Compositions and methods of modulating short-chain dehydrogenase activity

Abstract

To provide compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, and treating diseases, disorders or conditions for which modulation of 15-PGDH activity and / or prostaglandin levels is desired.SOLUTION: For example, the invention provides a compound having a thieno[2,3-b]pyridine partial structure represented by the general formula in the figure, or a pharmaceutically acceptable salt, tautomer or solvate thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 770,571, filed November 21, 2018, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Government funding This invention was made with government support under Grant Nos. R01CA127306, R01CA127306-03S1, 1P01CA95471-10, and 5P50CA150964 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention. [Background technology]

[0003] Short-chain dehydrogenases (SCDs) are a family of dehydrogenases that share only 15%-30% sequence identity, primarily similarities 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.

[0004] 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, consists of a homodimer with a 29 kDa subunit. This enzyme belongs to the evolutionarily conserved superfamily of short-chain dehydrogenase / reductase enzymes (SDRs) and, according to the recently approved nomenclature for human enzymes, is designated SDR36C1. 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.

[0005] Recent studies suggest 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 protection against thrombin-mediated cell death. 15-PGDH is well known to be responsible for the inactivation of prostaglandin E2 (PGE2), a downstream product of COX-2 metabolism. PGE2 has been shown to be beneficial for various biological processes, such as hair density, skin wound healing, and bone formation. Summary of the Invention [Means for solving the problem]

[0006] 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.

[0007] In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to the tissue or blood of a subject in an amount effective to inhibit the activity of short-chain dehydrogenase enzymes. The SCD inhibitor can be a 15-PGDH inhibitor that 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 (IA): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof. (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)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R3 is oxo, -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, where cycloalkyl and heterocycloalkyl 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 Each R 5 are independently 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 - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9is H or alkyl, or two R 9 are O, S(O) along with the N atom to which they are attached. t or N; R 10 is —OH, halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2) may include:

[0008] In some embodiments, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).

[0009] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl or -(CH2) p -cyclohexyl, where p is 1, 2 or 3.

[0010] In yet other embodiments, R 2 is -NH2.

[0011] In some embodiments, R 6 are each one or more R 3 is a 5- to 6-membered heterocyclyl or a 5- to 10-membered heteroaryl optionally substituted with

[0012] In other embodiments, R 6is one or more R 3 is a 5-6 membered heteroaryl optionally substituted with

[0013] In yet other embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0014] In some embodiments, R 7 are each one or more R 4 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).

[0015] In other embodiments, R 7 are each one or more 4 C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl optionally substituted with

[0016] In yet other embodiments, R 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, or 5- to 10-membered heteroaryl optionally substituted with

[0017] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m(C1-C6 alkyl).

[0018] In other embodiments, R 3 are -(C1-C3 alkyl)OH, -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH 2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0019] In yet other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0020] In some embodiments, R 4 is halogen, -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.

[0021] In some embodiments, n is 1.

[0022] In other embodiments, the compound has the formula (II): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is a 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl); R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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 - is alkyl; 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, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5are independently 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 - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9 is H or alkyl, or two R 9 are O, S(O) along with the N atom to which they are attached. t or N; X is N or CH; m is 0, 1 or 2; and t is 0, 1 or 2) It has.

[0023] In some embodiments, R 1 is a 3- to 5-membered cycloalkyl or -(C1-C6 alkylene)-(3- to 5-membered cycloalkyl).

[0024] In other embodiments, R 1 is cyclobutyl.

[0025] In yet other embodiments, R 1 is a bicyclic 4-6 membered cycloalkyl.

[0026] In some embodiments, R 7 are each one or more R 4C1-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).

[0027] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C4 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl optionally substituted with

[0028] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C3 alkyl, C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5-6-membered heteroaryl, optionally substituted with 7 are each one or more R 4 C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5-6-membered heteroaryl optionally substituted with

[0029] In other embodiments, R 7 are each one or more R 4 isopropyl, cyclopropyl, phenyl, pyridyl, or triazole optionally substituted with

[0030] In some embodiments, R 7 is -CF3, isopropyl, [ka] is.

[0031] In other embodiments, R 7 is CF3, isopropyl, [ka] is.

[0032] In yet other embodiments, R 7 CF3, [ka] is.

[0033] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0034] In other embodiments, R 3are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0035] In yet other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0036] In other embodiments, the compound has formula (III): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 C1-C6 haloalkyl, aryl, or heteroaryl optionally substituted with; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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 - is alkyl; Each R 5 are independently 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, -alkylene-COOH, -C(O)O-alkyl or -S(O) m - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 4 is halogen, alkyl or alkoxy; X is N or CH; and m is 0, 1 or 2 It has.

[0037] In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is -(C1-C4 alkylene)-(C1-C3 alkoxy).

[0038] In some embodiments, R 7 are each one or more R 4 is —CF 3 optionally substituted with —CF 3 , pyridyl, pyrazole, phenyl or triazole.

[0039] In other embodiments, R 7 is -CF3, pyridyl, fluorophenyl or triazole optionally substituted with one or more halogen or methyl.

[0040] In yet other embodiments, R 7 CF3, [ka] is.

[0041] In yet other embodiments, R 7 is CF3.

[0042] In yet other embodiments, R 7 teeth, [ka] is.

[0043] In some embodiments, R 7 teeth, [ka] is.

[0044] In other embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0045] In other embodiments, the compound has formula (IV): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl or -alkylene-heterocyclyl; R2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 is one or more R 4 is a 3- to 6-membered cycloalkyl optionally substituted with R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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 - is alkyl; R 4 is halogen, —CN, —NH2, —OH or C1-C3 alkyl; Each R 5 are independently 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, -alkylene-COOH, -C(O)O-alkyl or -S(O) m - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2 It has.

[0046] In some embodiments, R 7 is cyclopropyl.

[0047] In other embodiments, R 1 is a 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).

[0048] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl or -(CH2) p -cyclohexyl, where p is 1, 2 or 3.

[0049] In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is -(C1-C4 alkylene)-(C1-C3 alkoxy).

[0050] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0051] In some embodiments, R 3are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0052] In other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0053] In other embodiments, the compound has the formula (V): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl or -alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 heterocyclyl or heteroaryl substituted with; R 7 are each one or more R 4haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl); 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, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently H, C1-C6 alkyl, -(C1-C6 alkylene)-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), alkylene-COOH or -S(O) m (C1-C6 alkyl); or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2 It has.

[0054] In some embodiments, R 1 is cyclobutyl. In some embodiments, it is -(C1-C4 alkylene)-(C1-C3 alkoxy).

[0055] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2 or -N(R 5 ) (C1-C6 alkylene-OH).

[0056] In other embodiments, R 5 is H, C1-C6 alkyl, -(C1-C6 alkylene)-OH, or -S(O)2(C1-C3 alkyl).

[0057] In some embodiments, R 3 are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0058] In other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0059] In yet other embodiments, R 3 is -NHCH2CH2OH.

[0060] In some embodiments, R 6 are each one or more R 3 is a 5- to 6-membered heterocyclyl or a 5- to 10-membered heteroaryl optionally substituted with

[0061] In other embodiments, R 6 is one or more R 3 is a 5-6 membered heteroaryl optionally substituted with

[0062] In some embodiments, R 6 is one or more R 3 furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine optionally substituted with

[0063] In other embodiments, R 6 is thiazole, imidazole, oxazole, pyridine or pyrimidine.

[0064] In some embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0065] In other embodiments, R 6 is one or more R 3 is a 5-6 membered heterocyclyl selected from morpholine, pyridin-one or piperidine, optionally substituted by

[0066] In some embodiments, R 7 are each one or more R 4C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5-6-membered heteroaryl optionally substituted with

[0067] In other embodiments, R 7 is -CF3, each of which is one or more R 4 In yet another embodiment, R is cyclopropyl, phenyl, pyrazole, pyridyl, or triazole optionally substituted with 7 CF3, [ka] is.

[0068] In some embodiments, the compound has formula (VI): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is a fused bicyclic heterocyclyl or a fused bicyclic heteroaryl optionally substituted with R 7 are each one or more R 4 alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 )2, -C(O)-alkyl, -C(O)O-alkyl or -S(O) m - is alkyl; 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, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH, -C(O)-alkyl, -C(O)O-alkyl or -S(O) m - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; X is N or CH; and m is 0, 1 or 2 It has.

[0069] In some embodiments, R 6 are each one or more R 3 is an 8-10 membered fused bicyclic heteroaryl optionally substituted with

[0070] In some embodiments, R 7 are each one or more R 4C1-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).

[0071] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C4 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl optionally substituted with

[0072] In yet other embodiments, R 7 are each one or more R 4 C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally substituted with

[0073] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, optionally substituted with 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole optionally substituted with

[0074] In other embodiments, R 7 are each one or more R 4In other embodiments, R is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, optionally substituted with 7 are each one or more R 4 In a further embodiment, R is -CF3, cyclopropyl, phenyl, pyridyl, or triazole optionally substituted with 7 is isopropyl, [ka] is.

[0075] In a further embodiment, R 7 teeth, [ka] is.

[0076] In some embodiments, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).

[0077] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl or -(CH2) p -cyclohexyl, where p is 1, 2, or 3. In some embodiments, R 1 is cyclobutyl. In some embodiments, it is -(C1-C4 alkylene)-(C1-C3 alkoxy).

[0078] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5)2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0079] In other embodiments, R 3 are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0080] In some embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0081] In other embodiments, R 4 is halogen, -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.

[0082] In some embodiments, the compound has formula (VII): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 is -CF3, isopropyl, [ka] and; R 3 is oxo, -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, where cycloalkyl and heterocyclyl are each R 10 optionally replaced by; R 4 is C1-C3 alkyl; Each R 5 are independently 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 - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, wherein the heterocycle is 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9 is H or alkyl, or two R 9 are O, S(O) along with the N atom to which they are attached. t or N; R 10 is —OH, halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2; p is 0 or 1; and t is 0, 1 or 2) It has.

[0083] In some embodiments, the compound has formula (VIII): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 optionally substituted with [ka] and; R 7 are each one or more R 4 -CF3, isopropyl, cyclopropyl, cyclobutyl optionally substituted with [ka] and; R 3 is -NH2, -NH(C1-C3 alkyl), -NH(C1-C4 alkylene)-OH or C1-C3 alkyl; R 4 is C1-C3 alkyl; and X is N or CH It has.

[0084] In some 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

[0085] The 15-PGDH inhibitor can be provided in a topical composition that can be applied to the skin of a subject to promote and / or stimulate skin pigmentation and / or hair growth and / or inhibit hair loss, and / or treat skin damage or inflammation.

[0086] 15-PGDH inhibitors may also be administered to a subject to promote wound healing, tissue repair and / or tissue regeneration and / or tissue graft survival or regeneration.

[0087] In one embodiment, a 15-PGDH inhibitor 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.

[0088] In another embodiment, a 15-PGDH inhibitor can be administered to a subject in combination with a prostanoid agonist to enhance the therapeutic effect of the agonist in prostaglandin-responsive conditions.

[0089] In other embodiments, a 15-PGDH inhibitor 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.

[0090] In yet another embodiment, a 15-PGDH inhibitor can be administered to a tissue graft donor, a bone marrow graft donor, and / or a hematopoietic stem cell donor and / or a tissue graft, a bone marrow graft, and / or a hematopoietic stem cell graft to enhance the compatibility of the donor tissue graft, the donor bone marrow graft, and / or the donor hematopoietic stem cell graft. In one embodiment, a 15-PGDH inhibitor is administered ex vivo to a tissue graft, a bone marrow graft, and / or a hematopoietic stem cell graft. For example, a 15-PGDH inhibitor can be administered to a subject and / or a subject's bone marrow to enhance its compatibility as a donor graft, and / or to enhance the compatibility of a subject's hematopoietic stem cell product as a donor graft, and / or to enhance the compatibility of a subject's peripheral blood hematopoietic stem cell product as a donor graft, and / or to enhance the compatibility of a cord blood stem cell product as a donor graft, and / or to enhance the compatibility of a cord blood stem cell product as a donor graft, and / or to reduce the number of cord blood units required for transplantation.

[0091] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to reduce rejection of a tissue transplant, to enhance engraftment of a tissue and / or bone marrow transplant, to enhance engraftment of a bone marrow transplant after the subject or the subject's bone marrow has been treated with radiation therapy, chemotherapy, or immunosuppressive therapy, to enhance engraftment of a progenitor stem cell transplant, a hematopoietic stem cell transplant, or a cord blood stem cell transplant, to enhance engraftment of a hematopoietic stem cell transplant, or a cord blood stem cell transplant after the subject or the subject's bone marrow has been treated with radiation therapy, chemotherapy, or immunosuppressive therapy, and / or to reduce the number of units of cord blood required for transplant into the subject.

[0092] In other embodiments, 15-PGDH inhibitors can be administered to recipients of tissue graft transplants, bone marrow transplants and / or hematopoietic stem cell transplants or umbilical cord stem cell transplants to reduce the need for other treatments or the administration of growth factors.

[0093] In some embodiments, a 15-PGDH inhibitor can be administered to a subject or a tissue graft of a subject to reduce graft rejection, to enhance graft survival, and / or to enhance graft survival after treating the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy.

[0094] In other embodiments, a 15-PGDH inhibitor can be administered to a subject or to the subject's bone marrow 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 lung toxicity from radiation, and / or to reduce infection.

[0095] In yet other embodiments, 15-PGDH inhibitors are used to increase neutrophil counts after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood; to increase neutrophil counts in neutropenic subjects after administration of chemotherapy or radiation therapy; to increase neutrophil counts in subjects with neutropenia due to aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia following a viral infection; To increase platelet counts after hematopoietic cell transplantation from bone marrow, hematopoietic stem cells or umbilical cord blood, to increase platelet counts in subjects with thrombocytopenia after administration of chemotherapy or radiation therapy, to increase 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, to increase platelet counts in subjects with thrombocytopenia after hematopoietic cell transplantation from bone marrow, hematopoietic stem cells or umbilical cord blood, to increase platelet counts in subjects with thrombocytopenia after administration of chemotherapy or radiation therapy, to increase red blood cell counts, hematocrit, or hemoglobin levels after hematopoietic cell transplantation using umbilical cord blood; to increase red blood cell counts, hematocrit, or hemoglobin levels in anemic subjects after chemotherapy or radiation therapy; to increase red blood cell counts, 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, anemia after viral infection, or anemia of unknown cause 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 radiation therapy, and / or to increase bone marrow stem cells in subjects with aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced cytopenia, immune cytopenia, cytopenia following a viral infection or cytopenia.

[0096] In other embodiments, administration of a 15-PGDH inhibitor can be used to regulate hematopoietic stem cells and hematopoiesis. For example, a 15-PGDH inhibitor can be administered alone or in combination with a cytokine to a subject in need thereof to increase and / or mobilize hematopoietic stem cells and / or neutrophils in the subject's blood, bone marrow, and / or tissues.

[0097] In some embodiments, a 15-PGDH inhibitor can be administered in combination with G-CSF to increase neutrophils.

[0098] In other embodiments, the 15-PGDH inhibitor can be administered in combination with hematopoietic cytokines to increase neutrophils.

[0099] 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.

[0100] In other embodiments, 15-PGDH inhibitors can be administered in combination with hematopoietic cytokines to increase the number and / or mobilize peripheral blood hematopoietic stem cells.

[0101] In some embodiments, the 15-PGDH inhibitor can be administered in combination with a second agent, including, for example, plerixafor, for the purpose of increasing the number and / or mobilizing peripheral blood hematopoietic stem cells.

[0102] In another embodiment, a 15-PGDH inhibitor 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.

[0103] 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.

[0104] In other embodiments, a 15-PGDH inhibitor can be administered in combination with a second agent, including plerixafor, to increase and / or mobilize peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0105] 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.

[0106] In other embodiments, 15-PGDH inhibitors can be administered in combination with hematopoietic cytokines to increase the number of hematopoietic stem cells in the blood or bone marrow.

[0107] In other embodiments, a 15-PGDH inhibitor 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.

[0108] In other embodiments, 15-PGDH inhibitors can be administered to recipients of tissue graft transplants, bone marrow transplants and / or hematopoietic stem cell transplants or umbilical cord stem cell transplants to reduce the need for other treatments or the administration of growth factors.

[0109] In yet other embodiments, 15-PGDH inhibitors are used to increase neutrophil counts after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood; to increase neutrophil counts in neutropenic subjects after administration of chemotherapy or radiation therapy; to increase neutrophil counts in subjects with neutropenia due to aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia following a viral infection; to increase platelet counts after hematopoietic cell transplantation from bone marrow, hematopoietic stem cells or umbilical cord blood; to increase platelet counts in subjects with thrombocytopenia after administration of chemotherapy or radiation therapy; to increase 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; To increase red blood cell counts, hematocrit values, or hemoglobin levels after hematopoietic cell transplantation using umbilical cord blood; to increase red blood cell counts, hematocrit values, or hemoglobin levels in anemic subjects after chemotherapy or radiation therapy; to increase 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 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 radiation therapy, and / or to increase bone marrow stem cells in subjects with aplastic anemia, myelodysplasia, myelofibrosis, other bone marrow disorders, drug-induced cytopenia, immune cytopenia, cytopenia following a viral infection or cytopenia.

[0110] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to increase responsiveness to cytokines in the presence of cytopenia, wherein the cytopenia includes any of neutropenia, thrombocytopenia, lymphopenia, and anemia, and the cytokines having an increased responsiveness enhanced by the 15-PGDH inhibitor include any of G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist), and SCF.

