Compositions and Methods for Modulating the Activity of Short-Chain Dehydrogenases

Abstract

Compounds and methods for modulating 15-PGDH activity, modulating tissue prostaglandin levels, and treating a disease, disorder, or condition include the 15-PGDH inhibitors described herein, where modulation of 15-PGDH activity and / or prostaglandin levels is desired.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 770,571, filed on November 21, 2018, the disclosure of which is hereby incorporated by reference in its entirety.

[0003] Government funding

[0004] 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 OF THE INVENTION

[0005] Short-chain dehydrogenases (SCDs) are a family of dehydrogenases that have only 15% to 30% sequence identity and are mainly similar in the coenzyme-binding domain and the substrate-binding domain. In addition to their role in ethanol detoxification, SCDs are also involved in the synthesis and degradation of fatty acids, steroids, and some prostaglandins, and are thus involved in a variety of disorders (such as lipid storage diseases, myopathies, SCD deficiency, and certain genetic disorders).

[0006] 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 the key enzyme in the inactivation of many active prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids (HETEs) (e.g., by catalyzing the oxidation of PGE 2 to 15-keto-prostaglandin E2, 15k-PGE). The human enzyme is encoded by the HPGD gene and consists of a homodimer of subunits with a size of 29 kDa. This enzyme belongs to the evolutionarily conserved superfamily of short-chain dehydrogenases / reductases (SDRs), and according to the recently approved nomenclature of the human enzyme, it is named SDR36C1. To date, two forms of 15-PGDH enzyme activities have been identified (NAD+-dependent type I 15-PGDH encoded by the HPGD gene and type II NADP-dependent 15-PGDH, also known as carbonyl reductase 1 (CBR1, SDR21C1)). However, the preference of CBR1 for NADP and the high Km values of CBR1 for most prostaglandins suggest that most of the in vivo activity can be attributed to type I 15-PGDH encoded by the HPGD gene (hereinafter and throughout, simply referred to as 15-PGDH).

[0007] Recent studies have shown that inhibitors and activators of 15-PGDH may have therapeutic value. It has been shown that the incidence of colon tumors is increased in 15-PGDH knockout mouse models. More recent studies have involved increased 15-PGDH expression in protecting against thrombin-mediated cell death. It is well known that 15-PGDH is responsible for the inactivation of prostaglandin E2 (PGE 2 )(a downstream product of COX-2 metabolism). PGE 2 has been shown to be beneficial in a variety of biological processes such as hair density, skin wound healing, and bone formation. SUMMARY OF THE INVENTION

[0008] The embodiments described herein relate to compounds and methods for modulating the activity of short-chain dehydrogenases (SCDs) (e.g., 15-PGDH), modulating tissue prostaglandin levels, and / or treating a disease, disorder, or condition in which modulation of SCD (e.g., 15-PGDH) activity and / or prostaglandin levels is desired.

[0009] In some embodiments, the modulator of SCD can be an SCD inhibitor, and the SCD inhibitor can be administered to the tissue or blood of a subject in an amount effective to inhibit the activity of the short-chain dehydrogenase. The SCD inhibitor can be a 15-PGDH inhibitor, and the 15-PGDH inhibitor can be administered to the tissue or blood of a subject in an amount effective to increase the prostaglandin level in the tissue or blood. The 15-PGDH inhibitor can include a compound having the structure of formula (IA):

[0010]

[0011] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0012] R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclic group, or alkylene-heterocyclic group;

[0013] R 2 is -NH 2 、CN, or -NHC(O)alkyl;

[0014] R 6 is a heterocyclic group or heteroaryl, each optionally substituted with one or more R 3 ;

[0015] R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each optionally substituted with one or more R 4Substituted;

[0016] 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, heterocyclic group, -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 the cycloalkyl and the heterocyclic group are each optionally substituted by R 10 ;

[0017] 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted by R 8 ;

[0018] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted by the following: -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;

[0019] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 ;

[0020] R 8 is halogen, alkyl, or alkoxy;

[0021] R 9is H or alkyl, or two Rs 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0022] R 10 is -OH, halogen, alkyl, or alkoxy;

[0023] X is N or CH;

[0024] m is 0, 1, or 2;

[0025] n is 0, 1 or 2; and

[0026] t is 0, 1, or 2.

[0027] In some embodiments, 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 alkoxy), 3- to 6-membered heterocyclic group, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclic group).

[0028] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or -(CH 2 ) p -cyclohexyl; where p is 1, 2, or 3.

[0029] In still other embodiments, R 2 is -NH 2 .

[0030] In some embodiments, R 6 is a 5- to 6-membered heterocyclic group or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more Rs 3 .

[0031] In other embodiments, R 6 is an optionally one or more R 3 substituted 5- to 6-membered heteroaryl group.

[0032] In still other embodiments, R 6 is an optionally one or more R 3 substituted 8- to 10-membered bicyclic heteroaryl group.

[0033] In some embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclic group, 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 alkyl), each of which is optionally substituted with one or more R 4 .

[0034] In other embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic group, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .

[0035] In still other embodiments, R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .

[0036] In some embodiments, 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 alkyl).

[0037] In other embodiments, R 3 is -(C 1 -C 3 alkyl)OH, -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH2 CH 2 N(C 1 -C 3 alkyl) 2 、-N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 Alkyl), -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 、-NHSO 2 CH 3 、-N(C 1 -C 3 alkyl)SO 2 CH 3 、-OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 、-OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0038] In still other embodiments, R 3 Yes-NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0039] In some embodiments, 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), C1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic group.

[0040] In some embodiments, n is 1.

[0041] In other embodiments, the compound has the structure of formula (II):

[0042]

[0043] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0044] R 1 is 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocyclic group, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclic group);

[0045] R 2 is -NH 2 、CN, or -NHC(O)alkyl;

[0046] R 6 is a heterocyclic group or heteroaryl, each optionally substituted with one or more R 3 substituents;

[0047] R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each optionally substituted with one or more R 4 substituents;

[0048] R 3 is oxo, -OH, -O-alkylene-N(R 5 ) 2 、-N(R 5 ) 2 、-N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic group, -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;

[0049] R4 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted by R 8 ;

[0050] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted by the following: -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;

[0051] Alternatively, two Rs 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 ;

[0052] R 8 is halogen, alkyl, or alkoxy;

[0053] R 9 is H or alkyl, or two Rs 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0054] X is N or CH;

[0055] m is 0, 1, or 2; and

[0056] t is 0, 1, or 2.

[0057] In some embodiments, R 1 is 3- to 5-membered cycloalkyl or -(C 1 -C 6 alkylene)-(3- to 5-membered cycloalkyl).

[0058] In other embodiments, R 1 is cyclobutyl.

[0059] In still other embodiments, R 1is a bicyclic 4- to 6-membered cycloalkyl group.

[0060] In some embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclic, 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 alkyl), each of which is optionally substituted with one or more R 4 substituents.

[0061] In other embodiments, R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 substituents. In other embodiments, R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 substituents.

[0062] In other embodiments, R 7 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclic, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 substituents. In other embodiments, R 7 is C 1 -C 3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclic, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 substituents.

[0063] In other embodiments, R 7 is -CF 3 、isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R4 is substituted. In other embodiments, R 7 is -CF 3 , isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 substituents.

[0064] In some embodiments, R 7 is -CF 3 , isopropyl,

[0065] In other embodiments, R 7 is -CF 3 , isopropyl,

[0066] In still other embodiments, R 7 is -CF 3 ,

[0067] In some embodiments, 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 alkyl).

[0068] In other embodiments, R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C3 (alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 、 -NHCH 2 CH(CH 2 OH) 2 、 -N(C 1 -C 3 (alkyl)CH 2 CH(CH 2 OH) 2 、 -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 、 -NHCH 2 CH 2 NH 2 、 -N(C 1 -C 3 (alkyl)CH 2 CH 2 NH 2 、 -NHCH 2 CH 2 NH(C 1 -C 3 (alkyl)、 -NHCH 2 CH 2 N(C 1 -C 3 (alkyl) 2 、 -N(C 1 -C 3 (alkyl)CH 2 CH 2 NH(C 1 -C 3 (alkyl)、 -N(C 1 -C 3 (alkyl)CH 2 CH 2 N(C 1 -C 3 (alkyl) 2 、 -NHSO 2 CH 3 、 -N(C 1 -C 3 (alkyl)SO 2 CH 3 、 -OCH 2 CH2 OH, -OCH 2 CH 2 NH 2 、-OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0069] In still other embodiments, R 3 Yes-NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0070] In other embodiments, the compound has the structure of formula (III):

[0071]

[0072] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0073] R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl;

[0074] R 2 Yes-NH 2 , CN, or -NHC(O)alkyl;

[0075] R 6 is a heterocyclic group or a heteroaryl group, each of which is optionally substituted by one or more R 3 replace;

[0076] R 7 It is C 1 -C 6 haloalkyl, aryl or heteroaryl, each of which is optionally substituted by one or more R 4 replace;

[0077] 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(R5 ) 2 , -C(O)N(R 5 )(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O) m -alkyl;

[0078] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted with: -OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O) m -alkyl;

[0079] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ;

[0080] R 4 is halogen, alkyl, or alkoxy;

[0081] X is N or CH; and

[0082] m is 0, 1, or 2.

[0083] In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy).

[0084] In some embodiments, R 7 is -CF 3 , pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with one or more R 4 ;

[0085] In other embodiments, R 7 is -CF 3 , pyridyl, fluorophenyl, or triazole, which is optionally substituted with one or more halogens or methyl groups.

[0086] In still other embodiments, R 7 is -CF 3 ,

[0087] In still other embodiments, R 7 Yes - CF 3 .

[0088] In still other embodiments, R 7 yes

[0089] In some embodiments, R 7 yes

[0090] In other embodiments, R 6 is optionally replaced by one or more R 3 Substituted 8- to 10-membered bicyclic heteroaryl.

[0091] In other embodiments, the compound has the structure of Formula (IV):

[0092]

[0093] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0094] R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl;

[0095] R 2 Yes-NH 2 , CN, or -NHC(O)alkyl;

[0096] R 6 is a heterocyclic group or a heteroaryl group, each of which is optionally substituted by one or more R 3 replace;

[0097] R 7 is optionally replaced by one or more R 4 substituted 3- to 6-membered cycloalkyl;

[0098] 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;

[0099] R 4 is halogen, -CN, -NH 2 , -OH, or C 1 -C 3 alkyl;

[0100] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted with: -OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O) m -alkyl;

[0101] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ;

[0102] R 8 is halogen, alkyl, or alkoxy;

[0103] X is N or CH;

[0104] m is 0, 1, or 2.

[0105] In some embodiments, R 7 is cyclopropyl.

[0106] In other embodiments, R 1 is a 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), a 3- to 6-membered heterocyclic group, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclic group).

[0107] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH2 ) p - cyclopentyl, or -(CH 2 ) p - cyclohexyl; where p is 1, 2, or 3.

[0108] In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is -(C 1 - C 4 alkylene)-(C 1 - C 3 alkoxy).

[0109] In some embodiments, 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 alkyl).

[0110] In some embodiments, R 3 is -NH 2 , -N(C 1 - C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 - C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 - C3 alkyl)CH 2 CH(CH 2 OH) 2 、-NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 、-NHCH 2 CH 2 NH 2 、-N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 、-NHCH 2 CH 2 NH(C 1 -C 3 Alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 、-N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 Alkyl), -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 、-NHSO 2 CH 3 、-N(C 1 -C 3 alkyl)SO 2 CH 3 、-OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 、-OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C1 -C 3 alkyl) 2 。

[0111] In other embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0112] In other embodiments, the compound has the structure of formula (V):

[0113]

[0114] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0115] R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclic group, or -alkylene-heterocyclic group;

[0116] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0117] R 6 is a heterocyclic group or heteroaryl group, each of which is substituted by one or more R 3 substituents;

[0118] R 7 is haloalkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted by one or more R 4 substituents;

[0119] 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 -C6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -S(O) m (C 1 -C 6 alkyl);

[0120] 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted by R 8 substituted;

[0121] Each R 5 is independently H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-OH, which is optionally substituted by: -OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), alkylene-COOH, or -S(O) m (C 1 -C 6 alkyl);

[0122] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 substituted;

[0123] R 8 is halogen, alkyl, or alkoxy;

[0124] X is N or CH;

[0125] m is 0, 1, or 2.

[0126] In some embodiments, R 1 is cyclobutyl. In some embodiments, -(C 1 -C 4Alkylene)-(C 1 -C 3 alkoxy).

[0127] In some embodiments, R 3 is -O-(C 1 -C 6 alkylene)-N(R 5 ), 2 -N(R 5 ), 2 or -N(R 5 )(C 1 -C 6 alkylene-OH).

[0128] In other embodiments, R 5 is H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-OH, or -S(O) 2 (C 1 -C 3 alkyl).

[0129] In some embodiments, R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH2 NH 2 、 -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 、 -NHCH 2 CH 2 NH(C 1 -C 3 alkyl)、 -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 、 -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl)、 -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 、 -NHSO 2 CH 3 、 -N(C 1 -C 3 alkyl)SO 2 CH 3 、 -OCH 2 CH 2 OH、 -OCH 2 CH 2 NH 2 、 -OCH 2 CH 2 NH(C 1 -C 3 alkyl)、 or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 。

[0130] In other embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH。

[0131] In still other embodiments, R 3 is -NHCH2 CH 2 OH.

[0132] In some embodiments, R 6 is a 5- to 6-membered heterocyclic group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted with one or more R 3 substituents.

[0133] In other embodiments, R 6 is a 5- to 6-membered heteroaryl group optionally substituted with one or more R 3 substituents.

[0134] In some embodiments, R 6 is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each of which is optionally substituted with one or more R 3 substituents.

[0135] In other embodiments, R 6 is thiazole, imidazole, oxazole, pyridine, or pyrimidine.

[0136] In some embodiments, R 6 is an 8- to 10-membered bicyclic heteroaryl group optionally substituted with one or more R 3 substituents.

[0137] In other embodiments, R 6 is a 5- to 6-membered heterocyclic group optionally substituted with one or more R 3 substituents and selected from morpholine, pyridinone, or piperidine.

[0138] In some embodiments, R 7 is C 1 -C 3 haloalkyl, a 3-membered cycloalkyl group, phenyl, a 4-membered heterocyclic group, or a 5- to 6-membered heteroaryl group, each of which is optionally substituted with one or more R 4 substituents.

[0139] In other embodiments, R 7 is -CF 3 , cyclopropyl, phenyl, pyrazole, pyridinyl, or triazole, each of which is optionally substituted with one or more R 4 substituents. In still other embodiments, R 7 is -CF 3 ,

[0140] In some embodiments, the compound has the structure of formula (VI):

[0141]

[0142] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0143] R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclic, or alkylene-heterocyclic;

[0144] R 2 is -NH 2 、CN, or -NHC(O)alkyl;

[0145] R 6 is a fused bicyclic heterocyclic or a fused bicyclic heteroaryl, each optionally substituted by one or more R 3 substituents;

[0146] R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each optionally substituted by one or more R 4 substituents;

[0147] R 3 is oxo, -OH, -O-alkylene-N(R 5 ) 2 、-N(R 5 ) 2 、-N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic, -C(O)N(R 5 ) 2 、-C(O)-alkyl, -C(O)O-alkyl, or -S(O) m -alkyl;

[0148] 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, heterocyclic, or -alkylene-aryl, optionally substituted by R 8 substituents;

[0149] Each R 5 is independently H, alkyl, -alkylene-OH, optionally substituted by: -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 、-C(O)-alkyl, -C(O)O-alkyl, or -S(O) m -alkyl;

[0150] Alternatively, two Rs 5 together with the attached N atom can form a 4- to 7-membered heterocycle, which optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 ;

[0151] R 8 is halogen, alkyl, or alkoxy;

[0152] X is N or CH; and

[0153] m is 0, 1, or 2.

[0154] In some embodiments, R 6 is an 8- to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more Rs 3 ;

[0155] In some embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclic group, 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 alkyl), each of which is optionally substituted by one or more Rs 4 ;

[0156] In other embodiments, R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic group, or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more Rs 4 ; In other embodiments, R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic group, or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more Rs 4 ;

[0157] In still other embodiments, R 7 is C1 -C 3 alkyl, C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, phenyl, C3-C6 heterocyclic group, or C5-C6 heteroaryl, each optionally substituted with one or more R 4 substituents.

[0158] In other embodiments, R 7 is C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each optionally substituted with one or more R 4 substituents. In other embodiments, R 7 is C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each optionally substituted with one or more R 4 substituents.

[0159] In other embodiments, R 7 is -CF 3 3, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each optionally substituted with one or more R 4 substituents. In other embodiments, R 7 is -CF 3 3, cyclopropyl, phenyl, pyridyl, or triazole, each optionally substituted with one or more R 4 substituents. In further embodiments, R 7 is isopropyl,

[0160] In further embodiments, R 7 is

[0161] In some embodiments, R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, -(C 1 -C 6 alkylene)-(C3-C6 cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), C3-C6 heterocyclic group, or -(C 1 -C6 (alkylene)-(3- to 6-membered heterocyclic group).

[0162] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or -(CH 2 ) p -cyclohexyl; where p is 1, 2, or 3. In some embodiments, R 1 is cyclobutyl. In some embodiments, -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy).

[0163] In some embodiments, 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 alkyl).

[0164] In other embodiments, R 3 is -NH 2 、-N(C 1 -C 3 alkyl) 2 、-NHCH 2 CH 2 OH、-N(C 1 -C 3 alkyl)CH 2 CH2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 , -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -NHSO 2 CH 3 , -N(C 1 -C 3 alkyl)SO 2 CH 3 , -OCH 2 CH 2 , -OCH 2 CH2 NH 2 、 -OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0165] In some embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0166] In other embodiments, 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 haloalkyl, 3 - to 6 - membered cycloalkyl, or 3 - to 6 - membered heterocyclic group.

[0167] In some embodiments, the compound has the structure of formula (VII):

[0168]

[0169] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0170] R 1 is cyclobutyl or -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy);

[0171] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0172] R6 is a heterocyclic group or heteroaryl group, each of which is optionally substituted with one or more R 3 substituents;

[0173] R 7 is -CF 3 , isopropyl,

[0174] 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, heterocyclic group, -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 the cycloalkyl and the heterocyclic group are each optionally substituted with R 10 substituents;

[0175] R 4 is C 1 -C 3 alkyl;

[0176] Each R 5 is independently H, alkyl, -alkylene-OH, which is 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;

[0177] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 substituents;

[0178] R 8 is halogen, alkyl, or alkoxy;

[0179] R 9is H or alkyl, or two Rs 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle which optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0180] R 10 is -OH, halogen, alkyl, or alkoxy;

[0181] X is N or CH;

[0182] m is 0, 1, or 2;

[0183] p is 0 or 1; and

[0184] t is 0, 1, or 2.

[0185] In some embodiments, the compound has the structure of formula (VIII):

[0186]

[0187] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0188] R 1 is cyclobutyl or -(C 1 -C 4 -alkylene)-(C 1 -C 3 -alkoxy);

[0189] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0190] R 6 is each of which is optionally substituted with one or more Rs 3 ;

[0191] R 7 is -CF 3 , isopropyl, cyclopropyl, cyclobutyl, each of which is optionally substituted with one or more Rs 4 ;

[0192] R 3 is -NH 2 , -NH(C 1 -C 3 -alkyl), -NH(C 1 -C 4 -alkylene)-OH, or C 1 -C 3 -alkyl;

[0193] R 4 is C 1 -C 3 alkyl; and

[0194] X is N or CH.

[0195] In some embodiments, the compound or 15-PGDH inhibitor can inhibit the enzymatic activity of recombinant 15-PGDH at 15-PGDH concentrations of about 5 nM to about 10 nM at IC 50 less than 1 μM, at IC 50 less than 250 nM, at IC 50 less than 50 nM, at IC 50 less than 10 nM, at IC 50 less than 5 nM in recombinant, at IC 50 for about 2.5 nM to about 10 nM or less than about 2.5 nM.

[0196] 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 lesions or inflammation.

[0197] The 15-PGDH inhibitor can also be administered to a subject to promote wound healing, tissue repair, and / or tissue regeneration and / or engraftment or regeneration of tissue grafts.

[0198] In one embodiment, the 15-PGDH inhibitor can be administered to a subject to treat at least one of the following: oral ulcers, gum disease, colitis, ulcerative colitis, gastrointestinal ulcers, inflammatory bowel disease, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary hypertension, cardiovascular disease, and kidney disease.

[0199] In another embodiment, the 15-PGDH inhibitor can be administered to a subject in combination with a prostaglandin agonist to enhance the therapeutic effect of the agonist in prostaglandin-responsive disorders.

[0200] In other embodiments, the 15-PGDH inhibitor can be administered to a subject and / or a subject's tissue to increase tissue stem cells. For example, the 15-PGDH inhibitor can be administered to the bone marrow of a subject to increase the stem cells in that subject.

[0201] In still other embodiments, 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, and / or a bone marrow graft, and / or a hematopoietic stem cell graft to enhance the suitability of the donor tissue graft, the donor bone marrow graft, and / or the donor hematopoietic stem cell graft. In one embodiment, the 15-PGDH inhibitor is administered ex vivo to a tissue graft, and / or a bone marrow graft, and / or a hematopoietic stem cell graft. For example, the 15-PGDH inhibitor can be administered to a subject and / or the subject's bone marrow to enhance the suitability of the marrow as a donor graft, and / or to a preparation of the subject's hematopoietic stem cells to enhance the suitability of the stem cell preparation as a donor graft, and / or to a preparation of the subject's peripheral blood hematopoietic stem cells to enhance the suitability of the stem cell preparation as a donor graft, and / or to a preparation of cord blood stem cells to enhance the suitability of the stem cell preparation as a donor graft, and / or to a preparation of cord blood stem cells to reduce the number of cord blood units required for transplantation.

