria, a drug that causes or leads to myoglobinuria, or a drug that causes or leads to cystitis.

[0235] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to protect the subject's kidney from damage. In some embodiments, the subject is a human subject who has been or will be subjected to ischemic or nephrotoxic injury. In some embodiments, the human subject is subjected to oxidative damage (e.g., by free radicals such as reactive oxygen or nitrogen species).

[0236] In some embodiments, a 15-PGDH inhibitor can be administered to a human subject to protect the human subject's kidney from kidney damage during organ transplantation, such as kidney transplantation. The 15-PGDH inhibitor can be administered to a kidney transplant donor, a kidney transplant recipient, and / or a transplanted kidney in an amount effective to protect the transplant donor, the transplant recipient, and / or the transplanted kidney from damage. In certain embodiments, the human subject can be administered one or more doses of a 15-PGDH inhibitor before and / or after kidney transplantation (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 48, 72, 96, 168 hours, or 1 week, 2 weeks, 3 weeks, or 1 month). It will be understood that administration of a 15-PGDH inhibitor can protect the human subject's kidney from kidney damage during transplantation of other organs other than the kidney.

[0237] 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 previously described, inhibition of 15-PGDH activity may lead to 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 can also be used to increase bone mineral density, treat osteoporosis, promote fracture healing, or promote healing after bone surgery or joint replacement, or promote the healing of bone-to-bone implants, bone-to-prosthetic implants, dental implants, and bone grafts.

[0238] In yet another embodiment, the 15-PGDH inhibitors described herein may be effective in treating 15-PGDH-expressing cancers. Inhibiting 15-PGDH can inhibit the growth, proliferation, and metastasis of 15-PGDH-expressing cancers.

[0239] In yet another embodiment, the 15-PGDH inhibitors described herein may be effective in wound healing. Among various prostaglandins, PGE2 is known to function as a mediator of wound healing. Therefore, when skin is damaged by a wound or burn, inhibiting 15-PGDH activity can produce the therapeutic effect of PGE2 on the wound or burn.

[0240] Furthermore, as described above, increased prostaglandin levels have been shown to stimulate signaling through the Wnt signaling pathway by increasing 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 for purposes including promoting tissue regeneration or repair in organs including 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.

[0241] Symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that result in 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, but are not limited to, 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, and the like. Autoimmune diseases, fractures, cerebral edema, decreased cerebral blood flow, 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, bruises, 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 intravascular coagulation Disseminated intravascular coagulation syndrome (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic peripheral 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, ischemic reperfusion injury, laceration, left main trunk lesion, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson disease These conditions include Son's disease, peripheral arterial disease (PAD), 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 transplants, 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 tissue or organ wounds.

[0242] Other examples of genetic disorders, symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that result in or are associated with tissue damage and the need for tissue repair, suitable for 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.

[0243] 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.

[0244] In embodiments, ischemia is defined as 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, decreased cerebral blood flow, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic encephalopathy, or the like. 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 (types I and II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic peripheral telangiectasia, ischemic vascular disease, hyperoxia Wound, 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 trunk lesion, 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 Associated with at least one of the following conditions: peripheral neuropathy, 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, renal vascular disease, vascular inflammatory conditions, von Hippel-Lindau syndrome, and tissue or organ wounds.

[0245] In embodiments, a 15-PGDH inhibitor can be administered to a preparation of hematopoietic stem cells, such as peripheral blood hematopoietic stem cells or umbilical cord stem cells, in a subject 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.

[0246] Hematopoietic stem cells are pluripotent stem cells that give rise to all blood cell types in an organism, including the myeloid (e.g., monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, dendritic cells) and lymphoid (e.g., T cells, B cells, NK cells) lineages, as well as others known in the art (see U.S. Pat. No. 5,635,387 to Fei, R. et al.; U.S. Pat. No. 5,460,964 to McGlave et al.; U.S. Pat. No. 5,677,136 to Simmons, P. et al.; U.S. Pat. No. 5,750,397 to Tsukamoto et al.; U.S. Pat. No. 5,759,793 to Schwartz et al.; U.S. Pat. No. 5,681,599 to DiGuisto et al.; U.S. Pat. No. 5,716,827 to Tsukamoto et al.). Hematopoietic stem cells (HSCs) give rise to unipotent hematopoietic progenitor cells (HPCs) that are capable of generating the entire repertoire of mature blood cells over the lifetime of an organism.

[0247] Hematopoietic stem cells and hematopoietic progenitor cells are generally referred to herein as hematopoietic stem cells, unless otherwise specified, and are characterized by the antigenic marker CD34 (CD34 + In embodiments, hematopoietic stem cells can be identified by the presence of the antigen marker CD34 and the absence of lineage (lin) markers, and thus can be referred to as CD34. + / lin - It can be characterized as a cell.

[0248] The hematopoietic stem cells used in the methods described herein can be obtained from any suitable source of hematopoietic stem and progenitor cells and can be provided as a highly purified population of hematopoietic stem cells or as a composition containing about 0.01% to about 100% hematopoietic stem cells. For example, hematopoietic stem cells can be provided in compositions such as unfractionated bone marrow (in which 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.

[0249] Suitable sources of hematopoietic stem cells can be isolated or obtained from bodily organs that contain 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 them in their natural state. For example, "isolated cell population," "isolated cell source," or "isolated hematopoietic stem cells," etc., as used herein, refer to one or more cells that have been separated, in vivo or ex vivo, from their natural cellular environment and from association with other components of a tissue or organ, i.e., are not significantly associated with in vivo materials.

[0250] Hematopoietic stem cells can be obtained or isolated from adult bone marrow, including the femur, hip, rib, sternum, and other bones. Bone marrow aspirate containing hematopoietic stem cells can be obtained or isolated directly from the hip joint 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 donor stem and progenitor cells.

[0251] "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. To stimulate mobilization, hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or chemotherapeutic agents, are often used. 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 transplantation into a subject. For example, donors can be administered G-CSF and Mozobil (Genzyme Corporation) 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.

[0252] In embodiments, hematopoietic stem and progenitor cells (HSPCs) are obtained from umbilical cord blood, which can be collected by techniques known in the art (see, e.g., U.S. Pat. Nos. 7,147,626 and 7,131,958, which are incorporated by reference herein for such methodology).

[0253] In embodiments, HSPCs can be obtained from pluripotent stem cell sources, such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). As used herein, the term "induced pluripotent stem 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, the cell can then be programmed into a desired cell type, such as a hematopoietic stem or progenitor cell. As used herein, the term "reprogramming" refers to a method of increasing the potential of a cell to a more undifferentiated state. As used herein, the term "programming" refers to a method of decreasing the potential of a cell or differentiating a cell to a more differentiated state.

[0254] In embodiments, hematopoietic stem cells can be administered or contacted ex vivo with one or more 15-PGDH inhibitors described herein to provide a therapeutic composition. In embodiments, a therapeutic composition can 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.

[0255] In certain embodiments, the therapeutic composition comprises a cell population that is about 95% to about 100% hematopoietic stem cells. The present invention contemplates, in part, that the efficacy of stem cell therapy can be improved by using therapeutic compositions of highly purified hematopoietic stem cells, e.g., compositions comprising a cell population comprised of about 95% hematopoietic stem cells. Currently practiced transplantation methods typically use unfractionated mixtures of cells, in which hematopoietic stem cells comprise less than 1% of the total cell population.

[0256] In embodiments, a therapeutic composition comprises a cell population that is comprised of less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic stem cells. In embodiments, the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic stem cells. In embodiments, the cell population 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 about 100% hematopoietic stem cells.

[0257] Hematopoietic stem cells in the therapeutic compositions of the present invention can be autologous / autogeneic ("self") or non-autologous ("non-self", e.g., allogeneic, syngeneic, or xenogeneic) relative to the subject to which the therapeutic composition is administered. As used herein, "autologous" refers to cells derived from the same subject. As used herein, "allogeneic" refers to cells of the same species that are genetically different from the cells being compared. As used herein, "syngeneic" refers to cells of a different subject that are genetically identical to the cells being compared. As used herein, "xenogeneic" refers to cells of a different species than the cells being compared.

[0258] The hematopoietic stem cells used in the methods of the present invention can be used to deplete mature hematopoietic cells and their unipotent precursors, such as T cells, B cells, NK cells, dendritic cells, monocytes, granulocytes, and erythroid cells, from bone marrow aspirates, umbilical cord blood, or mobilized peripheral blood (mobilized leukapheresis product). Immuno-depletion removes mature, lineage-committed cells, for example, by labeling a solid substrate with antibodies that bind to a panel of so-called "lineage" antigens: CD2, CD3, CD11b, CD14, CD15, CD16, CD79, CD56, CD123, and CD235a. Subsequent steps can further purify the cell population, removing CD34+ Substrates labeled with antibodies that bind to antigens are used to isolate primitive hematopoietic stem 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.

[0259] In embodiments, the amount of hematopoietic stem cells in the therapeutic composition is at least 0.1 x 10 5 pieces, at least 0.5 x 10 5 Pieces, at least 1 x 10 5 pieces, at least 5 x 10 5 Pieces, at least 10 x 10 5 pieces, at least 0.5 x 10 6 pieces, at least 0.75 x 10 6 Pieces, at least 1 x 10 6 pieces, at least 1.25 x 10 6 pieces, at least 1.5 x 10 6 Pieces, at least 1.75 x 10 6 pieces, at least 2 x 10 6 pieces, at least 2.5 x 10 6 pieces, at least 3 x 10 6 pieces, at least 4 x 10 6 pieces, at least 5 x 10 6 Pieces, at least 10 x 10 6 Pieces, at least 15 x 10 6 Pieces, at least 20 x 10 6 Pieces, at least 25 x 10 6 or at least 30 x 10 6 There are individuals.

[0260] In embodiments, the amount of hematopoietic stem cells in the therapeutic composition is the amount of HSPCs in a portion or a single umbilical cord blood sample, or at least 0.1 x 10 5 At least 0.5 x 10 pieces / kg body weight 5 At least 1 x 10 pieces / kg body weight 5 At least 5 x 10 pieces / kg body weight 5 Pieces / kg body weight, at least 10 x 10 5 At least 0.5 x 10 pieces / kg body weight 6At least 0.75 x 10 pieces / kg body weight 6 At least 1 x 10 pieces / kg body weight 6 At least 1.25 x 10 pieces / kg body weight 6 At least 1.5 x 10 pieces / kg body weight 6 At least 1.75 x 10 pieces / kg body weight 6 At least 2 x 10 pieces / kg body weight 6 At least 2.5 x 10 pieces / kg body weight 6 At least 3 x 10 pieces / kg body weight 6 At least 4 x 10 pieces / kg body weight 6 At least 5 x 10 pieces / kg body weight 6 Pieces / kg body weight, at least 10 x 10 6 Pieces / kg body weight, at least 15 x 10 6 Pieces / kg body weight, at least 20 x 10 6 Pieces / kg body weight, at least 25 x 10 6 pieces / kg body weight or at least 30 x 10 6 Pieces / kg body weight.

[0261] Preparations of hematopoietic stem cells administered with one or more 15-PGDH inhibitors and / or therapeutic compositions comprising hematopoietic stem cells and one or more 15-PGDH inhibitors can be used to improve hematopoietic stem cell engraftment and treat ischemic or ischemic-damaged tissue, and reduce further damage to ischemic tissue by cell mobilization and / or repair damage to ischemic tissue, improve angiogenesis in ischemic tissue, improve tissue regeneration in ischemic sites, reduce necrosis or apoptosis in ischemic tissue and / or increase cell survival in ischemic sites. In certain embodiments, preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or therapeutic compositions of a 15-PGDH inhibitor and hematopoietic stem cells are useful for subjects in need of hematopoietic reconstitution, such as subjects who have undergone or will undergo myeloablative therapy.

[0262] Subjects who can 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 also include humans who are candidates for stem cell or bone marrow transplantation, such as during the course of treatment for malignant disease or as part of gene therapy. Subjects may also include individuals or animals who donate stem cells or bone marrow for allogeneic transplantation. In certain embodiments, subjects may have undergone myeloablative radiation therapy or chemotherapy, or may have experienced acute radiation or chemical injury resulting in bone marrow destruction. In certain embodiments, subjects may have undergone radiation therapy or chemotherapy, such as during various cancer treatments. Typical subjects include animals that exhibit abnormal amounts (lower or higher than those in "normal" or "healthy" subjects) of one or more physiological activities that can be modulated by drugs or stem cell or bone marrow transplantation.

[0263] Subjects who can be treated with the preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or therapeutic compositions of a 15-PGDH inhibitor and hematopoietic stem cells 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 such as Hurler disease, Hunter disease, mannosidosis, among others) or cancer, particularly a hematological malignancy, e.g., acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's lymphoma), multiple myeloma, myelodysplastic syndrome, 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).

[0264] 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 embodiments, the subject suffers from a disorder that is the result of an undesirable side effect or complication of another primary treatment, such as radiation therapy, chemotherapy, or treatment with myelosuppressive drugs such as 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.

[0265] Additionally, subjects suffering from the following conditions may also benefit from treatment using a 15-PGDH inhibitor-treated hematopoietic stem cell preparation and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells: lymphopenia, lymphorrhea, lymphostasis, erythropenia, erythroblastic degenerative disorders, erythroblastopenia, leukoerythroblastosis, erythrocytolysis, thalassemia, myelodysplasia, myelofibrosis, thrombocytopenia, disseminated intravascular coagulation (DIC), immune (autoimmune) hematopoietic disorders. Thrombocytopenic purpura (ITP), HIV-induced ITP, myelodysplasia, thrombotic disorders, thrombocytosis, congenital neutropenia (e.g., Kostmann syndrome, Shwachman-Diamond syndrome), tumor-associated neutropenia, childhood and adult cyclic neutropenia, post-infectious neutropenia, myelodysplastic syndromes, neutropenia associated with chemotherapy and radiotherapy, chronic granulomatous diseases, mucopolysaccharidoses, Diamond-Blackfan anemia, sickle cell disease, or beta-thalassemia major.

[0266] In embodiments, preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or therapeutic compositions of a 15-PGDH inhibitor and hematopoietic stem cells can 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, damage to or loss of organ function (including, but not limited to, damage to or loss of brain, kidney, or heart function), convulsions, claudication, numbness, tingling, weakness, pain, decreased wound healing, inflammation, skin discoloration, and gangrene.

[0267] In embodiments, the subject exhibits at least one symptom of ischemic tissue or tissue damaged by ischemia. In certain embodiments, the subject is a human having or at risk of having ischemic tissue or tissue damaged by ischemia, for example, a subject with diabetes, peripheral vascular disease, thromboangiitis obliterans, vasculitis, cardiovascular disease, coronary artery disease or heart failure, or cerebrovascular disease, cardiovascular disease, or cerebrovascular disease.

[0268] Specific examples of genetic disorders, symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with ischemia, or that increase a subject's risk of ischemia, or that result in one or more symptoms of ischemia in a subject, and are therefore suitable for treatment or amelioration using the methods described herein include, but are not limited to, acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage damage, and the like. Deficiency, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fractures, cerebral edema, decreased cerebral blood flow, 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, bruises, 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 injury, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic peripheral 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 trunk lesion, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis These include osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), 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 kidneys, vascular inflammatory conditions, von Hippel-Lindau syndrome, and tissue or organ wounds.

[0269] Other examples of genetic disorders, symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with ischemia, or that increase a subject's risk of ischemia, or that result in one or more symptoms of ischemia in a subject, that are suitable for 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.

[0270] 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.

[0271] 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.

[0272] In embodiments, a 15-PGDH inhibitor may be administered to a preparation of tissue stem cells, such as neural stem cells, mesenchymal stem cells or stem cells capable of generating other tissues, and / or to a preparation of pluripotent stem cells.

[0273] In embodiments, tissue stem cells can be obtained from pluripotent stem cell sources, such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). As used herein, the term "induced pluripotent stem 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 or progenitor cell. As used herein, the term "reprogramming" refers to a method of increasing the potential of a cell to a more undifferentiated state. As used herein, the term "programming" refers to a method of decreasing the potential of a cell or differentiating a cell to a more differentiated state.

[0274] In embodiments, tissue stem cells and / or pluripotent stem cells can be administered or contacted ex vivo with one or more 15-PGDH inhibitors described herein to provide a therapeutic composition. In embodiments, a therapeutic composition can comprise a population of tissue stem cells that have been treated ex vivo with one or more 15-PGDH inhibitors.

[0275] In certain embodiments, the therapeutic composition comprises a cell population that is about 95% to about 100% tissue stem cells. The present invention contemplates, in part, that the efficacy of stem cell therapy may be improved by using a therapeutic composition of highly purified tissue stem cells, for example, a composition comprising a cell population that is about 95% tissue stem cells.

[0276] In embodiments, a therapeutic composition comprises a cell population that is comprised of less than about 0.1%, less than 0.5%, less than 1%, less than 2%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30% tissue stem cells. In embodiments, the cell population comprises less than about 0.1%, less than 0.5%, less than 1%, less than 2%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30% tissue stem cells. In an embodiment, the cell population 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 about 100% tissue stem cells.

[0277] The tissue stem cells in the therapeutic compositions of the present invention can be autologous / autogeneic ("self") or non-autologous ("non-self", e.g., allogeneic, syngeneic, or xenogeneic) relative to the subject to which the therapeutic composition is administered. As used herein, "autologous" refers to cells derived from the same subject. As used herein, "allogeneic" refers to cells of the same species that are genetically different from the cells being compared. As used herein, "syngeneic" refers to cells of a different subject that are genetically identical to the cells being compared. As used herein, "xenogeneic" refers to cells of a different species from the cells being compared.