[0111] In some embodiments, 15-PGDH inhibitors can be administered to a subject to increase bone mineral density, to treat osteoporosis, to promote healing of bone fractures, to promote healing after bone surgery or joint replacement, and / or to promote healing of bone-to-bone implants, bone-to-prosthetic implants, dental implants, and bone grafts.

[0112] In other embodiments, a 15-PGDH inhibitor can be administered to a subject or to the subject's intestine to increase stem cell or cell proliferation in the intestine and / or to confer resistance to the toxic or lethal effects of exposure to radiation or the toxic, lethal or mucositis effects resulting from chemotherapy treatment.

[0113] In some embodiments, a 15-PGDH inhibitor can be administered to a subject or to the subject's intestine as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

[0114] In other embodiments, 15-PGDH inhibitors can be administered to a subject after liver surgery, living donor liver donation, liver transplant, or toxin-induced liver injury to increase liver regeneration and / or to promote recovery from or tolerance to liver toxins, including acetaminophen and related compounds.

[0115] In yet other embodiments, a 15-PGDH inhibitor can be administered to a subject to treat erectile dysfunction.

[0116] In yet another embodiment, a 15-PGDH inhibitor can be administered to inhibit at least one of the growth, proliferation, or metastasis of a 15-PGDH-expressing cancer.

[0117] Yet other embodiments described herein relate to methods of treating a subject in need of cell therapy, comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells 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.

[0118] In some embodiments, the subject has received human hematopoietic stem cells and / or has received a pharmaceutical and / or therapeutic composition.

[0119] In other embodiments, the subject has acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, severe aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH), pure red cell aplasia, amegakaryocytosis / congenital thrombocytopenia, severe myeloma, leukemia ... If you have combined immunodeficiency syndrome (SCID), Wiskott-Aldrich syndrome, beta-thalassemia major, 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.

[0120] 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 formulation 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.

[0121] In some embodiments, ischemia is caused by acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, cerebral edema, decreased cerebral perfusion pressure, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, Delayed wound healing, diabetes 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, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, hyperischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic reperfusion injury, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease The condition may be associated with at least one of peripheral arterial disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, inflammatory conditions of the blood vessels, von Hippel-Lindau syndrome, and tissue or organ wound.

[0122] Other embodiments relate to methods for treating and / or preventing fibrosis and various fibrotic diseases, disorders, or conditions by administering a 15-PGDH inhibitor. In some embodiments, the 15-PGDH inhibitors described herein 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.

[0123] 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 ... 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, fibrotic syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrous tissue, retroperitoneal fibrosis, hepatic fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis (bone marrow fibrosis), drug-induced 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.

[0124] In some embodiments, the method of treating or preventing a fibrotic disease, disorder or condition comprises administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof.

[0125] In some embodiments, 15-PGDH inhibitors 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.

[0126] In another embodiment, 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, or a combination thereof.

[0127] In other 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, or a combination thereof.

[0128] In some embodiments, 15-PGDH inhibitors may be used to treat or prevent cardiac fibrosis, for example, cardiac fibrosis and endomyocardial fibrosis.

[0129] In some embodiments, 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis.

[0130] In some embodiments, 15-PGDH inhibitors can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

[0131] In some embodiments, 15-PGDH inhibitors can be used to reduce or prevent scar formation in a subject.

[0132] In another embodiment, 15-PGDH inhibitors can be used to reduce or prevent scarring in the skin or scleroderma.

[0133] In various embodiments, the 15-PGDH inhibitor 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.

[0134] In another embodiment, 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, intestine, colon, skin, or heart, in 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 deposition in a tissue or organ, such as the kidney, lung, liver, intestine, colon, skin, or heart. Typically, excessive collagen secretion or deposition in an organ results from injury or damage. Such damage and damage can be organ-specific. The 15-PGDH inhibitor can be administered for a period sufficient to completely or partially reduce or alleviate collagen deposition levels in the tissue or organ. A sufficient period can be one week, one week to one month, one to two months, or two months or more. In chronic conditions, it can be advantageous to administer the 15-PGDH inhibitor lifelong.

[0135] Other embodiments described herein relate to the use of a 15-PGDH inhibitor 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. Administration of a 15-PGDH inhibitor in combination with a corticosteroid has been found to enhance the anti-inflammatory and / or immunosuppressive effects of the corticosteroid while attenuating corticosteroid-induced side effects and / or cytotoxicity. 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 with attenuated and / or reduced side effects or cytotoxicity for a longer period of time.

[0136] In some embodiments, the inflammatory and / or immune-mediated disease or disorder treated with a combination of a 15-PGDH inhibitor and a corticosteroid or a TNF inhibitor can include an intestinal, gastrointestinal, or bowel disorder. As described below, it has been found that inhibitors of short-chain dehydrogenase activity, such as a 15-PGDH inhibitor, 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 bowel disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0137] In other embodiments, 15-PGDH inhibitors can be used as glucocorticoid sensitivity enhancers to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in subjects experiencing corticosteroid dependence, corticoid resistance or unresponsiveness, or corticosteroid intolerance. For example, 15-PGDH inhibitors can be administered to subjects in combination with corticosteroids to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in subjects experiencing corticosteroid dependence, corticoid resistance or unresponsiveness, or corticosteroid intolerance.

[0138] 15-PGDH inhibitors can also be administered to a subject in combination with corticosteroids or TNF inhibitors to promote wound healing, tissue repair and / or tissue regeneration, and / or tissue graft survival or regeneration.

[0139] In some embodiments, a 15-PGDH inhibitor 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 cytotoxicity. DETAILED DESCRIPTION OF THE INVENTION

[0140] 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.

[0141] As used herein, the verb "comprise" and its conjugations, as used in the specification and claims, are used in an open sense and mean that the items that follow the word are included, but not 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.

[0142] Further, please note that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for using exclusive terminology, such as "only," "only," and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.

[0143] The term "pharmaceutically acceptable" means suitable for use in contact with the tissues of human beings and animals without undue 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.

[0144] 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 those 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, dehydrobiethylamine, 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.

[0145] Additionally, the 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.

[0146] The term "solvate" refers to a solvent addition form that contains a stoichiometric or non-stoichiometric amount of solvent.Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate that is formed is a hydrate, and when the solvent is alcohol, the solvate that is 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 maintains its molecular state as H2O, and such a combination can form one or more hydrates.

[0147] 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. Although 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.

[0148] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of an electron and a hydrogen atom occurs.

[0149] 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.

[0150] 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.

[0151] "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 listed 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.

[0152] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched chain divalent hydrocarbon radical having from 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.

[0153] "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. a) 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 10Alkenyl includes all of the moieties listed above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Alkenyl 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), iso-propenyl, 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, 3-nonenyl Examples of undecenyl include 1-decenyl, 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.

[0154] "Alkenylene" or "alkenylene chain" refers to a straight or branched chain hydrocarbon radical having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. 12Non-limiting examples 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.

[0155] "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 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 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, but also includes C6 alkynyl. 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.

[0156] "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.

[0157] "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.

[0158] "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.

[0159] "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, and 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.

[0160] "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, which 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 intended to include optionally substituted aryl groups.

[0161] 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.

[0162] "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.

[0163] An "aralkynyl" or "arylalkynyl" is 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.

[0164] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon. A carbocycle can contain from 3 to 20 carbon atoms in the ring. Carbocycles include aryl and cycloalkyl. Cycloalkenyl and cycloalkynyl are as defined herein. Unless otherwise specifically stated herein, a carbocyclyl group can be optionally substituted.

[0165] "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 rest 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.

[0166] "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 rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, 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.

[0167] "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 groups include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specifically stated in this specification, cycloalkynyl groups can be optionally substituted.

[0168] "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, or cycloalkynyl radical, as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

[0169] "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.

[0170] "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.

[0171] "Haloalkenyl" 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.

[0172] "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 member atom, which can be carbon or nitrogen. Unless otherwise specifically stated in the specification, heterocyclyl groups can be optionally substituted.

[0173] "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.

[0174] "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.

[0175] "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.

[0176] "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, N-heterocyclyl groups can be optionally substituted.

[0177] "Heteroaryl" refers to a 5- to 20-membered ring system radical having, as ring members, 1 to 13 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. 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.

[0178] "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.

[0179] "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.

[0180] "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.

[0181] "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.

[0182] 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.

[0183] 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; as well as 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, N-heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, and the like), replaced by bonds to other heteroatoms in various other groups. Halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and 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 with a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo groups, carbonyl groups, carboxyl groups, 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 with a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo groups, carbonyl groups, carboxyl groups, 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 g C(=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 It also means any of the above groups replaced by g and R hare the same or different and 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.

[0184] As used herein, the symbols [ka] (which may hereinafter be referred to as a "point of attachment bond") means a bond that is a point of attachment between two chemical entities, one of which is shown as being attached at the point of attachment bond and the other of which is not shown as being attached at the point of attachment bond. For example, [ka] indicates that chemical "A" is attached to another chemical via a point-of-attachment bond. Additionally, specific points of attachment to chemicals not shown can be identified by inference. For example, compound [ka] (Wherein, X is [ka] ) infers that the point of attachment bond is the bond shown as by which X is attached to the phenyl ring in the ortho position relative to the fluorine.

[0185] The phrases "parenteral administration" and "parenterally administered" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, including, but not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0186] The term "treating" is art-recognized and includes arresting, e.g., preventing the progression of, and alleviating, e.g., regressing, a 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.

[0187] 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.

[0188] 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 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.

[0189] 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 manifestation 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 the undesired condition, whereas if it is administered after clinical manifestation of the undesired condition, the treatment is therapeutic (i.e., intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects).

[0190] The terms "therapeutic agent," "drug," "medication," and "bioactive agent" are art-recognized and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition. These terms include, but are not limited to, pharmaceutically acceptable salts and prodrugs thereof. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; and they may be prodrugs in the form of ethers, esters, amides, etc., that become biologically activated upon administration to a patient or subject.

[0191] The phrases "therapeutically effective amount" or "pharmaceutically effective amount" are art-recognized terms. In certain embodiments, the term refers to that 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 the 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 for in vivo use is likely to depend on many factors, including: the rate of release of the agent from the polymer matrix (which will depend in part on the chemical and physical properties of the polymer); the properties of the agent; the mode and method of administration; and any other materials incorporated into the polymer matrix in addition to the agent.

[0192] The term "ED50" is art-recognized. In certain embodiments, ED50 refers to the dose of a drug which produces 50% of its maximum response or effect or the dose which produces a predetermined response in 50% of test subjects or preparations. The term "LD50" is art-recognized. In certain embodiments, LD50 refers to the dose of a drug that is lethal in 50% of test subjects. The term "therapeutic index" is art-recognized and refers to the therapeutic index of a drug, which is defined as LD50 / ED50.

[0193] "I C 50 The term "50% maximal inhibitory concentration" or "50% 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.).

[0194] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and therefore the description includes instances where the circumstance occurs. 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.

[0195] 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 also consists essentially of or consists of the recited process steps. Furthermore, it is 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.

[0196] All percentages and ratios used herein are by weight unless otherwise specified.

[0197] The term "neoplasm" refers to an abnormal mass of cells or tissue resulting from the formation of a new cell. This neoplasm can be benign, potentially malignant (precancerous), or malignant (cancerous). An adenoma is an example of a neoplasm.

[0198] The terms "adenoma," "colon adenoma," and "polyp" are used herein to describe any precancerous neoplasia of the colon.

[0199] As used herein, the term "colon" is intended to encompass the right colon (including the cecum), transverse colon, left colon, and rectum.

[0200] The terms "colorectal cancer" and "colon cancer" are used interchangeably herein to refer to cancerous neoplasia of the colon (as defined above, including the rectum).

[0201] The terms "gene expression" or "protein expression" include information about the amount of gene transcript or protein present in a sample and 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 data may be considered to relate to both gene expression and protein expression. For example, intracellular protein levels reflect the level of protein and the level of transcription, and such data are intended to be encompassed by the phrase "gene expression or protein expression information." Such information may be given in the form of amounts per cell, amounts relative to a reference gene or protein, unitless measurements, etc., and the term "information" should not be limited to a particular means of expression; it is intended to refer to any expression 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.

[0202] The terms "healthy" and "normal" are used interchangeably herein to refer to a subject or particular cell or tissue that is free from (at least below the limit of detection of) a disease state.

[0203] 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 and, where applicable to the described embodiments, single-stranded (such as sense or antisense) and double-stranded polynucleotides. In some embodiments, "nucleic acid" refers to inhibitory nucleic acids. 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.

[0204] 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.

[0205] The terms "inhibitor," "activator," and "modulator" of 15-PGDH expression or activity refer to inhibitory, activating, or modulating molecules (e.g., ligands, agonists, antagonists, and their homologs and mimetics), respectively, that are 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 naturally occurring and synthetic ligands and small chemical molecules.

[0206] 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 pigmentation or tanning. Known activities of prostaglandins also include ameliorating pulmonary arterial hypertension. The 15-PGDH inhibitors described herein can also be used to increase tissue stem cell numbers (by exposing the transplant tissue in vivo to a 15-PGDH inhibitor described herein to increase stem cell numbers before harvesting, by exposing harvested tissue ex vivo before transplantation into a recipient host, or by treating the transplant recipient) for purposes including increasing resistance to radiation-induced tissue damage, increasing resistance to environmental exposure to radiation, 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 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.

[0207] The 15-PGDH inhibitors described herein can be identified using assays in which putative modulator compounds are applied to cells expressing 15-PGDH, followed by determining their functional effect on 15-PGDH activity. Samples or assays containing 15-PGDH treated with potential activators, inhibitors, or modulators are compared to control samples containing no inhibitors, activators, or modulators to determine the extent of the effect. Control samples (untreated with modulators) 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.

[0208] 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.

[0209] In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to the tissue or blood of a subject in an amount effective to inhibit the activity of short-chain dehydrogenase enzymes. The SCD inhibitor can be a 15-PGDH inhibitor that 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 (IA): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof. (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)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is oxo, -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, where 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 Each R 5are independently 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 - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9 is H or alkyl, or two R 9 are O, S(O) along with the N atom to which they are attached. t or N; R 10 is —OH, halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2) may include:

[0210] In some embodiments, the 15-PGDH inhibitor has formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof. (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)alkyl; R 6 are each one or more R 3 heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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 - is alkyl; 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, alkoxy, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently 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 - alkyl; or Instead, two R 5can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9 is H or alkyl, or two R 9 are O, S(O) along with the N atom to which they are attached. t or N; X is N or CH; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2) may include:

[0211] In some embodiments, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).

[0212] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl or -(CH2) p -cyclohexyl, where p is 1, 2 or 3.

[0213] In yet other embodiments, R 2 is -NH2.

[0214] In some embodiments, R 6are each one or more R 3 is a 5- to 6-membered heterocyclyl or a 5- to 10-membered heteroaryl optionally substituted with

[0215] In other embodiments, R 6 is one or more R 3 is a 5-6 membered heteroaryl optionally substituted with

[0216] In yet other embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0217] In some embodiments, R 7 are each one or more R 4 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).

[0218] In other embodiments, R 7 are each one or more R 4 C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl optionally substituted with

[0219] In yet other embodiments, R 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, or 5- to 10-membered heteroaryl optionally substituted with

[0220] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5)(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0221] In other embodiments, R 3 are -(C1-C3 alkyl)OH, -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH 2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0222] In other embodiments, R 3are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0223] In yet other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0224] In some embodiments, R 4 is halogen, -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.

[0225] In some embodiments, n is 1.

[0226] In other embodiments, the 15-PGDH inhibitor is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and a compound selected from the group consisting of compounds selected from molecule numbers 198 to 434 in Table 1, or pharmaceutically acceptable salts thereof, tautomers thereof, and solvates thereof.

[0227] In another embodiment, the 15-PGDH inhibitor is selected from the compounds disclosed in any one of Examples 1-323 or a pharmaceutically acceptable salt thereof, a tautomer of the present invention, and a solvate thereof.

[0228] In some embodiments, the 15-PGDH inhibitor having formula I, IA, II, III, IV, V, VI, VII, or VIII (i.e., Formulas I-VIII) is not a compound having the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0229] In some embodiments, without being limited by theory, Applicants have unexpectedly and surprisingly found that R 1 We have discovered that a carbocyclyl group at this position increases the half-life of the compound. Half-life is an important parameter for therapeutic agents because it determines the duration of action of the agent; the longer the half-life, the longer the agent can exert a therapeutic effect in a subject. In some embodiments, 3- to 6-membered cycloalkyls, particularly 3- to 5-membered cycloalkyls such as cyclobutyl, have been observed to have desirable half-lives.

[0230] In other embodiments, the compound has the formula (II): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is a 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl); R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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, 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, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently 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 - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9 is H or alkyl, or two R9 are O, S(O) along with the N atom to which they are attached. t or N; X is N or CH; m is 0, 1 or 2; and t is 0, 1 or 2) It has.

[0231] In some embodiments, R 1 is a 3- to 5-membered cycloalkyl or -(C1-C6 alkylene)-(3- to 5-membered cycloalkyl).

[0232] In other embodiments, R 1 is cyclobutyl.

[0233] In yet other embodiments, R 1 is a bicyclic 4-6 membered cycloalkyl.

[0234] In some embodiments, R 7 are each one or more R 4 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).

[0235] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C4 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl optionally substituted with

[0236] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C3 alkyl, C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5-6-membered heteroaryl, optionally substituted with 7 are each one or more R 4 C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5-6-membered heteroaryl optionally substituted with

[0237] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, optionally substituted with 7 are each one or more R 4 is —CF 3 optionally substituted with cyclopropyl, phenyl, pyridyl, pyrazole or triazole.