[0202] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to reduce tissue graft rejection, to enhance tissue and / or bone marrow graft transplantation, to enhance bone marrow graft transplantation (after treating the subject or the subject's marrow with radiation therapy, chemotherapy or immunosuppressive therapy), to enhance progenitor stem cell graft, hematopoietic stem cell graft, or cord blood stem cell graft transplantation, to enhance hematopoietic stem cell graft or cord blood stem cell graft transplantation (after treating the subject or the subject's marrow with radiation therapy, chemotherapy or immunosuppressive therapy) and / or to reduce the number of cord blood units required for transplantation into a subject.

[0203] In other embodiments, a 15-PGDH inhibitor can be administered to a recipient of a tissue graft transplantation, a bone marrow transplantation, and / or a hematopoietic stem cell transplantation, or a cord blood stem cell transplantation to reduce the administration of other therapies or growth factors.

[0204] In some embodiments, after treating a subject or the subject's marrow with radiation therapy, chemotherapy or immunosuppressive therapy, the 15-PGDH inhibitor can be administered to the subject or the subject's tissue graft to reduce graft rejection, enhance graft transplantation and / or enhance graft engraftment.

[0205] In other embodiments, a 15-PGDH inhibitor can be administered to a subject or 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 pulmonary toxicity from radiation, and / or to reduce infection.

[0206] In still other embodiments, a 15-PGDH inhibitor can be administered to a subject to increase neutrophil counts (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood), to increase neutrophil counts in a subject with neutropenia (after chemotherapy administration or radiation therapy), to increase neutrophil counts in a subject with aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia after viral infection, to increase neutrophil counts in a subject with neutropia, to increase platelet counts (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood), to increase platelet counts in a subject with thrombocytopenia (after chemotherapy administration or radiation therapy), to increase platelet counts in a subject with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection, to increase platelet counts in a subject with thrombocytopenia, to increase red blood cell counts, or hematocrit, or hemoglobin levels (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or umbilical cord blood), to increase red blood cell counts, or hematocrit, or hemoglobin levels in a subject with anemia (after chemotherapy administration or radiation therapy), to increase red blood cell counts, or hematocrit, or hemoglobin level counts in a subject with aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other disorders of the bone marrow, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, anemia after viral infection, or anemia of unknown cause, to increase red blood cell counts, or hematocrit, or hemoglobin levels in a subject with anemia, 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 chemotherapy administration or radiation therapy), and / or to increase bone marrow stem cells in a subject with aplastic anemia, myelodysplasia, myelofibrosis, other disorders of the bone marrow, drug-induced cytopenia, immune cytopenia, cytopenia after viral infection, or cytopenia.

[0207] In other embodiments, administration of a 15-PGDH inhibitor can be used to modulate hematopoietic stem cells and hematopoiesis. For example, a 15-PGDH inhibitor can be administered alone or in combination with cytokines to a subject in need to increase and / or mobilize hematopoietic stem cells and / or neutrophils in the blood, marrow, and / or tissues of the subject.

[0208] In some embodiments, for the purpose of increasing neutrophils, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0209] In other embodiments, for the purpose of increasing neutrophils, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0210] In still other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0211] In other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0212] In some embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells, a 15-PGDH inhibitor can be administered in combination with a second agent (including, for example, Plerixafor).

[0213] In other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0214] In still other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0215] In other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation, a 15-PGDH inhibitor can be administered in combination with a second agent (including Plerixafor).

[0216] In still other embodiments, for the purpose of increasing the number of hematopoietic stem cells in blood or bone marrow, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0217] In other embodiments, for the purpose of increasing the number of hematopoietic stem cells in blood or bone marrow, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0218] In other embodiments, a 15-PGDH inhibitor can be administered to a subject and / or to the subject's tissue to increase tissue stem cells. For example, a 15-PGDH inhibitor can be administered to the bone marrow of a subject to increase stem cells in that subject.

[0219] In other embodiments, a 15-PGDH inhibitor can be administered to recipients of tissue graft transplantation, bone marrow transplantation, and / or hematopoietic stem cell transplantation, or umbilical cord stem cell transplantation to reduce the administration of other therapies or growth factors.

[0220] In still other embodiments, a 15-PGDH inhibitor can be administered to a subject to increase neutrophil count (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or cord blood), to increase neutrophil count in a subject with neutropenia (after chemotherapy administration or radiation therapy), to increase neutrophil count in a subject with aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia after viral infection, to increase neutrophil count in a subject with neutropia, to increase platelet count (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or cord blood), to increase platelet count in a subject with thrombocytopenia (after chemotherapy administration or radiation therapy), to increase platelet count in a subject with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia after viral infection, to increase platelet count in a subject with thrombocytopenia, to increase red blood cell count, or hematocrit, or hemoglobin level (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or cord blood), to increase red blood cell count, or hematocrit, or hemoglobin level in a subject with anemia (after chemotherapy administration or radiation therapy), to increase red blood cell count, or hematocrit, or hemoglobin level count in a subject with aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other disorders of the bone marrow, 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 level in a subject with anemia, to increase bone marrow stem cells (after hematopoietic cell transplantation with bone marrow, hematopoietic stem cells, or cord blood), to increase bone marrow stem cells in a subject (after chemotherapy administration or radiation therapy), and / or to increase bone marrow stem cells in a subject with aplastic anemia, myelodysplasia, myelofibrosis, other disorders of the bone marrow, drug-induced cytopenia, immune cytopenia, cytopenia after viral infection, or cytopenia.

[0221] In other embodiments, in the presence of cytopenia, a 15-PGDH inhibitor can be administered to a subject to increase responsiveness to cytokines, where the cytopenia includes any one of the following: neutropenia, thrombocytopenia, lymphocytopenia, and anemia; and where the cytokine has an increased responsiveness enhanced by the 15-PGDH inhibitor, and the 15-PGDH inhibitor includes any one of the following: G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist), and SCF.

[0222] In some embodiments, a 15-PGDH inhibitor can be administered to a subject to increase bone density, treat osteoporosis, promote fracture healing, or promote healing after bone surgery or joint replacement, and / or promote bone healing to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0223] In other embodiments, a 15-PGDH inhibitor can be administered to a subject or the intestine of a subject to increase stem cells or cell proliferation in the intestine, and / or confer resistance to the toxic or lethal effects of exposure to radiation or the toxic, lethal, or mucositis effects caused by treatment with chemotherapy.

[0224] In some embodiments, a 15-PGDH inhibitor can be administered to a subject or the intestine of a subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

[0225] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to increase liver regeneration after liver surgery, living liver donation, liver transplantation, or toxin-induced liver injury and / or to promote recovery from or resistance to liver toxins (acetaminophen and related compounds).

[0226] In still other embodiments, a 15-PGDH inhibitor can be administered to a subject to treat erectile dysfunction.

[0227] In yet other embodiments, a 15-PGDH inhibitor can be administered to inhibit at least one of growth, proliferation, or metastasis of a cancer that expresses 15-PGDH.

[0228] Still other embodiments described herein relate to methods of treating a subject in need of cell therapy. The method includes administering to the subject a therapeutically effective amount of a formulation and / or a therapeutic composition, the formulation comprising administering

[0229] the human hematopoietic stem cells of the 15-PGDH inhibitor described herein, the therapeutic composition comprising human hematopoietic stem cells and the 15-PGDH inhibitor described herein.

[0230] In some embodiments, the subject has received hematopoietic stem cells and / or has received the preparation and / or the therapeutic composition.

[0231] In other embodiments, the subject has acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, severe aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH), pure red cell aplasia, amegakaryocytosis / congenital thrombocytopenia, severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, β-thalassemia, sickle cell disease, Hurler's syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, idiopathic myelofibrosis, familial erythrophagocytic lymphohistiocytosis, solid tumors, chronic granulomatous disease, mucopolysaccharidosis, or Diamond-Blackfan anemia.

[0232] Other embodiments relate to a method of treating a subject having at least one symptom associated with ischemic tissue or tissue damaged by ischemia. The method comprises administering to the subject a therapeutically effective amount of a preparation and / or a therapeutic composition, the preparation comprising hematopoietic stem cells administered with a 15-PGDH inhibitor as described herein, the therapeutic composition comprising hematopoietic stem cells and a 15-PGDH inhibitor as described herein.

[0233] In some embodiments, the ischemia can be associated with at least one of the following: acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, brain edema, brain hypoperfusion, Buerger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity arterial ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, premalignancy, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral-bone cyst, thrombus, thrombotic brain ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory disorder, von Hippel-Lindau syndrome, and tissue or organ wound.

[0234] 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, a 15-PGDH inhibitor as 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, or conditions, all or part of which are characterized by the overproduction of fibrous material, including the overproduction of fibrotic material within the extracellular matrix or the replacement of normal tissue components by abnormal, non-functional, and / or excessive accumulation of matrix-related components.

[0235] Fibrotic diseases, disorders, or conditions that are all or part of which are characterized by the overproduction of fibrous material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), graft-versus-host disease of scleroderma, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive nephropathy, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fascilitis, eosinophilic fasciitis, common fibrosis syndromes characterized by the replacement of normal muscle tissue by varying degrees of fibrous tissue, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis (fibrosis of the bone marrow), drug-induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, collagenous colitis, acute fibrosis, organ-specific fibrosis, and the like.

[0236] In some embodiments, a method for treating or preventing a fibrotic disease, disorder, or condition includes administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof.

[0237] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent pulmonary fibrosis. The pulmonary fibrosis that can be treated can be selected from the group consisting of: pulmonary fibrosis, pulmonary arterial hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, anthracosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of a harmful gas, aerosol, chemical dust, smoke or vapor, drug-induced interstitial lung disease, or pulmonary arterial hypertension, and combinations thereof.

[0238] In other embodiments, a 15-PGDH inhibitor can be used to treat or prevent renal fibrosis. Renal fibrosis may be caused by renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end-stage renal disease or renal failure, or dialysis following a combination thereof.

[0239] In other embodiments, a 15-PGDH inhibitor can be used to treat or prevent liver fibrosis. Liver fibrosis can be caused by: chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins, or combinations thereof.

[0240] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent cardiac fibrosis, for example, myocardial fibrosis and endomyocardial fibrosis.

[0241] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent systemic sclerosis.

[0242] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent a fibrotic disease, disorder or condition caused by postoperative adhesion formation.

[0243] In some embodiments, a 15-PGDH inhibitor can be used to reduce or prevent scar formation in a subject.

[0244] In other embodiments, a 15-PGDH inhibitor can be used to reduce or prevent scar formation on the skin or scleroderma.

[0245] In various embodiments, a therapeutically effective amount of a 15-PGDH inhibitor can be administered to reduce the intensity, severity, or frequency of, or delay the onset of, at least one symptom or feature of a fibrotic disease, disorder, or condition, or other related disease, disorder, or condition.

[0246] In other embodiments, a 15-PGDH inhibitor can be used in a method for reducing or decreasing collagen secretion or collagen deposition in a tissue or organ (such as the lung, liver, intestine, colon, skin, or heart) of a subject. The method can include administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject can have or be at risk of excessive collagen secretion or collagen deposition in a tissue or organ (such as the kidney, lung, liver, intestine, colon, skin, or heart). Generally, excessive collagen secretion or collagen deposition in an organ is caused by injury or insult. Such injury and insult can be organ-specific. The 15-PGDH inhibitor can be administered for a sufficient period of time to completely or partially reduce or decrease the level of collagen deposition in the tissue or organ. The sufficient period of time can be within one week, or between 1 week and 1 month, or between 1 and 2 months, or 2 months or longer. For chronic conditions, the 15-PGDH inhibitor can be advantageously administered for life.

[0247] 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 abnormal activity of the immune system, and / or promote wound healing in a subject in need thereof. It has been found that a corticosteroid administered to a subject can induce 15-PGDH expression in the tissue of the subject. 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 reducing the adverse and / or cytotoxic effects induced by the corticosteroid. Treating an inflammatory disorder, immune disorder, and / or wound by administering a 15-PGDH inhibitor in combination with a corticosteroid can improve the therapeutic efficacy, and in some cases, the corticosteroid can be administered at a lower dose to achieve a similar effect, and in other cases, at a higher dose and for an extended period of time to reduce and / or mitigate the adverse or cytotoxic effects.

[0248] In some embodiments, the inflammatory and / or immune 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 an inhibitor of short-chain dehydrogenase activity (such as a 15-PGDH inhibitor) can be administered alone or in combination with a corticosteroid and a tumor necrosis factor (TNF)-α antagonist to a subject in need thereof to treat an intestinal, gastrointestinal, or bowel disorder (such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease).

[0249] In other embodiments, a 15-PGDH inhibitor can be used as a glucocorticoid sensitizer to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject who experiences corticosteroid dependence or corticosteroid resistance or is unresponsive or intolerant to corticosteroids. For example, a 15-PGDH inhibitor can be administered in combination with a corticosteroid to a subject to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject who experiences corticosteroid dependence or corticosteroid resistance or is unresponsive or intolerant to corticosteroids.

[0250] A 15-PGDH inhibitor can also be administered in combination with a corticosteroid or a TNF inhibitor to a subject to promote wound healing, tissue repair, and / or tissue regeneration and / or engraftment or regeneration of a tissue graft.

[0251] 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 mitigate corticosteroid-induced adverse and / or cytotoxic effects. Detailed Description

[0252] Although it is believed that the following terms are well understood by one of ordinary skill in the art, the following definitions are presented to facilitate the interpretation of the subject matter of this disclosure.

[0253] As used herein, the verb "comprising" and its variations, as used in the specification and claims, are used in its non-limiting sense to mean including the item(s) following the word, but not excluding items not specifically mentioned. The present invention may suitably "comprise" the steps, elements, and / or reagents recited in the claims, "consist of" or "consist essentially of".

[0254] It is further noted that the claims can be drafted to exclude any optional element. Thus, this statement is intended to serve as a basis for the use of exclusive terms such as "only", "solely", etc. or the use of "negative" limitations in relation to the recitation of claim elements.

[0255] The term "pharmaceutically acceptable" means suitable for use in contact with the tissues of humans 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 reasonable medical judgment.

[0256] The term "pharmaceutically acceptable salts" includes those salts obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, for example, 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. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with a suitable inorganic or organic acid via any of a number of known methods. The term "pharmaceutically acceptable salts" also includes those salts obtained by reacting an active compound acting as an acid with an inorganic or organic base to form a salt, for example, salts of ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, benzhydrylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, etc. Non-limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts, etc.

[0257] In addition, the salts of the compounds described herein may exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0258] The term "solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by the binding of one or more water molecules to a substance, where the water remains in its molecular state as H 2 O, and such binding can form one or more hydrates.

[0259] The compounds and salts described herein can exist in several tautomeric forms, including enol and imine forms, as well as keto and enamine forms, and geometric isomers and mixtures thereof. Tautomers exist in solution as mixtures of tautomeric forms. In the solid form, usually one tautomer predominates. Even though one tautomer can be described, this application includes all tautomers of the compounds of the invention. Tautomers are one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom, accompanied by the conversion of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism.

[0260] Among the various types of possible tautomerism, two are commonly observed. In keto-enol tautomerism, the migration of both an electron and a hydrogen atom occurs simultaneously.

[0261] Tautomerization can be catalyzed as follows: Base: 1. Deprotonation; 2. Formation of a delocalized anion (e.g., enolate); 3. Protonation at different positions of the anion; Acid: 1. Protonation; 2. Formation of a delocalized cation; 3. Protonation at different positions adjacent to the cation.

[0262] Unless otherwise indicated, as used herein, the following terms have the following meanings:

[0263] "Amino" means the -NH 2 group.

[0264] "Cyano" means the -CN group.

[0265] "Halo" or "halogen" means a bromo, chloro, fluoro, or iodo group.

[0266] "Hydroxy" (or "hydroxyl") means the -OH group.

[0267] "Imino" means the =NH substituent.

[0268] "Nitro" means the -NO 2 group.

[0269] "Oxo" means the =O substituent.

[0270] "Thioxo" means the =S substituent.

[0271] "Alkyl" or "alkyl group" refers to a fully saturated, straight-chain or branched hydrocarbon chain group having from one to twelve carbon atoms, which is attached to the remainder of the molecule by a single bond. It includes alkyl groups containing any number of carbon atoms from 1 to 12. An alkyl group containing up to 12 carbon atoms is C 1 -C 12 alkyl, and an alkyl group containing up to 10 carbon atoms is C 1 -C 10 alkyl, and an alkyl group containing up to 6 carbon atoms is C 1 -C 6 alkyl, and an alkyl group containing up to 5 carbon atoms is C 1 -C 5 alkyl. C 1 -C 5 alkyl includes C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl, and C 1 alkyl (i.e., methyl). C 1 -C 6 alkyl includes all of the foregoing for C 1 -C 5 alkyl but also includes C 6 alkyl. C 1 -C 10 alkyl includes all of the foregoing for C 1 -C 5 alkyl and C 1 -C 6 alkyl, but also includes C 7 , C 8 , C 9 , and C 10 alkyl. Similarly, C 1 -C 12 alkyl includes all of the foregoing, but also includes C 11 , and C 12 alkyl. C 1 -C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl (i-propyl, sec-propyl), n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted.

[0272] "Alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain group having from one to twelve carbon atoms. C 1 -C 12Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, vinylidene, propenylene, n-butenylene, propynylene, n-butynylene. The alkylene chain is attached to the remainder of the molecule by a single bond and is linked to the group by a single bond. The attachment points of the alkylene chain to the remainder of the molecule and to the group can be through one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, the alkylene group can be optionally substituted.

[0273] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon chain group having two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the remainder of the molecule by a single bond. Alkenyl groups including any number of carbon atoms from 2 to 12 are included. An alkenyl group having at most 12 carbon atoms is C 2 -C 12 alkenyl, an alkenyl group having at most 10 carbon atoms is C 2 -C 10 alkenyl, an alkenyl group having at most 6 carbon atoms is C 2 -C 6 alkenyl and an alkenyl group having at most 5 carbon atoms is C 2 -C 5 alkenyl. C 2 -C 5 Alkenyl includes C 5 alkenyl, C 4 alkenyl, C 3 alkenyl, and C 2 alkenyl. C 2 -C 6 Alkenyl includes all of the parts described above for C 2 -C 5 alkenyl but also includes C 6 alkenyl. C 2 -C 10 Alkenyl includes all of the parts described above for C 2 -C 5 alkenyl and C 2 -C 6 alkenyl, but also includes C 7 , C 8 , C 9 and C 10 alkenyl. Similarly, C 2 -C 12 alkenyl includes all of the foregoing parts, but also includes C 11 and C 12 alkenyl. C 2 -C 12Non-limiting examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specifically stated in the specification, alkyl groups may be optionally substituted.

[0274] “Alkenylene” or “alkenylene chain” refers to a straight-chain or branched-chain divalent hydrocarbon chain group having two to twelve carbon atoms and having one or more carbon-carbon double bonds. C 2 -C 12 Non-limiting examples of alkenylene groups include ethene, propene, butene, etc. The alkenylene chain is attached to the remainder of the molecule by a single bond and is connected to the group by a single bond. The attachment points of the alkenylene chain to the remainder of the molecule and to the group may be through one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, alkenylene groups may be optionally substituted.

[0275] “Alkynyl” or “alkynyl group” refers to a straight-chain or branched-chain hydrocarbon chain group having two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the remainder of the molecule by a single bond. Alkynyl groups including any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C 2 -C 12 Alkynyl, alkynyl groups containing up to 10 carbon atoms are C 2 -C 10 Alkynyl, alkynyl groups containing up to 6 carbon atoms are C2 -C 6 An alkynyl group and an alkynyl group containing up to 5 carbon atoms are C 2 -C 5 alkynyl group. C 2 -C 5 The alkynyl group includes C 5 alkynyl group, C 4 alkynyl group, C 3 alkynyl group, and C 2 alkynyl group. C 2 -C 6 The alkynyl group includes all the parts described above for C 2 -C 5 alkynyl group but also includes C 6 alkynyl group. C 2 -C 10 The alkynyl group includes all the parts described above for C 2 -C 5 alkynyl group and C 2 -C 6 alkynyl group, but also includes C 7 , C 8 , C 9 and C 10 alkynyl group. Similarly, C 2 -C 12 alkynyl group includes all the foregoing parts, but also includes C 11 and C 12 alkynyl group. C 2 -C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, pentynyl, etc. Unless otherwise specifically stated in the specification, the alkyl groups may be optionally substituted.

[0276] "Alkynylene" or "alkynylene chain" refers to a divalent hydrocarbon chain group having from two to twelve carbon atoms and having one or more carbon-carbon triple bonds. C 2 -C 12 Non-limiting examples of alkynylene include ethynylene, propynylene, etc. The alkynylene chain is attached to the remainder of the molecule by a single bond and is connected to the group by a single bond. The attachment points of the alkynylene chain to the remainder of the molecule and to the group may be through one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, the alkynylene group may be optionally substituted.

[0277] "Alkoxy" refers to a group having the formula -OR a wherein R a is an alkyl, alkenyl or alkynyl group containing from one to twelve carbon atoms as defined above. Unless otherwise specifically stated in the specification, the alkoxy group may be optionally substituted.

[0278] "Alkylamino" means a group having the formula -NHR a or -NR a R a wherein each R a is independently an alkyl, alkenyl or alkynyl group containing from one to twelve carbon atoms as defined above. Unless otherwise specifically stated in the specification, the alkylamino group may be optionally substituted.

[0279] "Alkylcarbonyl" means a -C(=O)R a moiety, wherein R a is an alkyl, alkenyl or alkynyl group as defined above. Non-limiting examples of alkylcarbonyl are the methylcarbonyl ("acetal") moiety. The alkylcarbonyl group is also referred to as "C w -C z acyl", where w and z represent the range of the number of carbons in R a as defined above. For example, "C 1 -C 10 acyl" means an alkylcarbonyl group as defined above, wherein R a is a C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl group as defined above. Unless otherwise specifically stated in the specification, the alkylcarbonyl may be optionally substituted.