[0278] Preparations of tissue stem cells administered with one or more 15-PGDH inhibitors and / or therapeutic compositions comprising tissue stem cells and one or more 15-PGDH inhibitors can be used to improve tissue stem cell engraftment and treatment of damaged tissue and reduce further tissue damage, and / or enhance repair of damaged tissue by stem cell mobilization, and / or increase cell survival at the site of tissue damage.

[0279] Symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that result in 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, but are not limited to, 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, and the like. Autoimmune diseases, fractures, cerebral edema, decreased cerebral blood flow, 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, bruises, 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 intravascular coagulation Disseminated intravascular coagulation syndrome (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic peripheral 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, ischemic reperfusion injury, laceration, left main trunk lesion, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson disease These conditions include Son's disease, peripheral arterial disease (PAD), 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 transplants, 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 tissue or organ wounds.

[0280] Other examples of genetic disorders, symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that result in or are associated with tissue damage and the need for tissue repair, suitable for 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.

[0281] 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.

[0282] In other embodiments, 15-PGDH inhibitors can be administered to bone marrow graft donors or hematopoietic stem cell donors to enhance the compatibility of donor bone marrow grafts or donor hematopoietic stem cell grafts.

[0283] In embodiments, a 15-PGDH inhibitor may also be administered to a subject's bone marrow to increase the subject's stem cells or to increase the suitability of the bone marrow as a donor graft.

[0284] In embodiments, a 15-PGDH inhibitor can be administered to a subject to reduce bone marrow graft rejection, enhance bone marrow graft engraftment, enhance hematopoietic stem cell graft or umbilical cord blood stem cell graft engraftment, enhance hematopoietic stem cell graft or umbilical cord stem cell graft engraftment, and / or reduce the number of units of umbilical cord blood required for transplant into the subject. For example, administration can be after treating the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy.

[0285] In 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 therapies or growth factors.

[0286] In embodiments, 15-PGDH inhibitors may be administered to subjects to enhance neutrophil recovery after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, 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-mediated neutropenia, idiopathic neutropenia, and after infection with viruses including, but not limited to, HIV, CMV, parvovirus.

[0287] In embodiments, a 15-PGDH inhibitor may be administered to a subject to enhance platelet recovery after bone marrow transplant, after umbilical cord blood transplant, after hematopoietic stem cell transplant, after conventional chemotherapy, after radiation therapy, in individuals with thrombocytopenia resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia resulting from other bone marrow diseases, drug-induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and after infection with viruses including, but not limited to, HIV, CMV, parvovirus.

[0288] In embodiments, 15-PGDH inhibitors can be administered to subjects to enhance hemoglobin recovery after bone marrow transplant, after umbilical cord blood transplant, after hematopoietic stem cell transplant, after conventional chemotherapy, after radiation therapy, 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 infection with viruses including but not limited to HIV, CMV, parvovirus.

[0289] In embodiments, 15-PGDH inhibitors can be administered to subjects to increase 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 following viral infections, and in individuals with cytopenias.

[0290] In embodiments, a 15-PGDH inhibitor may be administered to a subject with cytopenia, including but not limited to, neutropenia, thrombocytopenia, lymphopenia, and anemia, to enhance the response to cytokines administered to the subject. Cytokines whose response may be enhanced in SW033291 include, but are not limited to, G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, SCF, and TPO-RA (a thrombopoietin receptor agonist).

[0291] In further embodiments, a 15-PGDH inhibitor can be administered to a subject or a subject's tissue graft to reduce graft rejection, enhance graft survival after treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy or immunosuppressive therapy, confer resistance to the toxic or lethal effects of exposure to radiation, 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, reduce infection, and / or reduce radiation-induced pulmonary toxicity.

[0292] In embodiments, a 15-PGDH inhibitor may be administered to a recipient of tissue stem cell transplantation, for example, but not limited to, hematopoietic stem cells, neural stem cells, mesenchymal stem cells, or stem cells from other tissues, to promote tissue regeneration and repair after transplantation.

[0293] In embodiments, a 15-PGDH inhibitor can be administered in combination with G-CSF to increase neutrophils.

[0294] In embodiments, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine to increase neutrophils.

[0295] In yet another embodiment, a 15-PGDH inhibitor can be administered in combination with G-CSF to increase the number and / or mobilize peripheral blood hematopoietic stem cells.

[0296] In embodiments, a 15-PGDH inhibitor may be administered in combination with a hematopoietic cytokine to increase the number and / or mobilize peripheral blood hematopoietic stem cells.

[0297] In embodiments, a 15-PGDH inhibitor may be administered in combination with a second agent, including plerixafor, for the purpose of increasing the number and / or mobilizing peripheral blood hematopoietic stem cells.

[0298] In embodiments, a 15-PGDH inhibitor may be administered in combination with G-CSF to increase and / or mobilize peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0299] In yet another embodiment, 15-PGDH inhibitors can be administered in combination with hematopoietic cytokines to increase and / or mobilize peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0300] In embodiments, a 15-PGDH inhibitor may be administered in combination with a second agent, including plerixafor, for the purpose of increasing and / or mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0301] In yet another embodiment, a 15-PGDH inhibitor can be administered in combination with G-CSF to increase the number of hematopoietic stem cells in the blood or bone marrow.

[0302] In embodiments, a 15-PGDH inhibitor may be administered in combination with a hematopoietic cytokine to increase the number of hematopoietic stem cells in the blood or bone marrow.

[0303] In embodiments, 15-PGDH inhibitors can be used to treat and / or prevent fibrosis and various fibrotic diseases, disorders or conditions, and to reduce fibrotic symptoms such as collagen deposition, inflammatory cytokine expression and inflammatory cell infiltration.

[0304] In 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.

[0305] As used herein, the term "fibrotic" disease, disorder, or condition includes diseases, disorders, or conditions characterized in whole or in part by the excessive production of fibrous material, including the excessive production of fibrous material within the extracellular matrix or the replacement of normal tissue elements with abnormal, non-functional, and / or excessive accumulation of matrix-associated components. Fibrotic diseases, disorders, or conditions can include acute and chronic clinical or subclinical conditions in which fibrogenesis-associated biology or pathology is evident.

[0306] Examples of fibrotic diseases, disorders, and conditions include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, systemic 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, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial fibrosis, pulmonary ... These include interstitial lung disease, interstitial fibrosing 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, fibrosis syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrous tissue, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis (bone marrow fibrosis), drug-induced ergot, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, leprosy, collagenous colitis, acute fibrosis, and organ-specific fibrosis.

[0307] Specific 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 pathological and / or excessive deposition of extracellular matrix in affected tissues. Fibrosis is associated with inflammation and occurs as a symptom of underlying disease and / or is caused by surgical procedures or wound healing processes. Unchecked fibrosis can destroy the structure of underlying organs or tissues, commonly referred to as scarring.

[0308] In embodiments, the 15-PGDH inhibitor can be used to treat or prevent pulmonary fibrosis. The 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 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.

[0309] Pulmonary fibrosis is characterized by the progressive scarring of lung tissue, accompanied by fibroblast proliferation, excessive accumulation of extracellular matrix proteins, and abnormal alveolar structures. As the tissue thickens and stiffens, the lungs no longer function properly, leading to respiratory problems such as shortness of breath and ultimately to death. Pulmonary fibrosis can be caused by acute lung injury, viral infection, exposure to toxins, radiation, chronic disease, medications, or it can be idiopathic (i.e., no underlying cause has been identified).

[0310] The classic finding of idiopathic pulmonary fibrosis is diffuse peripheral scarring of the lungs with small bubbles (known as intraalveolar cysts) adjacent to the lung surface, often at the basal surface, and the outer membrane. Idiopathic pulmonary fibrosis often progresses slowly and relentlessly. Patients often present early with a dry, unexplained cough. Shortness of breath (dyspnea) then begins, triggered by a gradual decrease in activity and worsening over time. Eventually, shortness of breath becomes so severe that it limits all activity and occurs even while sitting still. Rarely, fibrosis progresses rapidly, causing dyspnea and disability within weeks to months of disease onset. This form of pulmonary fibrosis is called Herman-Rich syndrome.

[0311] 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. Eventually, the right ventricle weakens and loses its ability to pump sufficient blood to the lungs, leading to the development of heart failure. Pulmonary hypertension can also result from other medical conditions, such as chronic liver disease and cirrhosis; rheumatic diseases, such as scleroderma or systemic lupus erythematosus (lupus); and lung diseases, 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.

[0312] Chronic obstructive pulmonary disease (COPD) is a common lung disease often associated with chronic bronchitis or emphysema. Common symptoms include cough, mucus buildup, fatigue, wheezing, and respiratory infections.

[0313] Chronic bronchitis and emphysema are lung diseases that narrow the airways. This restricts airflow into and out of the lungs, causing shortness of breath (dyspnea). In clinical practice, COPD is defined by characteristically low airflow on pulmonary function tests.

[0314] Chronic bronchitis occurs when lung damage and inflammation occur in the large airways. A hallmark of chronic bronchitis in the lung airways is an increase in the number (hyperplasia) and size (hypertrophy) of airway goblet cells and mucus glands. This results in more mucus than normal in the airways, narrowing the airways and causing a productive cough. Microscopically, inflammatory cells are seen infiltrating the airway walls. Inflammation is followed by scarring and remodeling, thickening the walls and narrowing the airways. As chronic bronchitis progresses, squamous metaplasia (abnormal changes to the tissue lining the airways) and fibrosis (further thickening and scarring of the airway walls) occur. These changes result in airflow limitation and difficulty breathing.

[0315] Asthma is a chronic lung disease characterized by inflammation and constriction of the airways. Asthma causes repeated episodes of wheezing, chest tightness, shortness of breath, and coughing. Swelling and excessive mucus production can further constrict the airways, worsening the symptoms. There is evidence that increased matrix degradation may occur in asthma, which may contribute to the altered airway mechanics 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.

[0316] Cystic fibrosis (CF) is a recessive, multisystemic genetic disorder characterized by abnormal chloride and sodium transport across epithelia, resulting in thick, viscous secretions in the lungs, pancreas, liver, intestines, and reproductive tracts. Cystic fibrosis 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, impaired mucociliary clearance, and consequent inflammation, which can lead to fibrotic damage and structural changes in the lungs. Fibrotic lung damage progresses over time, leading to lung transplantation in some CF patients.

[0317] 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 infections of the lungs and sinuses (including, but not limited to, Staphylococcus aureus, Haemophilus influenzae, Mycobacterium avium, and Pseudomonas aeruginosa). aeruginosa), pneumonia, tuberculosis, bronchiectasis, hemoptysis, pulmonary hypertension (and resulting heart failure), hypoxia, respiratory failure, allergic bronchopulmonary aspergillosis, sinus mucus, sinus infections, facial pain, fever, excessive nasal discharge, development of nasal polyps, cardiopulmonary complications, CF-related diabetes, rectal prolapse, pancreatitis, malabsorption, intestinal obstruction, exocrine pancreatic insufficiency, biliary obstruction, and cirrhosis of the liver.

[0318] In embodiments, 15-PGDH inhibitors can be used to treat or prevent fibrotic diseases, disorders, or conditions caused by postoperative adhesion formation. Postoperative adhesion formation is a common complication of surgery. Adhesion formation due to mechanical injury, ischemia, and infection can increase postoperative morbidity and mortality. While it is possible to reduce the extent of adhesion formation through sophisticated surgical procedures, adhesion removal is rare, requiring effective adjuvant therapy. Reducing the fibrosis associated with this process can reduce surgical pain, obstruction, and other complications, and promote healing and recovery.

[0319] Wounds in mammalian tissue (e.g., lacerations, openings) result in tissue destruction and coagulation of the microvasculature 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 sequential 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 regions. The central, avascular wound cavity is anoxic, acidic, and hypercarbonated, with high lactic acid levels. Adjacent to the wound cavity is a gradient region of local anemia (ischemia) populated by dividing fibroblasts. Behind this primary region is a region of active collagen synthesis characterized by mature fibroblasts and numerous newly formed capillaries (i.e., angiogenesis). 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.

[0320] In 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 part of the natural healing process. Irregular collagen synthesis and deposition in a wound can lead to excessive, thick, or raised scar formation. Generally, the larger the wound, the longer it takes to heal and the greater the likelihood of problematic scarring.

[0321] In embodiments, 15-PGDH inhibitors can be used to reduce or prevent scar formation in the skin or scleroderma. There are several types of scars on 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, crimson-colored areas that tend to cover areas much larger than the original injury. Even if surgically removed, keloids tend to recur. Atrophic scars are depressions in the skin, sometimes similar to those resulting from severe acne. They are caused by inflammation, which destroys collagen during the remodeling process, leaving depressed areas.

[0322] In embodiments, 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis.Systemic sclerosis is a systemic connective tissue disease characterized by the deterioration of the microvasculature, impaired immune system, and the massive deposition of collagen and other matrix substances in connective tissue.Systemic sclerosis is a clinically heterogeneous systemic disease that affects the connective tissue of the skin and internal organs such as the gastrointestinal tract, lungs, heart, and kidneys.Reducing the fibrosis resulting from systemic sclerosis can improve the symptoms of affected tissues and / or prevent further complications.

[0323] In embodiments, 15-PGDH inhibitors can be used to treat or prevent liver fibrosis.Liver fibrosis can be caused by chronic liver disease, viral cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins.

[0324] Nonalcoholic steatohepatitis (NASH) is a common liver disease. NASH is similar to alcoholic liver disease, but occurs in people who drink little or no alcohol. The main characteristic of NASH is fat in the liver, along with inflammation and damage. Nevertheless, NASH can become severe and can lead to cirrhosis, where the liver becomes permanently damaged and scarred, and can no longer function properly.

[0325] 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 has progressed further or cirrhosis has developed. NASH progression can take years, even decades. The process can be halted or even reversed spontaneously without specific treatment. Alternatively, NASH can gradually worsen, causing scarring or fibrosis to develop and accumulate in the liver. As fibrosis worsens, cirrhosis develops, in which the liver becomes severely scarred and hardens, preventing it from functioning normally. While not all patients with NASH develop cirrhosis, once severe scarring or cirrhosis has occurred, few treatments can halt its progression. Patients 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 transplants are increasingly being performed on NASH patients. In the United States, NASH ranks as one of the leading causes of cirrhosis, after hepatitis C and alcoholic liver disease.

[0326] In embodiments, 15-PGDH inhibitors can be used to treat or prevent renal fibrosis, which can result from dialysis after renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease, or end-stage renal failure.

[0327] Kidney (renal) fibrosis results from the excessive formation of fibrous connective tissue in the kidney. Renal fibrosis results in significant morbidity and mortality, necessitating dialysis or kidney transplantation. Fibrosis can occur at both the filtration and reabsorption sites of the nephron, the functional unit of the kidney. Many factors can contribute to renal scarring, particularly impaired physiology involved in the autoregulation of glomerular filtration. This, in turn, leads to the replacement of normal structures by accumulated extracellular matrix. A range of alterations in individual cell physiology can result in the formation of numerous peptide and non-peptide fibrils that promote scarring by shifting the balance between extracellular matrix synthesis and degradation.

[0328] In embodiments, symptoms of fibrosis in tissues and organs may include inflammation. In these embodiments, a therapeutically effective amount of a 15-PGDH inhibitor administered to a subject in need thereof may be an amount effective to reduce or decrease the number of inflammatory cells in a tissue or organ. A relevant sample can be obtained from the subject to determine whether the number of inflammatory cells has been reduced or decreased. In a non-limiting embodiment, a beneficial effect can be assessed by demonstrating a decrease in the number of neutrophils in BAL fluid from a subject with cystic fibrosis. Excessive neutrophil recruitment to the airways of CF patients is a significant predictor of lung disease severity in CF and is therefore an important therapeutic target. Methods for measuring such cell numbers are well known in the art and include, but are not limited to, FACS techniques. In embodiments, the method can include reducing the number of neutrophil cells in BAL fluid from a subject compared to a control. For comparison, any suitable control, such as a cystic fibrosis subject not treated with a 15-PGDH inhibitor, can be used. In embodiments, a reduction in inflammatory cell numbers, such as neutrophil numbers, provides clinical benefit to the subject. In various embodiments, the reduction in inflammatory cell numbers is at least 5%, 10%, 15%, 20%, 25%, 50% or more compared to a control.

[0329] In another embodiment, the beneficial effect of a 15-PGDH inhibitor can be assessed by a decrease in one or more inflammatory biomarkers in a relevant sample from the subject. In various non-limiting embodiments, the inflammatory biomarkers can include or consist of one or more fibrosis-associated or proinflammatory cytokines. Such cytokines can 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 and include, but are not limited to, ELISA. Thus, in this embodiment, the method can further include a decrease in the amount of one or more inflammatory biomarkers in a sample from the subject compared to a control.

[0330] In embodiments, a 15-PGDH inhibitor can be used in a method for reducing or alleviating collagen secretion or collagen deposition in a tissue or organ, such as the lung, liver, skin, or heart, of a subject. The method can include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject can have or be at risk for excessive collagen secretion or collagen deposition in a tissue or organ, such as the kidney, lung, liver, intestine, colon, skin, or heart. Typically, excessive collagen secretion or collagen deposition in an organ is due to injury or damage. Such injury or damage is organ-specific. The 15-PGDH inhibitor can be administered for a sufficient period of time to completely or partially reduce or alleviate the level of collagen deposition in the tissue or organ. A sufficient period of time can be one week, one week to one month, one to two months, or more than two months. In the case of chronic conditions, it can be advantageous to administer the 15-PGDH inhibitor for the entire life.