[0238] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0239] In other embodiments, R 3are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0240] In yet other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0241] In some embodiments, without being limited by theory, Applicants have surprisingly and unexpectedly found that hERG inhibition (IC 50 ), to improve hERG activity, including block and efflux ratios, 7 It has been found that the substituents at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 6

[0242] In other embodiments, the compound has formula (III): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 C1-C6 haloalkyl, aryl, or heteroaryl optionally substituted with; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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 - is alkyl; Each R 5 are independently 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, -alkylene-COOH, -C(O)O-alkyl or -S(O) m - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 4is halogen, alkyl or alkoxy; X is N or CH; and m is 0, 1 or 2 It has.

[0243] In some embodiments, R 7 are R 4 is —CF 3 optionally substituted with —CF 3 , pyridyl, pyrazole, phenyl or triazole.

[0244] In other embodiments, R 7 is -CF3, pyridyl, fluorophenyl or triazole optionally substituted with halogen or methyl.

[0245] In other embodiments, R 7 CF3, [ka] is.

[0246] In other embodiments, R 7 is CF3 。

[0247] In yet other embodiments, R 7 teeth, [ka] is.

[0248] In some embodiments, R 7 teeth, [ka] is.

[0249] In some embodiments, R 7 teeth, [ka] is.

[0250] In other embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0251] In some embodiments, without being limited by theory, Applicants have surprisingly and unexpectedly found that R 7 We found that 3- to 6-membered cycloalkyl at the 5'-position can improve solubility while maintaining PDGH activity.

[0252] In other embodiments, the compound has formula (IV): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl or -alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 is one or more R 4 is a 3- to 6-membered cycloalkyl optionally substituted with R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, 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 - is alkyl; R4 is halogen, —CN, —NH2, —OH or C1-C3 alkyl; Each R 5 are independently 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, -alkylene-COOH, -C(O)O-alkyl or -S(O) m - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2 It has.

[0253] In some embodiments, R 7 is cyclopropyl.

[0254] In other embodiments, R 1 is a 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).

[0255] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl or -(CH2) p -cyclohexyl, where p is 1, 2 or 3.

[0256] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0257] In some embodiments, R 3 are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0258] In other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0259] In some embodiments, without being limited by theory, Applicants have surprisingly and unexpectedly found that R 6 R 3It has been found that the aryl group can be substituted with a group.

[0260] In other embodiments, the compound has the formula (V): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl or -alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 are each one or more R 4 haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl); 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, haloalkyl, cycloalkyl, heterocyclyl or R 8-alkylene-aryl optionally substituted with Each R 5 are independently H, C1-C6 alkyl, -(C1-C6 alkylene) optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R 9 )2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), alkylene-COOH or -S(O) m (C1-C6 alkyl); or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2 It has.

[0261] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2 or -N(R 5 ) (C1-C6 alkylene-OH).

[0262] In other embodiments, R 5 is H, C1-C6 alkyl, -(C1-C6 alkylene)-OH, or -S(O)2(C1-C3 alkyl).

[0263] In some embodiments, R 3are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0264] In other embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0265] In yet other embodiments, R 3 is -NHCH2CH2OH.

[0266] In some embodiments, R 6 are each one or more R 3 is a 5- to 6-membered heterocyclyl or a 5- to 10-membered heteroaryl optionally substituted with

[0267] In other embodiments, R 6 is one or more R 3 is a 5-6 membered heteroaryl optionally substituted with

[0268] In some embodiments, R 6 are each one or more R 3furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine optionally substituted with

[0269] In other embodiments, R 6 is thiazole, imidazole, oxazole, pyridine or pyrimidine.

[0270] In some embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0271] In other embodiments, R 6 is one or more R 3 is a 5-6 membered heterocyclyl selected from morpholine, pyridin-one or piperidine, optionally substituted by

[0272] In some embodiments, R 7 are each one or more R 4 C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5-6-membered heteroaryl optionally substituted with

[0273] In other embodiments, R 7 are each one or more R 4 is —CF 3 optionally substituted with cyclopropyl, phenyl, pyrazole, pyridyl or triazole.

[0274] In some embodiments, the compound has formula (VI): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl or alkylene-heterocyclyl; R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is a fused bicyclic heterocyclyl or a fused bicyclic heteroaryl optionally substituted with R 7 are each one or more R 4 alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl or —C(O)NR 5 - is alkyl; R 3 is oxo, -OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, -N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 )2, -C(O)-alkyl, -C(O)O-alkyl or -S(O) m - is alkyl; 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, haloalkyl, cycloalkyl, heterocyclyl or R 8 -alkylene-aryl optionally substituted with Each R 5 are independently H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH, -C(O)-alkyl, -C(O)O-alkyl or -S(O) m - alkyl; or Instead, two R 5can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; X is N or CH; and m is 0, 1 or 2 It has.

[0275] In some embodiments, R 6 are each one or more R 3 is an 8-10 membered fused bicyclic heteroaryl optionally substituted with

[0276] In some embodiments, R 7 are each one or more R 4 C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocycle, 5- to 10-membered heteroaryl, —C(O)(C1-C6 alkyl), —C(O)O(C1-C6 alkyl), or —C(O)NR 5 (C1-C6 alkyl).

[0277] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C4 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, optionally substituted with 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl optionally substituted with

[0278] In yet other embodiments, R 7 are each one or more R 4C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally substituted with

[0279] In other embodiments, R 7 are each one or more R 4 In another embodiment, R is C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, optionally substituted with 7 are each one or more R 4 C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole optionally substituted with

[0280] In other embodiments, R 7 are each one or more R 4 In other embodiments, R is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, optionally substituted with 7 are each one or more R 4 is —CF 3 optionally substituted with cyclopropyl, phenyl, pyridyl, or triazole.

[0281] In some embodiments, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).

[0282] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl or -(CH2) p-cyclohexyl, where p is 1, 2 or 3.

[0283] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0284] In other embodiments, R 3 are -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH( -C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0285] In some embodiments, R 3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0286] In other embodiments, R 4 is halogen, -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.

[0287] In some embodiments, the compound has formula (VII): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof (In the formula, R 1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 is heterocyclyl or heteroaryl optionally substituted with; R 7 is -CF3, isopropyl, [ka] and; R 3 is oxo, -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, where cycloalkyl and heterocyclyl are each R 10 optionally replaced by; R 4is C1-C3 alkyl; Each R 5 are independently 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 - alkyl; or Instead, two R 5 can form, together with the N atom to which they are attached, a 4- to 7-membered heterocycle optionally containing an additional heteroatom selected from O, S, or N, where the heterocycle is R 8 optionally replaced by; R 8 is halogen, alkyl or alkoxy; R 9 is H or alkyl, or two R 9 are O, S(O) along with the N atom to which they are attached. t or N; R 10 is —OH, halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2; p is 0 or 1; and t is 0, 1 or 2) It has.

[0288] In yet other embodiments, R 2 is -NH2.

[0289] In some embodiments, R 6 are each one or more R 3 is a 5- to 6-membered heterocyclyl or a 5- to 10-membered heteroaryl optionally substituted with

[0290] In other embodiments, R6 is one or more R 3 is a 5-6 membered heteroaryl optionally substituted with

[0291] In yet other embodiments, R 6 is one or more R 3 is an 8-10 membered bicyclic heteroaryl optionally substituted with

[0292] In some embodiments, R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl) or -S(O) m (C1-C6 alkyl).

[0293] In other embodiments, R 3 are -(C1-C3 alkyl)OH, -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH 2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl) or -OCH2CH2N(C1-C3 alkyl)2.

[0294] In yet other embodiments, R3 is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0295] In some embodiments, R 4 is halogen, -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.

[0296] In some embodiments, n is 1.

[0297] In some embodiments, the compound has formula (VIII): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof (In the formula, R 1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R 2 is —NH, CN, or —NHC(O)alkyl; R 6 are each one or more R 3 optionally substituted with [ka] and; R 7 are each one or more R 4 -CF3, isopropyl, cyclopropyl, cyclobutyl optionally substituted with [ka] and; R 3is -NH2, -NH(C1-C3 alkyl), -NH(C1-C4 alkylene)-OH or C1-C3 alkyl; R 4 is C1-C3 alkyl; and X is N or CH It has.

[0298] In some embodiments of Formula (VIII), R 1 is cyclobutyl. In some embodiments of Formula (VIII), R 1 is -(C1-C4 alkylene)-(C1-C3 alkoxy). In some embodiments of Formula (VIII), R 1 The -(C1-C4 alkylene)-(C1-C3 alkoxy) is -(C2-C3 alkylene)-(C1 alkoxy).

[0299] In some embodiments of Formula (VIII), R 2 is -NH2.

[0300] In some embodiments of Formula (VIII), R 6 teeth, [ka] is.

[0301] In some embodiments of Formula (VIII), R 3 is —NH. In some embodiments of Formula (VIII), R 3 is —NH(C1-C3 alkyl). In some embodiments of Formula (VIII), R 3 is —NH(C1-C4 alkylene)-OH (e.g., —NH(C2-C4 alkylene)-OH). In some embodiments of Formula (VIII), R 3 is C1-C3 alkyl (for example, methyl or ethyl).

[0302] In some embodiments of Formula (VIII), R 7is —CF3, isopropyl, cyclopropyl, or cyclobutyl. In some embodiments of Formula (VIII), R 7 In some embodiments of Formula (VIII), R 7 are each one or more R 4 optionally substituted with [ka] In some embodiments, each R 4 is independently selected from methyl or ethyl.

[0303] In some embodiments of Formula (VIII), X is —CH.

[0304] In some embodiments, the compound of formula (VIII) is shown in Table 2.

[0305] In one embodiment, the compounds of formula (VIII) exclude: [ka]

[0306] In some 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. Colonic 15-PGDH inhibition can be measured (e.g., by the assay described in this Example) 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 using an appropriate dose of a compound of the present disclosure. In some embodiments, colonic 15-PGDH inhibition is measured 30 minutes after administration. In certain embodiments, colonic 15-PGDH inhibition is measured at 4 hours. In some embodiments, a suitable dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 0, 15, 20, 30, 40, 50 mg / kg or more (including all values ​​and ranges between these values).

[0307] In one embodiment, lung, liver, intestine, skin, heart (or any other organ disclosed herein) 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 (including all times and ranges therebetween). In some embodiments, lung 15-PGDH inhibition is measured at 30 minutes. In certain embodiments, lung 15-PGDH inhibition is measured at 4 hours. In some embodiments, a suitable dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 0, 15, 20, 30, 40, 50 mg / kg or more, including all values ​​and ranges therein. In some 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 therein.

[0308] In some embodiments, a 15-PGDH inhibitor (e.g., having Formulas I-VIII) of the present disclosure, 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 30 minutes. In some 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 30 minutes. In some embodiments, compounds of the present disclosure, 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 some embodiments, compounds of the present disclosure, 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 some embodiments, compounds of the present disclosure, 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. In some embodiments, compounds of the present disclosure, when administered to a mammal at 10 mg / kg, inhibit colonic 15-PGDH activity by about 95% to 100% and any subranges thereof at 30 minutes. This is an unexpected and surprising result, since previously synthesized 15-PGDH inhibitors, such as Reference Compound C (Example B), when administered orally at 10 mpk, were not effective in inhibiting colonic 15-PGDH activity in 30 minutes. In fact, Reference Compound C actually increased colonic 15-PGDH activity, as indicated by a -55.2% inhibition.

[0309] In some embodiments, a disclosed 15-PGDH inhibitor (e.g., having Formulas I-VIII) 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 when administered to a mammal at 10 mg / kg. In some embodiments, a disclosed compound 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%) at 4 hours when administered to a mammal at 10 mg / kg. In some embodiments, compounds of the present disclosure, 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 some embodiments, compounds of the present disclosure, 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 some embodiments, compounds of the present disclosure, 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.

[0310] In some embodiments, a 15-PGDH inhibitor of the present disclosure (e.g., having Formulas I-VIII) is administered to a mammal at 10 mg / kg and inhibits lung, liver, intestine, skin, heart (or any other organ disclosed herein) 15-PGDH activity in 30 minutes 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 subrange therein. In some embodiments, compounds of the present disclosure 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 some embodiments, compounds of the present disclosure 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 some embodiments, compounds of the present disclosure inhibit pulmonary 15-PGDH activity in the range of about 80% to 100% and any subranges thereof at 30 minutes when administered to a mammal at 10 mg / kg.

[0311] In some embodiments, a 15-PGDH inhibitor of the present disclosure (e.g., having Formulas I-VIII) administered to a mammal at 10 mg / kg inhibits 15-PGDH activity in the lung, liver, intestine, skin, 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 subrange therein, within 4 hours. In some embodiments, compounds of the present disclosure 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 4 hours when administered to a mammal at 10 mg / kg. In some embodiments, compounds of the present disclosure 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 4 hours when administered to a mammal at 10 mg / kg. In some embodiments, compounds of the present disclosure inhibit pulmonary 15-PGDH activity in the range of about 80% to 100% and any subranges thereof at 4 hours when administered to a mammal at 10 mg / kg.

[0312] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have a human microsomal stability T of greater than 50 minutes. 1 / 2 In some embodiments, compounds of the present disclosure have a human microsomal stability of greater than 60 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of greater than 70 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of greater than 80 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have a human microsomal stability T of greater than 90 minutes. 1 / 2In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have a human microsomal stability T of greater than 100 minutes. 1 / 2 In some embodiments, compounds of the present disclosure have a human microsomal stability of greater than 110 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of greater than 120 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of greater than 130 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of greater than 145 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human 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 / 2 It has.

[0313] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have better human microsomal stability compared to 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, and WO 2018 / 218251, the disclosures of each of which are incorporated herein in their entirety for all purposes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 15 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 25 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 35 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 45 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 55 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 65 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 75 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 85 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 95 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 100 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 110 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 120 minutes longer than previously disclosed 15-PGDH inhibitors. 1 / 2In some embodiments, the 15-PGDH inhibitors of the present disclosure have the microsomal stability T of previously disclosed 15-PGDH inhibitors. 1 / 2 Human microsome stability T ranges from 15 minutes to approximately 120 minutes longer than 1 / 2 It has.

[0314] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have a human microsomal stability T that is at least 40 minutes longer than that of reference compound C (Example B). 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 70 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 80 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 90 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 100 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 110 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 120 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T in the range of 70 minutes to about 120 minutes longer than reference compound C. 1 / 2 It has.

[0315] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have a mouse microsomal stability T of greater than 10 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 50 minutes. 1 / 2In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 60 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 70 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 80 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 90 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 100 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 110 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mass microsomal stability T of greater than 120 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 130 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 140 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of greater than 145 minutes. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a 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 / 2 It has.

[0316] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) have a mouse microsomal stability T that is at least 10 minutes longer than that of reference compound C (Example B). 1 / 2In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 20 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 30 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 40 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T of at least 50 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 60 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 70 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 80 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 90 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 100 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 110 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 120 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 130 minutes longer than reference compound C. 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T of at least 140 minutes longer than reference compound C.1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a 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 / 2 It has.

[0317] EC for PGE2 induction 50 is determined using A549 cells treated with IL1-β for 24 hours. In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formulas I-VIII) inhibit PGE2-induced EC 50 In some embodiments, the EC 50 In some embodiments, the EC 50 In some embodiments, the EC 50 In some embodiments, the EC 50 In some embodiments, the EC 50 In some embodiments, the EC 50 In some embodiments, the EC 50 is at least four times lower than previously disclosed 15-PGDH inhibitors, e.g., those disclosed in the publications referenced 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. 50is 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 10-50 times lower than previously disclosed 15-PGDH inhibitors.

[0318] In some embodiments, the EC of a 15-PGDH inhibitor of the present disclosure (e.g., Formulas I-VIII) 50 is at least 5 times lower than that of reference compound C (Example B). 50 is at least 10-fold lower than that of the reference compound C. In some embodiments, EC 50 is at least 15-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 20-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 25-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 30-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 35-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 40-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 45-fold lower than that of reference compound C. In some embodiments, EC 50 is at least 50-fold lower than that of the reference compound C. In some embodiments, EC 50 is 5-fold and ∼50-fold lower than the reference compound C.

[0319] In certain embodiments, ia) at a concentration of 2.5 μM, a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct can stimulate 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); iia) at a concentration of 2.5 μM, a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct can stimulate a luciferase output level of greater than 75; iiia) at a concentration of 7.5 μM, a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct can stimulate a luciferase output level of greater than 70; iva) at a concentration of 7.5 μM, a negative control V9m cell line expressing a TK-Renilla luciferase reporter does not activate a level greater than 20; and va) has an IC of less than 1 μM. 50 The 15-PGDH inhibitors having the formulas (I-VIII) can be selected to inhibit the enzymatic activity of the recombinant 15-PGDH protein.

[0320] In other 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) not activating a negative control V9m cell line expressing a TK-Renilla luciferase reporter to luciferase levels greater than 20% of background at a concentration of 7.5 μM; and vb) having an IC of less than 1 μM. 50 and inhibits the enzymatic activity of recombinant 15-PGDH protein.

[0321] In some 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

[0322] 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, the various types of prostaglandins (A2, F) in the various compartments of the hair follicle or their adjacent skin environment are known to play an important role 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 prostaglandins, especially PGF 2a It has been reported that 15-PGDH inactivates prostaglandins and PGE2, causing scalp damage and alopecia (Michelet JF et al., 2008, Exp. Dermatol, 17(10), 821-8). Therefore, the compounds described herein that have suppressive or inhibitory activity against 15-PGDH, which decomposes prostaglandins, can improve scalp damage, prevent alopecia, and promote hair growth, and can be used in pharmaceutical compositions for preventing alopecia and promoting hair growth.

[0323] In other 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.

[0324] In some embodiments, a 15-PGDH inhibitor can be applied to the coverings of a subject, e.g., topically, 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).