[0280] "Aryl" means a hydrocarbon ring system group containing hydrogen, from 6 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, the aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from: phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, fluoranthene, fluorene, asym-indacene, sym-indacene, indane, indene, naphthalene, phenalene, phenanthrene, heptalene, pyrene, and benzo[ghi]perylene. Unless otherwise specifically stated in the specification, the term "aryl" is meant to include optionally substituted aryl groups.

[0281] "Aralkyl" or "arylalkyl" means a group having the formula -R b -R c wherein R b is an alkylene group as defined above and R c is one or more aryl groups as defined above. Aralkyl groups include, but are not limited to, benzyl, diphenylmethyl, etc. Unless otherwise specifically stated in the specification, the aralkyl group may be optionally substituted.

[0282] "Arylalkenyl" or "arylalkylene" refers to a group having the formula -R b -R c wherein R b is an alkenylene group as defined above and R c is one or more aryl groups as defined above. Unless otherwise specifically stated in the specification, the arylalkenyl group may be optionally substituted.

[0283] "Arylalkynyl" or "arylalkynylene" refers to a group having the formula -R b -R c wherein R b is an alkynylene group as defined above and R c is one or more aryl groups as defined above. Unless otherwise specifically stated in the specification, the arylalkynyl group may be optionally substituted.

[0284] "Carbocyclic group", "carbocyclic ring" ("carbocyclic ring" or "carbocycle") refers to a ring structure in which the atoms forming the ring are each carbon. The carbocyclic ring may contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl and cycloalkyl groups. Cycloalkenyl and cycloalkynyl groups as defined herein. Unless otherwise specifically stated in the specification, the carbocyclic group may be optionally substituted.

[0285] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon group consisting only of carbon and hydrogen atoms, which may include a fused, bridged or spiro ring system having from three to twenty carbon atoms (preferably from three to ten carbon atoms), and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the cycloalkyl group may be optionally substituted.

[0286] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms and having one or more carbon-carbon double bonds, which may include a fused, bridged or spiro ring system having from three to twenty carbon atoms (preferably from three to ten carbon atoms), and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, for example, bicyclo[2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, the cycloalkenyl group may be optionally substituted.

[0287] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms and having one or more carbon-carbon triple bonds, which may include a fused, bridged or spiro ring system having three to twenty carbon atoms (preferably three to ten carbon atoms), and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkynyl groups include, for example, cycloheptynyl, cyclooctynyl, etc. Unless otherwise specifically stated in the specification, the cycloalkynyl group may be optionally substituted.

[0288] "Cycloalkylalkyl" refers to a group having the formula -R b -R d wherein R b is an alkylene, alkenylene, or alkynylene group as defined above and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl group as defined above. Unless otherwise specifically stated in the specification, the cycloalkylalkyl group may be optionally substituted.

[0289] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, the haloalkyl group may be optionally substituted.

[0290] "Haloalkenyl" refers to an alkenyl group as defined above substituted with one or more halo groups as defined above, for example, 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise specifically stated in the specification, the haloalkenyl group may be optionally substituted.

[0291] "Haloalkynyl" refers to an alkynyl group as defined above substituted with one or more halo groups as defined above, for example, 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless otherwise specifically stated in the specification, the haloalkynyl group may be optionally substituted.

[0292] "Heterocyclic group", "heterocyclic ring" (either "heterocyclic ring" or "heterocycle") refers to a stable 3- to 20-membered non-aromatic, partially aromatic or aromatic ring group, which consists of two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heterocyclic group (heterocyclycl) or heterocyclic ring includes heteroaryl groups as defined below. Unless otherwise specifically stated in the specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, bridged and spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, aziridinyl, oxetanyl (oextanyl), dioxolanyl, thieno[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyridinone, etc. The point at which the heterocyclic group, heterocyclic ring (heterocyclic ring or heterocycle) is attached to the rest of the molecule by a single bond is through a ring member atom, which may be carbon or nitrogen. Unless otherwise specifically stated in the specification, the heterocyclic group may be optionally substituted.

[0293] "Heterocyclic group alkyl" refers to a group having the formula -R b -R e where R b is an alkylene group as defined above and R e is a heterocyclic group as defined above. Unless otherwise specifically stated in the specification, the heterocyclic group alkyl group may be optionally substituted.

[0294] "Heterocyclic group alkenyl" refers to a group having the formula -R b -R e where R b is an alkenylene group as defined above and R e is a heterocyclic group as defined above. Unless otherwise specifically stated in the specification, the heterocyclic group alkenyl group may be optionally substituted.

[0295] "Heterocyclic group alkynyl" refers to a group having the formula -R b -R e where R bis an alkynylene group as defined above and R e is a heterocyclic group as defined above. Unless otherwise specifically stated in the specification, the heterocyclic alkynyl group may be optionally substituted.

[0296] “N - heterocyclic group” means a heterocyclic group as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclic group to the remainder of the molecule is through a nitrogen atom in the heterocyclic group. Unless otherwise specifically stated in the specification, the N - heterocyclic group may be optionally substituted.

[0297] “Heteroaryl” means a 5 - to 20 - membered ring system group having one to thirteen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur as ring members. For the purposes of the present invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems, wherein at least one of the rings containing heteroatom ring members is aromatic. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized and the nitrogen atoms may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benz[b][1,4]oxazinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benz[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindolyl, iso - dihydroindolyl, isoquinolinyl, indazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - azaindolyl, oxazolyl, oxiranyl, 1 - oxidized pyridinyl, 1 - oxidized pyrimidinyl, 1 - oxidized pyrazinyl, 1 - oxidized pyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the heteroaryl group may be optionally substituted. azinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benz[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindolyl, iso - dihydroindolyl, isoquinolinyl, indazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - azaindolyl, oxazolyl, oxiranyl, 1 - oxidized pyridinyl, 1 - oxidized pyrimidinyl, 1 - oxidized pyrazinyl, 1 - oxidized pyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the heteroaryl group may be optionally substituted. azinyl, oxazolyl, oxiranyl, 1 - oxidized pyridinyl, 1 - oxidized pyrimidinyl, 1 - oxidized pyrazinyl, 1 - oxidized pyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the heteroaryl group may be optionally substituted.

[0298] “N - heteroaryl” means a heteroaryl group as defined above that contains at least one nitrogen, and wherein the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. Unless otherwise specifically stated in the specification, the N - heteroaryl group may be optionally substituted.

[0299] “Heteroarylalkyl” means a group having the formula -R b -R f wherein R b is an alkylene chain as defined above and R f is a heteroaryl group as defined above. Unless otherwise specifically stated in the specification, the heteroarylalkyl group may be optionally substituted.

[0300] “Heteroarylenyl” means a group having the formula -R b -R f wherein R b is an alkenylene chain as defined above and R f is a heteroaryl group as defined above. Unless otherwise specifically stated in the specification, the heteroarylenyl group may be optionally substituted.

[0301] “Heteroarylalkynyl” means a group having the formula -R b -R f wherein R b is an alkynylene chain as defined above and R f is a heteroaryl group as defined above. Unless otherwise specifically stated in the specification, the heteroarylalkynyl group may be optionally substituted.

[0302] “Thioalkyl” means a group having the formula -SR a wherein R a is an alkyl, alkenyl or alkynyl group containing from one to twelve carbon atoms as defined above. Unless otherwise specifically stated in the specification, the thioalkyl group may be optionally substituted.

[0303] As used herein, the term "substituted" means that in any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclic, N - heterocyclic, heterocyclicalkyl, heteroaryl, N - heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.), at least one hydrogen atom is replaced by a bond attached to a non - hydrogen atom, such non - hydrogen atoms including but not limited to: halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups (such as hydroxyl group, alkoxy group, and ester group); sulfur atoms in groups (such as thiol group, thioalkyl group, sulfone group, sulfonyl group, and sulfoxide group); nitrogen atoms in groups (such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N - oxide, imide, and enamine); silicon atoms in groups (such as trialkylsilyl group, dialkylarylsilyl group, alkyldiarylsilyl group, and triarylsilyl group); and other heteroatoms in various other groups. "Substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by a higher - order bond (e.g., double bond or triple bond) attached to a heteroatom, such heteroatoms as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups (such as imine, oxime, hydrazone, and nitrile). For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by - NR 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 SO 2 R h 、 - OC(=O)NR g R h 、 - OR g 、 - SR g 、 - SOR g 、 - SO 2 R g 、 - OSO 2 R g 、 - SO 2 OR g 、 =NSO 2 R g 、 and - SO 2 NR g R hSubstitution. "Substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH 2 SO 2 R g 、-CH 2 SO 2 NR g R h Substitution. In the foregoing, R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic group, N - heterocyclic group, heterocyclic group alkyl, heteroaryl, N - heteroaryl and / or heteroarylalkyl. "Substituted" further means that in any of the above groups, one or more hydrogen atoms are replaced by a bond bonded to the following: amino, cyano, hydroxy, imino, nitro, oxo, thio, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic group, N - heterocyclic group, heterocyclic group alkyl, heteroaryl, N - heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents may optionally be substituted by one or more of the above substituents.

[0304] As used herein, the symbol (which may hereinafter be referred to as "a point of attachment bond") represents a bond at the point of attachment between two chemical entities, where one is depicted as being attached to the point of attachment and the other is not depicted as being attached to the point of attachment. For example, represents that the chemical entity "A" is bonded to another chemical entity via a point of attachment bond. In addition, the specific point of attachment to an un - described chemical entity can be specified by inference. For example, the compound (where X is ) infers that the point of attachment bond is a bond through which X is depicted as attached to the benzene ring in the ortho - position relative to fluorine.

[0305] The phrases "parenteral administration" and "administered parenterally" are recognized terms in the art and include modes of administration other than enteral and topical administration, such as injection, and include, but are not limited to, intravenous, intramuscular, intrapleural, intravascular, intracardiac, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0306] The term "treat" is recognized in the art and includes inhibiting a disease, disorder, or condition in a subject, e.g., arresting its development; and alleviating a disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is not affected.

[0307] The term "prevent" is recognized in the art and includes preventing a disease, disorder, or condition from occurring in a subject who may be predisposed to the disease, disorder, or condition but has not yet been diagnosed as having it. Preventing a condition associated with a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has manifested.

[0308] A "patient", "subject", or "host" to be treated by the subject methods can mean a human or non-human animal, such as a mammal, fish, bird, reptile, or amphibian. Thus, subjects of the methods disclosed herein can be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cats, guinea pigs, or rodents. The term does not denote a particular age or sex. Thus, it is intended to cover adult and neonatal subjects, as well as fetuses, whether male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder.

[0309] The terms "prophylactic" or "therapeutic" treatment are recognized in the art and include administering to a host one or more of the subject compositions. If administered before the clinical manifestation of an undesired condition (e.g., a disease or other undesired state of a host animal), the treatment is prophylactic (i.e., it protects the host against the development of the undesired condition), while if administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., it is intended to attenuate, ameliorate, or stabilize the existing undesired condition or its side effects).

[0310] The terms "therapeutic agent", "drug", "medicament", and "bioactive substance" are well recognized in the art and include molecules and other agents of biological, physiological, or pharmacological activity that act locally or systemically in a patient or subject to treat a disease or disorder. These terms include, but are not limited to, pharmaceutically acceptable salts and prodrugs thereof. Such agents can be acidic, basic, or salts; they can be neutral molecules, polar molecules, or molecules capable of forming hydrogen-bonded complexes; they can be prodrugs in the form of ethers, esters, amides, etc., which are bioactivated when administered to a patient or subject.

[0311] The phrase "therapeutically effective amount" or "pharmaceutically effective amount" is a well-recognized term in the art. In certain embodiments, the term refers to the 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 treatment regimen. The effective amount can vary depending on such factors as the disease or disorder being treated, the particular targeting construct being administered, the size of the subject, or the severity of the disease or disorder. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation. In certain embodiments, the therapeutically effective amount of a therapeutic agent used in vivo will likely depend on a number of factors, including: the rate of release of the agent from the polymeric 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 polymeric matrix in addition to the agent.

[0312] The term "ED50" is well recognized in the art. In certain embodiments, ED50 means the dose at which a drug produces 50% of its maximal response or effect or alternatively the dose that produces a predetermined response in 50% of the test subjects or preparations. The term "LD50" is well recognized in the art. In certain embodiments, LD50 means the dose of a drug that is lethal in 50% of the test subjects. The term "therapeutic index" is a well-recognized term in the art (which refers to the therapeutic index of a drug) and is defined as LD50 / ED50.

[0313] The term "IC 50 " or "half-maximal inhibitory concentration" is intended to refer to the concentration of a substance (e.g., a compound or drug) required to inhibit 50% of a biological process or a component of a process, including proteins, subunits, organelles, ribonucleoproteins, etc.

[0314] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and thus the description includes both the circumstance where it occurs and the circumstance where it does not occur. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and thus this specification includes both structures where a non-hydrogen substituent is present and structures where a non-hydrogen substituent is not present.

[0315] Throughout the specification, when a composition is described as having, including, or containing a specific component, it is contemplated that the composition also consists essentially of, or consists of, the recited components. Similarly, in cases where a method or process is described as having, including, or containing specific process steps, such processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or the order for performing certain actions is not important so long as the compositions and methods described herein remain operable. Additionally, two or more steps or actions may be carried out simultaneously.

[0316] Unless otherwise indicated, all percentages and ratios used herein are by weight.

[0317] The term "neoplasm" refers to any abnormal mass of cells or tissue mass formed due to neoplasia. A neoplasm can be benign, potentially malignant (precancerous), or malignant (cancerous). An example of a neoplasm is an adenoma.

[0318] The terms "adenoma", "colonic adenoma", and "polyp" are used herein to describe any precancerous neoplasm of the colon.

[0319] As used herein, the term "colon" is intended to encompass the right colon (including the cecum), the transverse colon, the left colon, and the rectum.

[0320] The terms "colorectal cancer" and "colon cancer" are used interchangeably herein and refer to any cancerous neoplasm of the colon (including the rectum, as defined above).

[0321] The term "gene expression" or "protein expression" includes any information related to the amount of gene transcripts or proteins present in a sample, as well as information about the rate of production or accumulation or degradation of the gene or protein (e.g., reporter gene data, nuclear runoff experiment data, pulse-chase data, etc.). Certain types of data may be considered relevant to gene and protein expression. For example, the protein level in a cell reflects both the protein level and the transcriptional level, and such data is intended to be included within the phrase "gene or protein expression information". Such information can be provided in the form of amount per cell, amount relative to a control gene or protein, unitless measure, etc.; the term "information" is not limited to any particular representation and is intended to mean any representation that provides the relevant information. The term "expression level" refers to the amount reflected in or derived from gene or protein expression data, whether the data is for gene transcript accumulation or protein accumulation or protein synthesis rate, etc.

[0322] The terms "healthy" and "normal" are used interchangeably herein and refer to a subject, or a particular cell or tissue, that is free of a disease condition (at least within the limits of detection).

[0323] The term "nucleic acid" refers to polynucleotides, such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include analogs of RNA or DNA made from nucleotide analogs, and single-stranded (e.g., sense or antisense) and double-stranded polynucleotides (when applicable to the described embodiments). In some embodiments, "nucleic acid" refers to inhibitory nucleic acids. Some classes of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such classes of nucleic acids are well known in the art.

[0324] The embodiments described herein relate to compounds and methods for modulating SCD activity (e.g., 15-PGDH activity), modulating tissue prostaglandin levels, and / or treating a disease, disorder, or condition in which modulation of 15-PGDH activity and / or prostaglandin levels is desired.

[0325] The terms "inhibitor", "activator", and "modulator" of 15-PGDH expression or 15-PGDH activity are used respectively to refer to molecules that inhibit, activate, or modulate (identified using in vitro and in vivo assays directed at 15-PGDH expression or 15-PGDH activity), such as ligands, agonists, antagonists, and their homologs and mimetics. The term "modulator" includes inhibitors and activators. An inhibitor is an agent that, for example, inhibits the expression or binding of 15-PGDH, blocks stimulation in part or in whole, reduces, prevents, delays activation, inactivates, desensitizes, or down-regulates the activity of 15-PGDH, such as an antagonist. An activator is an agent that, for example, induces or activates the expression or binding of 15-PGDH, stimulates, stabilizes, increases, turns on, activates, promotes, or enhances activation, sensitizes, or up-regulates the activity of 15-PGDH, such as an agonist. Modulators include naturally occurring and synthetic ligands, small chemical molecules, and the like.

[0326] The 15-PGDH inhibitors described herein can provide a pharmacological method for raising prostaglandin levels in tissues. Known activities of prostaglandins include promoting hair growth, promoting skin pigmentation, and promoting the appearance of skin darkening or skin tanning. Known activities of prostaglandins also include improving pulmonary hypertension. For purposes including the following, the 15-PGDH inhibitors described herein can also be used to increase the number of tissue stem cells: increasing resistance to tissue damage caused by radiation, increasing resistance to environmental exposure to radiation, increasing the number of stem cells to increase the suitability of bone marrow or other types of transplantation (by in vivo exposure to the 15-PGDH inhibitors described herein before harvesting the transplanted tissue to increase the number of stem cells, or by in vitro exposure of the harvested tissue before transplantation into a recipient host, or by treatment of the transplant recipient). The 15-PGDH inhibitors described herein can also be used for purposes including promoting liver regeneration (including liver regeneration after hepatectomy and after toxic insult (such as a toxic insult that can be acetaminophen overdose)). It is also known that prostaglandin signaling can promote wound healing, protect the stomach from ulcers, and promote the healing of gastric and intestinal ulcers. Additionally, the 15-PGDH inhibitors described herein can promote the activity of human keratinocytes in a "healing" scratch of a keratinocyte culture. Thus, the 15-PGDH inhibitors described herein can also be used to heal ulcers in other tissues (including but not limited to the skin), and including but not limited to diabetic ulcers. Furthermore, the 15-PGDH inhibitors described herein can be used to treat erectile dysfunction.

[0327] Assays can be used, in which a putative modulator compound is applied to cells expressing 15-PGDH, to identify 15-PGDH inhibitors as described herein and then to determine the functional effect on 15-PGDH activity. Samples or assays containing 15-PGDH that have been treated with a potential activator, inhibitor, or modulator are compared to control samples without inhibitor, activator, or modulator to examine the extent of the effect. The relative 15-PGDH activity value of the control sample (not treated with the modulator) is designated as 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5%, or 1%.

[0328] An agent to be tested as a modulator of SCD (such as 15-PGDH) can be any small chemical molecule or compound. Generally, the test compound will be a small chemical molecule, natural product, or peptide. Assays are designed to screen large chemical libraries by automated assay steps and providing compounds from any convenient source to the assay (typically run in parallel (e.g., in a microtiter format in a robotic assay on a microtiter plate)). Modulators also include agents designed to increase the level of 15-PGDH mRNA or the level of translation of the mRNA.

[0329] In some embodiments, a modulator of SCD can be an SCD inhibitor, which can be administered to a subject's tissue or blood in an amount effective to inhibit the activity of short-chain dehydrogenase. The SCD inhibitor can be a 15-PGDH inhibitor, which can be administered to a subject's tissue or blood in an amount effective to increase the level of prostaglandins in the tissue or blood. 15-PGDH inhibitors can include compounds having the structure of formula (IA):

[0330]

[0331] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0332] R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclic, or alkylene-heterocyclic;

[0333] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0334] R 6 is heterocyclic or heteroaryl, each optionally substituted with one or more R 3 substituents;

[0335] R 7is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 substituents;

[0336] 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, heterocyclic, -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 the cycloalkyl and the heterocyclic are each optionally substituted with R 10 substituents;

[0337] 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, heterocyclic, or -alkylene-aryl, which is optionally substituted with R 8 substituents;

[0338] Each R 5 is independently H, alkyl, -alkylene-OH, which is 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;

[0339] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 substituents;

[0340] R 8 is a halogen, an alkyl group, or an alkoxy group;

[0341] R 9 is H or an alkyl group, or two Rs 9 together with the N atom to which they are attached may form a 4- to 7-membered heterocyclic ring, which heterocyclic ring optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0342] R 10 is -OH, a halogen, an alkyl group, or an alkoxy group;

[0343] X is N or CH;

[0344] m is 0, 1, or 2;

[0345] n is 0, 1, or 2; and

[0346] t is 0, 1, or 2.

[0347] In some embodiments, the 15-PGDH inhibitor may include a compound having the structure of formula (I):

[0348]

[0349] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0350] R 1 is an alkyl group, a haloalkyl group, a cycloalkyl group, an alkylene-cycloalkyl group, an alkylene-alkoxy group, a heterocyclic group, or an alkylene-heterocyclic group;

[0351] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0352] R 6 is a heterocyclic group or a heteroaryl group, each of which is optionally substituted by one or more Rs 3 substituted; R 7 is an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group, a heterocyclic group, a heteroaryl group, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted by one or more Rs 4 substituted;

[0353] R 3 is oxo, -OH, -O-alkylene-N(R 5 ) 2 , -N(R 5 ) 2 、-N(R5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic group, -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;

[0354] 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted by R 8 ;

[0355] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted by the following: -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;

[0356] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 ;

[0357] R 8 is halogen, alkyl, or alkoxy;

[0358] R 9 is H or alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0359] X is N or CH;

[0360] m is 0, 1, or 2;

[0361] n is 0, 1 or 2; and

[0362] t is 0, 1, or 2.

[0363] In some embodiments, 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 alkoxy), 3- to 6-membered heterocycloalkyl, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocycloalkyl).

[0364] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or -(CH 2 ) p -cyclohexyl; where p is 1, 2, or 3.

[0365] In still other embodiments, R 2 is -NH 2 .

[0366] In some embodiments, R 6 is a 5- to 6-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with one or more R 3 substituents.

[0367] In other embodiments, R 6 is a 5- to 6-membered heteroaryl optionally substituted with one or more R 3 substituents.

[0368] In still other embodiments, R 6 is an 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R 3 substituents.