[0331] 15-PGDH inhibitors for use in treating fibrotic diseases, disorders, or conditions and / or reducing collagen deposition can be identified using an assay in which a putative inhibitor compound is applied to cells expressing 15-PGDH and the effect on 15-PGDH activity is then measured. To determine the extent of effect, samples or assays containing 15-PGDH treated with a potential inhibitor are compared to control samples without the inhibitor. Control samples (untreated with a modulator) are assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value is approximately 80%, optionally 50%, 25%, 10%, 5%, or 1% of the control. Furthermore, in model organisms, PGE2 signaling stimulates liver regeneration and increases survival after exposure to hepatotoxic substances such as acetaminophen. Thus, the 15-PGDH inhibitors described herein can be used to increase liver regeneration and increase survival in other situations, including after liver resection, liver surgery, living donor liver, or liver transplant, or after exposure to hepatotoxic agents, including, but not limited to, acetaminophen and similar compounds.

[0332] PGE1 analogs have also been used to treat erectile dysfunction. Thus, in embodiments, the 15-PGDH inhibitors described herein can be used alone or in combination with prostaglandins to treat erectile dysfunction.

[0333] Other embodiments described herein relate to the use of a 15-PGDH inhibitor in combination with a corticosteroid to treat inflammation and / or reduce aberrant immune system activity in a subject in need thereof. It has been found that corticosteroids administered to a subject can induce 15-PGDH expression in the subject's tissues. It has been found that administering a 15-PGDH inhibitor in combination with a corticosteroid enhances the anti-inflammatory and / or immunosuppressive effects of the corticosteroid while attenuating corticosteroid-induced side effects and / or cytotoxic effects. By administering a 15-PGDH inhibitor in combination with a corticosteroid, the therapeutic effect of inflammation and / or immune disorders can be increased; in some instances, a lower dose of the corticosteroid can be administered to achieve similar effects, and in other instances, a higher dose can be administered to attenuate and / or prolong the duration of the attenuation and / or reduction of side effects or cytotoxic effects. A further embodiment described herein relates to the use of a 15-PGDH inhibitor in combination with a TNF-alpha inhibitor to treat inflammation and / or reduce aberrant immune system activity in a subject in need thereof.

[0334] In embodiments, 15-PGDH inhibitors can be administered in combination with corticosteroids and / or TNF inhibitors to treat intestinal, gastrointestinal, or intestinal disorders. Treated intestinal, gastrointestinal, or intestinal disorders include oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease. As described below, it has been found that inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered alone or in combination with corticosteroids to subjects in need thereof to treat intestinal, gastrointestinal, or intestinal disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0335] The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of oral cavity, intestinal, and / or gastrointestinal damage or disease, or inflammatory bowel disease (IBD), such as Crohn's disease, oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, and gastric ulcers. Gastritis and gastric ulcers, typical gastrointestinal diseases, are defined as pathological conditions in which the gastrointestinal mucosa is digested by gastric acid, resulting in ulcer formation. The gastric wall generally consists of the mucosa, submucosa, muscularis, and serosa. While gastric ulcers can even damage the submucosa and muscularis, gastritis only damages the mucosa. The incidence of gastritis and gastric ulcers is relatively high, but their causes remain unclear. It has been previously known that gastritis and gastric ulcers are caused by an imbalance between aggressive and defensive factors, i.e., an increase in aggressive factors such as increased secretion of gastric acid or pepsin, or a decrease in defensive factors such as structural or morphological defects in the gastric mucosa, decreased secretion of mucus or bicarbonate ions, and decreased prostaglandin production.

[0336] Currently available therapeutic agents for gastritis and gastric ulcers include various drugs for enhancing defense factors, such as antacids that neutralize already produced gastric acid without affecting gastric acid secretion, gastric acid secretion inhibitors, prostaglandin secretagogues, and gastric wall coating agents. In particular, prostaglandins are known to be essential for maintaining 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, particularly gastritis and gastric ulcers.

[0337] Furthermore, both corticosteroids and TNF-alpha antagonists are used to treat patients with ulcerative colitis and IBD. In a mouse model, a 15-PGDH inhibitor accelerates the healing of ulcerative colitis. The present inventors found that administering corticosteroids to mice increases colonic 15-PGDH levels, which should reduce the therapeutic efficacy of corticosteroids in treating colitis. This suggests that combining corticosteroids with a 15-PGDH inhibitor may be more effective in treating colitis (and IBD) than either drug alone.

[0338] Similarly, the present inventors have shown that TNF-alpha suppresses colonic 15-PGDH expression. This suggests that TNF-alpha antagonists increase colonic 15-PGDH expression, and this effect reduces the therapeutic efficacy of corticosteroids in treating colitis. This suggests that combining a TNF-alpha antagonist, such as the chimeric antibody Remicade (infliximab), with a 15-PGDH inhibitor may be more effective in treating colitis (and IBD) than either agent alone.

[0339] In embodiments, a 15-PGDH inhibitor and a corticosteroid or a 15-PGDH inhibitor and a TNF inhibitor can be provided in a topical composition or formulation used to treat inflammation and / or abnormal immune system activity associated with medical conditions such as atopic dermatitis, psoriasis, eczematous dermatitis, nummular dermatitis, irritant contact dermatitis, allergic contact dermatitis (such as poison ivy exposure, poison oak exposure, and poison sumac exposure), seborrheic dermatitis, stasis dermatitis, and other steroid-responsive skin diseases.

[0340] In embodiments, the 15-PGDH inhibitor and a corticosteroid or the 15-PGDH inhibitor and a TNF inhibitor provided in a topical composition can be used to treat, for example, acne vulgaris, alopecia, alopecia areata, vitiligo, eczema, eczema xerosis, keratosis pilaris, lichen planus, lichen sclerosus, lichen linearis, lichen simplex chronicus, prurigo nodularis, discoid lupus erythematosus, lymphocytic infiltrates of Jessner / Kanov, cutaneous lymphocytoma, pyoderma gangrenosum, pruritus ani, sarcoidosis, chondrodermatitis nodularis, and other inflammatory skin diseases.

[0341] Medical conditions that may be treated with a 15-PGDH inhibitor and a corticosteroid or a 15-PGDH inhibitor and a TNF inhibitor may also include, for example, keloids, hypertrophic scars, pretibial myxedema, and other infiltrative skin diseases. Additional medical conditions include, for example, granuloma annulare, diabetic necrobiosis lipoidica, sarcoidosis, and other non-infectious granulomas.

[0342] In yet another embodiment, the 15-PGDH inhibitors described herein can be administered in combination with corticosteroids or TNF inhibitors for wound healing, tissue regeneration, and / or tissue repair. Among various prostaglandins, PGE2 is known to function as a mediator of wound healing. Therefore, a 15-PGDH inhibitor can be administered to a subject receiving steroids, such as a subject undergoing treatment for a surgical wound, to enhance PGE2 and promote wound healing.

[0343] Furthermore, increased prostaglandin levels have been shown to stimulate signaling through the Wnt signaling pathway by increasing 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 promoting tissue regeneration or repair in subjects receiving corticosteroid therapy. 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.

[0344] In embodiments, 15-PGDH inhibitors can be used as glucocorticoid sensitizers to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitizers, and / or reverse glucocorticoid insensitivity in subjects experiencing corticosteroid dependence or corticoid resistance or refractoriness or intolerance to corticosteroids. The therapeutic effects of 15-PGDH inhibitors when used as glucocorticoid sensitizers include, but are not limited to, steroid sparing in corticosteroid-dependent patients, better response or tolerance to corticosteroids, achieving efficacy with the use of lower doses of corticosteroids, preventing individuals at risk of developing a refractory response or resistance or exacerbation in response to antigen exposure, infection, exercise or irritants, achieving optimal immune function, subjects or patients responding more easily when steroid administration is tapered or discontinued or after long-term administration of corticosteroids, reducing the risk of developing corticosteroid-associated adverse events such as opportunistic infections, bone loss, pathological fractures, diabetes, cataracts, and combinations thereof.

[0345] In embodiments, a 15-PGDH inhibitor can be administered to a subject in combination with a corticosteroid to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticosteroid resistance, or refractoriness or intolerance to corticosteroids. Conditions associated with glucocorticoid insensitivity can include various immunoinflammatory disorders / diseases and combinations thereof that are treated with steroids when treatment fails to achieve disease control or is ineffective, or is corticosteroid intolerant or dependent.

[0346] In embodiments, the 15-PGDH inhibitor and the corticosteroid or the 15-PGDH inhibitor and the TNF inhibitor are used in the treatment of glucocorticoid-resistant asthma, refractory rheumatoid arthritis, refractory inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, interstitial pulmonary fibrosis, cystic fibrosis, refractory ulcerative colitis, children with severe Crohn's disease, corticosteroid-refractory asthma, corticosteroid-refractory desquamative interstitial pneumonia, refractory inflammatory myopathy, refractory myasthenia gravis, refractory pemphigus vulgaris, methotrexate-refractory RA patients, refractory nephrotic syndrome, refractory multiple sclerosis refractory sprue-like disease, steroid-resistant sarcoidosis, refractory mucosal lesions of pemphigus vulgaris, refractory Schnitzler's syndrome, resistant dermatitis of the head and neck, severe refractory atopic dermatitis, refractory idiopathic thrombocytopenic purpura, refractory orbital myositis, refractory or recurrent lymphoma, severely ill patients with sepsis or acute respiratory distress syndrome (ARDS) and associated adrenal insufficiency, rosacea, polymyalgia rheumatica, giant cell arteritis, polymyositis, dermatomyositis, Kawasaki syndrome, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, stiff neck Mann's syndrome, corticosteroid-dependent systemic lupus erythematosus, corticosteroid-dependent multiple sclerosis, symptomatic corticosteroid-dependent asthma, primary Sjögren's syndrome, systemic vasculitis, polymyositis, organ transplantation, graft-versus-host disease, inflammatory diseases, autoimmune diseases, hyperproliferative diseases, lupus, osteoarthritis, rhinosinusitis, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, allergic rhinitis, urticaria, hereditary angioedema, tendinitis, bursitis, autoimmune chronic active hepatitis, cirrhosis, graft rejection, psoriasis, dermatitis, malignancy, leukemia, myeloma, lymphoma, Acute adrenal insufficiency, rheumatic fever, granulomatous diseases, immune proliferation / apoptosis, suppression and regulation of the hypothalamic-pituitary-adrenal (HPA) axis, hypercortisolism, regulation of Th1 / Th2 cytokine balance, chronic kidney disease, spinal cord injury, cerebral edema, thrombocytopenia, Little's disease, Addison's disease, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, nasal polyps, sepsis, bacterial infections, viral infections, rickettsial infections, parasitic infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing's syndrome, anxiety, sleep disorders, enhancement of memory and learning,Glucocorticoid-induced glaucoma, atopic dermatitis, drug hypersensitivity reactions, serum sickness, bullous dermatitis herpetiformis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, nonsuppurative thyroiditis, sympathetic ophthalmia, uveitis, ocular inflammatory conditions unresponsive to topical steroids, allergic bronchopulmonary aspergillosis, fulminant or disseminated pulmonary tuberculosis (when used concomitantly with appropriate chemotherapy), hypersensitivity pneumonitis, idiopathic bronchiolitis obliterans with organizing pneumonia, idiopathic eosinophilic pneumonia, idiopathic pulmonary fibrosis, and idiopathic pulmonary fibrosis, also treated with appropriate anti-PCP antibiotics. The present invention can be administered to a subject exhibiting one or more glucocorticoid-insensitive associated diseases, disorders, or conditions selected from the group consisting of hypoxemia-associated Pneumocystis carinii pneumonia (PCP) occurring in HIV(+) individuals, diuresis or remission of proteinuria in idiopathic nephrotic syndrome without uremia or nephrotic syndrome caused by lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, psoriatic arthritis, relapsing polychondritis, trichinellosis with neurological or myocardial involvement, and tuberculous meningitis.

[0347] Pharmaceutical Composition The 15-PGDH inhibitors described herein can 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 can be prepared by conventional methods by mixing the derivative with a pharmaceutically acceptable carrier or excipient or by diluting the 15-PGDH inhibitor with a diluent. The pharmaceutical composition may further contain fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, etc. The pharmaceutical composition can 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.

[0348] In embodiments, the pharmaceutical composition may be formulated into a parenteral or oral dosage form. Solid dosage forms for oral administration may be prepared by adding an excipient to the 15-PGDH inhibitor, optionally with a binder, disintegrant, lubricant, colorant, and / or flavoring agent, and molding the resulting mixture into tablets, sugar-coated pills, granules, powder, or capsules. Additives that can be added to the composition may be conventional additives in the art. 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, refined talc, stearic acid salts, sodium borate, and polyethylene glycol can be used as lubricants, and sucrose, orange peel, citric acid, and tartaric acid can be used as flavoring agents. In embodiments, the pharmaceutical composition can be made into an aerosol formulation (e.g., nebulized) for administration by inhalation.

[0349] The 15-PGDH inhibitors described herein can be combined with flavoring agents, buffers, stabilizers, etc., and can be incorporated into oral liquid dosage forms such as solutions, syrups, or elixirs according to conventional methods. An example of a buffering agent can be sodium citrate. Examples of stabilizers include tragacanth, acacia, and gelatin.

[0350] In embodiments, the 15-PGDH inhibitors described herein may be incorporated into an injectable dosage form for, for example, subcutaneous, intramuscular, or intravenous administration by adding a pH adjuster, buffer, stabilizer, relaxant, or 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. Local anesthetics may include procaine HCl, lidocaine HCl, etc. Relaxants may include sodium chloride, glucose, etc.

[0351] In embodiments, the 15-PGDH inhibitors described herein can be incorporated into suppositories in a conventional manner by adding a pharmaceutically acceptable carrier known in the art, e.g., polyethylene glycol, lanolin, cocoa butter, or fatty acid triglycerides, along with a surfactant such as Tween, if desired.

[0352] The pharmaceutical compositions 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. In embodiments, the 15-PGDH inhibitors described herein may be administered orally, intravenously, or intraperitoneally. The dosage may be a pharmaceutically effective amount. A pharmaceutically effective amount may be an amount of the 15-PGDH inhibitor that treats or improves alopecia, cardiovascular disease, gastrointestinal disease, wound, and renal disease. The pharmaceutically effective amount of the compound is determined appropriately 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 the like. Generally, the effective amount of the compound may be in the range of about 1 to 1,000 mg for oral administration, about 0.1 to 500 mg for intravenous administration, and about 5 to 1,000 mg for rectal administration. In general, the daily dose for adults ranges from about 0.1 to 5,000 mg, preferably up to about 1,000 mg, but cannot be determined uniformly because it depends on the age, sex, weight, and physical condition of the patient. The preparation can be administered once a day or several times a day in divided doses.

[0353] Cosmetic compositions containing 15-PGDH inhibitors may comprise any substance or preparation intended to come into contact with the various surface parts of the human body (epidermis, hair and hair system, nails, lips and external genitalia) or with the teeth or oral mucosa, exclusively or mainly for cleaning them, perfume them, modifying their appearance and / or correcting body odor and / or protecting them or keeping them in good condition.

[0354] The cosmetic composition may comprise a cosmetically acceptable medium, which may be water or a mixture of water and at least one solvent selected from hydrophilic organic solvents, lipophilic organic solvents, amphiphilic organic solvents, and mixtures thereof.

[0355] For topical application, the cosmetic composition can be administered in the form of an aqueous, alcoholic, aqueous-alcoholic, or oily solution or suspension, or in the form of a lotion or serum-type dispersion; in the form of a dispersion of a fatty phase in an aqueous phase (O / W) or vice versa (W / O); in the form of an emulsion with a liquid or semi-liquid consistency or pasty, obtained by multiple emulsion; in the form of a free or compressed powder, used as such or incorporated into a physiologically acceptable medium; in the form of microcapsules or microparticles; or in the form of vesicular dispersions of ionic and / or nonionic type. Thus, the cosmetic composition can be in the form of a salve, tincture, milk, cream, ointment, powder, patch, impregnated pad, solution, emulsion or vesicular dispersion, lotion, aqueous or non-aqueous gel, spray, suspension, shampoo, aerosol, or foam. The cosmetic composition can be non-aqueous or aqueous. It can also include solid preparations, such as soaps or cleansing cakes.

[0356] The cosmetic composition may include, in particular, hair care compositions, in particular shampoos, setting lotions, treatment lotions, styling creams or gels, hair restructuring lotions, masks, etc. The cosmetic composition may be a cream, hair lotion, shampoo, or conditioner. They may be used in particular in treatments by application, with or without rinsing, or in the form of a shampoo. Compositions in the form of foams, sprays, aerosols, or otherwise containing a propellant under pressure are also contemplated. Thus, the cosmetic composition may be in the form of a lotion, serum, milk, cream, gel, salve, ointment, powder, balm, patch, impregnated pad, cake, or foam.

[0357] In particular, compositions for application to the scalp or hair may be in the form of a hair care lotion (for example for daily or twice-weekly application), a shampoo or hair conditioner (particularly for twice-weekly or weekly application), a liquid or bar soap for cleansing the scalp (for daily application), a hairstyle-shaping product (lacquer, hair setting product or styling gel), a treatment mask or a foaming gel or cream for cleansing the hair. They may also be in the form of a hair dye or mascara to be applied with a brush or comb.

[0358] Furthermore, when applied topically to eyelashes or body hair, the composition may be in the form of a tinted or untinted mascara that is applied by brush to the eyelashes or beard or mustache. When administered by injection, the composition may be in the form of an aqueous lotion or an oily suspension. When used orally, 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.

[0359] The cosmetic composition may also contain, in a known manner, adjuvants common in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV-screening agents, odor absorbers, and dyes. The amounts of these various adjuvants are those commonly used in the cosmetic field, for example, from 0.1% to 20%, in particular up to 10%, of the total weight of the composition. Depending on their nature, these adjuvants can be incorporated into the fatty phase, the aqueous phase, and / or the lipid globules.