[0325] 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 cells surrounding the blood vessel walls (Yan, Cheng et al., 2006, J. Clin., Invest). Furthermore, suppression of prostaglandin production or loss of its activity can lead to degeneration of the endothelium in the blood vessel wall, platelet aggregation, and dysfunction of the smooth muscle cellular mechanisms. In particular, reduced intravascular prostaglandin production has been shown in patients with hypertension, including pulmonary arterial hypertension.

[0326] In other embodiments, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of oral, 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 incidence of gastritis and gastric ulcers is relatively high, but their causes remain unclear. Previously, they have been known to be caused by 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.

[0327] 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.

[0328] Furthermore, 15-PGDH inhibitors would be expected to protect against other forms of intestinal injury such as radiation toxicity, chemotherapy toxicity and chemotherapy-induced mucositis.

[0329] In the kidney, prostaglandins may play a role in regulating renal blood flow and urinary formation 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 intravenous administration of prostaglandins such as PGE1, PGE2, and PGI2. Furthermore, it has been reported that prostaglandins act as vasodilators in the kidney, and therefore, suppression of prostaglandin production in the kidney causes renal dysfunction (Hao, CM, 2008, Annu Rev Physiol, 70, 357.about.77).

[0330] 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.

[0331] As used herein, the term "renal dysfunction" includes manifestations such as: lower than normal creatinine clearance, lower than normal creatinine free water clearance, higher than normal blood urea, nitrogen, potassium and / or creatinine levels, altered 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.

[0332] PGE1, PGE2 and PGF 2aProstaglandins, 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 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, promote healing after bone surgery or joint replacement, or promote healing of bone-to-bone implants, bone-to-prosthetic implants, dental implants, and bone grafts.

[0333] In yet other embodiments, the 15-PGDH inhibitors described herein may be effective in treating 15-PGDH-expressing cancers. Inhibition of 15-PGDH can inhibit the growth, proliferation, and metastasis of 15-PGDH-expressing cancers.

[0334] In yet another embodiment, the 15-PGDH inhibitors described herein may be effective in wound healing. Among various prostaglandins, PGE2 is known to act as a mediator of wound healing. Therefore, when skin is damaged by a wound or burn, inhibiting 15-PGDH activity may result in the therapeutic effect of PGE2 on the wound or burn.

[0335] Furthermore, as described above, increased prostaglandin levels have been shown to stimulate signaling through the Wnt signaling pathway by increasing beta-catenin-mediated transcriptional activity. Wnt signaling is known to be an important pathway used 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 beta cells, kidney, bone, cartilage, and peripheral nerves.

[0336] Symptomatic conditions, trauma, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and the need for tissue repair, and are 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, bone marrow disease, osteoporosis ... Fractures, cerebral edema, decreased cerebral perfusion pressure, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes (types I and II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic peripheral telangiectasia, ischemic vascular disease, hyperoxia, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, hyperischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's These conditions include: 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, 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.

[0337] Other examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions, or other conditions causing or associated with tissue damage and the need for tissue repair that are suitable for treatment or amelioration using the methods of the present disclosure include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplant or graft.

[0338] In various embodiments, the methods described herein 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.

[0339] In some embodiments, ischemia is a condition selected from the group consisting of 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, fractures, cerebral edema, decreased cerebral perfusion pressure, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neurological disorders, and the like. Disorders, chronic infections, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusions, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes mellitus (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic peripheral telangiectasia, ischemic vascular disease, Hyperoxia, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, hyperischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemia-reperfusion injury, 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, The condition may be associated with at least one of peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, 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.

[0340] In some 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.

[0341] 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, e.g., Fei, R. et al., U.S. Pat. No. 5,635,387; McGlave et al., U.S. Pat. No. 5,460,964; Simmons, P. et al., U.S. Pat. No. 5,677,136; Tsukamoto et al., U.S. Pat. No. 5,750,397; Schwartz et al., U.S. Pat. No. 5,759,793; DiGuisto et al., U.S. Pat. No. 5,681,599; Tsukamoto et al., U.S. Pat. No. 5,716,827). Hematopoietic stem cells (HSCs) give rise to unipotent hematopoietic progenitor cells (HPCs) that are capable of generating the entire repertoire of mature blood cells over the lifetime of an organism.

[0342] Hematopoietic stem and progenitor cells, unless otherwise noted, are generally referred to herein as hematopoietic stem cells or hematopoietic stem and progenitor cells (HSPCs) and are characterized by the antigenic marker CD34 (CD34 + In some embodiments, hematopoietic stem cells can be identified by the presence of the antigen marker CD34 and the absence of lineage (lin) markers, and thus can refer to cells or populations ... + / lin - It can be characterized as a cell.

[0343] 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 highly purified populations of hematopoietic stem cells or as compositions 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.

[0344] Sources of hematopoietic stem cells can be isolated or obtained from bodily organs containing cells of hematopoietic origin. Isolated cells can include cells removed from their original environment. For example, cells are isolated if they are separated from some or all of the components that normally accompany them in their natural state. For example, "isolated cell population," "isolated cell source," or "isolated hematopoietic stem cells," etc., as used herein, refer to the in vitro or ex vivo separation of one or more cells from their natural cellular environment and association with other components of a tissue or organ (i.e., they are not significantly associated with in vivo materials).

[0345] 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 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, mobilization of donor stem and progenitor cells may be necessary to obtain sufficient quantities of hematopoietic stem cells for therapeutic use.

[0346] "Hematopoietic stem cell mobilization" refers to the release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukocyte separation 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 drugs, 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, G-CSF and Mozobil (Genzyme Corporation) can be administered to a donor to obtain a sufficient number of hematopoietic cells for transplantation. Other methods of hematopoietic stem cell mobilization will be apparent to those skilled in the art.

[0347] In some embodiments, the hematopoietic stem cells 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 herein by reference for such methodology).

[0348] In one embodiment, hematopoietic 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, the cells can then be programmed into a desired cell type, such as a hematopoietic stem cell or hematopoietic progenitor cell. As used herein, the term "reprogramming" refers to a method of increasing the potency of a cell to a more undifferentiated state. As used herein, the term "programming" refers to a method of decreasing the potency of a cell or differentiating a cell to a more differentiated state.

[0349] In some 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 one embodiment, 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 hematopoietic stem cells is whole bone marrow, umbilical cord blood, or mobilized peripheral blood.

[0350] In certain embodiments, a therapeutic composition comprises a cell population that is about 95% to about 100% hematopoietic stem cells. The present disclosure contemplates, in part, that the efficiency of stem cell therapy may be improved by using a therapeutic composition of highly purified hematopoietic stem cells, e.g., a composition comprising a cell population, the cells of which are about 95% hematopoietic stem cells. Currently practiced transplantation methods generally use unfractionated mixtures of cells, in which hematopoietic stem cells comprise less than 1% of the total cell population.

[0351] In some embodiments, a therapeutic composition comprises a cell population, wherein 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% hematopoietic stem cells. In some 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% hematopoietic stem cells. In other embodiments, the cell population comprises 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.

[0352] Hematopoietic stem cells in the therapeutic compositions of the present disclosure can be autologous / autogeneic ("self") or non-autologous ("non-self", e.g., allogeneic, syngeneic, or xenogeneic) relative to the subject to whom 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.

[0353] Hematopoietic stem cells for use in the disclosed methods can be obtained from bone marrow aspirates, umbilical cord blood, or mobilized peripheral blood (mobilized leukapheresis product) depleted of mature hematopoietic cells and their unipotent precursors, such as T cells, B cells, NK cells, dendritic cells, monocytes, granulocytes, and erythroid cells. Mature progenitor cells are depleted by immunodepletion, e.g., by labeling a solid substrate with antibodies that bind to a panel of so-called "lineage" antigens: CD2, CD3, CD11b, CD14, CD15, CD16, CD79, CD56, CD123, and CD235a. Subsequent steps can further purify the cell population, where CD34 + Primitive hematopoietic stem cells are isolated using a substrate labeled with an antibody that binds to the antigen. 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 with the methods described herein.

[0354] In one embodiment, 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 6pieces, 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.

[0355] In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is the amount of hematopoietic stem cells 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 6 At 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 6Pieces / kg body weight, at least 25 x 10 6 pieces / kg body weight or at least 30 x 10 6 Pieces / kg body weight.

[0356] 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 to reduce further damage to ischemic tissue and / or repair damage to ischemic tissue by cell mobilization, 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.

[0357] 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, the subject has undergone myeloablative radiation therapy or chemotherapy or experienced acute radiation or chemical injury resulting in bone marrow destruction. In certain embodiments, the subject has 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.

[0358] Subjects who may be treated with a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells 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 non-hematologic cancer such as acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, myelodysplastic syndrome, or a solid tumor (including breast cancer, ovarian cancer, brain cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer).

[0359] Subjects may also include those suffering from aplastic anemia, immune disorders (severe combined immunodeficiency syndrome or lupus), myelodysplasia, thalassemia, sickle cell disease, or Wiskott-Aldrich syndrome. In some embodiments, 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.

[0360] Additionally, subjects suffering from the following conditions may also benefit from treatment with 15-PGDH inhibitor-treated hematopoietic stem cell preparations and / or therapeutic compositions of 15-PGDH inhibitors and hematopoietic stem cells: lymphopenia, lymphorrhea, lymphostasis, erythropenia, erythroblastic degenerative disorders, erythroblastopenia, leukoerythroblastosis, erythrocytolysis, thalassemia, myelodysplasia, myelofibrosis, thrombocytopenia, disseminated intravascular coagulation (DIC), immune (autoimmune) thrombocytopenia. Inflammatory purpura (ITP), HIV-induced ITP, myelodysplasia, thrombotic disorders, thrombocytosis, congenital neutropenia (such as Kostmann syndrome and Shwachman-Diamond syndrome), tumor-associated neutropenia, childhood and adult cyclic neutropenia, post-infectious neutropenia, myelodysplastic syndromes, neutropenia associated with chemotherapy and radiotherapy, chronic granulomatous disease, mucopolysaccharidoses, Diamond-Blackfan anemia, sickle cell disease, or beta-thalassemia major.

[0361] In other embodiments, the 15-PGDH inhibitor-treated hematopoietic stem cell preparations and / or therapeutic compositions of 15-PGDH inhibitors 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 or loss of organ function (including, but not limited to, damage or loss of brain, kidney, or heart function), convulsions, claudication, numbness, tingling, weakness, pain, decreased wound healing, inflammation, skin discoloration, and gangrene.

[0362] In one embodiment, 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.

[0363] Illustrative examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions, or other conditions that cause or are associated with ischemia, or that increase a subject's risk of ischemia or result in one or more symptoms of ischemia in a subject, and thus are suitable for treatment or amelioration using the methods described herein include, but are not limited to, acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, and the like. Injury, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fractures, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, 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 Cardiac disorders, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic peripheral telangiectasia, ischemic vascular disease, hyperoxia, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, hyperischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic reperfusion injury, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis These conditions 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, 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, inflammatory conditions of the blood vessels, von Hippel-Lindau syndrome, and tissue or organ wounds.

[0364] Other specific examples of genetic disorders, symptomatic conditions, trauma, 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 present disclosure include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplantation or transplantation.

[0365] In various embodiments, the methods described herein 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.

[0366] In various embodiments, the present disclosure contemplates that the therapeutic cell compositions disclosed herein may be used to treat ischemic tissue where it is desirable to increase blood flow, oxygen supply, glucose supply, or nutrient supply to the tissue.

[0367] In some 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 giving rise to other tissues, and / or to a preparation of pluripotent stem cells.

[0368] In one embodiment, tissue stem cells can be obtained from pluripotent stem cell sources, such as iPSCs and ESCs.

[0369] In some 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 one embodiment, a therapeutic composition can comprise a population of tissue stem cells treated ex vivo with one or more 15-PGDH inhibitors.

[0370] In certain embodiments, a therapeutic composition comprises a cell population that is about 95% to about 100% tissue stem cells. The present disclosure contemplates, in part, that the efficiency of stem cell therapy may be improved by using a therapeutic composition of highly purified tissue stem cells, for example, a composition that comprises a cell population that is about 95% tissue stem cells.

[0371] In some embodiments, a therapeutic composition comprises a cell population, wherein 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 some 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 other embodiments, the cell population comprises 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.

[0372] The tissue stem cells in the therapeutic compositions described herein can be autologous / autogeneic or non-autologous to the subject to whom the therapeutic composition is administered.

[0373] 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 to treat damaged tissue and reduce further tissue damage, and / or to enhance repair of damaged tissue by stem cell mobilization, and / or to increase cell survival at the site of tissue damage.

[0374] Genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and the need for tissue repair, and are 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. Infectious diseases, fractures, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, 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, 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, hyperoxia, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, hyperischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic reperfusion injury, left main trunk lesion, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson disease These 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, 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.

[0375] Other examples of genetic disorders, symptomatic conditions, trauma, chronic conditions, medical interventions or other conditions causing or associated with tissue damage and the need for tissue repair suitable for treatment or amelioration using the methods of the present invention include ischemia resulting from surgery, chemotherapy, radiation therapy or cell, tissue or organ transplantation or transplantation.

[0376] 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.

[0377] In other embodiments, a 15-PGDH inhibitor may also be administered to the bone marrow of a subject to increase stem cell numbers in the subject or to increase the suitability of the bone marrow as a donor graft.

[0378] In yet other 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, and / or reduce the number of units of cord blood required for transplant into the subject. Administration can be after treatment of the subject or the subject's bone marrow with, for example, radiation therapy, chemotherapy, or immunosuppressive therapy.

[0379] In another embodiment, a 15-PGDH inhibitor can be administered to a recipient of a bone marrow transplant, hematopoietic stem cell transplant, or umbilical cord blood stem cell transplant to reduce the administration of other treatments or growth factors.

[0380] In some embodiments, a 15-PGDH inhibitor can be administered to a subject to enhance neutrophil recovery after bone marrow transplant, umbilical cord blood transplant, hematopoietic stem cell transplant, conventional chemotherapy, radiation therapy, and in individuals with neutropenia due to disease, including but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, neutropenia from other bone marrow diseases, drug-induced neutropenia, immune neutropenia, idiopathic neutropenia, and diseases following infection with viruses, including, but not limited to, HIV, CMV, and parvovirus.

[0381] In other embodiments, 15-PGDH inhibitors can be administered to subjects to enhance platelet recovery after bone marrow transplantation, umbilical cord blood transplantation, hematopoietic stem cell transplantation, conventional chemotherapy, radiation therapy, and in individuals with thrombocytopenia due to disease, including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia from other bone marrow diseases, drug-induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and diseases following infection with viruses, including, but not limited to, HIV, CMV, and parvovirus.

[0382] In yet other embodiments, 15-PGDH inhibitors can be administered to subjects to enhance hemoglobin recovery after bone marrow transplantation, umbilical cord blood transplantation, hematopoietic stem cell transplantation, conventional chemotherapy, radiation therapy, and in individuals with anemia due to disease, including but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, anemia from other bone marrow diseases, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, idiopathic anemia, and diseases following infection with viruses, including, but not limited to, HIV, CMV, and parvovirus.

[0383] In some 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.

[0384] In other embodiments, 15-PGDH inhibitors can be administered to subjects with cytopenias, including but not limited to, neutropenia, thrombocytopenia, lymphopenia, and anemia, to enhance the response to cytokines administered to the subject. Cytokines whose response can be enhanced by the 15-PGDH inhibitors described herein include G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, SCF, and TPO-RA (thrombopoietin receptor agonist).

[0385] In further embodiments, a 15-PGDH inhibitor can be administered to a subject or a subject's tissue graft after treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy or immunosuppressive therapy to reduce graft rejection, to enhance graft survival, 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 infection, and / or to reduce pulmonary toxicity from radiation.

[0386] In another embodiment, a 15-PGDH inhibitor can be administered to a recipient of tissue stem cell transplantation, including, but not limited to, hematopoietic stem cells, neural stem cells, mesenchymal stem cells, or other tissue stem cells, to accelerate tissue regeneration and repair after transplantation.

[0387] In some embodiments, a 15-PGDH inhibitor can be administered in combination with G-CSF to increase neutrophils.

[0388] In other embodiments, the 15-PGDH inhibitor can be administered in combination with hematopoietic cytokines to increase neutrophils.

[0389] In yet another embodiment, a 15-PGDH inhibitor 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.

[0390] In other embodiments, 15-PGDH inhibitors can be administered in combination with hematopoietic cytokines to increase the number of and / or mobilize peripheral blood hematopoietic stem cells.

[0391] In some embodiments, a 15-PGDH inhibitor 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.

[0392] In another embodiment, a 15-PGDH inhibitor 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.

[0393] 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.

[0394] In other embodiments, a 15-PGDH inhibitor can be administered in combination with a second agent, including plerixafor, to increase and / or mobilize peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[0395] 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.

[0396] In other embodiments, 15-PGDH inhibitors can be administered in combination with hematopoietic cytokines to increase the number of hematopoietic stem cells in the blood or bone marrow.

[0397] In other 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.

[0398] In some embodiments, a method for treating or preventing a fibrotic disease, disorder, or condition comprises administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor such that at least one symptom or characteristic of the fibrotic disease, disorder, or condition, or other related disease, disorder, or condition, is reduced in intensity, severity, or frequency, or delayed in onset.

[0399] 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.

[0400] 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, pulmonary fibrosis, 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, fibrotic 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.

[0401] 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 can be associated with inflammation, occur as a symptom of underlying disease, and / or occur during surgical procedures or wound healing processes. Unchecked fibrosis can destroy the structure of underlying organs or tissues, commonly referred to as scarring.

[0402] In some embodiments, 15-PGDH inhibitors 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.