[0369] In some embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6Haloalkyl, C3-C6 cycloalkyl, C6-C10 aryl, C3-C6 heterocyclic group, C5-C10 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 alkyl), each of which is optionally substituted with one or more R 4 substituents.

[0370] In other embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, phenyl, C3-C6 heterocyclic group, or C5-C10 heteroaryl, each of which is optionally substituted with one or more R 4 substituents.

[0371] In still other embodiments, R 7 is C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, phenyl, C5-C10 heteroaryl, each of which is optionally substituted with one or more R 4 substituents.

[0372] In some embodiments, 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 alkyl).

[0373] In other embodiments, R 3is -(C 1 -C 3 alkyl)OH, -NH 2 、-N(C 1 -C 3 alkyl) 2 、-NHCH 2 CH 2 OH、-N(C 1 -C 3 alkyl)CH 2 CH 2 OH、N(CH 2 CH 2 OH) 2 、-NHCH 2 CH(CH 2 OH) 2 、-N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 、-NHCH 2 CH 2 OCH 2 CH 2 OH、-NHCH 2 CH 2 OCH 2 CH 2 NH 2 、-NHCH 2 CH 2 NH 2 、-N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 、-NHCH 2 CH 2 NH(C 1 -C 3 alkyl)、-NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 、-N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl)、-N(C 1 -C 3 alkyl)CH 2 CH 2 N(C1 -C 3 alkyl) 2 、-NHSO 2 CH 3 、-N(C 1 -C 3 alkyl)SO 2 CH 3 、-OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 、-OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0374] In other embodiments, R 3 Yes-NH 2 、-N(C 1 -C 3 alkyl) 2 、-NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 、-NHCH 2 CH(CH 2 OH) 2 、-N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 、-NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 、-NHCH 2 CH 2 NH 2 、-N(C 1 -C3 (alkyl)CH 2 CH 2 NH 2 、 -NHCH 2 CH 2 NH(C 1 -C 3 alkyl)、 -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 、 -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl)、 -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 、 -NHSO 2 CH 3 、 -N(C 1 -C 3 alkyl)SO 2 CH 3 、 -OCH 2 CH 2 OH、 -OCH 2 CH 2 NH 2 、 -OCH 2 CH 2 NH(C 1 -C 3 alkyl)、 or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 。

[0375] In still other embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH。

[0376] In some embodiments, R 4 is halogen, -CN, -N(R 5 ) 2 、 -OH、 -O-(C1 -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 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic group.

[0377] In some embodiments, n is 1.

[0378] In other embodiments, the 15-PGDH inhibitor can include a compound selected from the group consisting of:

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397] and the molecule numbers 198 - 434 in Table 1, or a pharmaceutically acceptable salt thereof, its tautomer, and its solvate.

[0398] In other embodiments, the 15 - PGDH inhibitor is selected from the compounds disclosed in any one of Examples 1 - 323, or a pharmaceutically acceptable salt thereof, its tautomer, and its solvate.

[0399] In some embodiments and without being bound by theory, the applicant unexpectedly and surprisingly found that R

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415] In some embodiments and without being bound by theory, the applicant unexpectedly and surprisingly found that R 1The carbocyclic group at the [position] increases the half-life of the compound. The half-life is an important parameter of a therapeutic agent as it determines the duration of action of the agent - the longer the half-life, the longer the agent can exert its therapeutic effect in a subject. In some embodiments, 3- to 6-membered cycloalkyl groups (especially 3- to 5-membered cycloalkyl groups such as cyclobutyl) are observed to have a desirable half-life.

[0416] In other embodiments, the compound has the structure of formula (II):

[0417]

[0418] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0419] R 1 is 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocyclic group, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclic group);

[0420] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0421] R 6 is a heterocyclic group or heteroaryl, each optionally substituted with one or more R 3 substituents;

[0422] R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each optionally substituted with one or more R 4 substituents;

[0423] R 3 is oxo, -OH, -O-alkylene-N(R 5 ) 2 , -N(R 5 ) 2 , -N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic group, -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,

[0424] R4 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted by R 8 ;

[0425] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted by the following: -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;

[0426] Alternatively, two Rs 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 ;

[0427] R 8 is halogen, alkyl, or alkoxy;

[0428] R 9 is H or alkyl, or two Rs 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0429] X is N or CH;

[0430] m is 0, 1, or 2; and

[0431] t is 0, 1, or 2.

[0432] In some embodiments, R 1 is a 3- to 5-membered cycloalkyl or -(C 1 -C 6 alkylene)-(3- to 5-membered cycloalkyl).

[0433] In other embodiments, R 1 is cyclobutyl.

[0434] In still other embodiments, R 1is a bicyclic 4- to 6-membered cycloalkyl group.

[0435] In some embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl group, -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 substituents.

[0436] In other embodiments, R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl group, phenyl, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted with one or more R 4 substituents. In other embodiments, R 7 is C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl group, phenyl, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted with one or more R 4 substituents.

[0437] In other embodiments, R 7 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, a 3-membered cycloalkyl group, phenyl, a 4-membered heterocyclic group, or a 5- to 6-membered heteroaryl group, each of which is optionally substituted with one or more R 4 substituents. In other embodiments, R 7 is C 1 -C 3 haloalkyl, a 3-membered cycloalkyl group, phenyl, a 4-membered heterocyclic group, or a 5- to 6-membered heteroaryl group, each of which is optionally substituted with one or more R 4 substituents.

[0438] In other embodiments, R 7 is -CF 3, isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R 4 . In other embodiments, R 7 is -CF 3 , cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R 4 .

[0439] In some embodiments, R 3 is -O-(C 1 -C 6 alkylene)-N(R 5 ), -N(R 2 ), -N(R 5 )(C 2 -C 5 alkylene-OH), -C(O)N(R 1 ), -C(O)N(R 6 )(C 5 -C 2 alkylene-OH), -C(O)(C 5 -C 1 alkyl), -C(O)O(C 6 -C 1 alkyl), or -S(O) 6 (C 1 -C 6 alkyl). (C m -C 1 alkyl).

[0440] In other embodiments, R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -NHSO 2 CH 3 , -N(C 1 -C 3 alkyl)SO 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0441] In still other embodiments, R 3is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0442] In some embodiments and without being bound by theory, the Applicant unexpectedly and surprisingly found that the substituent at the R 7 position can be modified to improve hERG activity (including hERG inhibition (IC 50 ), block, and efflux rate). For example, in some embodiments, certain 6 - to 10 - membered aryl groups (e.g., optionally substituted phenyl) and 5 - to 10 - membered heteroaryl groups (e.g., optionally substituted pyridyl, pyrazole, and triazole) have favorable hERG properties. In some embodiments, certain C 1 -C 6 haloalkyl groups (e.g., -CF 3 ) exhibit improved hERG inhibition (IC50), along with improved half - life and solubility.

[0443] In other embodiments, the compound has the structure of formula (III):

[0444]

[0445] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0446] R 1 is cycloalkyl, alkylene - cycloalkyl, alkylene - alkoxy, heterocyclic group, or alkylene - heterocyclic group;

[0447] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0448] R 6 is a heterocyclic group or heteroaryl group, each of which is optionally substituted by one or more R 3 ;

[0449] R 7 is C 1 -C 6 haloalkyl, aryl, or heteroaryl, each of which is optionally substituted by one or more R 4 ;

[0450] R 3 is oxo, -OH, -O - alkylene - N(R 5 ) 2 , -N(R 5 ) 2 , -N(R5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic group, -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;

[0451] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted with: -OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O) m -alkyl;

[0452] Alternatively, two Rs 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ;

[0453] R 4 is halogen, alkyl, or alkoxy;

[0454] X is N or CH; and

[0455] m is 0, 1, or 2.

[0456] In some embodiments, R 7 is -CF 3 , pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with R 4 ;

[0457] In other embodiments, R 7 is -CF 3 , pyridyl, fluorophenyl, or triazole, which is optionally substituted with halogen or methyl.

[0458] In other embodiments, R 7 is -CF 3 ,

[0459] In still other embodiments, R 7 is -CF 3 .

[0460] In still other embodiments, R 7 is

[0461] In some embodiments, R 7 is

[0462] In some embodiments, R 7 is

[0463] In other embodiments, R 6 is an 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R 3 substituents.

[0464] In some embodiments and without being bound by theory, the applicant unexpectedly and surprisingly found that a 3- to 6-membered cycloalkyl at the R 7 position can improve solubility while maintaining PDGH activity.

[0465] In other embodiments, the compound has the structure of formula (IV):

[0466]

[0467] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0468] R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclic group, or -alkylene-heterocyclic group;

[0469] R 2 is -NH 2 、CN, or -NHC(O)alkyl;

[0470] R 6 is a heterocyclic group or heteroaryl, each optionally substituted with one or more R 3 substituents;

[0471] R 7 is a 3- to 6-membered cycloalkyl optionally substituted with one or more R 4 substituents;

[0472] R 3 is oxo, -OH, -O-alkylene-N(R 5 ) 2 、-N(R 5 ) 2 、-N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic group, -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;

[0473] R 4 is halogen, -CN, -NH 2 , -OH, or C 1 -C 3 alkyl;

[0474] Each R 5 is 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, -alkylene-COOH, -C(O)O-alkyl, or -S(O) m -alkyl;

[0475] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ;

[0476] R 8 is halogen, alkyl, or alkoxy;

[0477] X is N or CH;

[0478] m is 0, 1, or 2.

[0479] In some embodiments, R 7 is cyclopropyl.

[0480] In other embodiments, R 1 is a 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), a 3- to 6-membered heterocyclic group, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclic group).

[0481] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or -(CH 2 ) p -cyclohexyl; wherein p is 1, 2, or 3.

[0482] In some embodiments, 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 alkyl).

[0483] In some embodiments, R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -NHSO 2 CH 3 , -N(C 1 -C 3 alkyl)SO 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0484] In other embodiments, R3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0485] In some embodiments and without being bound by theory, the applicant unexpectedly and surprisingly found that the R 6 position can be substituted with certain R 3 groups to improve solubility and activity.

[0486] In other embodiments, the compound has the structure of formula (V):

[0487]

[0488] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0489] R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclic group, or -alkylene-heterocyclic group;

[0490] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0491] R 6 is a heterocyclic group or heteroaryl group, each of which is substituted with one or more R 3 substituents;

[0492] R 7 is haloalkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 substituents;

[0493] 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 6Alkylene-OH), -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -S(O) m (C 1 -C 6 alkyl);

[0494] 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted by R 8 substituted;

[0495] Each R 5 independently is H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-OH, which is optionally substituted by: -OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), alkylene-COOH, or -S(O) m (C 1 -C 6 alkyl);

[0496] Or alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 substituted;

[0497] R 8 is halogen, alkyl, or alkoxy;

[0498] X is N or CH;

[0499] m is 0, 1, or 2.

[0500] In some embodiments, R 3 is -O-(C1 -C 6 alkylene)-N(R 5 ) 2 、-N(R 5 ) 2 or -N(R 5 )(C 1 -C 6 alkylene-OH).

[0501] In other embodiments, R 5 is H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-OH, or -S(O) 2 (C 1 -C 3 alkyl).

[0502] In some embodiments, R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH2 、 -NHCH 2 CH 2 NH(C 1 -C 3 -NHCH 2 CH 2 N(C 1 -C 3 -alkyl), -NHCH 2 、 -N(C 1 -C 3 -alkyl)CH 2 CH 2 NH(C 1 -C 3 -alkyl), -N(C 1 -C 3 -alkyl)CH 2 CH 2 N(C 1 -C 3 -alkyl) 2 、 -NHSO 2 CH 3 、 -N(C 1 -C 3 -alkyl)SO 2 CH 3 、 -OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 、 -OCH 2 CH 2 NH(C 1 -C 3 -alkyl), or -OCH 2 CH 2 N(C 1 -C 3 -alkyl) 2 。

[0503] In other embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0504] In still other embodiments, R 3 is -NHCH 2 CH 2 OH.

[0505] In some embodiments, R 6is a 5- to 6-membered heterocyclic group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted with one or more R 3 substituents.

[0506] In other embodiments, R 6 is a 5- to 6-membered heteroaryl group optionally substituted with one or more R 3 substituents.

[0507] In some embodiments, R 6 is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each of which is optionally substituted with one or more R 3 substituents.

[0508] In other embodiments, R 6 is thiazole, imidazole, oxazole, pyridine, or pyrimidine.

[0509] In some embodiments, R 6 is an 8- to 10-membered bicyclic heteroaryl group optionally substituted with one or more R 3 substituents.

[0510] In other embodiments, R 6 is a 5- to 6-membered heterocyclic group optionally substituted with one or more R 3 substituents and selected from morpholine, pyridinone, or piperidine.

[0511] In some embodiments, R 7 is C 1 -C 3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclic group, or 5- to 6-membered heteroaryl group, each of which is optionally substituted with one or more R 4 substituents.

[0512] In other embodiments, R 7 is -CF 3 、cyclopropyl, phenyl, pyrazole, pyridinyl, or triazole, each of which is optionally substituted with one or more R 4 substituents.

[0513] In some embodiments, the compound has the structure of formula (VI):

[0514]

[0515] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0516] R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclic group, or alkylene-heterocyclic group;

[0517] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0518] R 6 is a fused bicyclic heterocyclic group or a fused bicyclic heteroaryl group, each of which is optionally substituted with one or more R 3 substituents;

[0519] R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 substituents;

[0520] R 3 is oxo, -OH, -O-alkylene-N(R 5 ) 2 , -N(R 5 ) 2 , -N(R 5 )(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclic group, -C(O)N(R 5 ) 2 , -C(O)-alkyl, -C(O)O-alkyl, or -S(O) m -alkyl;

[0521] 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, heterocyclic group, or -alkylene-aryl, which is optionally substituted with R 8 substituents;

[0522] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted with the following: -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -C(O)O-alkyl, or -S(O) m -alkyl;

[0523] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 substituents;

[0524] R 8 is a halogen, an alkyl group, or an alkoxy group;

[0525] X is N or CH; and

[0526] m is 0, 1, or 2.

[0527] In some embodiments, R 6 is an 8- to 10-membered fused bicyclic heteroaryl group, each of which is optionally substituted by one or more R 3 substituents.

[0528] In some embodiments, R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclic, 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 alkyl), each of which is optionally substituted by one or more R 4 substituents.

[0529] In other embodiments, R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic, or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more R 4 substituents. In other embodiments, R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic, or 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more R 4 substituents.

[0530] In still other embodiments, R 7 is C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclic, or 5- to 6-membered heteroaryl, each of which is optionally substituted by one or more R 4 substituents.

[0531] In other embodiments, R 7 is C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 . In other embodiments, R 7 is C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .

[0532] In other embodiments, R 7 is -CF 3 , isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 . In other embodiments, R 7 is -CF 3 , cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R4.

[0533] In some embodiments, R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(a 3- to 6-membered cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), a 3- to 6-membered heterocyclic group, or -(C 1 -C 6 alkylene)-(a 3- to 6-membered heterocyclic group).

[0534] In other embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or -(CH 2 ) p -cyclohexyl; where p is 1, 2, or 3.

[0535] In some embodiments, 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 alkyl).

[0536] In other embodiments, R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -NHSO 2 CH 3 , -N(C 1 -C 3 alkyl)SO 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NH(C 1 -C 3 alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .

[0537] In some embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH.

[0538] In other embodiments, 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 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic group.

[0539] In some embodiments, the compound has the structure of formula (VII):

[0540]

[0541] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0542] R 1 is cyclobutyl or -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy);

[0543] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0544] R 6 is a heterocyclic group or heteroaryl, each optionally substituted with one or more R 3 substituents;

[0545] R 7 is -CF 3 , isopropyl,

[0546] 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, heterocyclic group, -C(O)N(R 5 ) 2 , -C(O)N(R5 )(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O) m -alkyl, wherein the cycloalkyl and the heterocyclic group are each optionally substituted by R 10 ;

[0547] R 4 is C 1 -C 3 alkyl;

[0548] Each R 5 is independently H, alkyl, -alkylene-OH, which is optionally substituted by: -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;

[0549] Alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted by R 8 ;

[0550] R 8 is halogen, alkyl, or alkoxy;

[0551] R 9 is H or alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, which heterocycle optionally contains an additional heteroatom selected from O, S(O) t , or N;

[0552] R 10 is -OH, halogen, alkyl, or alkoxy;

[0553] X is N or CH;

[0554] m is 0, 1, or 2;

[0555] p is 0 or 1; and

[0556] t is 0, 1, or 2.

[0557] In still other embodiments, R 2 is -NH 2 .

[0558] In some embodiments, R6 is a 5- to 6-membered heterocyclic group or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one or more R 3 substituents.

[0559] In other embodiments, R 6 is a 5- to 6-membered heteroaryl group optionally substituted by one or more R 3 substituents.

[0560] In still other embodiments, R 6 is an 8- to 10-membered bicyclic heteroaryl group optionally substituted by one or more R 3 substituents.

[0561] In some embodiments, 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 alkyl).

[0562] In other embodiments, R 3 is -(C 1 -C 3 alkyl)OH、-NH 2 、-N(C 1 -C 3 alkyl) 2 、-NHCH 2 CH 2 OH、-N(C 1 -C 3 alkyl)CH 2 CH 2 OH、N(CH 2 CH 2 OH) 2 、-NHCH 2 CH(CH2 OH) 2 ,-N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 ,-NHCH 2 CH 2 OCH 2 CH 2 OH,-NHCH 2 CH 2 OCH 2 CH 2 NH 2 ,-NHCH 2 CH 2 NH 2 ,-N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 ,-NHCH 2 CH 2 NH(C 1 -C 3 alkyl),-NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 ,-N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl),-N(C 1 -C 3 alkyl)CH 2 CH 2 N(C 1 -C 3 alkyl) 2 ,-NHSO 2 CH 3 ,-N(C 1 -C 3 alkyl)SO 2 CH 3 ,-OCH 2 CH 2 OH,-OCH 2 CH 2 NH 2 ,-OCH 2 CH 2 NH(C 1 -C 3(alkyl), or -OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 。

[0563] In still other embodiments, R 3 is -NHCH 2 CH 2 OH or -N(CH 3 )CH 2 CH 2 OH。

[0564] In some embodiments, 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 haloalkyl, 3 - to 6 - membered cycloalkyl, or 3 - to 6 - membered heterocyclic group.

[0565] In some embodiments, n is 1.

[0566] In some embodiments, the compound has the structure of formula (VIII):

[0567]

[0568] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

[0569] R 1 is cyclobutyl or -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy);

[0570] R 2 is -NH 2 , CN, or -NHC(O)alkyl;

[0571] R 6 is each of which is optionally substituted with one or more R3 Substituted;

[0572] R 7 is -CF 3 , isopropyl, cyclopropyl, cyclobutyl, each of which is optionally substituted by one or more R 4 Substituted;

[0573] R 3 is -NH 2 , -NH(C 1 -C 3 alkyl), -NH(C 1 -C 4 alkylene)-OH, or C 1 -C 3 alkyl;

[0574] R 4 is C 1 -C 3 alkyl; and

[0575] X is N or CH.

[0576] In some embodiments having formula (VIII), R 1 is cyclobutyl. In some embodiments having formula (VIII), R 1 -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy). In some embodiments having formula (VIII), R 1 -(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy) is -(C 2 -C 3 alkylene)-(C 1 alkoxy).

[0577] In some embodiments having formula (VIII), R 2 is -NH 2 .

[0578] In some embodiments having formula (VIII), R 6 is

[0579] In some embodiments having formula (VIII), R 3 is -NH 2 . In some embodiments having formula (VIII), R 3is -NH(C 1 -C 3 alkyl). In some embodiments having formula (VIII), R 3 is -NH(C 1 -C 4 alkylene)-OH (e.g., -NH(C 2 -C 4 alkylene)-OH). In some embodiments having formula (VIII), R 3 is C 1 -C 3 alkyl (e.g., methyl or ethyl).

[0580] In some embodiments having formula (VIII), R 7 is -CF 3 , isopropyl, cyclopropyl, or cyclobutyl. In some embodiments having formula (VIII), R 7 is isopropyl. In some embodiments having formula (VII), R 7 is each of which is optionally substituted with one or more R 4 . In some embodiments, each R 4 is independently selected from methyl or ethyl.

[0581] In some embodiments having formula (VIII), X is -CH.

[0582] In some embodiments, the compounds having formula (VIII) are provided in Table 2.

[0583] In one embodiment, the compounds having formula (VIII) exclude:[[]]

[0584]

[0585] In some embodiments, the 15-PGDH inhibitors of the present disclosure inhibit colonic 15-PGDH activity in the range from 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 sub-range therein. Appropriate doses of the compounds of the present disclosure can be used to measure colonic 15-PGDH inhibition (e.g., using the assay described in this example) at 30 min, 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 hours (including all times between these values) after administration. 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, appropriate doses are 1, 2, 3, 4, 5, 6, 7, 8, 9, 0, 15, 20, 30, 40, 50, or more mg / kg, including all values and ranges between these values.

[0586] In one embodiment, appropriate doses of the compounds of the present disclosure can be used to measure 15-PGDH inhibition in the lung, liver, intestine, skin, heart (or any other organ disclosed herein) at 30 min, 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 longer (including all times and ranges between these values). 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, appropriate doses are 1, 2, 3, 4, 5, 6, 7, 8, 9, 0, 15, 20, 30, 40, 50, or more mg / kg, including all values and ranges between these values. In some embodiments, the 15-PGDH inhibitors of the present disclosure inhibit lung 15-PGDH activity in the range from 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 sub-range therein.