[0360] In embodiments, the 15-PGDH inhibitor can be administered in a combinatorial or combined therapy, which involves administering the 15-PGDH inhibitor together with one or more additional active agents. The phrase "combinatorial therapy" or "combination therapy" encompasses the administration of a 15-PGDH inhibitor and one or more therapeutic agents as part of a specific treatment regimen intended to provide a beneficial effect from the interaction of these therapeutic agents. The combined administration of these therapeutic agents typically occurs over a predetermined period of time (usually minutes, hours, days, or weeks, depending on the combination selected). "Combinatorial therapy" or "combination therapy" is intended to encompass not only sequential administration of these therapeutic agents, i.e., administration of each therapeutic agent at different times, but also substantially simultaneous administration of these therapeutic agents or at least two therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to a subject individual doses comprising a fixed ratio of each therapeutic agent or by administering to a subject multiple individual doses of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. The order in which the therapeutic agents are administered is not strictly important.

[0361] In embodiments, the additional active agent may be selected from lipoxygenase inhibitors, in particular those described in EP 648488, bradykinin inhibitors, in particular those described in EP 845700, prostaglandins and their derivatives, in particular those active agents described in WO 98 / 33497, WO 95 / 11003, JP 97-100091, JP 96-134242, agonists or antagonists of prostaglandin receptors and non-prostanoic acid analogues of prostaglandins, as described in EP 1 175 891 and EP 1 175 890, WO 01 / 74307, WO 01 / 74313, WO 01 / 74314, WO 01 / 74315 or WO 01 / 72268.

[0362] In embodiments, the 15-PGDH inhibitors may be administered alone or in combination with active agents 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, cromakalim, and diazoxide. Antiandrogens include 5-alpha-reductase inhibitors such as finasteride and compounds described in U.S. Patent No. 5,516,779, cyproterone 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 include selenium derivatives, ketoconazole, triclocarban, triclosan, zinc pyrithione, itraconazole, pyridinic acid, hinokitiol, mupirocin, and compounds described in European Patent No. 680745, glycine hydrochloride, benzoyl or benzyl peroxide, and minocycline. Anti-inflammatory agents include, for example, Cox-2 specific inhibitors 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).

[0363] 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]hexopyranose, benzalkonium chloride, benzethonium chloride, phenol, estradiol, chlorpheniramine maleate, chlorophyll derivatives, cholesterol, cysteine, methionine, benzyl nicotinate, menthol, peppermint oil, calcium pantothenate, panthenol, resorcinol, protein kinase C inhibitors, prostaglandin H synthase 1 or COX-1 or COX-2 activators, glycosidase inhibitors, glycosaminoglycanase inhibitors, pyroglutamic acid esters, hexasaccharide acids or acylhexasaccharide acids, substituted esters, hydroxybenzoates ... Examples of the anti-inflammatory agents include aryl ethylenes, N-acylated amino acids, flavonoids, derivatives and analogs of ascomycin, histamine antagonists, triterpenes such as ursolic acid, and the compounds described in U.S. Pat. Nos. 5,529,769; 5,468,888; and 5,631,282, saponins, proteoglycanase inhibitors, estrogen agonists and antagonists, pseudopterins, cytokine and growth factor promoters, IL-1 or IL-6 inhibitors, IL-10 promoters, TNF inhibitors, vitamins such as vitamin D, analogs of vitamin B12 and pantothenol, hydroxy acids, benzophenones, esterified fatty acids, and hydantoins.

[0364] The pharmaceutical and / or cosmetic compositions comprising the 15-PGDH inhibitors described herein may further contain at least one compound selected from, for example, prostaglandins, in particular prostaglandins PGE1, PGE2, salts thereof, esters thereof, analogs thereof and derivatives thereof, in particular those described in WO 98 / 33497, WO 95 / 11003, JP 97-100091 A and JP 96-134242 A, in particular agonists of prostaglandin receptors. Compounds include, in particular, agonists of the prostaglandin F2α receptor (in acid form or in precursor form, in particular in ester form), such as, for example, latanoprost, fluprostenol, cloprostenol, bimatoprost, unoprostone, agonists of the prostaglandin E2 receptor (and their precursors, in particular esters, such as travoprost), such as 17-phenyl PGE2, biprostol, butaprost, misoprostol, sulprostone, 16,16-dimethyl PGE2, 11-deoxy PGE1, 1-deoxy PGE1, agonists of the prostaglandin E2 receptor (and their precursors, in particular esters, such as travoprost), agonists of the prostacyclin (IP) receptor, such as cicaprost, iloprost, isocarbacycline, beraprost, epoprostenol, treprostinil, and their precursors, in particular 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) and their precursors, especially esters, I The compound may contain at least one compound such as an agonist of the thromboxane A2 (TP) receptor, such as -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) and its precursors, particularly esters.

[0365] Advantageously, the composition comprises at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or one prostaglandin derivative, such as PGF 2, in particular in saline form or in precursor form, in particular in the form of an ester (for example the isopropyl ester). 2α and series 2 prostaglandins, including PGE2, and their derivatives, such as 16,16-dimethyl PGE2, 17-phenyl PGF2, and 16,16-dimethyl PGF 2α 17-phenyl PGF 2α , saline or ester form of Series 1 prostaglandins, such as 11-deoxyprostaglandin E1, 1-deoxyprostaglandin E1, analogues thereof, in particular latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, biprostol, butaprost, misoprostol, salts thereof or esters thereof.

[0366] The present invention is further illustrated by the following examples, which are not intended to limit the scope of the claims. [Example]

[0367] Example A. Analysis of 15-PGDH inhibitors of the present invention This example provides data on 15-PGDH inhibitors using the assay described in U.S. Pat. No. 9,790,233, which is incorporated herein by reference in its entirety. The data show the IC of each compound for inhibition of the enzymatic activity of recombinant 15-PGDH in an in vitro assay. 50 The analogs are classified as follows: less than 2.5 nM (***), between 2.5 nM and 10 nM (**), or greater than 10 nM (*). Recombinant 15-PGDH is human unless otherwise specified. Additionally, the examples provide kinetic aqueous solubility data for selected analogs in citrate buffer solution at pH 7.

[0368] [Table 1]

[0369] [Table 2]

[0370] [Table 3]

[0371] [Table 4]

[0372] [Table 5]

[0373] [Table 6]

[0374] [Table 7]

[0375] Example B. Biological Assays Selected compounds of the present disclosure were measured for human microsomal stability (HLM), mouse microsomal stability (MLM), IC50 of hERG, Caco-2 permeability, CYP inhibition, and pharmacokinetic (PK) properties. PK studies were performed in mice using a single oral dose of 20 mg / kg to obtain Cmax and AUC, and a single IV dose of 5 mg / kg to obtain clearance (Cl). See Table 2.

[0376] In vitro microsomal metabolic stability assay Pooled liver microsomes (human and CD-1 mouse) were purchased from Corning or XenoTech LLC and stored in a -80°C freezer before use. The NADPH cofactor system, β-nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt, NADPH·4Na (NADPH) (Vendor: Chem-impex International, Catalog No. 00616), was used. Control compounds were testosterone, diclofenac, and propafenone.

[0377] Test Compounds and Reagents Stock solutions - test compounds were 10 mM in DMSO (dimethyl sulfoxide).

[0378] Working solution - Dilute the compound or control from the stock solution (10 mM) to 5 μL in 495 μL of 100% acetonitrile (concentration: 100 μM, 99% ACN, 1% DMSO; final concentration in the reaction: 1 μM, 0.99% ACN, 0.01% DMSO).

[0379] Potassium phosphate buffer 100 mM (pH 7.4 ± 0.1).

[0380] NADPH cofactor: An appropriate amount of NADPH powder was weighed and diluted in MgCl2 solution (working solution concentration: 10 mM NADPH and 10 mM MgCl2; final concentration in the reaction: 1 mM NADPH and 1 mM MgCl2).

[0381] Liver microsome preparation (0.5 mg / mL): An appropriate volume of microsomes (20 mg / mL) was pipetted into a 100 mM buffer solution (concentration: 0.56 mg / mL, final concentration in the reaction system: 0.5 mg / mL).

[0382] Assay procedure All liquid handling and incubations were performed using an automated workstation. Duplicates were obtained for each test condition (n=2).

[0383] 1) Empty "incubation" plates T60 and NCF60 were pre-heated for 10 minutes.

[0384] 2) Liver microsomes were diluted to 0.56 mg / mL in 100 mM phosphate buffer.

[0385] 3) 445 μL of microsome working solution (0.56 mg / mL) was transferred to pre-warmed "incubation" plates T60 and NCF60, which were then pre-incubated at 37°C for 10 minutes with constant shaking. 54 μL of liver microsomes was transferred to an empty plate, 6 μL of NADPH cofactor was added to the empty plate, and then 180 μL of quench solution was added to the empty plate.

[0386] 4) 5 μL of compound working solution (100 μM) was added to the "incubation" plates (T60 and NCF60) containing microsomes and mixed thoroughly three times.

[0387] 5) For NCF60 plates, add 50 μL of buffer and mix thoroughly three times. Start timing and incubate the plate at 37°C for 60 minutes with shaking.

[0388] 6) In the "Quench" plate TO, add 180 μL of Quench Solution and 6 μL of NADPH cofactor. Ensure the plate is cooled to prevent evaporation.

[0389] 7) For the T60 plate, mix thoroughly three times and immediately transfer 54 μL of the mixture to the "quench" plate at time 0. 44 μL of NADPH cofactor was then added to the incubation plate (T60). Start timing and incubate the plate with shaking for 60 minutes at 37°C.

[0390] 8) At 5, 10, 20, 30 and 60 minutes, 180 μL of quench solution was added to the "quench" plate, mixed once, and then 60 μL of sample from the T60 plate was transferred sequentially to the "quench" plate for each time point.

[0391] 9) For NCF60: After mixing once, 60 μL of the sample removed from the NCF60 incubation was transferred to the "Quench" plate containing Quench Solution at the 60 minute time point.

[0392] 10) All sample plates were shaken for 10 minutes and then centrifuged at 4000 rpm for 20 minutes at 4°C.

[0393] 11) 80 μL of the supernatant was transferred to 240 μL of HPLC water and mixed on a plate shaker for 10 minutes.

[0394] 12) Each bioanalysis plate was sealed and shaken for 10 minutes before BA analysis.

[0395] All samples were injected and analyzed using LC-MS / MS. To determine the in vitro elimination constants (ke) of the control and compounds, the peak area ratio of analyte / internal standard was converted to the percent remaining (% remaining) using the following formula:

number

[0396] Liver weight: 20 g / kg and 88 g / kg for humans and mice, respectively. To calculate liver clearance, 45 mg / g (mg microsomal protein / g liver weight) was used in the five species.

[0397] hERG testing in a manual patch clamp system Stable CHO-K1 cells expressing the hERG channel (Sophion Biosciences) were used.

[0398] Preparation of compounds Test compounds were dissolved in 100% DMSO to create stock solutions at each concentration, which were transferred to the compound plate and then dissolved in extracellular solution to achieve the final concentration for testing. Visual inspection for precipitates was performed prior to testing. If the ECS working solution was not clear, the solution was not used for testing. As a correction step, the final DMSO concentration of the ECS was increased by up to 0.3% to improve solubility. If the solution still did not become clear, the test for that concentration was discontinued. The final DMSO concentration was 0.30% or less for all concentrations of compound, vehicle (negative) control, and amitriptyline (positive) control.

[0399] electrophysiology hERG currents were recorded at room temperature using the whole-cell patch clamp technique. For axonal systems, the output signal from the amplifier was digitized using a DigiData 1440 A / DD / A board. Recording was controlled by Pclamp10 software. For the HEKA system, recording was controlled by PatchMaster software. Recorded cells were continuously perfused with bath solution from a perfusion system (approximately 1 ml / min) attached to the stage of an inverted or upright microscope. The perfusion tip was manually positioned under the microscope. Micropipettes were aspirated from borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK) using a programmable micropipette puller and heat-polished. The resistance of the pipette tip was 2–5 MΩ.

[0400] solution External solution (mM): HEPES 10, NaCl 145, KCl 4, CaCl2 2, MgCl2 1, glucose 10. pH adjusted to 7.4 with 1N NaOH, osmolality 290-320 mOsm. Filtered and kept at 4°C. Once prepared, ECS should be used within one month. Internal solution (nM): KOH 31.25, KCl 120, CaCl2 5.374, MgCl2 1.75, EGTA 10, HEPES 10, Na2-ATP 4. pH adjusted to 7.2 with 1N KOH, osmolality 280-310 mOsm. Filtered and kept at -20°C. This solution was stored for a maximum of 3 months.

[0401] Voltage Command Protocol To open the hERG channel, the voltage was first increased to +60 mV from a holding potential of -80 mV for 850 ms. The voltage was then reduced to -50 mV for 1275 ms, resulting in a "rebound" or tail current that was measured and collected for data analysis. Finally, the voltage was reduced to the holding potential (-80 mV). This voltage command protocol was repeated continuously every 15 s during the test (solvent control, test compound, and washout). For quality control, the minimum seal resistance was 500 MOhm, and the minimum specific hERG current (pre-compound) was 0.4 nA.

[0402] Application of compounds During the initial recording period, peak current amplitude was monitored until it stabilized (<5% change) over five sweeps. At this point, drug perfusion was initiated at the lowest concentration and continued for 5 min until the peak current was again stable over five sweeps, or if the peak current remained unchanged, higher drug concentrations were applied if necessary; otherwise, the experiment was terminated and the cell dish was discarded.

[0403] Data analysis Data were analyzed and fitted using Clampfit or Patchmaster and Prism. Percent inhibition values ​​for each test compound concentration were calculated from the recorded current responses: (1 - current measured under compound perfusion / current measured under solvent perfusion) × 100%.

[0404] In three or more concentration tests, IC 50 The values ​​are determined from the dose-response curve obtained by logistic fitting:

number

[0405] Caco-2 permeability test Caco-2 cells (obtained from ATCC) were seeded onto PET membranes in 96-well insert plates and cultured for 21–28 days before use in the transport assay. Monolayer integrity was verified by performing a Lucifer Yellow rejection assay. Monolayer quality was verified by measuring the unidirectional (A to B) permeability of nadolol (a low-permeability marker) and metoprolol (a high-permeability marker) and the bidirectional permeability of digoxin (a P-glycoprotein substrate marker) in duplicate wells. Nadolol and metoprolol were tested at 2.0 μM, and digoxin was tested at 10.0 μM.

[0406] Standard assay conditions for test compounds were as follows: Test concentration: 2.0 μM (DMSO ≤ 1%); Replicates: n = 2; Direction: A to B and B to A; Incubation time: 2 hours; Transport buffer: HBSS containing 10 mM HEPES, pH 7.40 ± 0.05; and Incubation conditions: 37±1°C, 5% CO2, relative saturated humidity.

[0407] For the TO sample, the dosing solution was removed and mixed with transport buffer containing the appropriate internal standard (IS) and stop solution. After incubation, the sample solution was removed from the donor and receiver wells and immediately mixed with stop solution. All samples, including the TO sample, donor sample, and receiver sample, were analyzed using LC / MS / MS. The concentration of the test compound was expressed as the peak area ratio of the analyte to the IS without using a standard curve.

[0408] Apparent permeability coefficients from A to B and B to A (P app ), solution recovery rate and discharge ratio (ER) were determined.

[0409] Microsomal CYP Inhibitors CYP450 enzyme activity was measured using a 5-in-1 marker substrate cocktail. For each reaction, enzyme activity in the presence of test compound at eight concentrations (0, 0.05, 0.15, 0.5, 1.5, 5.0, 15.0, or 50.0 μM) was measured in single replicates (n=1). Known inhibitors for each isoform were tested in duplicate (n=2) at a single concentration (3.0 μM) and included as positive controls.

[0410] Incubation mixtures containing 0.2 mg / ml pooled human liver microsomes (Corning, Xenotech, or other qualified vendors; pooled from multiple donors), marker substrates, and standard inhibitors (listed in the table below) or test compounds were warmed to 37° C. for 10 minutes. The reaction was initiated by the addition of NADPH (1.0 mM).

[0411] [Table 8]

[0412] The mixture was incubated at 37°C for 10 min, after which the reaction was stopped by adding ice-cold acetonitrile containing an internal standard (IS).

[0413] Metabolites generated from the marker substrate were measured by LC-MS / MS and evaluated based on the peak area ratio of the analyte to IS.

[0414] Residual activity (expressed as a percentage of control activity) was calculated; IC50 values ​​for test compounds were determined using SigmaPlot or XLfit with a 3- or 4-parameter logistic sigmoid equation.

[0415] Representative PK tests The pharmacokinetic (PK) profile and parameters of the compound were measured in male C57BL / 6J mice when administered as an intravenous (IV) bolus dose of 5 mg / kg and an oral gavage dose of 20 mg / kg. Plasma levels of the compound were quantified for up to 24 hours for each route of administration. Doses may be varied depending on the study.

[0416] Formulations: For IV administration, compounds were dissolved in 10% (w / v) Captisol in 10 mM citrate buffer (pH 3.5) at a concentration of 1 mg / kg. For oral administration, compounds were suspended in 0.5% (w / v) CMC-Na containing 0.2% (v / v) Tween 80 at a concentration of 2 mg / kg.

[0417] The appropriate amount of test compound was accurately weighed and mixed with the appropriate volume of solvent to obtain a clear solution. Vortexing in a water bath or sonication may be required. Animals were dosed within 4 hours after the formulation was prepared.