[0403] Pulmonary fibrosis is characterized by progressive scarring of lung tissue, accompanied by fibroblast proliferation, excessive accumulation of extracellular matrix proteins, and abnormal alveolar structure. As the tissue thickens and stiffens, the lungs no longer function properly, causing shortness of breath and other respiratory problems that can ultimately be fatal. Pulmonary fibrosis can be caused by acute lung injury, viral infection, exposure to toxins, radiation, chronic illness, medications, or it can be idiopathic (i.e., no underlying cause has been identified).

[0404] The classic finding of idiopathic pulmonary fibrosis is erosive scarring (known as emphysematous bullae) in peripheral areas of the lungs, often with small bubbles adjacent to the lung surface and often adjacent to the basal surface membrane. Idiopathic pulmonary fibrosis progresses slowly and often remains elusive over time. Initially, patients often complain of a dry, unexplained cough. Shortness of breath (dyspnea) then begins, triggered by a gradual decrease in activity, and worsens 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 onset. This form of pulmonary fibrosis is called Herman-Rich syndrome.

[0405] 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, resulting in 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.

[0406] Chronic obstructive pulmonary disease (COPD) is a common lung disease that is often associated with chronic bronchitis or emphysema. Common symptoms include cough, mucus buildup, fatigue, wheezing, and respiratory infections.

[0407] Chronic bronchitis and emphysema are lung diseases that narrow the airways, restricting airflow into and out of the lungs and causing shortness of breath (dyspnea). In clinical practice, COPD is defined by characteristically low airflow on pulmonary function tests.

[0408] Chronic bronchitis occurs when lung damage and inflammation occur in the large airways. In the lung airways, chronic bronchitis is characterized by an increase in the number (hyperplasia) and size (hypertrophy) of airway goblet cells and mucus glands. As a result, the airways fill with more mucus than normal, narrowing the airways and causing a productive cough. Microscopically, inflammatory cells are seen infiltrating the airway walls. Scarring and remodeling follow the inflammation, 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.

[0409] Asthma is a chronic lung disease characterized by inflammation and constriction of the airways. Asthma causes recurrent episodes of wheezing, chest tightness, shortness of breath, and coughing. Swelling and excessive mucus production can further constrict the airways and worsen symptoms. There is evidence that increased matrix degradation may occur in asthma, which may contribute to 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.

[0410] Cystic fibrosis (CF) is a recessive, multisystem genetic disorder characterized by abnormal chloride and sodium transport across epithelia, leading to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract. 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 resulting 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.

[0411] Common symptoms in subjects with cystic fibrosis include, but are not limited to, thick mucus buildup, heavy phlegm 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.

[0412] In another embodiment, 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 meticulous surgical procedures can reduce the extent of adhesion formation, removal of adhesions is rare, and effective adjuvant therapy is necessary. Reducing the fibrosis associated with this process could reduce surgical pain, obstruction, and other complications, and promote healing and recovery.

[0413] Wounds in mammalian tissues (e.g., lacerations, openings) result in tissue disruption 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 hypoxic, acidic, and hypercarbonated, with high lactic acid levels. Adjacent to the wound cavity is a gradient zone of local anemia (ischemia), which is caused by dividing fibroblasts. Behind the leading zone is a zone of active collagen synthesis, characterized by mature fibroblasts and numerous new 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.

[0414] In some embodiments, 15-PGDH inhibitors can be administered to a subject in need of treatment to reduce or prevent scar formation in the subject. Scar formation is a natural part of the healing process. 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.

[0415] In other 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 referred to as itches. 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 when 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 that destroys collagen during the remodeling process, leaving a depressed area.

[0416] In some embodiments, 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis. Systemic sclerosis is a systemic connective tissue disease characterized by changes in the microvasculature, impaired immune system, and 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. Reduction of fibrosis resulting from systemic sclerosis can improve symptoms and / or prevent further complications in affected tissues.

[0417] In other 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.

[0418] Nonalcoholic steatohepatitis (NASH) is a common liver disease. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The main 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.

[0419] 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 as the disease progresses or cirrhosis develops. NASH progression can take years, even decades. The process may be halted and, in some cases, begin to reverse spontaneously without specific treatment. Alternatively, NASH may gradually worsen, causing scarring or fibrosis to appear and accumulate in the liver. As fibrosis worsens, cirrhosis develops, causing the liver to become severely scarred and hard, preventing it from functioning normally. While not all patients with NASH develop cirrhosis, once severe scarring or cirrhosis occurs, few treatments can halt its progression. Patients with cirrhosis experience fluid retention, muscle wasting, intestinal bleeding, and liver failure. The only cure for advanced cirrhosis with liver failure is liver transplantation, which is increasingly being performed on people with NASH. In the United States, NASH ranks as one of the leading causes of cirrhosis, after hepatitis C and alcoholic liver disease.

[0420] In some embodiments, 15-PGDH inhibitors can be used to treat or prevent renal fibrosis, which can result from renal failure followed by dialysis, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease, or end-stage renal failure.

[0421] Kidney (renal) fibrosis results from the excessive formation of fibrous connective tissue in the kidney. Renal fibrosis causes significant morbidity and mortality, leading to the need for dialysis or kidney transplantation. Fibrosis can occur at both the filtration and reabsorption sites of the nephron, the functional unit of the kidney. Many factors may 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 spectrum of changes in the physiology of individual cells leads to the production of numerous peptide and non-peptide fibrinogens that stimulate a shift in the balance between extracellular matrix synthesis and degradation, promoting scarring.

[0422] In some embodiments, symptoms of fibrosis in tissues or 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 the number of inflammatory cells in a tissue or organ. A relevant sample can be obtained from the subject to determine the reduction in inflammatory cell counts. In a non-limiting embodiment, a beneficial effect can be assessed by demonstrating a reduction in neutrophil counts 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 counts are well known in the art and include, but are not limited to, FACS techniques. In some embodiments, the method can include reducing the number of neutrophil cells in BAL fluid from the subject compared to a control. Any appropriate control, such as a cystic fibrosis subject not treated with a 15-PGDH inhibitor, can be used for comparison. In some embodiments, a reduction in inflammatory cell counts, such as neutrophil counts, provides a 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.

[0423] In another embodiment, the beneficial effects of a 15-PGDH inhibitor can be assessed by a reduction 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 reducing the amount of one or more inflammatory biomarkers in the subject's sample compared to a control.

[0424] In another embodiment, 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, in 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 deposition in a tissue or organ, such as the kidney, lung, liver, intestine, colon, skin, or heart. Excessive collagen secretion or deposition in an organ typically results from injury or damage. Such injury or damage is organ-specific. The 15-PGDH inhibitor can be administered for a period sufficient to completely or partially reduce or alleviate collagen deposition levels in the tissue or organ. A sufficient period can be one week, one week to one month, one to two months, or two months or more. In chronic conditions, it can be advantageous to administer the 15-PGDH inhibitor lifelong.

[0425] 15-PGDH inhibitors for use in treating fibrotic conditions, disorders, or diseases 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 functional effect on 15-PGDH activity is then determined. Samples or assays containing 15-PGDH treated with potential inhibitors are compared to control samples without inhibitors to determine the degree of effect. Control samples (untreated with modulators) 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 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.

[0426] PGE1 analogs have also been used to treat erectile dysfunction. Thus, in some embodiments, the 15-PGDH inhibitors described herein can be used alone or in combination with a prostaglandin to treat erectile dysfunction.

[0427] 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 cytotoxicity. The administration of a 15-PGDH inhibitor in combination with a corticosteroid can increase the therapeutic efficacy of inflammation and / or immune disorders; in some instances, a lower dose of the corticosteroid can achieve similar efficacy, and in other instances, a higher dose can be administered with attenuated and / or reduced side effects or cytotoxicity for a longer period of time. Further embodiments herein relate 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.

[0428] In some embodiments, 15-PGDH inhibitors can be administered in combination with corticosteroids and / or TNF inhibitors to treat intestinal, gastrointestinal, or bowel disorders. Treated intestinal, gastrointestinal, or bowel disorders can 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 bowel disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0429] The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of oral, 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, two representative 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. Previously, they have been known to be caused by 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.

[0430] 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.

[0431] 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 increased colonic 15-PGDH levels, an effect that would reduce the therapeutic efficacy of corticosteroids in treating colitis. This suggests that the combination of corticosteroids and a 15-PGDH inhibitor is more effective in treating colitis (and IBD) than either drug alone.

[0432] 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, an effect that should reduce 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.

[0433] In other embodiments, the 15-PGDH inhibitor and a corticosteroid or the 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.

[0434] In other embodiments, the 15-PGDH inhibitor and corticosteroid or 15-PGDH inhibitor and 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 helicalis, and other inflammatory skin diseases.

[0435] 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.

[0436] 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 act 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.

[0437] Furthermore, increased prostaglandin levels have been shown to stimulate signaling through the Wnt signaling pathway by increasing beta-catenin-mediated transcriptional activity. Wnt signaling is known to be an important pathway used 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 beta cells, kidney, bone, cartilage, and peripheral nerves.

[0438] In other embodiments, 15-PGDH inhibitors can be used as glucocorticoid sensitizers to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in subjects experiencing corticosteroid dependence, or corticosteroid resistance or unresponsiveness, or corticosteroid intolerance. 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.

[0439] In some 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 unresponsiveness, or corticosteroid intolerance. Glucocorticoid-insensitivity-related conditions can include a range of immune-inflammatory disorders / diseases and combinations thereof that are treated with steroids when treatment fails to control the disease, are ineffective against, intolerant of, or dependent on corticosteroids.

[0440] In another embodiment, 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 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, steroid-resistant sarcoidosis, refractory atopic dermatitis, 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, steroid-resistant sarcoidosis ... Eichmann'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 those receiving appropriate anti-PCP antibiotic treatment. 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 Pneumocystis carinii pneumonia (PCP) associated with hypoxemia 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 aberrant neurological or myocardial invasion, and tuberculous meningitis.

[0441] It will be understood that other 15-PGDH inhibitors can be used in the methods described herein. These other 15-PGDH inhibitors include, for example, the tetrazole compounds of formula (I) and (II), the 2-alkylideneaminooxyacetamide compounds of formula (I), the heterocyclic compounds of formula (VI) and (VII), and the pyrazole compounds of formula (III) described in U.S. Patent Application Publication No. 2006 / 0034786 and U.S. Patent No. 7,705,041; the benzylidene-1,3-thiazolidine compounds of formula (I) described in U.S. Patent Application Publication No. 2007 / 0071699; the phenylfurylmethylthiazolidine-2,4-dione compounds and phenylthienylmethylthiazolidine-2,4-dione compounds described in U.S. Patent Application Publication No. 2007 / 0078175; No. 7,294,641; 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acids and salts as described in U.S. Pat. No. 4,725,676; and lactones; azo compounds as described in U.S. Pat. No. 4,889,846; and known 15-PGDH inhibitors, including azo compounds as described in PCT / US2014 / 060761 and U.S.2015 / 0072998A1 (all of which are incorporated herein by reference in their entireties).

[0442] 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 can 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.

[0443] In some embodiments, the pharmaceutical composition can be formulated into a parenteral or oral dosage form. Solid dosage forms for oral administration can be prepared by adding excipients, if necessary, to the 15-PGDH inhibitor along with binders, disintegrants, lubricants, colorants, and / or flavoring agents, and then molding the resulting mixture into tablets, sugar-coated pills, granules, powder, or capsules. Additives that can be added to the composition can be those commonly used in the art. For example, examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicates, etc. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate, and polypyrrolidone. Examples of disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. In addition, refined talc, stearic acid salts, sodium borate, and polyethylene glycol can be used as lubricants, and sucrose, bitter orange peel, citric acid, and tartaric acid can be used as flavoring agents. In some embodiments, the pharmaceutical compositions can be made into aerosol formulations (e.g., they can be nebulized) and administered by inhalation.

[0444] 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.

[0445] In some embodiments, the 15-PGDH inhibitors described herein can 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 pyrosulfate, EDTA, thioglycolic acid, and thiolactic acid. Local anesthetics can be procaine HCl, lidocaine HCl, etc. Relaxants can be sodium chloride, glucose, etc.

[0446] In other embodiments, the 15-PGDH inhibitors described herein can be incorporated into suppositories in a conventional manner by adding thereto a pharmaceutically acceptable carrier known in the art, e.g., polyethylene glycol, lanolin, cocoa butter, or fatty acid triglycerides, as needed, along with a surfactant such as Tween.

[0447] 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 some 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, for example, an amount of a 15-PGDH inhibitor for treating or ameliorating alopecia, cardiovascular disease, gastrointestinal disease, wounds, and kidney 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. Generally, the daily dose for an adult 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.

[0448] Cosmetic compositions containing 15-PGDH inhibitors may include 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 sexual organs) or with the teeth or oral mucosa, exclusively or mainly for the purposes of cleansing them, perfume them, modifying their appearance and / or correcting body odor and / or protecting them or keeping them in good condition.

[0449] 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 a hydrophilic organic solvent, a lipophilic organic solvent, an amphiphilic organic solvent, and mixtures thereof.

[0450] For topical application, the cosmetic composition can be applied in the form of an aqueous, alcoholic, aqueous-alcoholic, or oily solution or suspension, or in the form of a lotion or serum dispersion; in the form of an emulsion with a liquid or semi-liquid consistency or pasty, obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O), or by multiple emulsion; in the form of a free or compressed powder, either used as is or incorporated into a physiologically acceptable medium, or else in the form of microcapsules or microparticles, or in the form of a vesicular dispersion of ionic and / or nonionic type. Thus, it can be in the form of an ointment, 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. It can be non-aqueous or aqueous. It can also include solid preparations constituting soaps or cleansing cakes.

[0451] 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 subsequent rinsing, or in the form of a shampoo. Also contemplated are compositions in the form of a foam or a spray or aerosol, thus comprising a propellant under pressure. Thus, they may be in the form of a lotion, serum, milk, cream, gel, salve, ointment, powder, balm, patch, impregnated pad, cake, or foam.

[0452] In particular, compositions for application to the scalp or hair can 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 washing the hair. They can also be in the form of a hair dye or mascara to be applied with a brush or comb.

[0453] Furthermore, for topical application to eyelashes or body hair, the composition may be in the form of a tinted or untinted mascara that is applied with a brush to the eyelashes or beard or mustache. For administration of the composition by injection, the composition may be in the form of an aqueous lotion or an oily suspension. For oral use, the composition may be in the form of a capsule, granules, oral syrup, or tablet. According to certain embodiments, the composition is in the form of a hair cream or hair lotion, shampoo, hair conditioner, or mascara for hair or eyelashes.

[0454] The cosmetic composition may also contain, in a known manner, adjuvants commonly used in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV-blocking agents, odor absorbers, and dyes. The amounts of these various adjuvants are those commonly used in the cosmetic field, for example, 0.1% to 20%, particularly 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.

[0455] In some 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 phrases "combinatorial therapy" or "combination therapy" encompass the administration of a 15-PGDH inhibitor and one or more therapeutic agents as part of a specific treatment regimen intended to provide a beneficial effect from the synergistic action of these therapeutic agents. The administration of these therapeutic agents in combination generally 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 the administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject individual doses containing each therapeutic agent in a fixed ratio, or by administering 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.

[0456] In some 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 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, in particular those described in EP 1175891 and EP 1175890, WO 01 / 74307, WO 01 / 74313, WO 01 / 74314, WO 01 / 74315 or WO 01 / 72268.

[0457] In other embodiments, the 15-PGDH inhibitors can be administered in combination with active agents (single or in mixtures) such as vasodilators, prostanoid agonists, antiandrogens, cyclosporines and their analogs, antibacterial agents, triterpenes, etc. Vasodilators can include minoxidil and its derivatives, aminexil, 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, potassium channel agonists including cromakalim and diazoxide. Antiandrogens include 5-alpha-reductase inhibitors such as finasteride, compounds described in U.S. Patent No. 5,516,779, cyproterone acetate, azelaic acid, its salts and derivatives, 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, compounds described in European Patent No. 680745, clinicin 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).

[0458] 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, pantothenol, 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 hydroxybenzoates, ... Examples of the inhibitors include substituted ethylene aryls, N-acylated amino acids, flavonoids, derivatives and analogs of ascomycin, histamine antagonists, triterpenes such as ursolic acid, 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.

[0459] 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. These include, in particular, agonists of the prostaglandin F2α receptor (in acid form or in precursor form, in particular in ester form), such as 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 (and their precursors, in particular esters), such as cicaprost, iloprost, isocarbacycline, beraprost, epoprostenol, treprostinil, BW245C((4S) Prostaglandin D2 receptor agonists and precursors thereof, particularly esters thereof, such as (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), 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.

[0460] Advantageously, the composition comprises at least one 15-PGDH inhibitor as defined above and PGF 2, for example 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, 16,16-dimethyl PGE2, 17-phenyl PGF2, and 16,16-dimethyl PGF 2α 17-phenyl PGF 2α and derivatives thereof, such as 11-deoxyprostaglandin E1, 1-deoxyprostaglandin E1, in saline or ester form, series 1 prostaglandins, such as analogs thereof, in particular at least one prostaglandin or one prostaglandin derivative, such as latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, biprostol, butaprost, misoprostol, salts thereof or esters thereof.

[0461] The present invention is further illustrated by the following examples, which are not intended to limit the scope of the claims. [Example]

[0462] 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. Patent No. 9,790,233, which is incorporated herein by reference in its entirety. The data are based on the IC of each compound that inhibits the enzymatic activity of recombinant 15-PGDH in an in vitro assay. 50 Classification is made as follows: <2.5 nM (***), ≥2.5 nM <10 nM (**), or >10 nM (*). Recombinant 15-PGDH is human unless otherwise stated.