[0587] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., having Formulas I - VIII) are administered at 10 mg / kg in a mammal and at 30 minutes, inhibit colonic 15-PGDH activity in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) inhibit colonic 15-PGDH activity at 30 minutes in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) can inhibit colonic 15-PGDH activity at 30 minutes in the range from about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) inhibit colonic 15-PGDH activity at 30 minutes in the range from about 80% to 100% and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) inhibit colonic 15-PGDH activity at 30 minutes in the range from about 90% to 100% and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) inhibit colonic 15-PGDH activity at 30 minutes in the range from about 95% to 100% and any sub-range therein. This is an unexpected and surprising result because previously synthesized 15-PGDH inhibitors (such as reference compound C (Example B), when orally administered at 10 mpk) were not sufficient to inhibit colonic 15-PGDH activity at 30 minutes. In fact, as indicated by -55.2% inhibition, reference compound C actually increased the activity of colonic 15-PGDH.

[0588] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., having Formulas I-VIII) are administered at 10 mg / kg in a mammal and at 4 hours, inhibit colonic 15-PGDH activity in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) at 4 hours, inhibit colonic 15-PGDH activity in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) can at 4 hours, inhibit colonic 15-PGDH activity in the range from about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) at 4 hours, inhibit colonic 15-PGDH activity in the range from about 80% to 100% and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) at 4 hours, inhibit colonic 15-PGDH activity in the range from about 80% to 98% and any sub-range therein.

[0589] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., having Formulas I-VIII) are administered at 10 mg / kg in a mammal and at 30 minutes, inhibit 15-PGDH activity in the lung, liver, intestine, skin, heart (or any other organ disclosed herein) in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) inhibit lung 15-PGDH activity at 30 minutes in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) can inhibit lung 15-PGDH activity at 30 minutes in the range from about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered at 10 mg / kg in a mammal) inhibit lung 15-PGDH activity at 30 minutes in the range from about 80% to 100% and any sub-range therein.

[0590] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., having Formulas I-VIII) are administered to mammals at 10 mg / kg and at 4 hours, inhibit 15-PGDH activity in the lungs, liver, intestine, skin, heart (or any other organ disclosed herein) in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered to mammals at 10 mg / kg) inhibit lung 15-PGDH activity at 4 hours in the range from 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 sub-range therein. In some embodiments, the compounds of the present disclosure (when administered to mammals at 10 mg / kg) can inhibit lung 15-PGDH activity at 4 hours in the range from about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) and any sub-range therein. In some embodiments, the compounds of the present disclosure (when administered to mammals at 10 mg / kg) inhibit lung 15-PGDH activity at 4 hours in the range from about 80% to 100% and any sub-range therein.

[0591] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., Formula I-VIII) have a human microsomal stability T greater than 50 minutes 1 / 2 . In some embodiments, the compounds of the present disclosure have a human microsomal stability T greater than 60 minutes 1 / 2 . In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T greater than 70 minutes 1 / 2 . In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T greater than 80 minutes 1 / 2 . In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T greater than 90 minutes 1 / 2 . In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T greater than 100 minutes 1 / 2 . In some embodiments, the compounds of the present disclosure have a human microsomal stability T greater than 110 minutes 1 / 2 . In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T greater than 120 minutes 1 / 2。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T greater than 130 minutes 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T 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 。

[0592] In some embodiments, compared to previously disclosed 15-PGDH inhibitors, the 15-PGDH inhibitors of the present disclosure (e.g., of Formulas I-VIII) have higher human microsomal stability. See WO 2013 / 158649, WO 2015 / 065716, WO2016 / 144958, WO 2016 / 168472, WO 2018 / 017582, WO 2018 / 102552, WO 2018 / 145080, WO2018 / 187810, and WO 2018 / 218251, the disclosures of each of which are hereby incorporated by reference in their entirety for all purposes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 15 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 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 that is 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 that is at least 120 minutes longer than previously disclosed 15-PGDH inhibitors 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a microsomal stability T that is 15 minutes to about 120 minutes longer than that of previously disclosed 15-PGDH inhibitors 1 / 2 for human microsomal stability T 1 / 2 。

[0593] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., of 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 that is at least 70 minutes longer than that of Reference Compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 80 minutes longer than that of Reference Compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 90 minutes longer than that of Reference Compound C 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 that of Reference Compound C 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 that of Reference Compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is at least 120 minutes longer than that of Reference Compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsomal stability T that is 70 minutes to about 120 minutes longer than that of Reference Compound C 1 / 2 。

[0594] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., of Formulae I-VIII) have a mouse microsomal stability T greater than 10 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 50 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 60 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 70 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 80 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 90 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 100 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 110 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 120 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 130 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T greater than 140 minutes 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T 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 .

[0595] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., of Formulae I-VIII) have a mouse microsomal stability T at least 10 minutes longer than reference compound C (Example B) 1 / 2 In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T 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 that is at least 30 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 40 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 50 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 60 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 70 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 80 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 90 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 100 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 110 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 120 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 130 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is at least 140 minutes longer than that of reference compound C 1 / 2 。In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsomal stability T that is 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) longer than that of reference compound C 1 / 2 。

[0596] Use A549 cells that have been treated with IL1-β for 24 hours to determine the EC for inducing PGE2 50。In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., of Formulas I-VIII) have an EC for inducing PGE2 that is less than or equal to 10 nM 50 。In some embodiments, the EC 50 is less than or equal to 5 nM. In some embodiments, the EC 50 is less than or equal to 4 nM. In some embodiments, the EC 50 is less than or equal to 3 nM. In some embodiments, the EC 50 is less than or equal to 2 nM. In some embodiments, the EC 50 is less than or equal to 1 nM. In some embodiments, the EC 50 ranges from 10 nM to about 0.01 nM (including all values or sub-ranges therebetween). In some embodiments, the EC 50 is at least 4-fold less than previously disclosed 15-PGDH inhibitors (such as those disclosed in the publications referenced above). In some embodiments, the EC 50 is at least 8-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is at least 10-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is at least 15-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is at least 20-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is at least 30-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is at least 40-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is at least 50-fold less than previously disclosed 15-PGDH inhibitors. In some embodiments, the EC 50 is 10-fold to 50-fold less than previously disclosed 15-PGDH inhibitors.

[0597] In some embodiments, the EC of the 15-PGDH inhibitors of the present disclosure (e.g., of Formulas I-VIII) 50 is at least 5-fold less than Reference Compound C (Example B). In some embodiments, the EC 50 is at least 10-fold less than Reference Compound C. In some embodiments, the EC 50 is at least 15-fold less than Reference Compound C. In some embodiments, the EC 50 is at least 20-fold less than Reference Compound C. In some embodiments, the EC 50 is at least 25-fold less than Reference Compound C. In some embodiments, the EC 50At least 30 times smaller than reference compound C. In some embodiments, EC 50 At least 35 times smaller than reference compound C. In some embodiments, EC 50 At least 40 times smaller than reference compound C. In some embodiments, EC 50 At least 45 times smaller than reference compound C. In some embodiments, EC 50 At least 50 times smaller than reference compound C. In some embodiments, EC 50 At least 5 times to 50 times smaller than reference compound C.

[0598] In certain embodiments, the 15-PGDH inhibitors of formula (I-VIII) that can be selected can: ia) at a concentration of 2.5 μM, stimulate the Vaco503 receptor cell line expressing the 15-PGDH luciferase fusion construct to a luciferase output level greater than 70 (using a scale where a value of 100 represents a two-fold increase in reporter output over baseline); iia) at a concentration of 2.5 μM, stimulate the V9m receptor cell line expressing the 15-PGDH luciferase fusion construct to a luciferase output level greater than 75; iiia) at a concentration of 7.5 μM, stimulate the LS174T receptor cell line expressing the 15-PGDH luciferase fusion construct to a luciferase output level greater than 70; and iva) at a concentration of 7.5 μM, not stimulate the negative control V9m cell line expressing the TK-renilla luciferase reporter to a level greater than 20; and va) at an IC 50 Less than 1 μM, inhibit the enzymatic activity of recombinant 15-PGDH protein.

[0599] In other embodiments, the 15-PGDH inhibitor can: ib) at a concentration of 2.5 μM, stimulate the Vaco503 receptor cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output; iib) at a concentration of 2.5 μM, stimulate the V9m receptor cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output; iiib) at a concentration of 7.5 μM, stimulate the LS174T receptor cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output; ivb) at a concentration of 7.5 μM, not stimulate the negative control V9m cell line expressing the TK-renilla luciferase reporter to a luciferase level 20% greater than background; and vb) at an IC 50 Less than 1 μM, inhibit the enzymatic activity of recombinant 15-PGDH protein.

[0600] In some embodiments, the compound or 15-PGDH inhibitor can have an IC 50Less than 1 μM, at IC 50 Less than 250 nM, at IC 50 Less than 50 nM, at IC 50 Less than 10 nM, at IC 50 Less than 5 nM in recombinant, at IC 50 Inhibits the enzymatic activity of recombinant 15-PGDH when it is about 2.5 nM to about 10 nM or less than about 2.5 nM.

[0601] The 15-PGDH inhibitors described herein can be used to prevent or treat diseases associated with 15-PGDH and / or reduced prostaglandin levels and / or the need to increase prostaglandin levels in a subject. For example, as discussed above, prostaglandins are known to play an important role in hair growth. In particular, it has been shown that the internal storage of various types of prostaglandins (A 2 , F 2a , E 2 ) in various compartments of the hair follicle or its adjacent skin environment is crucial for maintaining and increasing hair density (Colombe L et al., 2007, Exp. Dermatol [Experimental Dermatology], 16(9), 762-9). It has been reported that 15-PGDH, which is involved in the degradation of prostaglandins (present in the dermal papilla of the hair follicle), inactivates prostaglandins, especially PGF 2a and PGE 2 , causing scalp damage and hair loss (Michelet J F et al., 2008, Exp. Dermatol [Experimental Dermatology], 17(10), 821-8). Therefore, the compounds described herein (which have suppressing or inhibitory activity against 15-PGDH that degrades prostaglandins) can improve scalp damage, prevent hair loss, and promote hair growth, and can be used in pharmaceutical compositions for preventing hair loss and promoting hair growth.

[0602] In other embodiments, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions (for promoting and / or inducing and / or stimulating the pigmentation of the skin and / or skin appendages, and / or as an agent for preventing and / or limiting the depigmentation and / or whitening of the skin and / or skin appendages, especially as an agent for preventing and / or limiting canities).

[0603] In some embodiments, the 15-PGDH inhibitor can be applied to the skin of a subject, for example, by topical application, to promote and / or stimulate the pigmentation of the skin and / or hair growth, inhibit hair loss, and / or treat skin damage or inflammation, such as skin damage caused by physical or chemical irritants and / or UV-exposure.

[0604] In still other embodiments, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for preventing or treating cardiovascular diseases and / or diseases of vascular insufficiency (such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary arterial hypertension). Prostaglandins, which are known to include prostaglandin homologs produced in vivo, can maintain the proper function of the vascular wall, particularly contributing to vasodilation in response to blood flow, preventing platelet aggregation, and regulating the proliferation of smooth muscle surrounding the vascular wall (Yan. Cheng et al., 2006, J. Clin., Invest [Journal of Clinical Investigation]). In addition, inhibition of prostaglandin production or loss of its activity causes degeneration of the endothelium in the vascular wall, platelet aggregation, and dysfunction of the cellular mechanisms in smooth muscle. Among them, in hypertensive patients including those with pulmonary arterial hypertension, the production of prostaglandins in blood vessels has been shown to be reduced.

[0605] In other embodiments, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for preventing or treating oral, intestinal, and / or gastrointestinal injuries or diseases, or inflammatory bowel diseases (such as oral ulcers, gum diseases, gastritis, colitis, ulcerative colitis, and gastric ulcers). Gastritis and gastric ulcers (representatives of gastrointestinal diseases) are defined as conditions in which the gastrointestinal mucosa is digested by gastric acid to form ulcers. In the gastric wall, which typically consists of the mucosa, submucosa, muscular layer, and serosa, gastric ulcers even damage the submucosa and muscular layer, while gastritis only damages the mucosa. Although the incidence rates of gastritis and gastric ulcers are relatively high, their causes are not yet clear. To date, they are known to be caused by an imbalance between attacking factors and defensive factors, namely, an increase in attacking factors (such as an increase in gastric acid or pepsin secretion), or a decrease in defensive factors (such as structural or morphological defects in the gastric mucosa, reduced secretion of mucus and bicarbonate ions, reduced prostaglandin production, etc.).

[0606] Currently available therapeutic agents for gastritis and gastric ulcers include various drugs for enhancing defensive factors, such as antacids (which do not affect gastric acid secretion but neutralize the gastric acid that has already been produced), inhibitors of gastric acid secretion, promoters of prostaglandin secretion, and coating agents for the gastric wall. In particular, prostaglandins are known to be essential for maintaining the mechanism of protecting and guarding the gastric mucosa (Wallace J L., 2008, Physiol Rev. [Physiological Reviews], 88(4), 1547 - 65, S.J. Konturek et al., 2005, Journal of Physiology and Pharmacology [Journal of Physiology and Pharmacology], 56(5)). Given the above, since the 15-PGDH inhibitors described herein exhibit suppressing or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect the gastric mucosa, they can effectively prevent or treat gastrointestinal diseases, particularly gastritis and gastric ulcers.

[0607] In addition, it is also contemplated that 15-PGDH inhibitors can be protected from other forms of intestinal injury, such as toxicity from radiation, toxicity from chemotherapy, and chemotherapy-induced mucositis.

[0608] In the kidney, prostaglandins regulate renal blood flow and can regulate urine formation through both renal vascular and tubular actions. In clinical studies, PGE 1 has been used to improve creatinine clearance in patients with chronic kidney disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, and to reduce urinary albumin excretion rate and N-acetyl-β-D-glucosaminidase levels (in patients with diabetic nephropathy) (see Porter, Am., 1989, J. Cardiol. [Journal of Cardiology], 64:22E-26E). In addition, U.S. Patent No. 5,807,895 discloses a method for preventing renal dysfunction by intravenous administration of prostaglandins such as PGE 1 、PGE 2 and PGI 2 . In addition, it has been reported that prostaglandins act as vasodilators in the kidney, and thus inhibition of prostaglandin production in the kidney leads to renal dysfunction (Hao. C M, 2008, Annu Rev Physiol [Annual Review of Physiology], 70, 357 to 77).

[0609] Therefore, the 15-PGDH inhibitors described herein that have suppressing or inhibitory activity against 15-PGDH, which degrades prostaglandins, can be effective in preventing or treating kidney diseases associated with renal dysfunction.

[0610] As used herein, the term "renal dysfunction" includes such manifestations as below-normal creatinine clearance, below-normal free water clearance, above-normal blood urea, nitrogen, potassium, and / or creatinine levels, altered renal enzyme (such as γ-glutamyl synthetase, alanine phosphatase, N-acetyl-β-D-glucosaminidase, or β-ω-microglobulin) activity; and increased proteinuria above normal levels.

[0611] It has also been shown that including PGE 1 、PGE 2 and PGF 2aProstaglandins stimulate bone resorption and bone formation to increase bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res. [Clinical Orthopaedics and Related Research], 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res. [European Journal of Experimental Musculoskeletal Research], 1, 1992, 8692). As mentioned above, considering that 15-PGDH inhibits the activity of prostaglandins, inhibition of 15-PGDH activity can lead to promotion of bone resorption and bone formation that is inhibited by 15-PGDH. Thus, the 15-PGDH inhibitors described herein can effectively promote bone resorption and bone formation by inhibiting 15-PGDH activity. The 15-PGDH inhibitors can be used to increase bone density, treat osteoporosis, promote fracture healing, or promote healing after bone surgery or joint replacement, or promote the healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0612] In still other embodiments, the 15-PGDH inhibitors described herein can be effective in treating cancers that express 15-PGDH. Inhibition of 15-PGDH can inhibit the growth, proliferation, and metastasis of cancers that express 15-PGDH.

[0613] In still other embodiments, the 15-PGDH inhibitors described herein can be effective in wound healing. Among various prostaglandins, PGE 2 is known to serve as a mediator of wound healing. Thus, when the skin is damaged by a wound or a burn, inhibition of 15-PGDH activity by PGE 2 can produce a therapeutic effect on the wound or the burn.

[0614] In addition, as discussed above, it has been shown that increased prostaglandin levels stimulate signaling through the Wnt signaling pathway via increased β-catenin-mediated transcriptional activity. Wnt signaling is known to be a key pathway employed by tissue stem cells. Thus, for the purpose of promoting tissue regeneration or repair of organs including the liver, colon, and bone marrow, the 15-PGDH inhibitors described herein can be used to increase the number of tissue stem cells. In addition, the 15-PGDH inhibitors described herein can be used to promote tissue regeneration or repair of additional organs including, but not limited to, the brain, eye, cornea, retina, lung, heart, stomach, small intestine, pancreas, pancreatic β-cells, kidney, bone, cartilage, and peripheral nerve.

[0615] Syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and require tissue repair and are thus amenable to treatment or alleviation 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 defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, bone fracture, brain edema, cerebral hypoperfusion, Buerger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity arterial ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, premalignancy, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombus, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and tissue or organ wounds.

[0616] Other illustrative examples of genetic disorders, syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and require tissue repair and are amenable to treatment or alleviation using the methods of the present disclosure include ischemia due to surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplantation or graft.

[0617] In various embodiments, the methods described herein are amenable to treating cerebral ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebral ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

[0618] In some embodiments, the ischemia is associated with at least one of the following: acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, fracture, brain edema, cerebral hypoperfusion, Buerger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity arterial ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, premalignancy, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombus, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular diseases of the kidney, vascular inflammatory disorders, Rendu-Osler-Weber syndrome, and tissue or organ wound.

[0619] In some embodiments, a 15-PGDH inhibitor can be administered to a preparation of a subject's hematopoietic stem cells (such as peripheral blood hematopoietic stem cells or cord blood stem cells) to improve the suitability of the stem cell preparation as a donor graft or to reduce the number of units of cord blood required for transplantation.

[0620] Hematopoietic stem cells are pluripotent stem cells that give rise to all blood cell types in an organism, including myeloid lineages (e.g., monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, dendritic cells), and lymphoid lineages (e.g., T cells, B cells, NK cells), and others known in the art (see Fei, R., et al., U.S. Patent No. 5,635,387; McGlave, et al., U.S. Patent No. 5,460,964; Simmons, P., et al., U.S. Patent No. 5,677,136; Tsukamoto, et al., U.S. Patent No. 5,750,397; Schwartz, et al., U.S. Patent No. 5,759,793; DiGuisto, et al., U.S. Patent No. 5,681,599; Tsukamoto, et al., U.S. Patent No. 5,716,827). Hematopoietic stem cells (HSCs) give rise to committed hematopoietic progenitor cells (HPCs) that can generate the entire repertoire of mature blood cells throughout the life of the organism.

[0621] Unless otherwise indicated, hematopoietic stem cells and hematopoietic progenitor cells are generally described herein as hematopoietic stem cells or hematopoietic stem and progenitor cells (HSPCs), and can refer to cells or populations of cells identified by the presence of the antigenic marker CD34 (CD34 + ). In some embodiments, hematopoietic stem cells can be identified by the presence of the antigenic marker CD34 and the absence of lineage (lin) markers, and thus hematopoietic stem cells are characterized as CD34 + / lin - cells.

[0622] The hematopoietic stem cells used in the methods described herein can be obtained from any suitable source of hematopoietic stem and progenitor cells and can be provided as a highly purified population of hematopoietic stem cells or as a composition comprising from about 0.01% to about 100% hematopoietic stem cells. For example, hematopoietic stem cells can be provided in a composition such as unfractionated bone marrow (where hematopoietic stem cells comprise less than about 1% of the bone marrow cell population), umbilical cord blood, placental blood, placenta, fetal blood, fetal liver, fetal spleen, umbilical cord jelly (Wharton's jelly), or mobilized peripheral blood.

[0623] The source of hematopoietic stem cells can be isolated or obtained from organs of the body that contain cells of hematopoietic origin. The isolated cells can include cells removed from their original environment. For example, a cell is isolated if it is separated from some or all of the components that normally accompany it (in its natural state). As used herein, for example, "isolated cell population", "isolated cell source", or "isolated hematopoietic stem cell" refers to the in vitro or ex vivo isolation of one or more cells from their natural cellular environment and from association with other components of a tissue or organ, i.e., it is not significantly associated with substances in vivo.

[0624] Hematopoietic stem cells can be obtained or isolated from the bone marrow of an adult, which includes the femur, hip, rib, sternum, and other bones. Bone marrow aspirates 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, umbilical cord stroma, placenta, fetal blood, fetal liver, or fetal spleen. In certain embodiments, mobilization of stem cells and progenitor cells in a donor may be required to harvest sufficient amounts of hematopoietic stem cells for therapeutic applications.

[0625] "Hematopoietic stem cell mobilization" refers to the release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukapheresis prior to stem cell transplantation. By increasing the number of stem cells harvested from a donor, the number of stem cells available for therapeutic applications can be significantly improved. Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or chemotherapeutic agents, are commonly used to stimulate mobilization. There are commercial stem cell mobilization drugs, and they can be used in combination with G-CSF to mobilize sufficient amounts of hematopoietic stem cells and progenitor cells for transplantation into a subject. For example, G-CSF and plerixafor (Mozobil) (Genzyme Corporation) can be administered to a donor to harvest sufficient amounts of hematopoietic cells for transplantation. Other methods of mobilizing hematopoietic stem cells will be apparent to those skilled in the art.

[0626] In some embodiments, hematopoietic stem cells are obtained from umbilical cord blood. Umbilical cord blood can be harvested according to techniques known in the art (see, for example, U.S. Patent Nos. 7,147,626 and 7,131,958, such methods are incorporated herein by reference).

[0627] 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 cell” or “iPSC” refers to non-pluripotent cells that have been reprogrammed to a pluripotent state. Once a subject's cells are reprogrammed to a pluripotent state, the cells can then be programmed into the desired cell type, such as hematopoietic stem cells or progenitors. As used herein, the term “reprogramming” refers to a method of increasing the potency of a cell to a less differentiated 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.

[0628] In some embodiments, hematopoietic stem cells can be administered or contacted ex vivo with one or more of the 15-PGDH inhibitors described herein to provide a therapeutic composition. In one embodiment, the 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, cord blood, or mobilized peripheral blood.