[0418] Two formulation samples were removed from each of the formulation solutions and transferred to 1.5 mL polypropylene microcentrifuge tubes, and dose verification was performed by LC / UV or LC-MS / MS.

[0419] For suspension formulations, samples were removed from the top, middle, and bottom of each preparation and transferred to 1.5 mL polypropylene microcentrifuge tubes, and dose verification was performed by LC / UV or LC-MS / MS. Formulations may vary depending on the study.

[0420] Administration For both IV and oral routes of administration, the dosage formulations were administered according to the institution's SOPs. Dose volumes were determined by animal weights collected on the morning of dosing.

[0421] Blood sample collection and plasma processing At each time point, approximately 0.03 mL of blood was collected from the saphenous vein of each animal. All blood samples were transferred to pre-chilled commercially available EDTA-K2 tubes and placed on wet ice until centrifugation.

[0422] Blood samples were processed for plasma by centrifugation at 3,200 g for 10 minutes at approximately 4° C. Plasma was collected, transferred to pre-labeled 96-well plates or polypropylene tubes, flash frozen on dry ice, and stored at −70±10° C. until analysis by LC / MS / MS.

[0423] Data analysis The plasma concentration data versus time were analyzed by a non-compartmental approach using the Phoenix WinNonlin 6.3 software program. Cl, Vdss, C0, Cmax, Tmax, T 1 / 2 Graphs of plasma concentration profiles versus time were obtained for AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf), %F and time.

[0424] [Table 9]

[0425] [Table 10]

[0426] Applicants have found that IC50 values ​​alone cannot predict in vivo efficacy, as in disease models. Additional pharmacokinetic and pharmacodynamic properties, human or mouse microsomal stability, Caco and hERG IC50 are important for in vivo efficacy. Without being bound by theory, in embodiments, clinical candidates should have at least two of the following characteristics: (i) human microsomal stability of ≥ 60 minutes; (ii) hERG IC50 of > 15 μM; (iii) high permeability by Caco permeability assay; or (iv) an efflux ratio (ER) of < 10. In embodiments, clinical candidates have at least two of the following characteristics: (i) human microsomal stability of ≥ 100 minutes; (ii) hERG IC50 of > 35 μM; (iii) high permeability by Caco permeability assay; or (iv) an efflux ratio (ER) of < 10. In embodiments, clinical candidates should have at least two of the following characteristics: (i) human microsomal stability of ≧100 minutes; (ii) hERG IC50 of >50 μM; (iii) high permeability by Caco permeability assay; or (iv) an efflux ratio (ER) of <10. In embodiments, clinical candidates should have at least two of the following characteristics: (i) human microsomal stability of ≧120 minutes; (ii) hERG IC50 of >75 μM; (iii) high permeability by Caco permeability assay; or (iv) an efflux ratio (ER) of <10. In embodiments, clinical candidates should have at least two of the following characteristics: (i) human microsomal stability of ≧145 minutes; (ii) hERG IC50 of >100 μM; (iii) high permeability by Caco permeability assay; or (iv) an efflux ratio (ER) of <10. In embodiments, clinical candidates should have: (i) human microsomal stability of ≥ 145 minutes; (ii) hERG IC50 > 100 μM; (iii) high permeability by Caco permeability assay; and (iv) efflux ratio (ER) < 10.

[0427] synthesis Example 1: Synthesis of 4-isopropyl-6-((2-methoxyethyl)sulfinyl)-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-5-amine (Compound 17, Table 1). [ka] Example 1A: 4-Hydroxy-6-isopropyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-5-carbonitrile. [ka] To a solution of methyl 2-cyano-4-methylpent-2-enoate (1.5 mmol, 232 mg) in EtOH (3 mL) was added 2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboximidamide hydrochloride (1.5 mmol, 320 mg, 1.0 equiv.) and potassium carbonate (3.0 mmol, 414 mg, 2.0 equiv.). The reaction mixture was stirred at 80 °C for 3 h. Upon completion, the reaction was acidified with concentrated HCl and diluted with EtOAc and water. The organic phase was separated, and the aqueous layer was extracted twice with EtOAc. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. ESI-MS (m / z): 295.1 [M+H] + .

[0428] Example 1B: 4-chloro-6-isopropyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-5-carbonitrile. [ka] A reaction mixture of 4-hydroxy-6-isopropyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-5-carbonitrile in POCl3 (1 mL) was stirred at 100 °C for 20 min. Upon completion (reaction progress was monitored by LCMS), the reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired compound. ESI-MS (m / z): 313.1 [M+H] + .

[0429] Example 1C: 1-((chloromethyl)sulfinyl)-2-methoxyethane. [ka] To a solution of (chloromethyl)(2-methoxyethyl)sulfane (500 mg, 3.57 mmol, 1.0 equiv.) in 25 mL of DCM was added mCPBA (678 mg, 1.1 mmol, 1.0 equiv.), and the reaction mixture was stirred at room temperature. After 1 h, the reaction was diluted with EtOAc and saturated NaHCO3 solution. The organic phase was separated, washed with saturated NaHCO3 solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified on a CombiFlash® purification system to give pure ((chloromethyl)sulfinyl)cyclobutane in 29% yield. 1 H NMR (400 MHz, chloroform-d) δ 4.64 (d, J = 10.8 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H), 3.95-3.76 (m, 2H), 3.40 (s, 3H), 3.21 (m, 1H), 3.05 (m, 1H).

[0430] Example 1D: 4-Isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-5-carbonitrile. [ka] To a solution of 4-chloro-6-isopropyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-5-carbonitrile (40 mg, 0.128 mmol) in DMF (500 μL) was added sodium sulfide (12 mg, 0.15 mmol, 1.2 equiv.), and the reaction mixture was stirred at 100° C. for 20 min. The reaction progress was followed by LCMS. Upon completion, two drops of concentrated HCl were added, and the reaction mixture was stirred in the hood for 10 min. ESI-MS (m / z): 311.0 [M+H] + The reaction mixture was diluted with CH3CN (1 mL) and Et3N (0.38 mmol, 39 mg), followed by the addition of 1-((chloromethyl)sulfinyl)-2-methoxyethane (0.38 mmol, 60 mg). The reaction mixture was stirred at 80 °C for 2 h. Upon completion, the reaction was diluted with EtOAc and water. The organic phase was separated, and the aqueous layer was extracted twice with EtOAc. The combined extracts were washed with saturated NaCl solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the product in 62% yield. ESI-MS (m / z): 431.1 [M+H] + .

[0431] Example 1: Synthesis of Compound 17. To a solution of 4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-5-carbonitrile (20 mg, 0.046 mmol) in DMF (0.5 mL) was added KOH (0.023 mmol, 2.6 mg in 26 μL of water). The reaction mixture was stirred at room temperature for 20 minutes (the reaction was monitored by TLC). Upon completion of the reaction, the reaction mixture was diluted with EtOAc and washed with 5% aqueous acetic acid. The organic phase was separated, and the aqueous layer was extracted twice with EtOAc, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography in 42% isolated yield. 1H NMR(400MHz, methylene chloride-d2)δ 9.83(d,J=2.1Hz,1H),9.24(d,J=2.1Hz,1H),8.10(s,1H),5.14(s,2H),4.28(s,3H),3.86(ddd,J=10.3,7.5,4.0Hz,1H),3.76-3.63(m,2H), 3.59(ddd,J=13.0,6.4,4.0Hz,1H),3.39(s,3H),3.27(ddd,J=13.0,7.5,4.2Hz,1H),1.53(dd,J=6.7,3.1Hz,6H).ESI-MS(m / z):431.1[M+H] + .

[0432] Example 2: Synthesis of (R)-2-(cyclobutylsulfinyl)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)thieno[2,3-b]pyridin-3-amine (compound 14). [ka] Example 2A: Synthesis of 1-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)ethenone. [ka] To a solution of (2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (10 g, 56.5 mmol) and acetic anhydride (28.8 g, 282 mmol, 26.6 mL) in dioxane (200 mL) and HO (20 mL) was added Pd(dppf)Cl.CHCl (4.61 g, 5.65 mmol) and KCO (23.4 g, 169 mmol). The mixture was stirred at 80 °C for 6 h. The solution was poured into water (300 mL) and extracted with ethyl acetate (500 mL * 2). The organic layer was concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 2:1 to 0:1) to give the target compound (1.6 g, 16% yield) as a yellow solid.

[0433] Example 2B: Synthesis of 2-bromo-1-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)ethanone. [ka] To a solution of Example 2A (1.5 g, 8.56 mmol) in THF (25 mL) was added tetrabutylammonium tribromide (2.89 g, 5.99 mmol). The mixture was stirred at 30°C for 3 hours, and then the reaction mixture was stirred at 70°C for 15 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL * 2). The filtrate was concentrated under reduced pressure to give the desired compound (1.5 g, 68% yield) as a yellow solid.

[0434] Example 2C: Synthesis of 1-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2-(triphenylphosphoranylidene)ethanone. [ka] To a solution of Example 2B (1.3 g, 5.12 mmol) and triphenylphosphine (1.34 g, 5.12 mmol) in THF (15 mL) was added TEA (1.04 g, 10.2 mmol, 1.4 mL). The mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with 20 mL of toluene to give the desired compound (2.3 g, crude) as a red solid.

[0435] Example 2D: Synthesis of 2-oxaspiro[3.3]heptan-6-ylmethanol. [ka] To a solution of ethyl 2-oxaspiro[3.3]heptane-6-carboxylate (1.7 g, 9.99 mmol) in THF (15 mL) was added LiAlH (417 mg, 10.9 mmol) in THF (5 mL) over 0.5 h at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding saturated ammonium chloride (20 mL) at 0 °C and extracted with 150 mL of ethyl acetate (50 mL * 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL * 3), dried over Na SO , filtered, and concentrated under reduced pressure to give the target compound (1.1 g, 85% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.71(s,2H),4.62(s,2H),3.54(s,2H),2.34-2.30(m,3H),2.01-1.97(m,2H).

[0436] Example 2E: Synthesis of 2-oxaspiro[3.3]heptane-6-carbaldehyde [ka] To a solution of Example 2D (1.08 g, 8.43 mmol) in DCM (20 mL) was added DMP (4.29 g, 10.1 mmol, 3.1 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under pressure to give the desired compound (450 mg, 42% yield) as a yellow oil.

[0437] Example 2F: Synthesis of 1-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-(2-oxaspiro[3.3]heptan-6-yl)prop-2-en-1-one [ka] To a solution of Example 2E (369 mg, 2.93 mmol) in acetonitrile (20 mL) was added Example 2C (1.28 g, 2.93 mmol). The mixture was heated to 60 °C and stirred for 12 h. After cooling, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 5:1 to 0:1 to ethyl acetate:methanol = 30:1 to 0:1) to give the target compound (350 mg, 42% yield) as a white solid.

[0438] Example 2G: Synthesis of 6-(2-methylpyrazolo[3,4-b]pyridin-5-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)-2-sulfanyl-3,4-dihydropyridine-3-carbonitrile. [ka] To a solution of Example 2F (300 mg, 1.06 mmol) and 2-cyanothioacetamide (424 mg, 4.24 mmol) was added TEA (321 mg, 3.18 mmol, 0.4 mL) in ACN (10 mL). The mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to give the desired compound (386 mg, crude) as a yellow oil.

[0439] Example 2H: Synthesis of 6-(2-methylpyrazolo[3,4-b]pyridin-5-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)-2-sulfanyl-pyridine-3-carbonitrile [ka] To a solution of Example 2G (386 mg, 1.06 mmol) was added TEA (213 mg, 2.11 mmol, 0.3 mL) in ACN (10 mL) under O. The mixture was stirred at 80 °C for 10 min. The reaction mixture was concentrated under reduced pressure to give the target compound (383 mg, crude) as a yellow oil.

[0440] Example 2I: Synthesis of (R)-2-(((cyclobutylsulfinyl)methyl)thio)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)nicotinonitrile [ka] To a solution of Example 2H (383 mg, 1.05 mmol) in DMF (5 mL), triethylamine (2.0 equivalents) and (R)-((bromomethyl)sulfinyl)cyclobutane (207 mg, 1.05 mmol) were added. The mixture was stirred at 25° C. for 15 minutes. The mixture was concentrated, and the crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.1% TFA)-ACN]) to obtain the target compound (200 mg, 39% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 9.26(d,J=2.4Hz,1H),8.97(d,J=2.4Hz,1H),8.14(s,1H),7.51(s,1H),4 .90(s,2H),4.70-4.66(m,3H),4.32(s,3H),4.07(d,J=12.8Hz,1H),3.80- 3.74(m,1H),3.68-3.66(m,1H),2.94-2.89(m,2H),2.80-2.74(m,1H),2. 50-2.44(m,3H),2.32-2.27(m,1H),2.13-2.10(m,2H),2.02-1.99(m,1H).

[0441] Example 2: Synthesis of Compound 14 [ka] Example 2: To a solution of Example 2I (190 mg, 396 μmol, 1 equiv.) in methanol and N,N-dimethylformamide was added potassium hydroxide solution (5%, 0.6 equiv.). The mixture was stirred at 25° C. for 10 minutes. The mixture was neutralized with aqueous acetic acid (10%) and concentrated. The residue was purified by reverse-phase HPLC to give the desired compound (135 mg, 70% yield, 98% purity) as a yellow solid. Optical rotation was measured, showing a specific rotation of +75.984°; LCMS: (ES+) m / z (M+H)+ = 480.2. 1 H NMR(400MHz,CDCl3)δ 9.29(d,J=2.0Hz,1H),8.56(d,J=2.4Hz,1H),7.95(s,1H),7.49(s,1H), 5.09(s,2H),4.91(s,2H),4.67(d,J=6.8Hz,1H),4.63(d,J=6.4Hz,1H),4 .29(s,3H),4.09-4.05(m,1H),3.94-3.91(m,1H),2.87-2.82(m,3H),2.7 5-2.68(m,1H),2.40-2.37(m,3H),2.32-2.27(m,1H),2.13-2.05(m,2H).

[0442] Example 3: Synthesis of (R)-3-amino-2-((2-methoxyethyl)sulfinyl)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-phenylthieno[2,3-b]pyridine-5-carbonitrile (Compound 9) [ka] Example 3A: Synthesis of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile [ka] To a solution of trimethoxymethylbenzene (15 g, 82.3 mmol, 14.1 mL) in pyridine (40 mL) was added propanedinitrile (10.9 g, 165 mmol, 10.4 mL). The mixture was stirred at 110 °C for 7 h. After cooling, HCl (12 M, 82.4 mL) was added and the mixture was stirred at 100 °C for an additional 2.5 h. The reaction mixture was cooled and filtered. The filter cake was collected and used directly in the next step. The target compound (7.7 g, 37% yield) was obtained as a yellow solid.

[0443] Example 3B: Synthesis of 2-amino-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-phenylpyridine-3,5-dicarbonitrile [ka] To a solution of Example 3A (6.7 g, 26.3 mmol, 1.0 equiv.) in tetrahydrofuran and water was added sodium carbonate (2.0 equiv.). 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 equiv.) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4-b]pyridine (10.2 g, 39.5 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The mixture was concentrated, and water was added. The mixture was extracted with dichloromethane, and the combined organic phases were concentrated. The residue was purified by column chromatography to give the desired compound (2.2 g, 24% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.98(d,J=2.0Hz,1H),8.77(d,J=2.4Hz,1H),8.64(s,1H),8.48(s,2H),7.68-7.59(m,5H),4.26(s,3H).

[0444] Example 3C: Synthesis of 2-chloro-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-phenylpyridine-3,5-dicarbonitrile [ka] To a solution of Example 3B (2.2 g, 6.26 mmol) in MeCN (40 mL) were added CuCl (1.68 g, 12.5 mmol) and isopentyl nitrite (1.47 g, 12.5 mmol, 1.69 mL). The mixture was stirred at 60 °C for 16 h. 1 M HCl (30 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 5:1 to 0:1 to ethyl acetate:MeOH = 50:1). The target compound (0.2 g, 9% yield) was obtained as a yellow solid. 1 H NMR(400MHz,MeOD)δ 8.31(s,1H),8.28(d,J=1.8Hz,1H),8.06-8.01(m,1H),7.69-7.57(m,5H),4.27(s,3H).

[0445] Example 3D: Synthesis of 2-mercapto-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-phenylpyridine-3,5-dicarbonitrile [ka] To a solution of Example 3C (0.17 g, 458 μmol) in dimethylformamide (2 mL) was added NaS (42.9 mg, 550 μmol). The mixture was stirred at 100° C. for 0.5 h. The mixture was concentrated to afford the target compound (0.17 g, crude) as a yellow oil.

[0446] Example 3E: Synthesis of (R)-2-((((2-methoxyethyl)sulfinyl)methyl)thio)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-4-phenylpyridine-3,5-dicarbonitrile [ka] Example 3E was prepared by the procedure used in Example 2I starting from Example 3D (170 mg, 461 μmol), KI (153 mg, 923 μmol), and (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane (72.3 mg, 461 μmol) to afford the desired compound (170 mg, 75%) as a yellow solid.

[0447] Example 3: Synthesis of Compound 9 [ka] Compound 9 was prepared by the procedure used in Example 2 starting from Example 3E (170 mg, 348 μmol) to give the desired compound (10.2 mg, 6% yield, 98.7% purity) as a yellow solid. Optical rotation was measured, showing a specific rotation of +53.216°; LCMS: (ES+) m / z (M+H)+ = 489.1. 1 H NMR(400MHz,CDCl3)δ 9.21(d,J=2.4Hz,1H),8.67(d,J=2.4Hz,1H),8.00(s,1H),7.60-7.53(m,3H),7.48-7.41(m,2H),4.44(s, 2H),4.24(s,3H),3.82-3.7(m,1H),3.66-3.59(m,1H),3.55-3.47(m,1H),3.31(s,3H),3.23-3.16(m,1H).