[0463] [Table 1]

[0464] [Table 2]

[0465]

Table 3

[0466]

Table 4

[0467]

Table 5

[0468]

Table 6

[0469]

Table 7

[0470]

Table 8

[0471]

Table 9

[0472]

Table 10

[0473]

Table 11

[0474]

Table 12

[0475]

Table 13

[0476]

Table 14

[0477]

Table 15

[0478] Table 16

[0479]

Table 17

[0480]

Table 18

[0481] Table 19

[0482] Table 20

[0483] Table 21

[0484] Table 22

[0485] Table 23

[0486] Table 24

[0487] Table 25

[0488] Table 26

[0489] Table 27

[0490] Table 28

[0491] Table 29

[0492]

Table 30

[0493] Table 31

[0494] Table 32

[0495]

Table 33

[0496] Table 34

[0497] Table 35

[0498] Table 36

[0499] Table 37

[0500] Table 38

[0501] Table 39

[0502] Table 40

[0503] Table 41

[0504] Table 42

[0505] Table 43

[0506] Table 44

[0507] Table 45

[0508] Table 46

[0509] Table 47

[0510] Table 48

[0511] Table 49

[0512]

Table 50

[0513] Table 51

[0514] Table 52

[0515] Table 53

[0516] Table 54

[0517] Table 55

[0518] Table 56

[0519] Table 57

[0520] Table 58

[0521] Table 59

[0522] Table 60

[0523] Table 61

[0524] Table 62

[0525] Table 63

[0526] Table 64

[0527] Table 65

[0528] Table 66

[0529] Table 67

[0530] Table 68

[0531] Table 69

[0532] Table 70

[0533] Table 71

[0534] Table 72

[0535] Table 73

[0536] Table 74

[0537] Table 75

[0538] Table 76

[0539] Table 77

[0540] Table 78

[0541] Table 79

[0542] Table 80

[0543] Table 81

[0544] Table 82

[0545] Table 83

[0546] Table 84

[0547] Table 85

[0548] [Table 86]

[0549] [Table 87]

[0550] [Table 88]

[0551] [Table 89]

[0552] [Table 90]

[0553] [Table 91]

[0554] [Table 92]

[0555] [Table 93]

[0556] [Table 94]

[0557] Example B. Biological Assays The activity of compounds (EC50 (nM)) in inducing PGE2 from IL1-β-treated A549 cells was determined in the culture medium of A549 cells stimulated with IL1-β for 24 hours. Metabolic stability was determined by incubating compounds at a concentration of 10 μM in the presence of microsomes from mouse liver. Compound concentrations were monitored over time by HPLC / MS, and half-lives were calculated from the slope of the best-fit line for Ln[compound] versus time.

[0558] Additionally, reference compounds and selected compounds described herein were orally administered to mice at 10 mg / kg (mpk). Colonic 15-PGDH activity was assessed at 30 minutes. As shown in Table 2, reference compound A was not effective in inhibiting colonic 15-PGDH activity at 30 minutes and actually showed increased activity, as indicated by -55.2% inhibition. In comparison, compounds described herein demonstrated inhibition of colonic 15-PGDH activity at 30 minutes. Similar assays were performed at 4 hours.

[0559] In Table 2, reference compounds A, B and C have the following structures:

[0560] Reference compound: [ka] For the disclosure of Reference Compounds A-C, see WO 2015 / 065716 and WO 2018 / 218251, the disclosures of each of which PCT applications are incorporated herein by reference in their entirety for all purposes.

[0561] [Table 95]

[0562] Applicants have found that IC50 values ​​alone are not predictive of in vivo efficacy, as in disease models. In vivo inhibition of 15-PGDH, human microsomal stability, hERG IC 50Additional pharmacokinetic and pharmacodynamic properties, such as EC50 for PGE2 elevation and EC50 for PGE2 elevation, are important for in vivo efficacy. Without being bound by theory, in certain embodiments, clinical candidates should have two or more of the following properties: (i) mouse colon enzyme inhibition ≥ 70% or ≥ 90% after 30 minutes of 10MPK(PO); (ii) human microsomal stability ≥ 60 minutes; (iii) hERG IC 50 >15; and (iv) a PGE2-elevating EC50 ≦10 nM. In some embodiments, a clinical candidate has three or more of the properties (i), (ii), (iii), and (iv). In some embodiments, a clinical candidate has properties (i), (ii), (iii), and (iv). For example, a compound having mouse colon enzyme inhibition after 30 minutes of 10 MPK of ≧90% or ≧70% may exhibit in vivo efficacy if such a compound also exhibits, for example, a combination of any two or more of: (ii) a human microsomal stability of ≧60 minutes; (iii) a hERG IC50 of >15; and / or (iv) an EC50 ≦10 nM. Such compounds with in vivo efficacy are encompassed by the formulas disclosed herein, e.g., Formula VIII.

[0563] Additionally, the plasma concentration of a compound disclosed herein (e.g., a compound of Formula VIII and / or Table 2) can be measured using known techniques, for example, to determine the maximum blood concentration, the time to reach the maximum blood concentration, and the area under the plasma concentration curve.

[0564] synthesis [ka] Example 1A: 6-Thioxo-4-(trifluoromethyl)-1,6-dihydro-[2,3'-bipyridine]-5-carbonitrile. Cyanothioacetamide (207 mg, 2.07 mmol) was added to a solution of 4,4,4-trifluoro-1-(pyridin-3-yl)butane-1,3-dione (300 mg, 1.38 mmol) and DABCO (155 mg, 1.38 mmol) in EtOH at room temperature. The reaction mixture was stirred under reflux. Upon completion of the reaction, the mixture was left overnight at 0°C, filtered, and the collected solid was dried to give the title compound in quantitative yield. ESI-MS (m / z): 282.1 [M+H] + .

[0565] [ka] Example 1B: 6-(((butylthio)methyl)thio)-4-(trifluoromethyl)-[2,3′-bipyridine]-5-carbonitrile. A mixture of 6-thioxo-4-(trifluoromethyl)-1,6-dihydro-[2,3′-bipyridine]-5-carbonitrile (4.91 mmol, 1380 mg), butyl(chloromethyl)sulfane (4.91 mmol, 677 mg, 1.0 equiv.), and EtN (7.36 mmol, 750 mg, 1.0 mL, 1.5 equiv.) in dry CHCN (32.0 mL) was stirred at 80° C. for 20 min. The reaction mixture was then 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 599 mg of the desired product. 1H NMR(400MHz,chloroform-d)δ 9.32(dt,J=2.4,0.8Hz,1H),8.79(ddd,J=4.9,1.7,0.7Hz,1H),8.39(dddd,J=8.1,2.4,1.7,0.6Hz,1H),7.78(s,1H),7.50(ddt,J=8.1,4. 8,0.8Hz,1H),4.51(s,2H),2.75(t,J=7.8Hz,2H),1.72-1.60(m,2H),1.42(h,J=7.4Hz,2H),0.92(t,J=7.3,3H).ESI-MS(m / z):384.1[M+H] + .

[0566] [ka] Example 1C: 6-(((butylsulfinyl)methyl)thio)-4-(trifluoromethyl)-[2,3′-bipyridine]-5-carbonitrile. To a solution of (((butylthio)methyl)thio)-4-(trifluoromethyl)-[2,3′-bipyridine]-5-carbonitrile (570 mg, 1.49 mmol) in CHCl / AcOH (1:1, 0.27 M) was added HO (372 μL, 30% aqueous solution). The reaction mixture was stirred at 32 °C for 40 min. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 553 mg (93%) of the desired compound. 1 H NMR(400MHz,chloroform-d)δ 9.28(s,1H),8.80(dd,J=4.8,1.5Hz,1H),8.49(ddt,J=8.1,2.6,1.5Hz,1H),7.87(s,1H),7.55(ddt,J=8.0,4.9,1.0Hz,1H),4.71(d,J=13 .3Hz,1H),4.54(d,J=13.3Hz,1H),3.00-2.80(m,2H),1.90-1.75(m,2H),1.61-1.37(m,2H),0.96(t,J=7.4,3H).ESI-MS(m / z):400.0[M+H] + .

[0567] [ka] Example 1: 2-(butylsulfinyl)-6-(pyridin-3-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine. To a solution of 6-(((butylsulfinyl)methyl)thio)-4-(trifluoromethyl)-[2,3'-bipyridine]-5-carbonitrile (410 mg, 1.03 mmol) in DMF (6.7 mL) / MeOH (3.35 mL) was added KOH (0.62 mmol, 34.7 mg, 347 μL in water). The reaction mixture was stirred at 32 °C for 10 min. Upon completion, the reaction was diluted with EtOAc and acidified to pH 7 with 5% aqueous AcOH. The organic phase was separated, and the aqueous layer was extracted twice with EtOAc, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired product. 1 H NMR(400MHz, methylene chloride-d2)δ 9.33(dd,J=2.4,0.9Hz,1H),8.72(dd,J=4.8,1.7Hz,1H),8.46(ddd,J=8.0,2.4,1. 6Hz,1H),8.11(d,J=0.8Hz,1H),7.49(ddd,J=8.0,4.8,0.9Hz,1H),5.24(s,2H),3. 33(ddd,J=12.9,9.0,6.2Hz,1H),3.17(ddd,J=12.9,9.1,6.8Hz,1H),1.90-1.68(m ,2H),1.52(dd,J=7.3,2.5Hz,2H),0.97(t,J=7.3Hz,3H).ESI-MS(m / z):400.1[M+H] + .

[0568] The enantiomers of Example 1 were separated on a 1 cm Chiralpak AD-H column using 50% EtOH and 50% Hexane at a flow rate of 5 mL / min with an injection volume of 400 μL (concentration 10 mg / mL). The first peak was at 7.8 min and the second peak at 15.1 min.

[0569] [ka] Example 2: 2-((3-Methoxypropyl)sulfinyl)-6-(pyridin-3-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue example 1. 1 H NMR(500MHz, methylene chloride-d2)δ 9.37(s,1H),8.76(s,1H),8.50(ddd,J=8.1,2.3,1.5Hz,1H),8.14(s,1H),7.53(dd,J=8.0,4.7Hz,1H),5.27(s,2H),3.56(t,J=5.9Hz, 2H),3.41(ddd,J=13.0,8.4,6.5Hz,1H),3.37(s,3H),3.30(ddd,J=13.0,8.4,6.3Hz,1H),2.19-1.96(m,2H).ESI-MS(m / z):416.1[M+H] + .

[0570] The enantiomers of Example 2 were separated on a 2 cm Chiralpak AD-H column using 100% EtOH at a flow rate of 10 mL / min with an injection volume of 600 μL (concentration 8 mg / mL). The first peak was at 20 min and the second peak at 41 min.

[0571] [ka] Example 3: 2-((2-Methoxyethyl)sulfinyl)-6-(pyridin-3-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue example 1. 1H NMR(500MHz, methylene chloride-d2)δ 9.37(s,1H),8.76(d,J=4.3Hz,1H),8.54-8.42(m,1H),8.14(s,1H),7.53( ddd,J=8.0,4.8,0.9Hz,1H),5.23(s,2H),3.90(ddd,J=9.9,7.6,3.7Hz,1H) ,3.71(ddd,J=10.1,6.3,4.0Hz,1H),3.66(ddd,J=12.9,6.3,3.7Hz,1H),3 .42(s,3H),3.35(ddd,J=12.8,7.6,4.0Hz,1H).ESI-MS(m / z):402.1.[M+H] + .

[0572] The enantiomers of Example 3 were separated on a 2 cm Chiralpak AD-H column using 80% EtOH and 20% hexane at a flow rate of 10 mL / min with an injection volume of 600 μL (concentration 8 mg / mL). The first peak was observed at 21.9 min and the second peak at 30 min.

[0573] [ka] Example 4: 2-(Cyclobutylsulfinyl)-6-(pyridin-3-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue example 1. 1 H NMR(400MHz, methylene chloride-d2)δ 9.33(s,1H),8.72(s,1H),8.59-8.37(m,1H),8.09(s,1H),7.49(dd,J=8.0,4.8Hz,1H),5.18(s,2H),4.04-3.90 (m,1H),2.89-2.71(m,1H),2.51-2.36(m,1H),2.36-2.19(m,2H),2.18-1.99(m,2H).ESI-MS(m / z):398.1[M+H] + .

[0574] [ka] Example 5: 2-((2-Methoxyethyl)sulfinyl)-6-(pyrimidin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue example 1. 1 H NMR(400MHz, methylene chloride-d2)δ 9.46(s,2H),9.30(s,1H),8.10(s,1H),5.21(s,2H),3.87(ddd,J=9.4,7.7,3.5Hz,1H),3.7 3-3.59(m,2H),3.39(s,3H),3.32(ddd,J=12.6,7.6,3.6Hz,1H).ESI-MS(m / z):403.0[M+H] + .

[0575] [ka] Example 6: 2-((3-Methoxypropyl)sulfinyl)-6-(pyrimidin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue example 1. 1 H NMR(400MHz, methylene chloride-d2)δ 9.46(s,2H),9.30(s,1H),7.97(s,1H),5.26(s,2H),3.53(t,J=5.9Hz,2H),3.42-3.35(m,1H), 3.34(s,3H),3.27(ddd,J=13.0,8.3,6.3Hz,1H),2.17-1.91(m,2H).ESI-MS(m / z):417.1[M+H] + .

[0576] [ka] Example 7A: 6-(2-aminopyrimidin-5-yl)-2-chloro-4-(trifluoromethyl)nicotinonitrile. To a degassed solution of 2,6-dichloro-4-(trifluoromethyl)nicotinonitrile (100 mg, 0.416 mmol), (2-aminopyrimidin-5-yl)boronic acid (0.39 mmol, 55.0 mg, 0.95 equiv.), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.019 mmol, 16 mg, 5 mol%) in degassed dioxane (1.0 mL) was added degassed 2 M aqueous sodium carbonate solution (0.5 mL), and the reaction mixture was stirred under nitrogen at 100° C. for 2.5 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, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography in 51% isolated yield (64 mg). ESI-MS (m / z): 300.0 [M+H] + .

[0577] [ka] Example 7B: 6-(2-aminopyrimidin-5-yl)-2-((((2-methoxyethyl)thio)methyl)thio)-4-(trifluoromethyl)nicotinonitrile. To a solution of 6-(2-aminopyrimidin-5-yl)-2-chloro-4-(trifluoromethyl)nicotinonitrile (64 mg, 0.214 mmol) in DMF (200 μL) was added sodium sulfide (18.3 mg, 0.24 mmol, 1.1 equiv.) and the reaction mixture was stirred at 100° C. for 20 min. The reaction progress was followed by LCMS. Upon completion (approximately 20 min), concentrated HCl was added and the reaction mixture was stirred in the hood for 10 min. ESI-MS (m / z): 298.0 [M+H] + .

[0578] The reaction mixture was diluted with CH3CN (1.50 mL). Et3N (0.65 mmol, 65.6 mg, 90 μL, 3.0 equiv.) was added, followed by (chloromethyl)(2-methoxyethyl)sulfane (0.428 mmol, 60 mg, 2.0 equiv.). The reaction mixture was stirred at room temperature for 15 min. 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 24 mg of product (28%). 1 H NMR(400MHz,chloroform-d)δ 9.03(s,2H),7.59(s,1H),5.52(s,2H),4.55(s,2H),3.67(t,J=6.0Hz,2H),3.38(s,3H),2.90(t,J=6.0Hz,2H).ESI-MS(m / z):402.1[M+H] + .

[0579] [ka] Example 7C: Following the synthetic procedure described for the preparation of Analog Example 1, 6-(2-aminopyrimidin-5-yl)-2-((((2-methoxyethyl)sulfinyl)methyl)thio)-4-(trifluoromethyl)nicotinonitrile was prepared in 99% isolated yield via standard oxidation with hydrogen peroxide. 1 H NMR(400MHz,chloroform-d)δ 9.03(s,2H),7.65(s,1H),6.15(s,2H),4.78(d,J=13.2Hz,1H),4.67(d,J=13.1Hz,1H),3.98(ddd,J=10.7,6.0,3.6Hz,1H),3.80(ddd,J =11.0,8.4,3.1Hz,1H),3.40(s,3H),3.18(ddd,J=13.8,8.5,3.7Hz,1H),3.07(ddd,J=13.8,6.0,3.1Hz,1H).ESI-MS(m / z):418.1[M+H] + .

[0580] [ka] Example 7: Following the synthetic procedure described for the preparation of Analog Example 1, 6-(2-aminopyrimidin-5-yl)-2-((2-methoxyethyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared in 71% isolated yield via a standard cyclization reaction with potassium hydroxide. 1 H NMR(400MHz,acetone-d6)δ 9.14(s,2H),8.25(s,1H),6.59(s,2H),5.40(s,2H),3.85(ddd,J=10.7,7.9,4.2Hz,1H),3.70(ddd,J=10.5,5 .8,4.5Hz,1H),3.52(ddd,J=13.2,5.9,4.2Hz,1H),3.35(s,3H),3.33-3.27(m,1H).ESI-MS(m / z):418.1[M+H] + .

[0581] [ka] Example 8: 6-(2-aminopyrimidin-5-yl)-2-((3-methoxypropyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.06(s,2H),7.93(s,1H),5.46(s,2H),5.20(s,2H),3.52(t,J=5.9Hz,2H),3.41-3.34(m,1H), 3.34(s,3H),3.25(ddd,J=13.2,8.3,6.5Hz,1H),2.16-1.88(m,2H).ESI-MS(m / z):432.1[M+H] + .