[0629] In certain embodiments, the therapeutic composition comprises a cell population, wherein the cell population is about 95% to about 100% hematopoietic stem cells. This disclosure contemplates in part that therapeutic compositions using highly purified hematopoietic stem cells (e.g., compositions comprising a cell population wherein the cells comprise about 95% hematopoietic stem cells) can improve the efficiency of stem cell therapy. Currently practiced transplantation methods typically use ungraded cell mixtures, wherein hematopoietic stem cells comprise less than 1% of the total cell population.

[0630] In some embodiments, the therapeutic composition comprises a cell population, wherein the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic stem cells. In some embodiments, the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic stem cells. In other embodiments, the cell population is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10%-15%, about 15%-20%, about 20%-25%, about 25%-30%, about 30%-35%, about 35%-40%, about 40%-45%, about 45%-50%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%-95%, or about 95% to about 100% hematopoietic stem cells.

[0631] Relative to the subject to whom the therapeutic composition is administered, the hematopoietic stem cells in the therapeutic composition of the present disclosure can be autologous / self ("per se") or non-autologous ("non-per se", e.g., allogeneic, syngeneic, or xenogeneic). As used herein, "autologous" refers to cells 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 from different subjects that are genetically identical to the cells being compared. As used herein, "xenogeneic" refers to cells of a different species compared to the cells being compared.

[0632] The hematopoietic stem cells used in the methods of the present disclosure can be depleted of mature hematopoietic cells (such as T cells, B cells, NK cells, dendritic cells, monocytes, granulocytes, erythroid cells) and their committed precursors from bone marrow aspirates, cord blood, or mobilized peripheral blood (apheresis products). The mature lineage-committed cells are depleted by immunodepletion, e.g., by labeling a solid matrix with antibodies that bind to a set of so-called "lineage" antigens (CD2, CD3, CD11b, CD14, CD15, CD16, CD79, CD56, CD123, and CD235a). Subsequent steps can be performed to further purify the cell population, where the matrix labeled with antibodies that bind to the CD34 + antigen is used to isolate primitive hematopoietic stem cells. Kits for purifying stem cells and progenitors from various cell sources are commercially available and, in certain embodiments, these kits are suitable for use with the methods described herein.

[0633] In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is at least 0.1x10 5 cells, at least 0.5x10 5 cells, at least 1x10 5 cells, at least 5x10 5 cells, at least 10x10 5 cells, at least 0.5x10 6 cells, at least 0.75x10 6 cells, at least 1x10 6 cells, at least 1.25x10 6 cells, at least 1.5x10 6 cells, at least 1.75x10 6 cells, at least 2x10 6 cells, at least 2.5x10 6 cells, at least 3x10 6 cells, at least 4x106 cells, at least 5x10 6 cells, at least 10x10 6 cells, at least 15x10 6 cells, at least 20x10 6 cells, at least 25x10 6 cells, or at least 30x10 6 cells.

[0634] In one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is the amount of hematopoietic stem cells in a fraction or unit volume of blood, or is at least 0.1x10 5 cells / kg body weight, at least 0.5x10 5 cells / kg body weight, at least 1x10 5 cells / kg body weight, at least 5x10 5 cells / kg body weight, at least 10x10 5 cells / kg body weight, at least 0.5x10 6 cells / kg body weight, at least 0.75x10 6 cells / kg body weight, at least 1x10 6 cells / kg body weight, at least 1.25x10 6 cells / kg body weight, at least 1.5x10 6 cells / kg body weight, at least 1.75x10 6 cells / kg body weight, at least 2x10 6 cells / kg body weight, at least 2.5x10 6 cells / kg body weight, at least 3x10 6 cells / kg body weight, at least 4x10 6 cells / kg body weight, at least 5x10 6 cells / kg body weight, at least 10x10 6 cells / kg body weight, at least 15x10 6 cells / kg body weight, at least 20x10 6 cells / kg body weight, at least 25x10 6 cells / kg body weight, or at least 30x10 6 cells / kg body weight.

[0635] A hematopoietic stem cell preparation administered with one or more 15-PGDH inhibitors and / or a therapeutic composition comprising hematopoietic stem cells and one or more 15-PGDH inhibitors can be used to improve hematopoietic stem cell transplantation and treat ischemic or ischemically damaged tissues, and reduce further damage to ischemic tissues and / or repair damage to ischemic tissues (by cell recruitment), improve angiogenesis in ischemic tissues, improve tissue regeneration at the ischemic site, reduce ischemic tissue necrosis or apoptosis, and / or increase cell survival at the ischemic site. In certain embodiments, a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells can be used in a subject in need of hematopoietic reconstitution, such as a subject who has undergone or is planning to undergo myeloablative therapy.

[0636] Subjects (which can 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) can include subjects who have or have been diagnosed with various types of leukemia, anemia, lymphoma, myeloma, immunodeficiency disorders, and solid tumors. Subjects also include those who are candidates for stem cell transplantation or bone marrow transplantation (such as during the treatment of a malignant disease or as part of a gene therapy). Subjects can also include individuals or animals that donate stem cells or bone marrow for allogeneic transplantation. In certain embodiments, the subject may have undergone myeloablative radiation therapy or chemotherapy, or may have experienced acute radiation or chemical insult that results in myeloablation. In certain embodiments, the subject may have undergone radiation therapy or chemotherapy, such as during the treatment of various cancers. Typical subjects include animals that exhibit an abnormal amount (an amount lower or higher than that of a "normal" or "healthy" subject) of one or more physiological activities that can be modulated by a pharmaceutical agent or a stem cell or bone marrow transplantation.

[0637] Subjects (which can be treated with a hematopoietic stem cell preparation treated with a 15-PGDH inhibitor and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells) can also include subjects who receive chemotherapy or radiation therapy for cancer, as well as those who suffer from (e.g., have) non-malignant blood disorders, particularly immunodeficiencies (such as SCID, Fanconi anemia, severe aplastic anemia, or congenital hemoglobinopathies, or metabolic storage diseases (such as Hurler's disease, Hunter's disease, mannosidosis, etc.)), or cancer (particularly hematological malignancies such as acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, myelodysplastic syndrome, or non-hematological cancers such as solid tumors (including breast cancer, ovarian cancer, brain cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer)).

[0638] Subjects can also include subjects with aplastic anemia, immune disorders (severe combined immunodeficiency syndrome or lupus), myelodysplasia, thalassemia, sickle cell disease, or Wiskott-Aldrich syndrome. In some embodiments, the subject has a disorder resulting from an unwanted side effect or a complication of another primary treatment (such as radiation therapy, chemotherapy, or treatment with a myelosuppressive drug (such as zidovadine, chloramphenicol, or ganciclovir)). Such disorders include neutropenia, anemia, thrombocytopenia, and immune dysfunction. Other subjects may have a disorder caused by an infection (e.g., viral infection, bacterial infection, or fungal infection) that causes damage to bone marrow stem cells or progenitor cells.

[0639] In addition, subjects with the following conditions can also benefit from the treatment 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: lymphopenia, lymphorrhea, lymphostasis, erythropenia, erythrodegenerative disorders, erythroblastopenia, erythroleukocytosis; erythrocyte fragmentation, thalassemia, myelodysplasia, myelofibrosis, thrombocytopenia, disseminated intravascular coagulation (DIC), immune (autoimmune) thrombocytopenic purpura (ITP), HIV-induced ITP, myelodysplasia; thrombocytotic disease, thrombocytosis, congenital neutropenia (such as Kostmann's syndrome and Schwachman-Diamond syndrome), tumor-associated neutropenia, cyclic neutropenia in children and adults; post-infectious neutropenia; myelodysplastic syndrome; neutropenia associated with chemotherapy and radiotherapy; chronic granulomatous disease; mucopolysaccharidosis; Diamond-Blackfan anemia; sickle cell disease; or β-thalassemia.

[0640] In other embodiments, a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and / or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells can be used in a cell-based therapy for treating ischemic tissue or treating or alleviating one or more symptoms associated with tissue ischemia, including but not limited to impaired or lost organ function (including but not limited to impaired or lost brain, kidney, or heart function), cramps, claudication, numbness, tingling, weakness, pain, reduced wound healing, inflammation, skin discoloration, and gangrene.

[0641] 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 person having ischemic tissue or tissue damaged by ischemia or at risk thereof, such as a subject having diabetes, peripheral vascular disease, thromboangiitis obliterans, vasculitis, cardiovascular disease, coronary artery disease or heart failure, or cerebrovascular disease, cardiovascular disease, or cerebrovascular disease.

[0642] Illustrative examples of genetic disorders, syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage, or increase the subject's risk of ischemia, or cause the subject to exhibit multiple or more ischemic symptoms and, thus, are suitable for treatment or alleviation 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 defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity arterial ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, premalignant carcinoma, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombus, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory disorder, von Hippel-Lindau syndrome, and tissue or organ wound.

[0643] Other illustrative examples of genetic disorders, syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage, or increase the ischemic risk of a subject, or cause a subject to exhibit multiple or more ischemic symptoms and are amenable to treatment or alleviation using the methods disclosed herein include ischemia caused by surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplantation or grafting.

[0644] In various embodiments, the methods described herein are applicable to treating cerebral ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebral ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

[0645] In various embodiments, the present disclosure contemplates that the therapeutic cell compositions disclosed herein can be used to treat ischemic tissue where an increase in tissue blood flow, oxygen supply, glucose supply, or nutrient supply is desired.

[0646] In some embodiments, a 15-PGDH inhibitor can be administered to a preparation of tissue stem cells (such as neural stem cells, mesenchymal stem cells, or stem cells that can give rise to other tissues) and / or a preparation of pluripotent stem cells.

[0647] In one embodiment, the tissue stem cells can be obtained from a pluripotent stem cell source, such as iPSCs and ESCs.

[0648] In some embodiments, the tissue stem cells and / or pluripotent stem cells can be administered or contacted ex vivo with one or more of the 15-PGDH inhibitors described herein to provide a therapeutic composition. In one embodiment, the therapeutic composition can include a population of tissue stem cells treated ex vivo with one or more 15-PGDH inhibitors.

[0649] In certain embodiments, the therapeutic composition includes a cell population, wherein the cell population is about 95% to about 100% tissue stem cells. The present disclosure contemplates in part that therapeutic compositions using highly purified tissue stem cells (such as compositions comprising a cell population wherein the cells comprise about 95% tissue stem cells) can improve the efficiency of stem cell therapy.

[0650] In some embodiments, the therapeutic composition comprises a cell population, wherein the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% tissue stem cells. In some embodiments, the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% tissue stem cells. In other embodiments, the cell population is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10%-15%, about 15%-20%, about 20%-25%, about 25%-30%, about 30%-35%, about 35%-40%, about 40%-45%, about 45%-50%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%-95%, or about 95% to about 100% tissue stem cells.

[0651] Relative to the subject to whom the therapeutic composition will be administered, the tissue stem cells in the therapeutic composition described herein can be autologous / self or non-autologous.

[0652] A preparation of tissue stem cells administered with one or more 15-PGDH inhibitors and / or a therapeutic composition comprising tissue stem cells and one or more 15-PGDH inhibitors can be used to improve tissue stem cell transplantation and treat damaged tissue, and further reduce tissue damage and / or enhance the repair of damaged tissue (by stem cell recruitment) and / or increase cell survival at the site of tissue damage.

[0653] Genetic disorders, syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and require tissue repair and, accordingly, are amenable to treatment or alleviation 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 defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes mellitus, diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity arterial ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral artery disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, premalignancy, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplantation, spinal cord injury, stroke, subchondral bone cysts, thrombus, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular diseases of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and tissue or organ wounds.

[0654] Other illustrative examples of genetic disorders, syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and require tissue repair and are amenable to treatment or alleviation using the methods of the present invention include ischemia caused by surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplantation or grafting.

[0655] In other embodiments, a 15-PGDH inhibitor can be administered to a bone marrow transplant donor or a hematopoietic stem cell donor to enhance the suitability of the donor bone marrow graft or the donor hematopoietic stem cell graft.

[0656] In other embodiments, a 15-PGDH inhibitor can also be administered to the bone marrow of a subject to increase stem cells in the subject or improve the suitability of the marrow as a donor graft.

[0657] In still other embodiments, a 15-PGDH inhibitor can be administered to a subject to reduce bone marrow graft rejection, to enhance bone marrow graft transplantation, to enhance transplantation of a hematopoietic stem cell graft or a cord blood stem cell graft, to enhance transplantation of a hematopoietic stem cell graft or a cord blood stem cell graft, and / or to reduce the number of units of cord blood required for transplantation into the subject. Administration can be, for example, after treating the subject or the subject's marrow with radiation therapy, chemotherapy, or immunosuppressive therapy.

[0658] In other embodiments, the 15-PGDH inhibitor can be administered to a recipient of a bone marrow transplant, a hematopoietic stem cell transplant, or a cord blood stem cell transplant to reduce the administration of other therapies or growth factors.

[0659] In some embodiments, a 15-PGDH inhibitor can be administered to a subject to enhance recovery of neutrophils after bone marrow transplantation, after cord blood transplantation, after transplantation with hematopoietic stem cells, after conventional chemotherapy, after radiation therapy, and in individuals with neutropenia from diseases (including but not limited to aplastic anemia, myelodysplasia, myelofibrosis, neutropenia from other bone marrow diseases, drug-induced neutropenia, immune neutropenia, idiopathic neutropenia), as well as after infection with viruses (including but not limited to HIV, CMV, and parvovirus).

[0660] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to enhance recovery of platelets after bone marrow transplantation, after cord blood transplantation, after transplantation with hematopoietic stem cells, after conventional chemotherapy, after radiation therapy, and in individuals with neutropenia from diseases (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), as well as after infection with viruses (including but not limited to HIV, CMV, and parvovirus).

[0661] In still other embodiments, a 15-PGDH inhibitor can be administered to a subject to enhance hemoglobin recovery after bone marrow transplantation, after umbilical cord blood transplantation, after transplantation with hematopoietic stem cells, after conventional chemotherapy, after radiation therapy, and in individuals with anemia from diseases (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), as well as after infection with viruses (including but not limited to HIV, CMV, and parvovirus).

[0662] In some embodiments, a 15-PGDH inhibitor can be administered to a subject to increase the number of bone marrow stem cells after bone marrow transplantation, after umbilical cord blood transplantation, after transplantation with hematopoietic stem cells, after conventional chemotherapy, after radiation therapy, in individuals with other bone marrow diseases, in individuals with cytopenia after viral infection, and in individuals with cytopenia.

[0663] In other embodiments, a 15-PGDH inhibitor can be administered to a subject to enhance the response to cytokines administered to an individual with cytopenia, which cytopenia includes but is not limited to neutropenia, thrombocytopenia, lymphopenia, and anemia. Cytokines (the response to which can be enhanced by the 15-PGDH inhibitors described herein) include but are not limited to: G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, SCF, and TPO-RA (thrombopoietin receptor agonist).

[0664] In additional embodiments, a 15-PGDH inhibitor can be administered to a subject or a tissue graft of the subject to reduce graft rejection, to enhance graft transplantation, to enhance graft transplantation after treating the subject or the subject's marrow with radiation therapy, chemotherapy, or immunosuppressive therapy, to confer resistance to the toxic or lethal effects of exposure to radiation, to confer resistance to the toxic effects of Cytoxan, fludarabine, the toxic effects of chemotherapy, or the toxic effects of immunosuppressive therapy, to reduce infection, and / or to reduce pulmonary toxicity from radiation.

[0665] In other embodiments, a 15-PGDH inhibitor can be administered to the recipient of a tissue stem cell transplantation (including but not limited to transplantation with hematopoietic stem cells, neural stem cells, mesenchymal stem cells, or stem cells for other tissues), thereby promoting tissue regeneration and repair after transplantation.

[0666] In some embodiments, for the purpose of increasing neutrophils, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0667] In other embodiments, for the purpose of increasing neutrophils, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0668] In still other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0669] In other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0670] In some embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells, a 15-PGDH inhibitor can be administered in combination with a second agent (including plerixafor).

[0671] In other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0672] In still other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0673] In other embodiments, for the purpose of increasing the number of peripheral blood hematopoietic stem cells and / or mobilizing these peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation, a 15-PGDH inhibitor can be administered in combination with a second agent (including plerixafor).

[0674] In still other embodiments, for the purpose of increasing the number of hematopoietic stem cells in blood or bone marrow, a 15-PGDH inhibitor can be administered in combination with G-CSF.

[0675] In other embodiments, for the purpose of increasing the number of hematopoietic stem cells in blood or bone marrow, a 15-PGDH inhibitor can be administered in combination with a hematopoietic cytokine.

[0676] In other embodiments, a 15-PGDH inhibitor can be used to treat and / or prevent fibrosis and various fibrotic diseases, disorders or conditions, and reduce fibrotic symptoms such as collagen deposition, inflammatory cytokine expression and inflammatory cell infiltration.

[0677] In some embodiments, a method of treating or preventing a fibrotic disease, disorder, or condition comprises administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor to reduce the intensity, severity, or frequency of, or delay the onset of, at least one symptom or feature of the fibrotic disease, disorder, or condition, or of another related disease, disorder, or condition.

[0678] As used herein, the term “fibrotic” disease, disorder, or condition includes a disease, disorder, or condition that is characterized, in whole or in part, by the overproduction of fibrous material (including the overproduction of fibrotic material within the extracellular matrix or the replacement of normal tissue components by the abnormal, non-functional, and / or excessive accumulation of matrix-related components). Fibrotic diseases, disorders, or conditions can include acute and chronic, clinical or subclinical manifestations, in which fibrosis that is relevant to the biology or pathology is evident.

[0679] Examples of fibrotic diseases, disorders, and conditions include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), graft-versus-host disease of scleroderma, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive nephropathy, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., glomerulosclerosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, common fibrosis syndromes characterized by the replacement of normal muscle tissue by varying degrees of fibrous tissue, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis (fibrosis of the bone marrow), drug-induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecologic cancer, Kaposi's sarcoma, Hansen's disease, collagenous colitis, acute fibrosis, organ-specific fibrosis, and the like.

[0680] Exemplary organ-specific fibrotic disorders include, but are not limited to, pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis, asthma, chronic obstructive pulmonary disease, liver fibrosis, kidney fibrosis, NASH, and the like. Many fibrotic diseases, disorders, or conditions disrupt and / or expand the deposition of the extracellular matrix in the affected tissues. Fibrosis may be associated with inflammation, occur as a symptom of an underlying disease, and / or be caused by a surgical procedure or the wound healing process. Untreated fibrosis can lead to the destruction of the underlying organ or tissue structure, commonly referred to as scarring.

[0681] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent pulmonary fibrosis. The pulmonary fibrosis can be selected from the group consisting of: pulmonary fibrosis, pulmonary arterial hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, anthracosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of a noxious gas, aerosol, chemical dust, smoke, or vapor, drug-induced interstitial lung disease, or pulmonary arterial hypertension, and combinations thereof.

[0682] Pulmonary fibrosis is characterized by progressive scarring of lung tissue, accompanied by fibroblast proliferation, excessive accumulation of extracellular matrix proteins, and abnormal alveolar structure. The thickened and stiff tissue makes it difficult for the lungs to function properly, leading to breathing problems such as shortness of breath and can ultimately be fatal. Pulmonary fibrosis can be caused by acute lung injury, viral infection, exposure to toxins, radiation, chronic diseases, drugs, or it can also be idiopathic (i.e., no underlying cause is found).

[0683] Classic findings of idiopathic pulmonary fibrosis show diffuse peripheral scarring of the lungs, which have small air bubbles (called bullae) in the outer lining near the lung surface, usually at the bottom of the lungs. Idiopathic pulmonary fibrosis typically progresses slowly and continuously. Early on, patients often complain of a dry, unexplained cough. Then, shortness of breath (dyspnea) begins and worsens over time (caused by less and less activity). Eventually, the shortness of breath becomes inability to breathe, limiting all activities and occurring even at rest. In rare cases, fibrosis can progress rapidly, where dyspnea and inability to breathe occur within weeks to months of the onset of the disease. This form of pulmonary fibrosis is called Hamman-Rich syndrome.

[0684] Pulmonary hypertension is marked by elevated blood pressure in the pulmonary vascular system, which includes the pulmonary arteries, pulmonary veins, and / or pulmonary capillaries. The abnormal high pressure strains the right ventricle of the heart excessively, causing it to enlarge. Over time, the right ventricle may weaken and lose its ability to pump sufficient blood into the lungs, leading to the development of heart failure. Pulmonary hypertension can occur due to other medical conditions such as chronic liver disease and cirrhosis; rheumatologic disorders (such as scleroderma or systemic lupus erythematosus (lupus)); and lung conditions (including tumors, emphysema, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis). Pulmonary fibrosis may cause narrowing of the pulmonary blood vessels that leads to pulmonary hypertension.

[0685] Chronic obstructive pulmonary disease (COPD) is a common lung disease that is typically associated with chronic bronchitis or emphysema. Symptoms usually include coughing, mucus buildup, fatigue, wheezing, and respiratory infections.

[0686] Chronic bronchitis and emphysema are lung diseases in which the airways narrow. This results in restricted airflow in and out of the lungs, causing shortness of breath (dyspnea). In clinical practice, COPD is defined by typically low airflow in pulmonary function tests.

[0687] Lung damage and inflammation in the large airways result in chronic bronchitis. In the lung airways, the hallmark of chronic bronchitis is an increased number (hyperplasia) and increased size (hypertrophy) of the airway goblet cells and mucus glands. As a result, there is more mucus than normal in the airways, causing the airways to narrow and leading to a productive cough. Microscopically, inflammatory cells infiltrate the airway wall. After inflammation, scarring and remodeling occur, which makes the wall thicken and also causes airway narrowing. As chronic bronchitis progresses, squamous metaplasia (abnormal changes in the tissue lining the inside of the airways) and fibrosis (further thickening and scarring of the airway wall) occur. The result of these changes is airflow restriction and dyspnea.