[0448] Example 4: Synthesis of (R)-4-cyclobutyl-6-(imidazo[1,2-a]pyrazin-3-yl)-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-3-amine (Compound 11) [ka] Example 4A: Synthesis of 3-(1-ethoxyvinyl)imidazo[1,2-a]pyrazine [ka] To a solution of 3-bromoimidazo[1,2-a]pyrazine (2.7 g, 13.6 mmol) in DMF (36 mL) was added tributyl(1-ethoxyvinyl)tin (1 equivalent) and Pd(PPh)Cl (0.05 equivalent) under N. The mixture was stirred at 100 °C for 12 h. The mixture was diluted with ethyl acetate (100 mL) and treated with aqueous potassium fluoride (12 g KF in 20 mL water). The solution was stirred at 25 °C for 0.5 h. The solution was filtered. The filtrate was diluted with H2O (80 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The target compound (2.3 g, crude) was obtained as a brown solid.

[0449] Example 4B: Synthesis of 1-(imidazo[1,2-a]pyrazin-3-yl)ethanone [ka] To a solution of Example 4A (2.3 g, 12.2 mmol) in THF (50 mL) was added HCl (1 M, 19.5 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by adding saturated NaHCO (60 mL) at 25 °C, and then extracted with dichloromethane (100 mL * 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with DMF (30 mL) at 25 °C for 5 minutes. The target compound (1.3 g, 66%) was obtained as a brown solid.

[0450] Example 4C: Synthesis of (E)-3-cyclobutyl-1-(imidazo[1,2-a]pyrazin-3-yl)prop-2-en-1-one [ka] To a solution of Example 4B (900 mg, 5.58 mmol) and cyclobutanecarbaldehyde (1 equivalent) in ethyl alcohol (15 mL) was added piperidine (2 equivalents). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 5:1 to 0:1 to ethyl acetate:methanol = 30:1 to 0:1). The target compound (600 mg, 47%) was obtained as a brown solid.

[0451] Example 4D: Synthesis of 4-cyclobutyl-6-(imidazo[1,2-a]pyrazin-3-yl)-2-mercaptonicotinonitrile [ka] To a solution of Example 4C (400 mg, 1.36 mmol) and 2-cyanothioacetamide (204 mg, 2.04 mmol) in MeCN (4 mL) was added TEA (0.4 mL). The mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was used in the next step without further purification.

[0452] Example 4E: Synthesis of (R)-4-cyclobutyl-6-(imidazo[1,2-a]pyrazin-3-yl)-2-((((2-methoxyethyl)sulfinyl)methyl)thio)nicotinonitrile [ka] Example 4E was prepared by the procedure used in Example 2I starting from Example 4D (400 mg, 1.30 mmol) and (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane (245 mg, 1.56 mmol) to afford the desired compound (200 mg, 73%) as a brown solid. 1H NMR(400MHz,CDCl3)δ 9.52(dd,J1=4.8Hz,J1=1.2Hz,1H),9.26(d,J=1.2Hz,1H),8.35(s,1H),8 .20(d,J=4.4Hz,1H),7.50(s,1H),4.85-4.78(m,1H),4.70-4.64(m,1H), 4.04-3.96(m,1H),3.92-3.80(m,2H),3.43(s,3H),3.28-3.19(m,1H),3. 15-3.07(m,1H),2.65-2.55(m,2H),2.36-2.16(m,3H),2.03-1.95(m,1H).

[0453] Example 4: Synthesis of Compound 11 [ka] Compound 11 was prepared by the procedure used in Example 2 starting from Example 4E (270 mg, 631 μmol) to give the desired compound (171.9 mg, 63% yield, 98.9% purity) as a yellow solid. Optical rotation was measured, showing a specific rotation of +148.851°; LCMS: (ES+) m / z (M+H)+ = 428.2. 1 H NMR(400MHz,CDCl3)δ 9.81(dd,J1=4.4Hz,J2=1.6Hz,1H),9.23(d,J=1.6Hz,1H),8.43(s,1H),8. 12(d,J=4.8Hz,1H),7.68(d,J=0.4Hz,1H),5.14(s,2H),4.28-4.16(m,1H) ,3.95-3.88(m,1H),3.77-3.69(m,1H),3.69-3.61(m,1H),3.44(s,3H),3. 35-3.25(m,1H),2.61-2.38(m,4H),2.28-2.14(m,1H),2.11-2.00(m,1H).

[0454] Example 5: Synthesis of (R)-6-(imidazo[1,2-a]pyrazin-3-yl)-2-((2-methoxyethyl)sulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)thieno[2,3-b]pyridin-3-amine (Compound 13) [ka] Example 5A: (R)-6-(imidazo[1,2-a]pyrazin-3-yl)-2-((((2-methoxyethyl)sulfinyl)methyl)thio)-4-(1-methyl-1H-pyrazol-5-yl)nicotinonitrile [ka] To a solution of Example 4B (247 mg, 1.5 mmol) and 2-methylpyrazole-3-carbaldehyde (253 mg, 2.3 mmol) in EtOH (2 mL) was added DBU (467 mg, 3.1 mmol). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give Example 5A (400 mg, crude) as a yellow solid.

[0455] Example 5B: [ka] To a solution of Example 5A (50 mg, 0.20 mmol) and 2-cyanothioacetamide (40 mg, 0.39 mmol) in DMF (1 mL) was added NaH (24 mg, 0.59 mmol, 60% purity). The mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched by the addition of MeOH (1 mL) at 25° C. and then concentrated under reduced pressure to give the target compound (65 mg, crude) as a yellow liquid, which was used in the next step without further purification.

[0456] Example 5C: [ka] To a solution of Example 5B (70 mg, 0.20 mmol) and (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane (33 mg, 0.20 mmol) in DMF (0.2 mL), KI (70 mg, 0.40 mmol) and TEA (43 mg, 0.40 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA condition; column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 28%-38%, 7 min) to give the target compound (60 mg, 63% yield) as a yellow solid.

[0457] Example 5: Synthesis of Compound 13 [ka] Compound 13 was prepared by the procedure used in Example 2 starting from Example 5C (50 mg, 0.11 mmol) to give the desired compound (17 mg, 33% yield, 98% purity) as a yellow solid. Optical rotation was measured, showing a specific rotation of +129.967°; LCMS: (ES + ) m / z (M+H) + =454.1. 1 H NMR(400MHz,CDCl3)δ=9.77(m,1H),9.18(d,J=1.6Hz,1H),8.32(s,1H),8.10(d,J=4.8Hz,1H),7.62(d,J=1.8Hz,1H),7.60(s,1H),6. 45(m,1H),4.57-4.39(m,2H),3.82-3.79(m,1H),3.79(s,3H),3.69-3.61(m,1H),3.58-3.50(m,1H),3.34(s,3H),3.24-3.18(m,1H).

[0458] Example 6 Synthesis of 2-[(R)-cyclobutanesulfinyl]-6-{imidazo[1,2-a]pyrimidin-3-yl}-4-(1-methyl-1H-pyrazol-5-yl)thieno[2,3-b]pyridin-3-amine (Compound 5) [ka] Starting from Example 5B and (R)-((bromomethyl)sulfinyl)cyclobutane, compound 5 was prepared according to the procedure used in Example 5. Compound 5 was isolated as a yellow solid. Optical rotation was measured, which showed a specific rotation of +47.325°; LCMS: (ES + ) m / z (M+H) + =450.2. 1 H NMR(400MHz,CDCl3)δ 8.63-8.62(m,1H),8.53-8.51(m,1H),8.38(s,1H),8.30(s,1H),7.67-7.66(d,J=1.2Hz,1H),6.97-6.95(m,1H),6.50(s,1H),4 .61-4.51(m,2H),4.00-3.92(m,1H),3.79(s,3H),2.89-2.80(m,1H),2.41-2.37(m,2H),2.29-2.28(m,1H),2.13-2.09(m,2H).

[0459] Example 7: 4-Cyclobutyl-2-(2-methoxyethanesulfinyl)-6-{pyrido[2,3-b]pyrazin-7-yl}thieno[2,3-b]pyridin-3-amine (Compound 7) [ka] Example 7A: 4-Cyclobutyl-2-((((2-methoxyethyl)thio)methyl)thio)-6-(pyrido[2,3-b]pyrazin-7-yl)nicotinonitrile [ka] To a solution of cyclobutanecarboxylic acid (20 g, 199 mmol) in tetrahydrofuran (300 mL) was added CDI (34.01 g, 209 mmol). The mixture was stirred at 60 °C for 1 h. After cooling to 25 °C, magnesium chloride (22.82 g, 239 mmol) and potassium monoethyl malonate (37.40 g, 219 mmol) were added to the mixture, and the reaction was stirred at 60 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 100:1) to give the target compound (30 g, 88% yield) as a yellow liquid. 1 H NMR(400MHz,CDCl3)δ 4.15-4.09(m,2H),3.39-3.28(m,3H),2.25-2.16(m,2H),2.11-2.05(m,2H),1.97-1.85(m,1H),1.81-1.72(m,1H),1.21(t,J=7.2Hz,3H).

[0460] Example 7B: [ka] To a solution of Example 7A (10 g, 58.75 mmol) in methyl alcohol (100 mL) were added potassium hydroxide (4.94 g, 88.13 mmol) and 2-cyanothioacetamide (8.83 g, 88.13 mmol). The mixture was stirred at 70° C. for 12 hours. The reaction mixture was filtered to give crude Example 7B (12 g) as a yellow solid.

[0461] Example 7C: [ka] To a solution of Example 7B (5 g, 24.2 mmol) in acetonitrile (50 mL) were added triethylamine (7.36 g, 72.7 mmol) and (chloromethyl)(2-methoxyethyl)sulfane (2.73 g, 19.4 mmol). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude Example 7C (7.5 g) as a yellow oil.

[0462] Example 7D: [ka] To a solution of Example 7C (7.5 g, 24.2 mmol) in tetrahydrofuran (100 mL) were added potassium tert-butoxide (5.42 g, 48.3 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (12.95 g, 36.2 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 100:1) to give the target compound (10 g), which was used in the next step without further purification.

[0463] Example 7E: [ka] To a solution of Example 7D (1.0 g, 2.26 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added sodium carbonate (2.0 equiv.). Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 equiv.) and pyrido[2,3-b]pyrazin-7-ylboronic acid (790 mg, 4.52 mmol) were added to the mixture. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The mixture was concentrated, diluted with water (30 mL), and extracted with dichloromethane (30 mL * 3). The organic phase was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 1:1) to give the target compound (0.2 g, 20% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 10.01(d,J=2.4Hz,1H),9.08(d,J=1.6Hz,1H),9.06(d,J=2.4Hz,1H),9.00(d,J=1.6Hz,1H),7.85(s,1H),4.61(s,2H),4.38-4. 33(m,1H),3.57(t,J=6.4Hz,2H),3.40(s,3H),2.97(t,J=6.4Hz,2H),2.58-2.41(m,4H),2.26-2.15(m,1H),2.09-2.01(m,1H).

[0464] Example 7F: [ka] To a solution of Example 7E (0.14 g, 330 μmol) in chloroform (2 mL), acetic acid (25 equivalents) and hydrogen peroxide (75 mg, 661 μmol, 63 μL, 30% purity) were added. The mixture was stirred at 20° C. for 1 hour. The mixture was basified with saturated sodium bicarbonate solution to pH=7 and extracted with dichloromethane (10 mL*3). The combined organic phase was concentrated to give the target compound (0.12 g, 82% yield) as a yellow solid.

[0465] Example 7: Synthesis of Compound 7 [ka] Compound 7 was prepared by the procedure used in Example 2 starting from Example 7F (0.1 g, 227 μmol) to give the desired compound (6.0 mg, 5% yield) as a yellow solid. LCMS: (ES + ) m / z (M+H) + =440.2. 1H NMR(400MHz,CDCl3)δ 10.01(d,J=2.4Hz,1H),9.12-9.09(m,2H),9.02(d,J=2.0Hz,1H),7.89(s,1H),5.17(s,2H),4.29-4.27(m,1H),3.93-3.88(m,1H),3.74-3. 70(m,1H),3.67-3.63(m,1H),3.43(s,3H),3.35-3.29(m,1H),2.59-2 .53(m,2H),2.51-2.44(m,2H),2.26-2.18(m,1H),2.09-2.05(m,1H).

[0466] Example 8: Synthesis of (R)-2-(cyclobutylsulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)-6-(quinoxalin-6-yl)thieno[2,3-b]pyridin-3-amine (Compound 1) [ka] Compound 1 was prepared by the procedure used in Example 4, starting from 3-bromoimidazo[1,2-a]pyrazine and using (R)-((bromomethyl)sulfinyl)cyclobutane. The target compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +165.379°; LCMS: (ES + ) m / z (M+H) + =461.2. 1 H NMR(400MHz,DMSO-d6)δ=9.06-8.94(m,3H),8.77(d,J=8.8Hz,1H),8.34(s,1H),8.24(d,J=8.8Hz,1H),7.71(s,1H),6.68 (s,1H),5.20-4.78(m,2H),3.90(m,J=8.0Hz,1H),3.75(s,3H),2.77-2.60(m,1H),2.29-2.11(m,3H),2.09-1.87(m,2H).

[0467] Example 9 Synthesis of 2-[(R)-2-methoxyethanesulfinyl]-4-(1-methyl-1H-pyrazol-5-yl)-6-(quinoxalin-6-yl)thieno[2,3-b]pyridin-3-amine (Compound 4) [ka] Compound 4 was prepared in a manner similar to that used in Example 8 using (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane. The desired compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +86.501°; LCMS; (ES + ) m / z (M+H) + =465.2. 1 H NMR(400MHz,DMSO-d6)δ=9.09-8.95(m,3H),8.79(d,J=9.2Hz,1H),8.37(s,1H),8.25(d,J=8.8Hz,1H),7.72(m,1 H),6.69(s,1H),5.18-4.94(m,2H),3.76(m,4H),3.69-3.61(m,1H),3.41(m,1H),3.29(s,3H),3.28-3.21(m,1H).

[0468] Example 10: Synthesis of 2-[(R)-cyclobutanesulfinyl]-4-(1-methyl-1H-pyrazol-5-yl)-6-(quinazolin-6-yl)thieno[2,3-b]pyridin-3-amine (Compound 10) [ka] Compound 10 was prepared by the procedure used in Example 4, starting with 6-bromoquinazoline and using (R)-((bromomethyl)sulfinyl)cyclobutane. The target compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +171.791°; LCMS: (ES + ) m / z (M+H) + =461.2. 1H NMR(400MHz,CDCl3)δ 9.53(s,1H),9.38(s,1H),8.74-8.70(m,2H),8.19(d,J=9.2Hz,1H),7.79(s,1H),7.69(s,1H),6.53(d,J=10.0Hz,1H),4.62 -4.52(m,2H),4.00-3.92(s,1H),3.78(s,3H),2.88-2.79(m,1H),2.47-2.37(m,2H),2.31-2.26(m,1H),2.12-2.01(m,2H).

[0469] Example 11: Synthesis of 2-[(R)-2-methoxyethanesulfinyl]-4-(1-methyl-1H-pyrazol-5-yl)-6-(quinazolin-6-yl)thieno[2,3-b]pyridin-3-amine (Compound 15) [ka] Compound 15 was prepared in a manner similar to that used in Example 10 using (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane. The desired compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +55.805°; LCMS: (ES+) m / z (M+H)+ = 465.1. 1 H NMR(400MHz,CDCl3)δ 9.54(s,1H),9.39(s,1H),8.75-8.71(m,2H),8.21-8.18(m,1H),7.81(s,1H),7.69(s,1H),6.53(d,J=8.4Hz,1H),4 .60-4.52(m,2H),3.89-3.87(m,1H),3.79(s,3H),3.73(s,1H),3.63-3.61(m,1H),3.41(s,3H),3.31-3.29(m,1H).

[0470] Example 12: Synthesis of 2-[(R)-cyclobutanesulfinyl]-4-(1-methyl-1H-pyrazol-5-yl)-6-(quinazolin-7-yl)thieno[2,3-b]pyridin-3-amine (Compound 2) [ka] Compound 2 was prepared by the procedure used in Example 4, starting from 7-bromoquinazoline and using (R)-((bromomethyl)sulfinyl)cyclobutane. The target compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +127.389°; LCMS: (ES + ) m / z (M+H) + =461.2. 1 H NMR(400MHz,CDCl3)δ 9.48(s,1H),9.40(s,1H),8.69(s,1H),8.58-8.55(m,1H),8.09(d,J=8.4Hz,1H),7.84(s,1H),7.69(d,J=1.6Hz,1H),6.52(s,1H), 4.64-4.54(m,2H),3.97(t,J=8.0Hz,1H),3.79(s,3H),2.87-2.81(m,1H),2.45-2.34(m,2H),2.29-2.25(m,1H),2.13-2.07(m,2H).

[0471] Example 13: Synthesis of 2-[(R)-2-methoxyethanesulfinyl]-4-(1-methyl-1H-pyrazol-5-yl)-6-(quinazolin-7-yl)thieno[2,3-b]pyridin-3-amine (compound 16). [ka] Compound 16 was prepared in a manner similar to that used in Example 12 using (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane. The desired compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +57.551°; LCMS: (ES + ) m / z (M+H) + =465.2. 1H NMR(400MHz,CDCl3)δ 9.47(s,1H),9.39(s,1H),8.69(s,1H),8.57(d,J=8.4Hz,1H),8.09(d,J=8.8Hz,1H),7.85(s,1H),7.70(s,1H),6.53(s, 1H),4.62-4.54(m,2H),3.89-3.86(m,1H),3.80(s,3H),3.72(s,1H),3.63-3.60(m,1H),3.41(s,3H),3.32-3.29(m,1H).