[0582] [ka] Example 9: 6-(6-aminopyridin-3-yl)-2-((3-methoxypropyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 8.81(s,1H),8.26(dd,J=8.7,2.4Hz,1H),7.96(s,1H),6.66(d,J=9.0Hz,1H),5.18(s,2H),5.03(s,2H),3.52(t ,J=5.9Hz,2H),3.43-3.35(m,1H),3.33(s,3H),3.29-3.18(m,1H),2.05-1.96(m,2H).ESI-MS(m / z):431.1[M+H] + .

[0583] [ka] Example 10: 6-(6-aminopyridin-3-yl)-2-((2-methoxyethyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 8.82(s,1H),8.26(dd,J=8.9,2.3Hz,1H),7.97(s,1H),6.66(d,J=8.7Hz,1H),5.14(s,2H),4.97(s,2 H),3.90-3.80(m,1H),3.71-3.56(m,2H),3.38(s,3H),3.33-3.24(m,1H).ESI-MS(m / z):417.1[M+H] + .

[0584] [ka] Example 11: 2-((3-Methoxypropyl)sulfinyl)-6-(2-methylpyrimidin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1H NMR(400MHz, methylene chloride-d2)δ 9.35(s,2H),8.06(s,1H),5.25(s,2H),3.52(t,J=5.9Hz,2H),3.42-3.35(m,1H),3.34 (s,3H),3.30-3.22(m,1H),2.80(s,3H),2.11-1.90(m,2H).ESI-MS(m / z):431.1[M+H] + .

[0585] [ka] Example 12: 2-((2-Methoxyethyl)sulfinyl)-6-(2-methylpyrimidin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.35(s,2H),8.06(d,J=1.2Hz,1H),5.20(s,2H),3.87(ddd,J=9.5,7.6,3.4Hz,1H),3.73-3.58( m,2H),3.39(s,3H),3.32(ddd,J=12.9,7.6,3.6Hz,1H),2.81(s,3H).ESI-MS(m / z):417.0[M+H] + .

[0586] [ka] Example 13: 2-((5-(3-amino-2-(cyclobutylsulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrimidin-2-yl)amino)ethan-1-ol was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1H NMR(500MHz, methylene chloride-d2)δ 9.06(s,2H),7.92(s,1H),6.03(s,1H),5.17(s,2H),4.06-3.95(m,1H),3.88(t,J=5.5Hz,2H),3.71(td,J=5.7,3.0Hz,2H) ,2.90-2.77(m,1H),2.50-2.37(m,1H),2.37-2.30(m,1H),2.30-2.22(m,1H),2.17-2.04(m,2H).ESI-MS(m / z):458.1[M+H] + .

[0587] [ka] Example 14: 2-((5-(3-amino-2-((3-methoxypropyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrimidin-2-yl)amino)ethan-1-ol was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.03(s,2H),7.89(s,1H),6.01(s,1H),5.19(s,2H),3.95-3.79(m,2H),3.6 8(td,J=5.7,4.4Hz,2H),3.52(t,J=5.9Hz,2H),3.41-3.31(m,1H),3.33(s,3 H),3.24(ddd,J=13.0,8.2,6.5Hz,1H),3.00(s,1H),2.18-1.86(m,2H).ESI-MS(m / z):476.1[M+H] + .

[0588] [ka] Example 15: 2-((5-(3-amino-2-((2-methoxyethyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrimidin-2-yl)amino)ethan-1-ol was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1H NMR(400MHz, methylene chloride-d2)δ 9.05(s,2H),7.97(s,1H),6.16(s,1H),5.15(s,2H),3.90-3.78(m,3H),3.73-3.53 (m,4H),3.38(s,3H),3.30(ddd,J=12.1,7.5,3.7Hz,1H).ESI-MS(m / z):462.1[M+H] + .

[0589] [ka] Example 16: 2-((5-(3-amino-2-((2-methoxyethyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrimidin-2-yl)(methyl)amino)ethan-1-ol was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.05(s,2H),7.90(s,1H),5.14(s,2H),3.88(s,4H),3.87-3.81(m,1H),3.71-3.5 6(m,2H),3.38(s,3H),3.32(s,3H),3.31-3.24(m,1H).ESI-MS(m / z):476.1[M+H] + .

[0590] [ka] Example 17: 2-((5-(3-amino-2-((3-methoxypropyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrimidin-2-yl)(methyl)amino)ethan-1-ol was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1H NMR(400MHz, methylene chloride-d2)δ 9.06(s,2H),7.90(s,1H),5.19(s,2H),3.89(s,4H),3.51(t,J=5.9Hz,2H),3.40-3.34(m,1H),3.33( s,3H),3.32(s,3H),3.24(ddd,J=13.1,8.3,6.6Hz,1H),2.18-1.86(m,2H).ESI-MS(m / z):490.1[M+H] + .

[0591] [ka] Example 18: 2-((5-(3-amino-2-(cyclobutylsulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrimidin-2-yl)(methyl)amino)ethan-1-ol was prepared using the synthetic procedure described for the preparation of analogue Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.04(s,2H),7.89(s,1H),5.13(s,2H),3.97(p,J=8.1Hz,1H),3.88(s,4H),3.32(s,3H),2.87-2 .73(m,1H),2.45-2.35(m,1H),2.35-2.17(m,2H),2.15-1.93(m,2H).ESI-MS(m / z):472.1[M+H] + .

[0592] [ka] Example 19A: 6-oxo-4-phenyl-2-(pyridin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile. A solution of benzaldehyde (1.00 g, 9.4 mmol), ethyl cyanoacetate (1064 mg, 9.4 mmol), and a catalytic amount of piperidine in MeOH (15 mL) was stirred at room temperature overnight. The solvent was evaporated to give the desired product in quantitative yield.

[0593] The crude product (3.0 mmol, 603 mg) was dissolved in EtOH (8 mL), nicotinimidamide hydrochloride (1.5 equiv, 4.5 mmol, 706 mg) and potassium carbonate (3.0 equiv, 9 mmol, 1.24 g) were added, and the reaction mixture was stirred at 80 °C overnight. Upon completion, the reaction mixture was filtered, and the resulting solid was suspended in water and dried to give 6-oxo-4-phenyl-2-(pyridin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile (260 mg). ESI-MS (m / z): 275.1 [M+H]+.

[0594] [ka] Example 19B: 4-Chloro-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile. A reaction mixture of 6-oxo-4-phenyl-2-(pyridin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile in POCl (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 EtO was added. The resulting solid / oil was separated from the liquid, dried, and used in the next step without further purification. ESI-MS (m / z): 293.1 [M+H].

[0595] [ka] Example 19C: 4-(((butylthio)methyl)thio)-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile. To crude 4-(((butylthio)methyl)thio)-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile (300 mg, 1.0 mmol) in DMF (1 mL) was added sodium sulfide (85 mg, 1.09 mmol, 1.09 equiv.) and the reaction mixture was stirred at 100° C. for 20 min. The reaction progress was followed by LCMS. Upon completion of the reaction, concentrated HCl was added and the reaction mixture was stirred in the hood for 10 min. ESI-MS (m / z): 291.0 [M+H]+.

[0596] The reaction mixture was diluted with CH3CN (3 mL). Et3N (500 mg, 4.95 mmol) was added, followed by butyl(chloromethyl)sulfane (3.0 mmol, 414 mg). The reaction mixture was stirred at room temperature for 15 min. 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 243 mg of product (62%). 1 H NMR(400MHz,chloroform-d)δ 9.83(s,1H),9.43(d,J=8.8Hz,1H),9.03(s,1H),8.28-8.02(m,3H),7.75-7.47(m,3H),4.53(s,2H),2.76(t,J =7.4Hz,2H),1.64(p,J=7.4Hz,2H),1.43(h,J=7.3Hz,2H),0.92(t,J=7.4Hz,3H).ESI-MS(m / z):393.1[M+H]+.

[0597] [ka] Example 19D: Following the synthetic procedure described for the preparation of Analog Example 1, 4-(((butylsulfinyl)methyl)thio)-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile was prepared in 98% isolated yield via standard oxidation with hydrogen peroxide. 1 H NMR (400 MHz, chloroform-d) δ 9.76 (s, 1H), 8.86 (d, J = 8.1 Hz, 1 H),8.82(d,J=6.9Hz,1H),8.19-8.12(m,2H),7.68-7.56(m,4H),4.77(d,J=13.2Hz,1H),4.59(d,J=13.3Hz,1H ),3.05-2.85(m,2H),1.95-1.74(m,2H),1.64-1.43(m,2H),0.97(t,J=7.3Hz,3H).ESI-MS(m / z):409.1[M+H]+.

[0598] [ka] Example 19: 6-(butylsulfinyl)-4-phenyl-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine. To a solution of 6-(butylsulfinyl)-4-phenyl-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine (0.47 mmol, 193 mg) in DMF (3.0 mL) was added KOH (0.35 mmol, 20 mg, 0.75 equivalents in 200 μL of water). The reaction mixture was stirred at room temperature for 20 min (the reaction was monitored by TLC). Upon completion, the reaction mixture was diluted with EtOAc and washed with a 5% aqueous solution of 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 48% isolated yield. 1 H NMR(400MHz, methylene chloride-d2)δ 9.72(s,1H),8.92-8.77(m,1H),8.71(d,J=4.7Hz,1H),7.85-7.71(m,2H), 7.71-7.55(m,3H),7.45(dd,J=8.0,4.8Hz,1H),4.83(s,2H),3.28(ddd,J= 12.7,9.0,6.1Hz,1H),3.13(ddd,J=12.8,9.1,6.6Hz,1H),1.85-1.59(m,2 H),1.59-1.38(m,2H),0.97(t,J=7.6Hz,3H).ESI-MS(m / z):409.1[M+H]+.

[0599] The enantiomers of Example 19 were separated on a 1 cm Chiralpak AD-H column using 75% EtOH and 25% hexane at a flow rate of 5 mL / min with an injection volume of 400 μL (concentration 10 mg / mL). The first peak was observed at 5.5 min and the second peak at 14.7 min.

[0600] [ka] Example 20: 6-((3-Methoxypropyl)sulfinyl)-4-phenyl-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine was prepared using the synthetic procedure described for the preparation of analogue Example 19. 1 H NMR (400 MHz, methylene chloride-d2) δ 9.72(dd,J=2.0,1.0Hz,1H),8.89-8.77(m,1H),8.71(dd,J=4.7,1.7Hz,1H) ,7.83-7.70(m,2H),7.70-7.57(m,3H),7.45(ddd,J=8.0,4.8,1.0Hz,1H),4 .83(s,2H),3.50(t,J=5.9Hz,2H),3.38-3.28(m,1H),3.32(s,3H),3.22(dd d,J=12.8,8.1,6.4Hz,1H),2.09-1.89(m,2H).ESI-MS(m / z):425.1[M+H]+.

[0601] The enantiomers of Example 20 were separated on a 1 cm Chiralpak AD-H column using 100% EtOH at a flow rate of 5 mL / min with an injection volume of 500 μL (concentration 10 mg / mL). The first peak was observed at 8.34 min and the second peak at 27.5 min.

[0602] [ka] Example 21: 6-(Cyclobutylsulfinyl)-4-phenyl-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine was prepared using the synthetic procedure described for the preparation of analogue Example 19. 1 H NMR(400MHz, methylene chloride-d2)δ 9.73(s,1H),8.80(d,J=8.0Hz,2H),7.81-7.67(m,2H),7.69-7.57(m,3H),7.55-7.30(m,1H),4.80(s,2H),3 .94(p,J=8.1Hz,1H),2.89-2.67(m,1H),2.50-2.16(m,3H),2.18-2.01(m,2H).ESI-MS(m / z):407.1[M+H]+.

[0603] [ka] Example 22: 6-(Cyclobutylsulfinyl)-4-cyclopropyl-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine was prepared using the synthetic procedure described for the preparation of analogue Example 19. 1 H NMR(400MHz, methylene chloride-d2)δ 9.70-9.57(m,1H),8.71(dt,J=8.0,2.0Hz,1H),8.68(dd,J=4.9,1.7Hz,1H),7.47-7.35(m,1H),5.26(s,2H),3.92(p,J=8.0Hz,1H),2.88-2.73 (m,1H),2.68(tt,J=8.1,4.7Hz,1H),2.45-2.17(m,3H),2.17-1.99(m,2H),1.64-1.46(m,2H),1.34-1.18(m,2H).ESI-MS(m / z):371.1[M+H]+.

[0604] [ka] Example 23: 4-Cyclopropyl-6-((2-methoxyethyl)sulfinyl)-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine was prepared using the synthetic procedure described for the preparation of analogue Example 19. 1 H NMR(400MHz, methylene chloride-d2)δ 9.63(dd,J=2.2,0.9Hz,1H),8.71(ddd,J=8.0,2.2,1.7Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),7.42( ddd,J=8.0,4.8,0.9Hz,1H),5.25(s,2H),3.86(ddd,J=10.5,7.6,4.0Hz,1H),3.68(ddd,J=10.5,6 .3,4.3Hz,1H),3.58(ddd,J=13.0,6.3,4.0Hz,1H),3.39(s,3H),3.27(ddd,J=13.1,7.5,4.3Hz,1H ),2.66(tt,J=8.0,4.7Hz,1H),1.59-1.54(m,2H),1.30-1.25(m,2H).ESI-MS(m / z):375.1[M+H]+.

[0605] [ka] Example 24: 4-Cyclopropyl-6-((3-methoxypropyl)sulfinyl)-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-5-amine was prepared using the synthetic procedure described for the preparation of analogue Example 19. 1 H NMR(400MHz, methylene chloride-d2)δ 9.63(dd,J=2.2,0.9Hz,1H),8.71(ddd,J=8.0,2.2,1.7Hz,1H),8.68(dd,J=4.8,1.7Hz ,1H),7.41(ddd,J=8.0,4.8,0.9Hz,1H),5.30(s,2H),3.52(t,J=5.9Hz,2H),3.37-3.2 8(m,1H),3.34(s,3H),3.22(ddd,J=13.0,8.3,6.4Hz,1H),2.67(tt,J=8.0,4.7Hz,1H) ,2.11-1.91(m,2H),1.60-1.47(m,2H),1.30-1.22(m,2H).ESI-MS(m / z):389.1[M+H]+.

[0606] [ka] Example 25A: 2-Bromo-1-(thiazol-2-yl)ethan-1-one. n-BuLi (24.7 mL, 61.7 mmol, 2.5 M in hexane) was added dropwise to a solution of 2-thiazole (5.0 g, 59 mmol) in anhydrous diethyl ether (50 mL) at −78° C. After 15 min, ethyl bromoacetate (6.84 mL, 61.7 mmol) was added, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction mixture was treated with AcOH (7 mL) and then diluted with water (100 mL) and ether (60 mL). The organic layer was separated, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was suspended in hexane and heated to reflux for 15 min, then the product was decanted to remove the impure oil. This procedure was repeated five times to give a white solid in 88% yield. 1H NMR(400MHz,CDCl3)δ 8.05(d,J=3.0Hz,1H),7.77(d,J=3.0Hz,1H),4.71(s,2H).

[0607] [ka] Example 25B: 1-(Thiazol-2-yl)-2-(triphenyl-γ5-phosphanylidene)ethan-1-one. To a solution of 2-bromo-1-(thiazol-2-yl)ethan-1-one (10.7 g, 0.0517 mol) in toluene (337.7 mL) was added triphenylphosphine (14.1 g, 0.0539 mol) in portions. The mixture was stirred at room temperature for 3 hours. The yellowish precipitate was removed by filtration and washed several times with toluene and then petroleum ether. Water was added to the precipitate, and the pH was adjusted to 10 by dropwise treatment with 1N NaOH (pH 7, resulting in a color change from yellow to orange). The mixture was stirred at room temperature for 30 minutes. The precipitate was removed by filtration and washed several times with water. The resulting orange solid was heated at 50°C under vacuum to remove the water, affording the dried product in 96% yield. 1 H NMR(400MHz,CDCl3)δ 7.82(d,J=3.1Hz,1H),7.72(ddd,J=12.8,8.3,1.4Hz,6H),7.61-7.54(m,3H),7.51-7.45 (m,6H),7.38(dd,J=3.1,1.3Hz,1H),5.00(d,J=23.3Hz,1H).ESI-MS(m / z):387.9[M+H]+.

[0608] [ka] Example 25C: (E)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-1-(thiazol-2-yl)prop-2-en-1-one. To a solution of 1,5-dimethyl-1H-imidazole-2-carbaldehyde (2.25 mmol, 250 mg) in CHCN (5 mL) was added 1-(thiazol-2-yl)-2-(triphenyl-γ5-phosphanylidene)ethan-1-one (2.25 mmol, 871.6 mg, 1.0 equiv.). The reaction mixture was stirred at 90° C. for 48 h. Upon completion, the solvent was evaporated, and the residue was purified by flash chromatography to give 306 mg of product. 1 H NMR(400MHz,chloroform-d)δ 8.39(d,J=15.5Hz,1H),8.09(d,J=3.0Hz,1H),7.97(s,1H),7.82(d,J=15. 6Hz,1H),7.75(d,J=3.0Hz,1H),4.05(s,3H).ESI-MS(m / z):221.0[M+H]+.