[0688] Asthma is a chronic lung disease characterized by inflammation and airway constriction. Asthma results in a cycle of wheezing, chest tightness, shortness of breath, and coughing. Swelling and excessive mucus production can further cause airway constriction and worsening of symptoms. There is evidence that increased matrix degradation may occur in asthma, and this may lead to mechanical changes in the airways in asthma (Roberts et al. (1995) Chest 107:111S - 117S, incorporated herein by reference in its entirety). Treatment of extracellular matrix degradation can improve asthma symptoms.

[0689] Cystic fibrosis is a recessive multisystem genetic disorder characterized by abnormal transport of chloride and sodium across epithelial cells, leading to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract. Cystic fibrosis is caused by mutations in the protein cystic fibrosis transmembrane conductance regulator (CFTR). Lung disease is caused by airway obstruction due to mucus accumulation, reduced mucociliary clearance, and resulting inflammation, which can cause fibrotic damage and structural changes in the lungs. Fibrotic lung damage progresses over time, leading to the need for lung transplantation in some patients with cystic fibrosis.

[0690] Common symptoms in subjects with cystic fibrosis include, but are not limited to, thick mucus accumulation, copious sputum production, frequent chest infections, frequent coughing, frequent shortness of breath, inflammation, decreased exercise capacity, opportunistic infections in the lungs and sinuses (including, but not limited to, Staphylococcus aureus, Haemophilus influenzae, Mycobacterium aviium, and Pseudomonas aeruginosa), pneumonia, tuberculosis, bronchiectasis, hemoptysis, pulmonary hypertension (and resulting heart failure), hypoxia, respiratory failure, allergic bronchopulmonary aspergillosis, mucus in the paranasal sinuses, sinus infections, facial pain, fever, excessive nasal drainage, nasal polyp development, cardiorespiratory complications, CF-related diabetes, rectal prolapse, pancreatitis, malabsorption, intestinal obstruction, exocrine pancreatic insufficiency, biliary obstruction, and cirrhosis.

[0691] In other embodiments, 15-PGDH inhibitors can be used to treat or prevent fibrotic diseases, disorders, or conditions caused by postoperative adhesion formation. Postoperative adhesion formation is a common complication of surgery. Adhesion formation from mechanical injury, ischemia, and infection can increase morbidity and mortality after surgery. Although meticulous surgical procedures can reduce the extent of adhesion formation, adhesions are rarely resected and effective adjuvant therapies are needed. Reducing fibrosis associated with this process can reduce pain, obstruction, and other surgical complications and promote healing and recovery.

[0692] Wounds (e.g., lacerations, openings) in mammalian tissue result in tissue disruption and clotting of the microvasculature at the wound surface. Repair of such tissue represents an ordered, controlled 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 well characterized and in some instances quantified (see, e.g., Hunt, T.K., et al., “Coagulation and macrophage stimulation of angiogenesis and wound healing” in Surgical Wound, pp. 1-18, edited by F. Dineen & G. Hildrick-Smith (Lea & Febiger, Philadelphia: 1981)). The cellular morphology consists of three distinct zones. The central avascular wound space is hypoxic, acidotic, and hypercarbic and has a high lactate level. Adjacent to the wound space is a gradient zone of local anemia (ischemia) that is populated by dispersed fibroblasts. Behind the leading zone is an area of active collagen synthesis characterized by mature fibroblasts and many newly formed capillaries (i.e., neovascularization). U.S. Patent Nos. 5,015,629 and 7,022,675 (each incorporated herein by reference) disclose methods and compositions for increasing the rate of wound repair.

[0693] In some embodiments, a 15-PGDH inhibitor can be used to reduce or prevent scar formation in a subject by administering to a subject in need of treatment. Scar formation is a natural part of the healing process. Disordered collagen synthesis and deposition in a wound can result in excessive, thick, or raised scar formation. Generally, the larger the wound, the longer it takes to heal and the greater the chance of a problem scar.

[0694] In other embodiments, a 15-PGDH inhibitor can be used to reduce or prevent scar formation on the skin or in scleroderma. There are several types of scars on the skin. Hypertrophic scars are raised, pink areas that are within the boundaries of the original injury. They are often described as itchy. In some cases, hypertrophic scars shrink and disappear on their own. Keloids are raised, dark red areas that tend to cover a much larger area than the original injury. Even when surgically removed, keloids often recur. Atrophic scars are depressions in the skin, like those sometimes formed by severe acne. They are caused by inflammation that destroys collagen during the remodeling process, leaving a depressed area.

[0695] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent systemic sclerosis. Systemic sclerosis is a systemic connective tissue disease characterized by microvascular alterations, immune system disorders, and massive deposition of collagen and other matrix substances in connective tissue. Systemic sclerosis is a clinically heterogeneous systemic disorder that affects the connective tissue of the skin and internal organs (such as the gastrointestinal tract, lungs, heart, and kidneys). Reduction of fibrosis resulting from systemic sclerosis can improve symptoms in affected tissues and / or prevent further complications.

[0696] In other embodiments, a 15-PGDH inhibitor can be used to treat or prevent liver fibrosis. Liver fibrosis can be caused by: chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions, and exposure to toxins.

[0697] Non-alcoholic steatohepatitis (NASH) is a common liver disease. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The main features of NASH are fat in the liver as well as inflammation and damage. However, NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer functions properly.

[0698] NASH is usually a silent disease with few or no symptoms. Patients usually feel well in the early stages and only start to have symptoms (such as fatigue, weight loss, and weakness) once the disease is more advanced or cirrhosis develops. The progression of NASH can take several years or even decades. The process can stop and in some cases may even reverse on its own without specific therapy. Or NASH may slowly worsen, leading to the appearance and accumulation of scarring or fibrosis in the liver. As fibrosis worsens, cirrhosis develops, in which the liver becomes severely scarred, hardened, and unable to function properly. Not everyone with NASH will develop cirrhosis, but once severe scarring or cirrhosis is present, there are few treatments that can stop the progression. People with cirrhosis experience fluid retention, muscle wasting, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and the number of NASH patients receiving transplants is increasing. NASH is listed as one of the leading causes of cirrhosis in the United States, second only to hepatitis C and alcoholic liver disease.

[0699] In some embodiments, a 15-PGDH inhibitor can be used to treat or prevent kidney fibrosis. Kidney fibrosis may be caused by renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end-stage renal disease, or dialysis after renal failure.

[0700] Renal (kidney) fibrosis results from the excessive formation of fibrous connective tissue in the kidney. Renal fibrosis causes significant morbidity and mortality and leads to the need for dialysis or kidney transplantation. Fibrosis can occur in the filtering or reabsorptive components of the nephron (the functional unit of the kidney). Many factors can lead to kidney scarring, particularly physiological disorders involving the autoregulation of glomerular filtration. This in turn results in the replacement of normal structure by an accumulated extracellular matrix. Spectral changes in individual cell physiology lead to the production of a large number of peptide and non-peptide fibrinogens, which stimulate a change in the balance between extracellular matrix synthesis and degradation in favor of scar formation.

[0701] In some embodiments, symptoms of tissue or organ fibrosis may include inflammation. In these embodiments, a therapeutically effective amount of a 15-PGDH inhibitor administered to a subject in need can be an amount effective to reduce or decrease the inflammatory cell count in the tissue or organ. A relevant sample can be obtained from the subject to determine the reduction or decrease in the inflammatory cell count. In non-limiting embodiments, the beneficial effect can be evaluated by demonstrating a reduction in the neutrophil count in the BAL fluid from a subject with cystic fibrosis. The excessive recruitment of neutrophils in the airways of CF patients is an important predictor of the severity of lung disease 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 technology. In some embodiments, the method can include reducing the neutrophil count in the BAL fluid from the subject compared to a control. Any suitable control can be used for comparison, such as a cystic fibrosis subject not treated with a 15-PGDH inhibitor. In some embodiments, a reduction in the inflammatory cell count, such as the neutrophil count, provides a clinical benefit to the subject. In various embodiments, the reduction in the inflammatory cell count compared to a control is at least 5%, 10%, 15%, 20%, 25%, 50%, or more.

[0702] In another embodiment, the beneficial effects of a 15-PGDH inhibitor can be evaluated by a decrease in one or more inflammatory biomarkers in a relevant sample from a subject. In various non-limiting embodiments, the inflammatory biomarker can comprise or consist of one or more of a cytokine or inflammatory cytokine associated with fibrosis. 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 amounts of such biomarkers are well known in the art and include, but are not limited to, ELISA. Thus, in this embodiment, these methods can further comprise a decrease in the amount of one or more inflammatory biomarkers in a sample from a subject as compared to a control.

[0703] In other embodiments, a 15-PGDH inhibitor can be used in a method for reducing or decreasing collagen secretion or collagen deposition in a tissue or organ (such as the lung, liver, skin, or heart) of a subject. The method can comprise administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof. The subject can have or be at risk of having excessive collagen secretion or collagen deposition in a tissue or organ (such as the kidney, lung, liver, intestine, colon, skin, or heart). Generally, excessive collagen secretion or collagen deposition in an organ is caused by injury or insult. Such injury and insult are organ-specific. The 15-PGDH inhibitor can be administered for a sufficient period of time to completely or partially reduce or decrease the level of collagen deposition in the tissue or organ. The sufficient period of time can be within one week, or between 1 week and 1 month, or between 1 and 2 months, or 2 months or longer. For chronic conditions, the 15-PGDH inhibitor can be advantageously administered for life.

[0704] Assays can be used to identify 15-PGDH inhibitors for treating fibrotic diseases, disorders, or conditions and / or reducing collagen deposition, wherein a putative inhibitor compound is applied to cells expressing 15-PGDH and then the functional effect on

[0705] 15-PGDH activity is determined. A sample or assay containing 15-PGDH treated with a potential inhibitor is compared to a control sample without an inhibitor to examine the extent of the effect. The relative 15-PGDH activity value of the control sample (not treated with a modulator) is designated as 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5%, or 1%. Additionally, in a model organism, PGE 2Signaling stimulates liver regeneration and increases survival after exposure to hepatotoxins such as acetaminophen. Thus, the 15-PGDH inhibitors described herein can be used to increase liver regeneration after hepatectomy, in other situations including after liver surgery, after living liver donation, or after receiving a liver transplant, or to increase liver regeneration and increase survival after exposure to hepatotoxins including but not limited to acetaminophen and similar compounds.

[0706] 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 prostaglandins to treat erectile dysfunction.

[0707] Other embodiments described herein relate to the use of 15-PGDH inhibitors in combination with corticosteroids to treat inflammation and / or reduce abnormal activity of the immune system in a subject in need thereof. It has been found that corticosteroids administered to a subject can induce 15-PGDH expression in the tissues of the subject. It has been found that administration of a 15-PGDH inhibitor in combination with a corticosteroid enhances the anti-inflammatory and / or immunosuppressive effects of the corticosteroid while reducing the adverse and / or cytotoxic effects induced by the corticosteroid. Treating inflammatory and / or immune disorders by administering a 15-PGDH inhibitor in combination with a corticosteroid can improve therapeutic efficacy and, in some cases, allow the corticosteroid to be administered at a lower dose to achieve a similar effect and, in other cases, at a higher dose and for an extended period of time to reduce and / or mitigate adverse or cytotoxic effects. Further embodiments herein relate to the use of 15-PGDH inhibitors in combination with TNFα inhibitors to treat inflammation and / or reduce abnormal activity of the immune system in a subject in need thereof.

[0708] In some embodiments, a 15-PGDH inhibitor can be administered in combination with a corticosteroid and / or a TNF inhibitor to treat intestinal, gastrointestinal, or bowel disorders. Intestinal, gastrointestinal, or bowel disorders that can be treated 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 a subject 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.

[0709] The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for preventing or treating oral, intestinal, and / or gastrointestinal injuries or diseases, or inflammatory bowel disease (IBD) (such as Crohn's disease, oral ulcers, gum diseases, gastritis, colitis, ulcerative colitis, and gastric ulcers). Gastritis and gastric ulcers (representatives of gastrointestinal diseases) are defined as conditions in which the gastrointestinal mucosa is digested by gastric acid to form ulcers. In the gastric wall, which usually consists of the mucosa, submucosa, muscular layer, and serosa, gastric ulcers even damage the submucosa and muscular layer, while gastritis only damages the mucosa. Although the incidence of gastritis and gastric ulcers is relatively high, their causes are not yet clear. So far, it is known that they are caused by an imbalance between attack factors and defense factors, that is, an increase in attack factors, such as an increase in gastric acid or pepsin secretion, or a decrease in defense factors, such as structural or morphological defects of the gastric mucosa, reduced secretion of mucus and bicarbonate ions, reduced production of prostaglandins, etc.

[0710] Currently available therapeutic agents for gastritis and gastric ulcers include various drugs for enhancing defense factors, such as antacids (which do not affect gastric acid secretion but neutralize the gastric acid that has already been produced), inhibitors of gastric acid secretion, promoters of prostaglandin secretion, and coating agents for the gastric wall. In particular, prostaglandins are known to be essential in maintaining the mechanisms that protect and defend the gastric mucosa (Wallace J L., 2008, Physiol Rev. [Annual Review of Physiology], 88(4), 1547 - 65, S.J. Konturek et al., 2005, Journal of Physiology and Pharmacology [Journal of Physiology and Pharmacology], 56(5)). In view of the above, since the 15-PGDH inhibitors described herein exhibit suppression or inhibitory activity against 15-PGDH, which degrades the prostaglandins that protect the gastric mucosa, they can effectively prevent or treat gastrointestinal diseases, especially gastritis and gastric ulcers.

[0711] In addition, both corticosteroids and TNFα antagonists are used in the treatment of patients with ulcerative colitis and IBD. In a mouse model, 15-PGDH inhibitors accelerate the healing of ulcerative colitis. We have found that administering corticosteroids to mice elevates the level of colonic 15-PGDH, and this effect reduces the therapeutic efficacy of corticosteroids in the treatment of colitis. This indicates that the combination of corticosteroids and 15-PGDH inhibitors should be more effective in the treatment of colitis (and IBD) than either agent alone.

[0712] Similarly, we have shown that TNF-α inhibits colonic 15-PGDH expression. This suggests that TNF-α antagonists would increase colonic 15-PGDH expression, an effect that would reduce the therapeutic efficacy of corticosteroids in the treatment of colitis. This suggests that combinations of TNF-α antagonists (such as the chimeric antibody REMICADE (infliximab)) and 15-PGDH inhibitors should be more effective than either agent alone in the treatment of colitis (and IBD).

[0713] In other embodiments, 15-PGDH inhibitors and corticosteroids or 15-PGDH inhibitors and TNF inhibitors can be provided in the form of a topical composition or formulation and 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 (e.g., poison ivy exposure, poison oak exposure, and poison sumac exposure), seborrheic dermatitis, stasis dermatitis, and other steroid-responsive skin diseases.

[0714] In other embodiments, 15-PGDH inhibitors and corticosteroids or 15-PGDH inhibitors and TNF inhibitors provided in the form of a topical composition can be used to treat, for example, acne vulgaris, alopecia, alopecia greata, vitiligo, eczema, xerotic eczema, keratosis pilaris, lichen planus, lichen sclerosus, lichen striatus, lichen simplex chronicus, prurigo nodularis, discoid lupus erythematosus, Jessner / Kanof's lymphocytic infiltration, lymphacytoma cutis, pyoderma gangrenosum, pruritus ani, sarcoidosis, chondrodermatitis nodularis helices, and other inflammatory skin disorders.

[0715] Medical conditions treatable by 15-PGDH inhibitors and corticosteroids or 15-PGDH inhibitors and TNF inhibitors can also include, for example, keloids, hypertrophic scars, pretibial myxedema, and other infiltrative skin disorders. Additional medical conditions include, for example, granuloma annulare, necrobiosis lipoidica diabeticorum, sarcoidosis, and other non-infectious granulomas.

[0716] In still other embodiments, 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 the various prostaglandins, PGE 2As a medium for wound healing. Thus, a 15-PGDH inhibitor can be administered to a subject receiving steroids (including those for healing wounds from surgery undergone) to enhance PGE 2 and promote wound healing.

[0717] In addition, increased prostaglandin levels have been shown to stimulate signaling through the Wnt signaling pathway via increased β-catenin-mediated transcriptional activity. Wnt signaling is known to be a key pathway employed by tissue stem cells. Thus, for the purpose of promoting tissue regeneration or repair, including in subjects receiving corticosteroid treatment, the 15-PGDH inhibitors described herein can be used to increase the number of tissue stem cells. In addition, the 15-PGDH inhibitors described herein can be used to promote tissue regeneration or repair of additional organs, which additional organs include but are not limited to the brain, eye, cornea, retina, lung, heart, stomach, small intestine, pancreas, pancreatic β-cells, kidney, bone, cartilage, and peripheral nerve.

[0718] In other embodiments, a 15-PGDH inhibitor can be used as a glucocorticoid sensitizer to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject who has experienced corticosteroid dependence or corticosteroid resistance or is non-responsive or intolerant to corticosteroids. The therapeutic effects of a 15-PGDH inhibitor (when used as a glucocorticoid sensitizer) include any but are not limited to: sparing steroids in corticosteroid-dependent patients, better responsiveness or tolerance to corticosteroids, achieving efficacy with lower doses of corticosteroids, preventing an individual from being at risk of developing refractory responses or dependence or exacerbation in response to antigen exposure, infection, exercise, or stimuli, achieving optimal immune function, making a subject or patient more responsive when the administration of steroids is tapered or stopped or after long-term corticosteroid administration, and reducing the risk of developing corticosteroid-related adverse events such as opportunistic infections, bone loss, pathologic fractures, diabetes, cataracts, and combinations thereof.

[0719] In some embodiments, a 15-PGDH inhibitor can be administered in combination with a corticosteroid to a subject to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse glucocorticoid insensitivity in a subject who has experienced corticosteroid dependence or corticosteroid resistance or is non-responsive or intolerant to corticosteroids. Conditions associated with glucocorticoid insensitivity can include a range of immune-inflammatory disorders / diseases treated with steroids when treatment fails to achieve disease control or is ineffective or intolerant or not steroid-dependent, and combinations thereof.

[0720] In other embodiments, a 15-PGDH inhibitor and a corticosteroid or a 15-PGDH inhibitor and a TNF inhibitor can be administered to a subject who exhibits one or more glucocorticoid-insensitivity-related diseases, disorders, or conditions selected from the group consisting of: glucocorticoid-refractory 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 muscle disease, refractory myasthenia gravis, refractory pemphigus vulgaris, methotrexate-refractory RA patients, refractory nephrotic syndrome, refractory multiple sclerosis, refractory celiac-like disease, steroid-refractory sarcoidosis, refractory mucosal lesions of pemphigus vulgaris, refractory Schnitzler syndrome, head and neck recalcitrant dermatitis, severe refractory atopic dermatitis, refractory idiopathic thrombocytopenic purpura, refractory orbital myositis, refractory or recurrent lymphoma, critically ill patients with sepsis or acute respiratory distress syndrome (ARDS) and relative adrenal insufficiency, rosacea, polymyalgia rheumatica, giant cell arteritis, polymyositis, dermatomyositis, Kawasaki disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, stiff-person 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, sinusitis, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, allergic rhinitis, urticaria, hereditary angioedema, tendinitis, bursitis, autoimmune chronic active hepatitis, cirrhosis, transplant rejection, psoriasis, dermatitis, malignancies, leukemia, myeloma, lymphoma, acute adrenal insufficiency, rheumatic fever, granulomatosis, immunoproliferation / apoptosis, hypothalamic-pituitary-adrenal (HPA) axis inhibition or regulation, Cushing's syndrome, Th1 / Th2 cytokine balance regulation, chronic kidney disease, spinal cord injury, brain edema, thrombocytopenia, Little's syndrome, 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, enhancing memory and learning, glucocorticoid-induced glaucoma, atopic dermatitis, drug hypersensitivity, serum sickness, bullous herpetiform dermatitis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, non-suppurative thyroiditis, sympathetic ophthalmia, uveitis,Ocular inflammatory conditions that are unresponsive to topical steroids, allergic bronchopulmonary aspergillosis, fulminant or disseminated tuberculosis when used in conjunction with appropriate chemotherapy, hypersensitivity pneumonitis, idiopathic bronchiolitis obliterans with organizing pneumonia, idiopathic eosinophilic pneumonia, idiopathic pulmonary fibrosis, Pneumocystis carinii pneumonia (PCP) associated with hypoxemia in HIV(+) individuals (who are also receiving treatment with appropriate anti-PCP antibiotics), diuresis or remission of proteinuria in idiopathic or lupus nephrotic syndrome (without uremia), ankylosing spondylitis, polymyalgia rheumatica, psoriatic arthritis, relapsing polychondritis, trichinosis with nerve or myocardial involvement, and tuberculous meningitis.

[0721] It should be understood that other 15-PGDH inhibitors can be used in the methods described herein. These other 15-PGDH inhibitors can include known 15-PGDH inhibitors (including, for example, tetrazole compounds of formula (I) and (II) described in U.S. Patent Application Publication No. 2006 / 0034786 and U.S. Patent No. 7,705,041, 2-alkylideneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formula (VI) and (VII), and pyrazole compounds of formula (III); benzylidene-1,3-thiazolidine compounds of formula (I) described in U.S. Patent Application Publication No. 2007 / 0071699; phenylfuranylmethylthiazolidine-2,4-dione and phenylthiophenylmethylthiazolidine-2,4-dione compounds described in U.S. Patent Application Publication No. 2007 / 0078175; thiazolidinedione derivatives described in U.S. Patent Application Publication No. 2011 / 0269954; phenylfuran, phenylthiophene, or phenylpyrazole compounds described in U.S. Patent No. 7,294,641; 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acid and salts described in U.S. Patent No. 4,725,676; and lactones; azo compounds described in U.S. Patent No. 4,889,846; and 15-PGHD inhibitors described in PCT / US 2014 / 060761 and U.S. Patent Application Publication No. 2015 / 0072998A1, all of which are incorporated herein by reference in their entirety).