[0472] Example 14: Synthesis of 2-(cyclobutanesulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)-6-(1,8-naphthyridin-3-yl)thieno[2,3-b]pyridin-3-amine and its enantiomers (compounds 12, 26 and 27). [ka] Compounds 12, 26, and 27 were prepared in a manner similar to that used in Example 7. The target compounds were isolated as yellow solids. LCMS: (ES+) m / z (M+H)+ = 461.2. 1 H NMR(400MHz,DMSO-d6)9.91(d,J=2.8Hz,1H),9.34(d,J=2.4Hz,1H),9.14(dd,J 1=4.4Hz,J2=2.0Hz,1H),8.61(dd,J1=4.0Hz,J2=2.0Hz,1H),8.30(s,1H),7.74 -7.70(m,2H),6.69(s,1H),5.11-4.96(m,2H),3.90(q,J=8.0Hz,1H),3.74(s,3 H),2.71-2.62(m,1H),2.26-2.14(m,3H),2.07-1.99(m,1H),1.90-1.80(m,1H).

[0473] The enantiomers were separated by SFC (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 55% to 55%, 4.0 min; 50 min), to give the (+) enantiomer (20 mg, 38% yield, 98% purity, 99% ee) and the (-) enantiomer (21 mg, 40% yield, 99% purity, 97% ee) as yellow solids. Optical rotation measurements showed specific rotations of +175.541° and -130.767°.

[0474] Example 15: Synthesis of 4-cyclobutyl-2-(2-methoxyethanesulfinyl)-6-(1,8-naphthyridin-3-yl)thieno[2,3-b]pyridin-3-amine (Compound 6) [ka] Compound 6 was prepared in a manner similar to that used in Example 7. The target compound was isolated as a yellow solid. LCMS: (ES + ) m / z (M+H) + =439.1. 1 H NMR(400MHz,CDCl3)9.83(d,J=2.4Hz,1H),9.17-9.16(m,1H),8.91(d,J=2.4Hz,1H),8.35-8.32 m,1H),7.5(s,1H),7.58-7.53(m,1H),5.15(s,2H),4.30-4.21(m,1H),3.93-3.87(m,1H),3.74-3.69(m,1H), 3.66-3.60(m,1H),3.42(s,3H),3.30-3.27(m,1H),2.60-2.40(m,4H),2.27-2.15(m,1H),2.10-2.02(m,1H).

[0475] Example 16: Synthesis of 2-(2-methoxyethanesulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)-6-(1,5-naphthyridin-3-yl)thieno[2,3-b]pyridin-3-amine (Compound 3) [ka] Compound 6 was prepared in a manner similar to that used in Example 7. The target compound was isolated as a yellow solid. LCMS: (ES+) m / z (M+H)+ = 465.2. 1 H NMR(400MHz,CDCl3)δ 9.82(d,J=2.0Hz,1H),9.09-9.06(m,1H),9.04-9.01(m,1H),8.52-8.48(m,1H),7.85(s,1H),7.75-7.70(m,2H),6.59-6.53(m,1H) ),4.60(d,J=26.4Hz,2H),3.95-3.88(m,1H),3.82(s,3H),3.79-3.71(m,1H),3.69-3.60(m,1H),3.43(s,3H),3.36-3.28(m,1H).

[0476] Example 17: Synthesis of 5-{3-amino-2-[2-methoxyethanesulfinyl]-4-(propan-2-yl)thieno[2,3-b]pyridin-6-yl}pyrimidin-2-amine and its enantiomers (compounds 18 and 19). [ka] Example 17 was prepared in a manner similar to that used for Example 7. The target compound was isolated as a yellow solid. LCMS: (ES + ) m / z (M+H) + =392.1. 1 H NMR(400MHz,CDCl3)δ 9.02(s,2H),7.50(s,1H),5.35(s,2H),5.09(s,2H),3.94-3.87(m,1H),3.81-3 .61(m,3H),3.43(s,3H),3.35-3.27(m,1H),1.48(dd,J1=6.8Hz,J2=4.0Hz,6H).

[0477] The enantiomers (compounds 18 and 19) were separated by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O MEOH]; B%: 60% to 60%, 3.8 min; 99 min), to give the (+) enantiomer (76.0 mg, 42% yield, 98.7% purity, 98.7% ee) and the (-) enantiomer (61.4 mg, 34% yield, 98.4% purity, 93.9% ee) as yellow solids. Optical rotation measurements showed specific rotations of +159.997° and -134.476°.

[0478] Example 18: Synthesis of 5-{3-amino-2-[(cyclobutanesulfinyl]-4-(propan-2-yl)thieno[2,3-b]pyridin-6-yl}pyrimidin-2-amine and its enantiomers (compounds 20 and 21). [ka] Example 18 was prepared in a manner similar to that used for Example 7. The target compound was isolated as a yellow solid. LCMS: (ES+) m / z (M+H)+ = 388.1. 1 H NMR(400MHz,CDCl3)δ 8.99(m,2H),7.47(s,1H),5.28(s,2H),3.99-3.95(m,1H),3.81-3.76(m,1H),2.89-2. 80(m,1H),2.41-2.37(m,2H),2.27-2.25(m,1H),2.12-2.06(m,2H),1.47-1.44(m,6H).

[0479] The enantiomers (compounds 20 and 21) were separated by SFC (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B%: 60% to 60%, 6.4; 150 min) to give the (+) enantiomer (40.7 mg, 35% yield, 99% purity, 100% ee) and the (-) enantiomer (108.7 mg, 93% yield, 99% purity, 100% ee) as yellow solids. Optical rotation measurements showed specific rotations of +73.213° and -51.454°.

[0480] Example 19: Synthesis of 5-{3-amino-2-[(R)-2-methoxyethanesulfinyl]-4-(propan-2-yl)thieno[2,3-b]pyridin-6-yl}-N-methylpyrimidin-2-amine and its enantiomers (compounds 22 and 23). [ka] Example 19 was prepared in a manner similar to that used for Example 7. The target compound was isolated as a yellow solid. LCMS: (ES + ) m / z (M+H) + =406.2.

[0481] 1 H NMR(400MHz,CDCl3)δ 8.99(m,2H),7.47(s,1H),5.40(s,1H),5.06(s,2H),3.90-3.88(m,1H),3.74- 3.61(m,3H),3.42(s,3H),3.30-3.29(m,1H),3.10(d,J=4.8Hz,3H),1.45(dd,J 1= 6.8Hz;J2=3.6Hz,6H).

[0482] The enantiomers (compounds 22 and 23) were separated by SFC (column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O MeOH]; B%: 40% to 40%, 2.1 min; 110 min), to give the (+) enantiomer (36.6 mg, 48% yield, 99% purity, 100% ee) and the (-) enantiomer (15.7 mg, 20% yield, 99% purity, 97% ee) as yellow solids. Optical rotation measurements showed specific rotations of +26.829° and -43.948°.

[0483] Example 20: Synthesis of 4-tert-butyl-2-[(R)-2-methoxyethanesulfinyl]-6-{2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}thieno[2,3-b]pyridin-3-amine (Compound 28). [ka] Compound 28 was prepared in a manner similar to that used in Example 2. The desired compound was isolated as a yellow solid. Optical rotation was measured and showed a specific rotation of +52.958°; LCMS: (ES+) m / z (M+H)+ = 444.1. 1 H NMR(500MHz,DMSO-d6)δ 9.37(d,J=2.0Hz,1H),8.99(d,J=2.0Hz,1H),8.57(s,1H),7.94(s,1H),5.53(s,2H),4.25(s, 3H),3.77-3.74(m,1H),3.63-3.61(m,1H),3.46-3.44(m,1H),3.34-3.29(m,4H),1.65(s,9H).

[0484] Example 21: 4-tert-Butyl-2-[(R)-2-methoxyethanesulfinyl]-6-{2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl}thieno[2,3-b]pyridin-3-amine (compound 29). [ka] Compound 29 was prepared in a manner similar to that used in Example 2. The desired compound was isolated as a yellow solid. Optical rotation was measured and showed a specific rotation of +60.649°; LCMS: (ES+) m / z (M+H)+ = 445.1. 1 H NMR(500MHz,DMSO-d6)δ 9.56(s,1H),9.16(d,J=2.0Hz,1H),8.02(s,1H),5.55(s,2H),4.61(s,3H),3.79-3 .77(m,1H),3.64-3.62(m,1H),3.46-3.44(m,1H),3.33-3.21(m,4H),1.66(s,9H).

[0485] Example 22: Synthesis of 5-{3-amino-4-tert-butyl-2-[(R)-cyclobutanesulfinyl]thieno[2,3-b]pyridin-6-yl}pyrimidin-2-amine (compound 35). [ka] Compound 35 was prepared in a manner similar to that used in Example 4. The desired compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +141.610°; LCMS: (ES + ) m / z (M+H) + =402.1. 1 H NMR(400MHz,CDCl3)δ 9.00(s,2H),7.59(s,1H),5.38(s,2H),5.29(s,2H),4.09-4.01(m,1H),2.88-2. 80(m,1H),2.43-2.38(m,2H),2.26-2.25(m,1H),2.12-2.08(m,2H),1.66(s,9H).

[0486] Example 23: Synthesis of 6-{3-amino-2-[(R)-cyclobutanesulfinyl]-4-(propan-2-yl)thieno[2,3-b]pyridin-6-yl}-3-methyl-3,4-dihydropyrimidin-4-one (compound 33). [ka] Compound 33 was prepared in a manner similar to that used in Example 4. The desired compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +84.623°; LCMS: (ES + ) m / z (M+H) + =403.2. 1 H NMR(400MHz,CDCl3)δ 8.24(s,1H),8.20(s,1H),7.57(s,1H),5.17(s,2H),4.04-3.94(m,1H),3.86-3.77(m,1H),3.60(s,3H),2.90 -2.79(m,1H),2.49-2.34(m,2H),2.32-2.22(m,1H),2.18-2.05(m,2H),1.48(dd,J1=10.4Hz,J2=6.8Hz,6H).

[0487] Compound 33 can be prepared in a manner similar to that used in Example 4, for example, by using 6-bromo-3-methylpyrimidin-4(3H)-one instead of 3-bromoimidazo[1,2-a]pyrazine, isobutyraldehyde instead of cyclobutanecarbaldehyde, and (R)-((bromomethyl)sulfinyl)cyclobutane instead of (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane. 6-Bromo-3-methylpyrimidin-4(3H)-one is available from commercial sources (e.g., AstaTech catalog number AC9854) or can be prepared by methylating 6-bromopyrimidin-4(3H)-one as described in Example 140 (Step A) of WO 2014 / 081617.

[0488] Example 24: Synthesis of 6-{3-amino-2-[(R)-2-methoxyethanesulfinyl]-4-(propan-2-yl)thieno[2,3-b]pyridin-6-yl}-3-methyl-3,4-dihydropyrimidin-4-one (compound 34). [ka] Compound 34 was prepared in a manner similar to that used in Example 23 using (R)-1-((chloromethyl)sulfinyl)-2-methoxyethane. The desired compound was isolated as a yellow solid. Optical rotation was measured, showing a specific rotation of +48.960°; LCMS: (ES+) m / z (M+H)+ = 407.2. 1 H NMR(400MHz,CDCl3)δ 8.24(s,1H),8.21(s,1H),7.59(s,1H),5.13(s,2H),3.94-3.87(m,1H),3.84-3.76(m,1H),3.75-3 .69(m,1H),3.68-3.62(m,1H),3.61(s,3H),3.43(s,3H),3.36-3.28(m,1H),1.50(t,J=6.8Hz,6H).

[0489] Example 25: Synthesis of 2-(cyclobutanesulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)-6-{2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}thieno[2,3-b]pyridin-3-amine (compound 30). [ka] Compound 30 was prepared in a manner similar to that used in Example 7. The target compound was isolated as a yellow solid. LCMS: (ES + ) m / z (M+H) + =467.1. 1 H NMR(500MHz,CDCl3)δ 8.38(s,1H),7.77(s,1H),7.64(s,1H),7.46(s,1H),6.46(s,1H),5.19(s,1H),4.51-4.27(m,2H)4.26-4.25(m,2H),3.94- 3.92(m,1H),3.73(s,3H),3.64-3.62(m,2H),2.80-2.78(m,1H),2.37-2.33(m,2H),2.23-2.22(m,1H),2.09-2.05(m,2H).

[0490] Example 26: Synthesis of 2-(cyclobutanesulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)-6-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)thieno[2,3-b]pyridin-3-amine (compound 31). [ka] Example 26A: tert-butyl 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate [ka] 1-Methyl-3,5-dinitro-pyridin-2-one (2.0 g, 10.0 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (2.2 g, 11.0 mmol) were suspended in MeOH (20 mL), and the resulting mixture was treated with NH3H2O ​​(4.55 g, 39.0 mmol, 5 mL, 30% purity). The resulting mixture was heated at 70 °C for 5 h and then allowed to stand at 30 °C for 12 h. The mixture was concentrated to remove the solvent. The reaction mixture was partitioned between water (30 mL) and DCM (90 mL). The organic phase was separated, washed with brine (20 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the target compound (2 g, 71% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ=9.25(d,J=2.0Hz,1H),8.28-8.18(m,1H),4.72(s,2H),3.81(t,J=6.4Hz,2H),3.12(t,J=5.8Hz,2H),1.51(s,9H).

[0491] Example 26B: tert-Butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. [ka] To a solution of Example 26A (0.2 g, 716 μmol) in MeOH (5 mL) was added Pd / C (0.1 g, 10% purity) under N. The suspension was degassed under vacuum and purged with H multiple times. The mixture was stirred under H (15 psi) at 20° C. for 2 h. The mixture was filtered to remove the solid. The filtrate was then concentrated to remove the solvent, affording the desired compound (180 mg, crude) as a colorless oil.

[0492] Example 26C: tert-Butyl 3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. [ka] CuBr (241.9 mg, 1.08 mmol) was added to a solution of Example 26B (180 mg, 722 μmol) in MeCN (6 mL) at 20° C., followed by the dropwise addition of t-butyl nitrite (89.3 mg, 866 μmol) at 0° C. The reaction was stirred at 0° C. for 1 h and then at 20° C. for 12 h. The mixture was poured into 30 mL of water, filtered, and extracted three times with 30 mL of EA each. The combined organic phases were washed twice with 30 mL of brine, dried over NaSO, filtered, and concentrated to remove the solvent, affording the target compound (200 mg, 88% yield) as a brown oil.

[0493] Example 26D: tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. [ka] To a solution of Example 26C (150 mg, 479 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (182 mg, 718 μmol), and KOAc (141 mg, 1.44 mmol) in dioxane (3 mL) was added Pd(dppf)Cl.CHCl (78.2 mg, 95.8 μmol). The mixture was stirred at 100 °C under N for 2 hours. The resulting dioxane solution was used directly in the next reaction.

[0494] Example 26F: tert-Butyl 3-(5-cyano-6-(((cyclobutylthio)methyl)thio)-4-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. [ka] Example 26E was prepared in a manner similar to that used to prepare Example 7D. A mixture of Example 26D (170 mg, 472 μmol), Example 26E (219 mg, 472 μmol), Pd(dppf)Cl.CHCl (38.5 mg, 47.2 μmol), and KCO (130 mg, 944 μmol) in dioxane (3 mL) and HO (1 mL) was degassed and purged with N three times. The mixture was stirred under N at 80° C. for 2 hours. The reaction mixture was partitioned between water (30 mL) and EA (100 mL). The organic phase was separated, washed with brine (30 mL*2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the target compound (90 mg, yield 35%) as a yellow solid.

[0495] Example 26G: tert-Butyl 3-(5-cyano-6-(((cyclobutylsulfinyl)methyl)thio)-4-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. [ka] To a solution of Example 26F (80 mg, 146 μmol) in CHCl (3 mL) was added HOAc (175 mg, 2.92 mmol) and HO (82.6 mg, 729 μmol, 30% purity) at 0° C. The mixture was stirred at 20° C. for 4 h. The mixture was quenched by adding 10 mL of NaHCO solution and 20 mL of saturated NaSO solution. The reaction mixture was partitioned between water (10 mL) and DCM (50 mL). The organic phase was separated and washed with brine (20 mL*2), dried over NaSO, filtered, and concentrated under reduced pressure to give the target compound (95 mg, crude) as a yellow solid.

[0496] Example 26H: tert-Butyl 3-(3-amino-2-(cyclobutylsulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)thieno[2,3-b]pyridin-6-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. [ka] To a solution of Example 26G (90 mg, 159 μmol) in DMF (3 mL) and MeOH (3 mL) was added KOH (17.9 mg, 319 μmol). The mixture was stirred at 20° C. for 1 hour. The mixture was quenched by adding 10 mL of water. The yellow solid was filtered and used in the next step without purification.

[0497] Example 26: Synthesis of compound 31. [ka] To a solution of Example 26H (80 mg, 142 μmol) in DCM (4 mL) was added formic acid (4.88 g, 4.00 mL). The mixture was stirred at 40° C. for 3 hours. The mixture was poured into 200 mL of saturated NaHCO3 solution. The mixture was extracted with DCM (50 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na2SO4, and concentrated to remove the solvent. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 mm*5 um; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 21%~51%, 10 min) to give the target compound (9 mg, 13% yield) as a yellow solid. LCMS: (ES + ) m / z (M+H) + =465.1. 1 H NMR(400MHz,CDCl3)δ=9.06(s,1H),8.14(s,1H),7.68(d,J=1.6Hz,1H),7.61(s,1H),6.50(d,J=6.4Hz,1H),4.63-4.45(m,2H),4.19(s,2H),3.9 8-3.90(m,1H),3.76(s,3H),3.37-3.30(m,2H),3.13-3.06(m,2H),2.93 -2.74(m,1H),2.44-2.33(m,2H),2.29-2.21(m,1H),2.15-2.05(m,2H).