[0609] [ka] Example 25D: 2-(((butylthio)methyl)thio)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-6-(thiazol-2-yl)nicotinonitrile. To a suspension of (E)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-1-(thiazol-2-yl)prop-2-en-1-one (0.45 mmol, 100 mg) and 2-cyanothioacetamide (1.35 mmol, 135 mg, 3.0 equiv) in EtOH (1.5 mL) was added 3 drops of piperidine. After stirring at 80 °C for 2 h, EtOH was evaporated and the crude product was redissolved in 2 mL of CH3CN. Then, butyl(chloromethyl)sulfane (1.30 mmol, 180 mg, 3.0 equiv.) and EtN (1.30 mmol, 131 mg, 181 μL) were added, and the reaction mixture was stirred at 80 °C for 20 min. 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 119 mg of a mixture of the desired product (ESI-MS (m / z): 403.6 [M+H]) and a CN by-product (ESI-MS (m / z): 378.1 [M+H]). 1 H NMR(400MHz,chloroform-d)δ 8.09(s,1H),8.08(s,1H),8.00(d,J=3.1Hz,1H),7.61(d,J=3.1Hz,1H),4.52(s,2H),4.01(s,3H),275(t ,J=7.2Hz,2H),1.69-1.58(m,2H),1.47v1.33(m,2H),0.91(t,J=7.3Hz,3H).ESI-MS(m / z):403.6[M+H]+

[0610] [ka] Example 25E: 2-(((butylsulfinyl)methyl)thio)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-6-(thiazol-2-yl)nicotinonitrile. To a solution of the product from the previous step (119 mg) in CHCl / AcOH (1:1, 0.15 M) was added HO (68 μL, 30% aqueous solution). The reaction mixture was stirred at 32 °C for 40 min. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 89 mg of the desired compound. 1 H NMR(400MHz,chloroform-d)δ 8.17(s,1H),8.07(s,1H),8.00(d,J=3.1Hz,1H),7.64(d,J=3.1Hz,1H),4.69(d,J=13.2Hz,1H),4.45(d,J=13.2Hz,1H),4.03(s,3H) ),3.02-2.88(m,1H),2.88-2.77(m,1H),1.88-1.77(m,2H),1.54-1.41(m,2H),0.95(t,J=7.3Hz,3H).ESI-MS(m / z):419.0[M+H]+.

[0611] [ka] Example 25: 2-(butylsulfinyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-6-(thiazol-2-yl)thieno[2,3-b]pyridin-3-amine. To a solution of 2-(((butylsulfinyl)methyl)thio)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-6-(thiazol-2-yl)nicotinonitrile (43 mg) in DMF (700 μL) / MeOH (350 μL) was added KOH (0.06 mmol, 3.4 mg, 1.8 M in water). The reaction mixture was stirred at 32° C. for 10 min. Upon completion, the reaction was diluted with EtOAc and acidified to pH 7 with 5% aqueous AcOH. The organic phase was separated, and the aqueous layer was extracted twice with EtOAc, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired product. 1H NMR(400MHz, methylene chloride-d2)δ 8.26(s,1H),8.09(s,1H),7.97(d,J=3.1Hz,1H),7.60(d,J=3.1Hz,1H),5.67(s,2H),4.03(s,3H),3.26(ddd,J=12.7,9.0,6.2Hz, 1H),3.12(ddd,J=12.8,9.0,6.6Hz,1H),1.86-1.67(m,2H),1.57-1.39(m,2H),0.95(t,J=7.3Hz,3H).ESI-MS(m / z):419.1[M+H]+.

[0612] [ka] Example 26: Following the synthetic procedure described for the preparation of analogue Example 25, 2-(butylsulfinyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)-6-(thiazol-2-yl)thieno[2,3-b]pyridin-3-amine was prepared in 12% isolated yield via a standard cyclization reaction with potassium hydroxide. 1 H NMR (400 MHz, methylene chloride-d2) δ 8.38 (s, 1H), 8.23 ​​(s, 1H), 7.97 (d, J = 3.2 Hz, 1 H),7.60(d,J=3.1Hz,1H),5.63(s,2H),3.80(s,3H),3.26(ddd,J=12.9,9.1,6.2Hz,1H),3.12(ddd,J=12.8 ,9.1,6.6Hz,1H),1.89-1.66(m,2H),1.57-1.42(m,2H),0.95(t,J=7.4Hz,3H).ESI-MS(m / z):419.1[M+H]+.

[0613] The enantiomers of Example 26 were separated on a 2 cm Chiralcel OD-H column using 100% EtOH at a flow rate of 10 mL / min with an injection volume of 600 μL (concentration 10 mg / mL). The first peak was observed at 15.0 min and the second peak at 21.0 min.

[0614] [ka] Example 27: Following the synthetic procedure described for the preparation of analogue Example 25, 2-(butylsulfinyl)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-6-(thiazol-2-yl)thieno[2,3-b]pyridin-3-amine was prepared in 12% isolated yield via a standard cyclization reaction with potassium hydroxide. 1 H NMR(400MHz, methylene chloride-d2)δ 8.18(s,1H),7.96(d,J=3.1Hz,1H),7.59(d,J=3.2Hz,1H),5.71(s,2H),3.65(s,3H),3.26(ddd,J=12.8,9.1,6.1Hz,1H),3.11(dd d,J=12.8,9.2,6.5Hz,1H),2.57(s,3H),1.84-1.66(m,2H),1.56-1.40(m,2H),0.95(t,J=7.3Hz,3H).ESI-MS(m / z):433.1[M+H]+.

[0615] [ka] Example 28: 2-((2-Methoxyethyl)sulfinyl)-6-(2-methyl-2H-pyrazylo[3,4-b]pyridin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.43(d,J=2.4Hz,1H),8.83(d,J=2.4Hz,1H),8.14(s,1H),8.11(s,1H),5.18(s,2H),4.29(s,3H),3.87(ddd,J=9. 7,7.5,3.5Hz,1H),3.74-3.56(m,2H),3.39(s,3H),3.32(ddd,J=13.0,7.6,3.7Hz,1H).ESI-MS(m / z):456.2[M+H] + .

[0616] The enantiomers of Example 28 were separated on a 2 cm Chiralpak AD-H column using 20% ​​hexane and 80% EtOH at a flow rate of 10 mL / min with an injection volume of 600 μL (concentration 10 mg / mL). The first peak was observed at 13.0 min and the second peak at 20.0 min.

[0617] [ka] Example 29: 2-((3-Methoxypropyl)sulfinyl)-6-(2-methyl-2H-pyrazylo[3,4-b]pyridin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.43(d,J=2.3Hz,1H),8.83(d,J=2.3Hz,1H),8.14(s,1H),8.11(s,1H),5.23(s,2H),4.29(s,3H),3.53(t,J=5.9Hz,2 H),3.43-3.35(m,1H),3.34(s,3H),3.26(ddd,J=13.0,8.3,6.5Hz,1H),2.11-1.96(m,2H).ESI-MS(m / z):470.2[M+H] + .

[0618] [ka] Example 30: 2-(Cyclobutylsulfinyl)-6-(2-methyl-2H-pyrazylo[3,4-b]pyridin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1H NMR(400MHz, methylene chloride-d2)δ 9.42(d,J=2.3Hz,1H),8.81(d,J=2.3Hz,1H),8.12(s,1H),8.11(s,1H),5.17(s,2H),4.29(s,3H),4.05-3.91( m,1H),2.89-2.72(m,1H),2.47-2.36(m,1H),2.36-2.20(m,2H),2.16-2.03(m,2H).ESI-MS(m / z):452.1[M+H] + .

[0619] The enantiomers of Example 30 were separated on a 2 cm Chiralcel OD-H column using 40% hexane and 60% EtOH at a flow rate of 10 mL / min with an injection volume of 600 μL (concentration 10 mg / mL). The first peak was observed at 17.5 min and the second peak at 23.0 min.

[0620] [ka] Example 31: 2-((2-methoxyethyl)sulfinyl)-6-(2-morpholinopyrimidin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.08(s,2H),7.92(s,1H),5.15(s,2H),3.97-3.90(m,4H),3.86(ddd,J=9.8,7.6,3.7Hz,1H),3.81-3.7 2(m,4H),3.71-3.57(m,2H),3.38(s,3H),3.29(ddd,J=12.9,7.6,3.9Hz,1H).ESI-MS(m / z):488.2[M+H] + .

[0621] [ka] Example 32: 2-((3-methoxypropyl)sulfinyl)-6-(2-morpholinopyrimidin-5-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.08(s,2H),7.92(s,1H),5.19(s,2H),4.00-3.89(m,4H),3.82-3.71(m,4H),3.51(t,J=5.9Hz,2H),3.41- 3.29(m,1H),3.33(s,3H),3.24(ddd,J=13.0,8.2,6.5Hz,1H),2.10-1.95(m,2H).ESI-MS(m / z):502.1[M+H] + .

[0622] [ka] Example 33: 2-((2-methoxyethyl)sulfinyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 8.09(s,1H),8.05(d,J=0.8Hz,1H),5.11-3.97(m,1H),3.90-3.80(m,1H),3 .71-3.54(m,2H),3.38(s,3H),3.35-3.22(m,1H).ESI-MS(m / z):405.1[M+H] + .

[0623] [ka] Example 34: 2-((3-methoxypropyl)sulfinyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1H NMR(400MHz, methylene chloride-d2)δ 8.08(s,1H),8.05(d,J=0.8Hz,1H),7.74(d,J=0.8Hz,1H),5.15(s,2H),3.97(s,3H),3.51(t,J=5.9Hz,2H),3. 41-3.29(m,1H),3.33(s,3H),3.22(ddd,J=13.0,8.1,6.7Hz,1H),2.11-1.93(m,2H).ESI-MS(m / z):419.1[M+H] + .

[0624] [ka] Example 35: 2-(Cyclobutylsulfinyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 8.07(s,1H),8.04(s,1H),7.73(s,1H),5.10(s,2H),4.06-3.88(m,1H),3.97(s,3H) ,2.89-2.67(m,1H),2.47-2.15(m,3H),2.15-1.94(m,2H).ESI-MS(m / z):401.1[M+H] + .

[0625] [ka] Example 36: 6-(2-aminopyrimidin-5-yl)-2-(cyclobutylsulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Example 7. 1 H NMR(400MHz, methylene chloride-d2)δ 9.05(s,2H),7.92(s,1H),5.40(s,2H),5.15(s,2H),3.97(p,J=8.0Hz,1H),2.87-2.68(m ,1H),2...

Claims

1. Formula (IA): 【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)alkyl; R ６ Each of the R ３ is a 5-6 membered heteroaryl optionally substituted with R ７ Each of the R ４ alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl or -C(O)NR ５ - alkyl; R ３ is oxo, -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, wherein said cycloalkyl and said 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 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; or Instead, two R ５ can form together with the N atom to which they are attached a 4- to 7-membered heterocycle optionally containing additional heteroatoms selected from O, S or N, wherein said heterocycle is ８ optionally substituted with; R ８ is halogen, alkyl or alkoxy; R ９ is H or alkyl, or two R ９ are O, S(O) together with the N atom to which they are attached. ｔ or N; R １０ is -OH, halogen, alkyl or alkoxy; X is N or CH; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2. or a pharma- ceutically acceptable salt, tautomer or solvate thereof (Note that the compound has the following formula: 【Chemistry 2】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 and wherein the compound does not have a formula selected from the group consisting of:

2. R １ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, -(C １ ~C ６ alkylene)-(3- to 6-membered cycloalkyl), -(C １ ~C ６ alkylene)-(C １ ~C ６ 2. The compound of claim 1, which is -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclyl), or a salt or solvate thereof.

3. R ２ is -NH ２ 2. The compound of claim 1, wherein:

4. R ７ Each of the R ４ C optionally substituted with １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(O)(C １ ~C ６ alkyl), -C(O)O(C １ ~C ６ alkyl) or -C(O)NR ５ (C １ ~C ６ 2. The compound of claim 1, wherein R is an alkyl group.

3. The compound of claim 1, wherein R is an alkyl group.

5. R ３ is -O-(C １ ~C ６ alkylene)-N(R ５ ) ２ , -N(R ５ ) ２ , -N(R ５ ) (C １ ~C ６ alkylene-OH), -C(O)N(R ５ ) ２ , -C(O)N(R ５ ) (C １ ~C ６ alkylene-OH), -C(O)(C １ ~C ６ alkyl), -C(O)O(C １ ~C ６ alkyl) or -S(O) ｍ (C １ ~C ６ 2. The compound of claim 1, wherein R is an alkyl group.

3. The compound of claim 1, wherein R is an alkyl group.

6. R ４ is halogen, -CN, -N(R ５ ) ２ , -OH, -O-(C １ ~C ６ alkylene)-OH, -S(O) ｍ (C １ ~C ６ alkyl), -C(O)(C １ ~C ６ alkyl), -C(O)-(3- to 6-membered cycloalkyl), C １ ~C ６ Alkyl, C １ ~C ６ The compound of claim 1, which is haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl, or a salt or solvate thereof.

7. The compound of claim 1, or a salt or solvate thereof, wherein n is 1.

8. Formula (II): 【Chemistry 3】 (In the formula, R １ is 3- to 6-membered cycloalkyl, -(C １ ~C ６ alkylene)-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocyclyl or -(C １ ~C ６ alkylene)-(3- to 6-membered heterocyclyl); R ２ is -NH ２ , CN or -NHC(O)alkyl; R ６ Each of the R ３ is a 5-6 membered heteroaryl optionally substituted with R ７ Each of the R ４ alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl or -C(O)NR ５ - alkyl; R ３ is oxo, -OH, -O-alkylene-N(R ５ ) ２ , -N(R ５ ) ２ , -N(R ５ ) (alkylene-OH), alkyl, 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; 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, haloalkyl, cycloalkyl, heterocyclyl or R ８ -alkylene-aryl optionally substituted with 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; or Instead, two R ５ can form together with the N atom to which they are attached a 4- to 7-membered heterocycle optionally containing additional heteroatoms selected from O, S or N, wherein said heterocycle is ８ optionally substituted with; R ８ is halogen, alkyl or alkoxy; R ９ is H or alkyl, or two R ９ are O, S(O) together with the N atom to which they are attached. ｔ or N; X is N or CH; m is 0, 1 or 2; and t is 0, 1 or 2.

2. The compound of claim 1 having the structure:

9. R １ is a 3- to 5-membered cycloalkyl, or -(C １ ~C ６ 9. The compound according to claim 8, which is:

10. R １ is cyclobutyl, or a salt or solvate thereof.

11. The compound according to claim 8, or a salt or solvate thereof, wherein R 1 is a bicyclic 4- to 6-membered cycloalkyl.

12. R ７ Each of the R ４ C optionally substituted with １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(O)(C １ ~C ６ alkyl), -C(O)O(C １ ~C ６ alkyl) or -C(O)NR ５ (C １ ~C ６ 9. The compound of claim 8, or a salt or solvate thereof, wherein

13. R ７ Each of the R ４ C optionally substituted with １ ~C ４ Alkyl, C １ ~C ６ 9. The compound of claim 8, which is haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, or a salt or solvate thereof.

14. R ３ is -O-(C １ ~C ６ alkylene)-N(R ５ ) ２ , -N(R ５ ) ２ , -N(R ５ ) (C １ ~C ６ alkylene-OH), -C(O)N(R ５ ) ２ , -C(O)N(R ５ ) (C １ ~C ６ alkylene-OH), -C(O)(C １ ~C ６ alkyl), -C(O)O(C １ ~C ６ alkyl) or -S(O) ｍ (C １ ~C ６ 9. The compound of claim 8, or a salt or solvate thereof, wherein

15. 【Chemical 4】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, selected from the group consisting of:

16. The compound of claim 1.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a salt or solvate thereof, and a pharma- ceutically acceptable excipient or carrier.

18. A pharmaceutical composition for use in a method for treating inflammatory bowel disease, comprising: The method comprises administering to a human subject in need of said treatment a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a salt or solvate thereof; A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a salt or solvate thereof.

19. A method comprising: (i) a method of treating a subject in need of cell therapy, comprising administering to said subject a therapeutically effective amount of a formulation comprising human hematopoietic stem cells and a compound according to any one of claims 1 to 16 or a salt or solvate thereof, and / or a therapeutic composition comprising human hematopoietic stem cells and a compound according to any one of claims 1 to 16 or a salt or solvate thereof; or (ii) a method for treating a subject having at least one condition associated with ischemic tissue or tissue damaged by ischemia, comprising administering to said subject a therapeutically effective amount of a formulation comprising a compound according to any one of claims 1 to 16 or a salt or solvate thereof, and / or a therapeutic composition comprising human hematopoietic stem cells and a compound according to any one of claims 1 to 16 or a salt or solvate thereof; or (iii) a method of increasing neutrophils in a subject in need thereof, comprising administering to said subject a compound according to any one of claims 1 to 16 or a salt or solvate thereof; or (iv) a method of increasing the number of and / or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, comprising administering to said subject a compound according to any one of claims 1 to 16, or a salt or solvate thereof; or (v) a method for increasing the number of hematopoietic stem cells in the blood or bone marrow of a subject, comprising administering to the blood or bone marrow of a subject a compound according to any one of claims 1 to 16, or a salt or solvate thereof; or (vi) a method for the treatment and / or prevention of a fibrotic disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a salt or solvate thereof; or (vii) a method of treating an intestinal, gastrointestinal or bowel disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a salt or solvate thereof, alone or in combination with a corticosteroid and / or a tumor necrosis factor alpha (TNFα) inhibitor; or (viii) a method of treating an intestinal, gastrointestinal or bowel disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a salt or solvate thereof, and a corticosteroid; or (ix) a method of treating inflammation and / or suppressing immune system activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a salt or solvate thereof, and a corticosteroid; or (x) a method of treating glucocorticoid insensitivity, restoring corticosteroid sensitivity, enhancing glucocorticoid sensitivity or reversing glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticosteroid resistance or refractoriness or intolerance to corticosteroids, comprising administering to said subject exhibiting one or more glucocorticoid insensitivity associated pathologies a pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a salt or solvate thereof in combination with a corticosteroid, wherein said glucocorticoid insensitivity associated pathologies are immune-inflammatory disorders / diseases in which treatment with steroids fails to achieve disease control or are ineffective, intolerant or dependent on corticosteroids and combinations thereof; A pharmaceutical composition for use in A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a salt or solvate thereof.

Images