[0498] Example 27: 2-(2-Methoxyethanesulfinyl)-4-(1-methyl-1H-pyrazol-5-yl)-6-{2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}thieno[2,3-b]pyridin-3-amine (compound 32). [ka] Compound 32 was prepared in a manner similar to that used in Example 7. The target compound was isolated as a yellow solid. LCMS: (ES+) m / z (M+H)+ = 471.1. 1H NMR(500MHz,CDCl3)δ 8.39(s,1H),7.78(s,1H),7.65(s,1H),7.48(s,1H),6.47-6.46(m,1H),5.18(s,1H),4.49-4.43(m,2H)4.27-4.2 6(m,2H),4.26-4.25(m,1H),4.26-3.86(m,3H),3.74(s,3H),3.65-3.62(m,1H),3.62(s,3H),3.38-3.25(m,1H).

[0499] Example 28: Synthesis of 2-[2-methoxyethanesulfinyl]-4-(propan-2-yl)-6-(quinoxalin-6-yl)thieno[2,3-b]pyridin-3-amine and its enantiomers (compounds 24 and 25). [ka] Example 28 was prepared in a manner similar to that used for Example 7. The desired compound was isolated as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.90-8.88(m,2H),8.71(d,J=1.6Hz,1H),8.66-8.64(m,1H),8.22-8.19(m,1H),7.86(s,1H),5.12(s,2H),4.02-3.9 1(m,1H),3.83-3.80(m,1H),3.72-3.63(m,2H),3.42(s,3H),3.35-3.31(m,1H),1.50(dd,J1=6.8Hz;J2=8.8Hz,6H).

[0500] The enantiomers (compounds 24 and 25) were separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 50% to 50%, 4.3 min; 60 min), to give the (+) enantiomer (107.5 mg, 84% yield, 98% purity, 100% ee) and the (-) enantiomer (58.7 mg, 46% yield, 99% purity, 98% ee) as yellow solids. Optical rotation was measured, showing specific rotations of +49.022° and -46.314°; LCMS: (ES+) m / z (M+H)+ = 427.1. 1 H NMR(400MHz,CDCl3)δ 8.88-8.85(m,2H),8.67(d,J=2.0Hz,1H),8.63-8.60(m,1H),8.19-8.15(m,1H),7.84(s,1H),5.11(s,2H),3.89-3.8 0(m,1H),3.73-3.70(m,1H),3.67-3.62(m,2H),3.42(s,3H),3.32-3.29(m,1H),1.50(dd,J1=6.8Hz;J2=21.6Hz,6H).

[0501] Numbered Embodiments Embodiment 1. Formula (I): [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and each of these is one or more R 3 optionally substituted with; R 7is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 3 is -OH, -O-alkylene-OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), -N(R 5 )(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 )2, -C(O)N(R 5 )(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl or -S(O) m -alkyl, and cycloalkyl and heterocyclyl are each R 10 optionally replaced by; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with R 4 is oxo, and R 7 is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl; Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 10 is —OH, halogen, C1-C6 alkyl or C1-C6 alkoxy; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 A compound of the formula [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0502] Embodiment 2. R 1 The compound of embodiment 1, wherein is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy).

[0503] Embodiment 3. R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p -cyclohexyl or -(CH2) p 3. The compound of embodiment 1 or 2, wherein:

[0504] Embodiment 4. R 2 The compound of any one of embodiments 1-3, wherein is —NH 2 .

[0505] Embodiment 5. R 6 teeth, [ka] The compound of any one of embodiments 1-4, wherein

[0506] Embodiment 6. R 11 The compound of any one of embodiments 1-5, wherein is H or methyl.

[0507] Embodiment 7. R 7 is phenyl, alkyl, or cycloalkyl, each of which may be one or more R 4 The compound of any one of embodiments 1-6, optionally substituted with

[0508] Embodiment 8. R 7 The compound of any one of embodiments 1-7, wherein is a straight or branched chain acyclic C1-C6 alkyl.

[0509] Embodiment 9. R 7 The compound of any one of embodiments 1-8, wherein is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or t-butyl.

[0510] Embodiment 10. The compound of any one of embodiments 1-9, wherein X is CH.

[0511] Embodiment 11. The compound of any one of embodiments 1 to 10, wherein n is 1.

[0512] Embodiment 12. Formula (II): [ka] (In the formula, R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy); R 6 teeth, [ka] and; R 7is a straight or branched chain acyclic C1-C6 alkyl; R 11 is H or C1-C6 alkyl; and n is 0, 1 or 2 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0513] Embodiment 13. [ka] 13. The compound of embodiment 1 or 12, selected from: or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0514] Embodiment 14. Formula (III): [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m-alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with, where R4 is oxo and R7 is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl; Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 A compound of the formula [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0515] Embodiment 15. R 1 The compound of embodiment 14, wherein is C1-C6 alkyl, C3-C6 cycloalkyl, or -(C1-C3 alkylene)-(C1-C3 alkoxy).

[0516] Embodiment 16. R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -Cyclopentyl, -(CH2) p -cyclohexyl or -(CH2) p 16. The compound of embodiment 14 or 15, wherein:

[0517] Embodiment 17. R 2 The compound of any one of embodiments 14-16, wherein is —NH 2 or —CN.

[0518] Embodiment 18. R 6 teeth, [ka] 18. The compound of any one of embodiments 14-17, wherein

[0519] Embodiment 19. R 7 is alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which may be one or more R 4 The compound of any one of embodiments 14-18, optionally substituted with:

[0520] Embodiment 20. The compound of any one of embodiments 14-19, wherein n is 1.

[0521] Embodiment 21. [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0522] Embodiment 22. Formula (IV): [ka] (In the formula, R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is -NH, CN, or -NHC(O)(C-C alkyl); R 6 teeth, [ka] and; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 -alkyl, each of which may be one or more R 4 optionally substituted with; R 4 is oxo, halogen, -CN, -N(R 5 )2, -OH, -O-alkylene-OH, -S(O) m -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8-alkylene-aryl optionally substituted with R 4 is oxo, and R 7 is aryl or heteroaryl, the oxo does not violate the valence of the aryl or heteroaryl; Each R 5 are independently selected from H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) m - is alkyl; R 8 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 9 is H or C1-C6 alkyl; R 11 is H or C1-C6 alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2 A compound of the formula [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0523] Embodiment 23. [ka] or a pharmaceutically acceptable salt, tautomer or solvate thereof.

[0524] Embodiment 24. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 23 and a pharmaceutically acceptable carrier or excipient.

[0525] Embodiment 25. Use of a compound of any one of embodiments 1 to 23 as a short-chain dehydrogenase inhibitor for inhibiting the activity of a short-chain dehydrogenase enzyme.

[0526] Embodiment 28. Use of a compound of any one of embodiments 1 to 23 as a 15-PGDH inhibitor for inhibiting the activity of the 15-PGDH enzyme.

[0527] Embodiment 29. A method 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 administered with a compound of any one of embodiments 1-23 and / or a therapeutic composition comprising human hematopoietic stem cells and a compound of any one of embodiments 1-23.

[0528] Embodiment 30. A method of treating a subject having at least one condition 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 administered with a compound of any one of embodiments 1-23 and / or a therapeutic composition comprising human hematopoietic stem cells and a compound of any one of embodiments 1-23.

[0529] Embodiment 31. A method of increasing neutrophils in a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 1-23.

[0530] Embodiment 32. A method of increasing the number and / or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 1-23.

[0531] Embodiment 33. A method of increasing the number of hematopoietic stem cells in t...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R ２ is -NH ２ , CN or —NHC(O)(C １ ~C ６ alkyl); R ６ teeth, 【Chemistry 2】 and each of these is one or more R ３ optionally substituted with; R ７ is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR ５ -alkyl, each of which is selected from one or more R ４ optionally substituted with; R ３ is —OH, —O-alkylene-OH, —O-alkylene-N(R ５ ) ２ , -N(R ５ ) ２ , -N(R ５ ) (alkylene-OH), —N(R ５ ) (alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, —C(O)N(R ５ ) ２ , -C(O)N(R ５ ) (alkylene-OH), —C(O)-alkyl, —C(O)O-alkyl or —S(O) ｍ -alkyl, and the cycloalkyl and the heterocyclyl are each R １０ optionally substituted with; R ４ is oxo, halogen, -CN, -N(R ５ ) ２ , —OH, —O-alkylene-OH, —S(O) ｍ -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R ８ -alkylene-aryl optionally substituted with R ４ is oxo, and R ７ is aryl or heteroaryl, oxo does not violate the valence of said aryl or said heteroaryl; Each R ５ are independently H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH ２ , -alkylene-N(R ９ ) ２ , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH ２ , —C(O)-alkyl, —C(O)O-alkyl, -alkylene-COOH or —S(O) ｍ - alkyl; R ８ is a halogen, C １ ~C ６ Alkyl or C １ ~C ６ is alkoxy; R ９ is H or C １ ~C ６ is alkyl; R １０ is -OH, halogen, C １ ~C ６ Alkyl or C １ ~C ６ is alkoxy; R １１ is H or C １ ~C ６ is alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2. The compound of formula (I) is: 【Transformation 3】 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

2. R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl or -(C １ ~C ３ alkylene)-(C １ ~C ３ 2. The compound, salt or solvate of claim 1, wherein:

3. R １ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ２ ) ｐ -cyclopropyl, -(CH ２ ) ｐ -cyclobutyl, -(CH ２ ) ｐ -cyclopentyl, -(CH ２ ) ｐ -cyclohexyl or -(CH ２ ) ｐ -OCH ３ 2. The compound, salt or solvate of claim 1, wherein:

4. R ２ is NH ２ 2. The compound, salt or solvate of claim 1, wherein:

5. R ６ teeth, 【Chemistry 4】 2. The compound, salt or solvate of claim 1, wherein:

6. R １１ The compound, salt or solvate of claim 1 , wherein is H or methyl.

7. R ７ is phenyl, alkyl, or cycloalkyl, each of which may be one or more R ４ 2. The compound, salt or solvate of claim 1, optionally substituted with:

8. R ７ is a straight or branched chain acyclic C １ ~C ６ 2. The compound, salt or solvate of claim 1, wherein: R is alkyl.

9. R ７ The compound, salt or solvate of claim 1, wherein is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl.

10. 2. The compound, salt or solvate of claim 1, wherein X is CH.

11. 2. The compound, salt or solvate of claim 1, wherein n is 1.

12. Formula (II): 【Transformation 5】 (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl or -(C １ ~C ３ alkylene)-(C １ ~C ３ alkoxy); R ６ teeth, 【Transformation 6】 and R ７ is a straight or branched chain acyclic C １ ~C ６ is alkyl; R １１ is H or C １ ~C ６ is alkyl; and n is 0, 1 or 2. or a pharmaceutically acceptable salt, tautomer or solvate thereof.

13. The following formula: 【Transformation 7】 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer or solvate thereof.

14. Formula (III): 【Transformation 8】 (In the formula, R １ is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R ２ is -NH ２ , CN or —NHC(O)(C １ ~C ６ alkyl); R ６ teeth, 【Chemistry 9】 and R ７ is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR ５ -alkyl, each of which is selected from one or more R ４ optionally substituted with; R ４ is oxo, halogen, -CN, -N(R ５ ) ２ , —OH, —O-alkylene-OH, —S(O) ｍ -alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R ８ -alkylene-aryl optionally substituted with R ４ is oxo, and R ７ is aryl or heteroaryl, oxo does not violate the valence of said aryl or said heteroaryl; Each R ５ are independently H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH ２ , -alkylene-N(R ９ ) ２ , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH ２ , —C(O)-alkyl, —C(O)O-alkyl, -alkylene-COOH or —S(O) ｍ - alkyl; R ８ is a halogen, C １ ~C ６ Alkyl or C １ ~C ６ is alkoxy; R ９ is H or C １ ~C ６ is alkyl; R １１ is H or C １ ~C ６ is alkyl; X is N or CH; m is 0, 1 or 2; and n is 0, 1 or 2. The compound of formula (I) is: 【Chemistry 10】 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

15. R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl or -(C １ ~C ３ alkylene)-(C １ ~C ３ 15. The compound, salt or solvate of claim 14, wherein:

16. R １ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ２ ) ｐ -cyclopropyl, -(CH ２ ) ｐ -cyclobutyl, -(CH ２ ) ｐ -cyclopentyl, -(CH ２ ) ｐ -cyclohexyl or -(CH ２ ) ｐ -OCH ３ 15. The compound, salt or solvate of claim 14, wherein:

17. R ２ is NH ２ or -CN.

18. R ６ teeth, 【Chemistry 11】 15. The compound of claim 14, wherein:

19. R ７ is alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which may be selected from one or more R ４ 15. The compound, salt or solvate of claim 14, optionally substituted with:

20. 15. The compound, salt or solvate of claim 14, wherein n is 1.

21. The following formula: 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 15. The compound of claim 14, or a pharmaceutically acceptable salt, tautomer or solvate thereof.

22. The following formula: 【Chemistry 16】 or a pharmaceutically acceptable salt, tautomer or solvate thereof.

23. A pharmaceutical composition comprising a compound, salt or solvate according to any one of claims 1 to 22 and a pharmaceutically acceptable excipient or carrier.

24. A pharmaceutical composition comprising a compound, salt or solvate according to any one of claims 1 to 22 for inhibiting the activity of a short-chain dehydrogenase enzyme.

25. A pharmaceutical composition comprising a compound, salt or solvate according to any one of claims 1 to 22 for use in inhibiting 15-PGDH enzyme activity.

26. 26. The composition of claim 25, which inhibits 15-PGDH enzyme activity, The enzyme activity of recombinant 15-PGDH was measured at a recombinant 15-PGDH concentration of 5 nM to 10 nM with an IC of less than 1 μM. ５０ , or an IC of less than 250 nM ５０ , or IC<50 nM ５０ , or IC<10 nM ５０ , or IC<5 nM ５０ inhibited by; Increases prostaglandin levels in target tissues; Promoting and / or stimulating skin pigmentation and / or hair growth and / or inhibiting hair loss and / or treating skin damage or inflammation; Promoting wound healing, tissue repair and / or tissue regeneration; Treating 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, heart disease, or kidney disease; Increases tissue stem cells; Enhance the compatibility of donor tissue grafts, donor bone marrow grafts, and / or donor hematopoietic stem cell grafts for donation; Increase the number of stem cells in a subject; Increase the suitability of bone marrow as a donor graft; Reduce tissue graft rejection; Enhances tissue and / or bone marrow graft survival; Enhance bone marrow graft survival after treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy; Enhances engraftment of progenitor stem cell grafts, hematopoietic stem cell grafts, or umbilical cord blood stem cell grafts; enhances the engraftment of hematopoietic stem cell grafts or umbilical cord stem cell grafts after treating a subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy; reducing the number of units of cord blood required for transplant into a subject; Reduce graft rejection; Enhance graft survival; enhance graft survival after treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy; conferring resistance to the toxic or lethal effects of exposure to radiation; confers resistance to the toxic effects of Cytoxan, fludarabine, chemotherapy, or immunosuppressive therapy; reducing infection; Increases neutrophil counts after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; Increase neutrophil counts in neutropenic subjects following chemotherapy administration or radiation therapy; Increases 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 following a viral infection; Increases neutrophil counts in neutropenic subjects; Increases platelet counts after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; Increase platelet count in subjects with thrombocytopenia following chemotherapy administration or radiation therapy; Increases platelet counts in subjects with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia following a viral infection; Increases platelet count in subjects with thrombocytopenia; Increases red blood cell count, hematocrit, or hemoglobin levels after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; Increase red blood cell count, or hematocrit, or hemoglobin level in anemic subjects following chemotherapy administration or radiation therapy; Increases red blood cell count, hematocrit, or hemoglobin levels in subjects with aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other bone marrow disorders, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, post-viral anemia, or anemia of unknown cause; increasing red blood cell count, or hematocrit, or hemoglobin level in an anemic subject; Increase bone marrow stem cells after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; increasing bone marrow stem cells in a subject following chemotherapy or radiation therapy; Increase bone marrow stem cells in subjects with aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced cytopenia, immune cytopenia, post-viral cytopenia or cytopenia; Increased responsiveness to cytokines, including any of G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist) or SCF, in the presence of cytopenias, including any of neutropenia, thrombocytopenia, lymphopenia or anemia, with increased responsiveness potentiated by a 15-PGDH inhibitor; Reduces radiation-induced lung toxicity; Increasing bone density, treating osteoporosis, promoting fracture healing, or promoting healing after bone surgery or joint replacement; Promotes healing of bone-to-bone implants, bone-to-prosthetic implants, dental implants and bone grafts; Increases stem cells in the intestinal tract; Increases stem cells in the intestinal tract and confers resistance to the toxic or lethal effects of exposure to radiation or the toxic, lethal or mucositis effects resulting from chemotherapy treatment; conferring resistance to the toxic or lethal effects of exposure to radiation or the toxic, lethal or mucositis effects resulting from chemotherapy treatment; Treating colitis, ulcerative colitis or inflammatory bowel disease; Increases liver regeneration after liver surgery, living donor liver, liver transplant, or toxic liver injury; Promoting recovery from or tolerance to liver toxins, including acetaminophen and related compounds; Treating erectile dysfunction; or Inhibiting at least one of the growth, proliferation, or metastasis of 15-PGDH-expressing cancer; composition.

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