[0722] The 15-PGDH inhibitors described herein can be provided in the form of a pharmaceutical composition or a cosmetic composition according to the pathological or cosmetic condition or disorder being treated. A pharmaceutical composition containing the 15-PGDH inhibitor (as an active ingredient) described herein can be manufactured by mixing the derivative with one or more pharmaceutically acceptable carriers or one or more excipients or diluting the 15-PGDH inhibitor according to conventional methods. The pharmaceutical composition can further contain fillers, anti-caking agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, etc. The pharmaceutical composition can be formulated into a suitable formulation according to methods known to those skilled in the art such that upon administration to a mammal, an immediate, controlled, or sustained release of the 15-PGDH inhibitor can be provided.

[0723] 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 needed, together with binders, disintegrants, lubricants, coloring agents, and / or flavoring agents to the 15-PGDH inhibitor and shaping the resulting mixture into the form of tablets, dragees, granules, powders, or capsules. The additives that can be added to the composition can be common additives in the art. For example, examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicates, etc. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of disintegrants include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, glyceryl monostearate, and lactose. Further, purified talc, stearates, 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 composition can be made into an aerosol formulation (e.g., they can be nebulized) for administration via inhalation.

[0724] According to conventional methods, the 15-PGDH inhibitors described herein can be combined with flavoring agents, buffering agents, stabilizing agents, etc. and incorporated into oral liquid dosage forms such as solutions, syrups, or elixirs. An example of a buffering agent can be sodium citrate. Examples of stabilizing agents include tragacanth, gum arabic, and gelatin.

[0725] In some embodiments, the 15-PGDH inhibitors described herein can be incorporated into, for example, injection dosage forms for subcutaneous, intramuscular, or intravenous routes (by adding pH regulators, buffers, stabilizers, relaxants, local anesthetics thereto). Examples of pH regulators and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Local anesthetics can be procaine HCl, lidocaine HCl, etc. Relaxants can be sodium chloride, glucose, etc.

[0726] In other embodiments, the 15-PGDH inhibitors described herein can be incorporated into suppositories according to conventional methods by adding pharmaceutically acceptable carriers known in the art, such as polyethylene glycol, lanolin, cocoa butter, or fatty acid triglycerides, and, if desired, together with surfactants (such as Tween).

[0727] The pharmaceutical composition can be formulated into various dosage forms as discussed above and then administered by various routes, including oral, inhalation, transdermal, subcutaneous, intravenous, or intramuscular routes. In some embodiments, the 15-PGDH inhibitors described herein can be administered orally, intravenously, or intraperitoneally. The dosage can be a pharmaceutically effective amount. The pharmaceutically effective amount can be, for example, the amount of the 15-PGDH inhibitor that treats or improves hair loss, cardiovascular diseases, gastrointestinal diseases, wounds, and kidney diseases. The pharmaceutically effective amount of the compound will be appropriately determined according to the type and severity of the disease being treated, the age, sex, weight, and physical condition of the patient being treated, the route of administration, the duration of the therapy, etc. Generally, the effective amount of the compound can 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 is in the range of about 0.1 to 5,000 mg, preferably about up to 1,000 mg, and cannot be uniformly determined as it depends on the age, sex, weight, and physical condition of the patient being treated. The formulation can be administered in divided doses once or several times a day.

[0728] The cosmetic composition containing the 15-PGDH inhibitor can include any substance or preparation intended to come into contact with various superficial parts of the human body (epithelium, body hair and hair systems, nails, lips, and external genital organs) or teeth or oral mucosa (solely or mainly for the purpose of cleaning them, giving them fragrance, modifying their appearance, and / or correcting body odor and / or protecting them or keeping them in good condition).

[0729] The cosmetic composition can contain a cosmetically acceptable medium, which can be water or a mixture of water and at least one solvent selected from the group consisting of hydrophilic organic solvents, lipophilic organic solvents, amphiphilic organic solvents, and mixtures thereof.

[0730] For topical application, the cosmetic composition may be administered in the form of an aqueous, alcoholic, water-alcoholic or oily solution or suspension, a lotion or serum-type dispersion, an emulsion having a liquid or semi-liquid consistency or a paste (obtained by dispersing the fatty phase in the aqueous phase (O / W) or vice versa (W / O)), or multiple emulsions, free or compacted powders (either as such or incorporated into a physiologically acceptable medium), or other microcapsules or microparticles, or a vesicular dispersion of the ionic and / or non-ionic type. Thus, it may be in the form of an ointment, tincture, emulsion, cream, ointment, powder, patch, impregnated pad, solution, emulsion or vesicular dispersion, lotion, aqueous or anhydrous gel, spray, suspension, shampoo, aerosol or foam. It may be anhydrous or aqueous. It may also comprise a solid preparation constituting a soap or cleansing cake.

[0731] The cosmetic composition may particularly comprise a hair care composition, and particularly a shampoo, styling lotion, treatment lotion, styling cream or gel, restructuring lotion for hair, hair mask, etc. The cosmetic composition may be a cream, hair lotion, shampoo, or hair conditioner. These may be used particularly in the treatment of the application or in the form of a shampoo, which may or may not be rinsed after the application. It is also intended to be in the form of a foam, or a spray or aerosol form, and then a composition comprising a propellant under pressure. Thus, it may be in the form of a lotion, serum, emulsion, cream, gel, ointment, paste, powder, pomade, patch, impregnated pad, cake or foam.

[0732] Particularly, the composition for application to the scalp or hair may be in the form of, for example, a hair care lotion for daily or twice-weekly application, particularly a shampoo or hair conditioner for twice-weekly or weekly application, a liquid or solid soap for daily application for cleansing the scalp, a hair shaping product (hair setting agent, hair shaping product, or hairspray), a treatment hair mask, or a foam gel or cream for cleansing the hair. These may also be in the form of a hair dye or mascara applied with a brush or comb.

[0733] Furthermore, for topical application to the eyelashes or body hair, the composition may be in the form of a colored or uncolored mascara for application with a brush to the hairs of the eyelashes or beard or mustache. For a composition administered by injection, the composition may be in the form of an aqueous lotion or an oily suspension. For oral use, the composition may be in the form of capsules, granules, oral syrup, or tablets. According to a particular embodiment, the composition is in the form of a hair pomade or hair lotion, shampoo, hair conditioner, or mascara for the hair or for the eyelashes.

[0734] In a known manner, the cosmetic composition may also contain adjuvants conventional in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV screening agents, odor absorbers, and dyes. The amounts of these different adjuvants are those conventionally used in the cosmetic field and are, for example, from about 0.1% to 20%, especially less than or equal to 10%, of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and / or into the lipid globules.

[0735] In some embodiments, the 15-PGDH inhibitor can be administered in a combinatorial therapy or combination therapy that includes the administration of the 15-PGDH inhibitor together with one or more additional active agents. The phrases "combinatorial therapy" or "combination therapy" include the administration of the 15-PGDH inhibitor and one or more therapeutic agents as part of a specific treatment regimen designed to provide a beneficial effect from the combined action of these therapeutic agents. The combined administration of these therapeutic agents is typically carried out over a defined period (usually minutes, hours, days or weeks, depending on the combination selected). "Combinatorial therapy" or "combination therapy" is intended to include the administration of these therapeutic agents in a sequential manner, i.e., where each therapeutic agent is administered at a different time, and in a substantially simultaneous manner or at least two of the therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject separate doses of each therapeutic agent having a fixed ratio or multiple separate doses for each therapeutic agent. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including but not limited to the oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or different routes. The order of administration of the therapeutic agents is not very critical.

[0736] In some embodiments, the additional active agents can be particularly selected from lipoxygenase inhibitors as described in EP 648488, especially bradykinin inhibitors as described in EP 845700, prostaglandins and their derivatives (especially those described in WO 98 / 33497, WO 95 / 11003, JP 97-100091, JP 96-134242), agonists or antagonists of prostaglandin receptors, and nonprostanoic analogues of prostaglandins (such as those described in EP 1175891 and EP 1175890, WO 01 / 74307, WO 01 / 74313, WO 01 / 74314, WO 01 / 74315 or WO 01 / 72268).

[0737] In other embodiments, a 15-PGDH inhibitor can be administered alone or as a mixture with an active agent such as a vasodilator, a prostaglandin agonist, an antiandrogen, cyclosporine and its analogs, an antimicrobial agent, a triterpene. Vasodilators can include potassium channel agonists (including minoxidil and its derivatives, amilnone and compounds (described in U.S. Patent Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694, 5,438,058, 4,973,474), chromakalin and diazoxide. Antiandrogens can include 5α-reductase inhibitors such as finasteride and compounds (described in U.S. Patent No. 5,516,779), cyprosterone acetate, azelaic acid and its salts and derivatives, and compounds described in U.S. Patent No. 5,480,913, flutamide and compounds (described in U.S. Patent Nos. 5,411,981, 5,565,467 and 4,910,226). Antimicrobial compounds can include selenium derivatives, ketoconazole, triclocarban, triclosan, zinc pyrithione, itraconazole, picolinic acid, hinokitiol, mipirocine, and compounds described in EP 680745, clindamycin hydrochloride, benzoyl peroxide or benzyl peroxide, and minocycline. Anti-inflammatory agents can include inhibitors specific for Cox-2 such as, for example, 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, for example, zileuton (F.J. Alvarez & R.T. Slade, Pharmaceutical Res. 1992; 9(11):1465-1473).

[0738] Other active compounds that can be present in pharmaceutical and / or cosmetic compositions can include: aminexil and its derivatives, 60-[(9Z,12Z) octadeca-9,12-dienoyl] pyranose, benzalkonium chloride, benzethonium chloride, phenol, estradiol, chlorpheniramine maleate, chlorophyll derivatives, cholesterol, cysteine, methionine, benzyl nicotinate, menthol, peppermint oil, calcium pantothenate, panthenol, resorcinol, protein kinase C inhibitors, prostaglandin H synthase 1 or COX-1 activators, or COX-2 activators, glycosidase inhibitors, glycosaminoglycanase inhibitors, pyroglutamate esters, hexosaccharidic acids or acyl hexosaccharidic acids, substituted vinyl aromatics, N-acylated amino acids, flavonoids, derivatives and analogs of FK506, histamine antagonists, triterpenes (such as ursolic acid and the compounds described in U.S. Patent No. 5,529,769, U.S. Patent No. 5,468,888, U.S. Patent No. 5,631,282), saponins, proteoglycanase inhibitors, estrogen agonists and antagonists, pseudopterins, cytokine and growth factor enhancers, IL-1 or IL-6 inhibitors, IL-10 enhancers, TNF inhibitors, vitamins (such as vitamin D, vitamin B12 and analogs of panthotenol), hydroxy acids, benzophenones, esterified fatty acids, and hydantoins.

[0739] Pharmaceutical and / or cosmetic compositions comprising a 15-PGDH inhibitor as described herein can additionally contain, for example, at least one compound selected from prostaglandins, particularly prostaglandin PGE 1 、PGE 2 , its salts, its esters, its analogs and its derivatives, particularly those described in WO 98 / 33497, WO 95 / 11003, JP 97-100091, JP 96-134242, particularly agonists of prostaglandin receptors. It can particularly contain at least one compound such as an agonist of the prostaglandin F 2 α receptor (acid form or precursor form, particularly ester form), such as, for example, latanoprost, fluprostenol, cloprostenol, bimatoprost, unoprostone, an agonist of the prostaglandin E 2 receptor (and its precursor, particularly ester, such as travoprost), such as 17-phenyl PGE 2 , vapiprost, butaprost, misoprostol, sulprostone, 16,16-dimethyl PGE 2 , 11-deoxy PGE 1 , 1-deoxy PGE 1, agonists of prostacyclin (IP) receptors and their precursors (especially esters), such as cicaprost, iloprost, isocarbacycline, beraprost, epoprostenol, treprostinil, prostaglandin D 2 agonists of receptors and their precursors (especially esters), such as BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidine heptanoic acid), BW246C ((4R)-(3-[(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidine heptanoic acid), agonists of thromboxane A2 (TP) receptors and their precursors (especially esters), such as I-BOP ([1S-[1a,2a(Z),3b(1E,3S),4a]]-7-[3-[3-hydroxy-4-[4-(iodophenoxy)-1-butenyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptanoic acid).

[0740] Advantageously, the composition may comprise at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or a prostaglandin derivative, such as, for example, prostaglandins of series 2 (including, in particular, the salt form or the precursor form, especially the ester form (e.g., isopropyl ester) of PGF 2α and PGE 2 , its derivatives, such as 16,16-dimethyl PGE 2 、17-phenyl PGE 2 and 16,16-dimethyl PGF 2α 17-phenyl PGF 2α ), prostaglandins of series 1 (such as 11-deoxyprostaglandin E1 in the salt form or ester form, 1-deoxyprostaglandin E1 is its analogue, in particular latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, veliprost, butaprost, misoprostol, its salts or its esters).

[0741] The present invention is further illustrated in the following examples, which are not intended to limit the scope of the claims.

[0742] Examples

[0743] Example A. Analysis of 15 - PGDH inhibitors of the present invention

[0744] 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 shows the IC 50Classified as: <2.5 nM (***), ≥2.5 nM and ≤10 nM (**), or >10 nM (*). Recombinant 15-PGDH is human unless otherwise specified.

[0745] Table 1

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839] Example B. Bioassay

[0840] As determined in the culture medium of A549 cells that had been stimulated with IL1-β for 24 hours, the activity of the compound to induce PGE2 (EC50, in nM) from IL1-β-treated A549 cells was determined. The metabolic stability was determined by incubating the compound at a concentration of 10 μM in the presence of microsomes derived from mouse liver. The compound concentration over time was monitored by HPLC / MS, and the half-life was calculated from the slope of the best-fit line of Ln[compound] versus time.

[0841] Meanwhile, a reference compound and a selected compound described herein were orally administered to mice at 10 mg / kg (mpk). Colonic 15-PGDH activity was evaluated at 30 minutes. As shown in Table 2, the reference compound A was not sufficient to effectively inhibit colonic 15-PGDH activity at 30 minutes and actually showed increased activity (as indicated by -55.2% inhibition). In contrast, the compounds described herein demonstrated inhibition of colonic 15-PGDH activity at 30 minutes. A similar assay was conducted at 4 hours.

[0842] In Table 2, reference compounds A, B, and C have the following structures.

[0843] Reference compounds:

[0844]

[0845] See the disclosures of reference compounds A-C in WO 2015 / 065716 and WO 2018 / 218251, the disclosures of each PCT application are hereby incorporated by reference in their entirety for all purposes.

[0846] Table 2

[0847]

[0848]

[0849] 1 The indication “(R)” before the compound number represents the (R) isomer of the compound shown in Table 1. The stereoisomer indication relates to the sulfoxide sulfur atom.

[0850] The applicant has found that only the IC50 value cannot predict in vivo efficacy, such as in disease models. Other pharmacokinetic and pharmacodynamic properties (such as in vivo inhibition of 15-PGDH, human microsomal stability, hERG IC 50 , and EC50 for PGE2 elevation) are important for in vivo efficacy. Without being bound by theory, in certain embodiments, a clinical candidate should have two or more of the following characteristics: (i) ≥70% or ≥90% inhibition of mouse colonic enzyme at 30 minutes after 10 MPK (PO); (ii) human microsomal stability ≥60 minutes; (iii) hERG IC 50> 15; and (iv) PGE2 elevated EC50 ≤ 10 nM. In some embodiments, the clinical candidate has three or more of the features (i), (ii), (iii), and (iv). In some embodiments, the clinical candidate has the features (i), (ii), (iii), and (iv). For example, a compound with ≥ 90% or even ≥ 70% mouse colon enzyme inhibition 30 minutes after 10 MPK (if this compound also exhibits, for example, (ii) human microsomal stability ≥ 60 minutes; (iii) hERG IC 50 > 15; and / or any combination of two or more of (iiv) EC50 ≤ 10 nM) may exhibit in vivo efficacy. The formulas disclosed herein (e.g., formula VIII) include such compounds with in vivo efficacy.

[0851] In addition, the plasma concentration of the compounds disclosed herein (e.g., compounds of formula VIII and / or Table 2) can be measured using known techniques to determine, for example, the maximum blood concentration, the time to reach the maximum blood concentration, and the area under the plasma concentration curve.

[0852] Synthesis

[0853]

[0854] Example 1A: 6-Thioxo-4-(trifluoromethyl)-1,6-dihydro-[2,3'-bipyridine]-5-carbonitrile. At room temperature, 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. The reaction mixture was stirred under reflux. Once the reaction was complete, the mixture was allowed to stand overnight at 0 °C, filtered, and the dried solid was collected to give the title compound in quantitative yield. ESI-MS (m / z): 282.1 [M+H] + .

[0855]

[0856] 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 Et 3 N (7.36 mmol, 750 mg, 1.0 ml, 1.5 equiv) in dry CH 3Stir in CN (32.0 mL) at 80 °C for 20 min. Then dilute the reaction mixture with EtOAc and water. Separate the organic phase and extract the aqueous layer with EtOAc twice. Wash the combined extracts with saturated NaCl solution, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography to give 599 mg of the desired product. 1 H NMR (400 MHz, chloroform-d) δ 9.32 (dt, J = 2.4, 0.8 Hz, 1H), 8.79 (ddd, J = 4.9, 1.7, 0.7 Hz, 1H), 8.39 (dddd, J = 8.1, 2.4, 1.7, 0.6 Hz, 1H), 7.78 (s, 1H), 7.50 (ddt, J = 8.1, 4.8, 0.8 Hz, 1H), 4.51 (s, 2H), 2.75 (t, J = 7.8 Hz, 2H), 1.72 - 1.60 (m, 2H), 1.42 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3, 3H). ESI-MS (m / z): 384.1 [M + H] + 。

[0857]

[0858] 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 3 / AcOH (1:1, 0.27 M) add H 2 O 2 (372 μL, 30% solution in water). Stir the reaction mixture at 32 °C for 40 min. Once complete, dilute the reaction with EtOAc and wash with saturated NaHCO 3 solution, dry over magnesium sulfate, filter and concentrate under reduced pressure to give 553 mg (93%) of the desired compound. 11H NMR (400 MHz, chloroform-d) δ 9.28 (s, 1H), 8.80 (dd, J = 4.8, 1.5 Hz, 1H), 8.49 (ddt, J = 8.1, 2.6, 1.5 Hz, 1H), 7.87 (s, 1H), 7.55 (ddt, J = 8.0, 4.9, 1.0 Hz, 1H), 4.71 (d, J = 13.3 Hz, 1H), 4.54 (d, J = 13.3 Hz, 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] + 。

[0859]

[0860] 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. Once complete, the reaction was diluted with EtOAc and acidified to pH 7 with a 5% aqueous solution of 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 1H NMR (400 MHz, methylene chloride-d 2 ) δ 9.33 (dd, J = 2.4, 0.9 Hz, 1H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.46 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.49 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.24 (s, 2H), 3.33 (ddd, J = 12.9, 9.0, 6.2 Hz, 1H), 3.17 (ddd, J = 12.9, 9.1, 6.8 Hz, 1H), 1.90 - 1.68 (m, 2H), 1.52 (dd, J = 7.3, 2.5 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 400.1 [M+H] + 。

[0861] On a 1 cm Chiralpak AD-H column, the enantiomers of Example 1 were separated 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 was at 15.1 min.

[0862]

[0863] 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 the analogue of Example 1. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ 9.37 (s, 1H), 8.76 (s, 1H), 8.50 (ddd, J = 8.1, 2.3, 1.5 Hz, 1H), 8.14 (s, 1H), 7.53 (dd, J = 8.0, 4.7 Hz, 1H), 5.27 (s, 2H), 3.56 (t, J = 5.9 Hz, 2H), 3.41 (ddd, J = 13.0, 8.4, 6.5 Hz, 1H), 3.37 (s, 3H), 3.30 (ddd, J = 13.0, 8.4, 6.3 Hz, 1H), 2.19 - 1.96 (m, 2H). ESI-MS (m / z): 416.1 [M+H] + 。

[0864] On a 2 cm Chiralpak AD-H column, the enantiomers of Example 2 were separated 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 was at 41 min.

[0865]

[0866] 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 the analogue of Example 1. 1 H NMR (500 MHz, methylene chloride-d 2)δ9.37(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] + 。

[0867] On a 2 cm Chiralpak AD - H column, the enantiomers of Example 3 were separated using 80% EtOH and 20% hexane at a flow rate of 10 mL / min and an injection volume of 600 μL (concentration 8 mg / ml). The first peak was at 21.9 min and the second peak was at 30 min.

[0868]

[0869] Example 4: 2 - (Cyclobutanesulfinyl) - 6 - (pyridin - 3 - yl) - 4 - (trifluoromethyl)thieno[2,3 - b]pyridin - 3 - amine was prepared using the synthetic procedure described for the preparation of Analog Example 1. 1 H NMR(400 MHz, methylene chloride - d 2 )δ9.33(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] + 。

[0870]

[0871] 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 Analog Example 1. 1 H NMR(400 MHz, methylene chloride - d 2) 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, 3.5 Hz, 1H), 3.73 - 3.59 (m, 2H), 3.39 (s, 3H), 3.32 (ddd, J = 12.6, 7.6, 3.6 Hz, 1H). ESI-MS (m / z): 403.0 [M+H] + 。

[0872]

[0873] Example 6: 2-((3-Methoxypropyl)sulfinyl)-6-(pyrimidin-5-yl)-4-(trifluoromethyl)thiopheno[2,3-b]pyridin-3-amine was prepared using the synthetic procedure described for the preparation of Analog Example 1. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 9.46 (s, 2H), 9.30 (s, 1H), 7.97 (s, 1H), 5.26 (s, 2H), 3.53 (t, J = 5.9 Hz, 2H), 3.42 - 3.35 (m, 1H), 3.34 (s, 3H), 3.27 (ddd, J = 13.0, 8.3, 6.3 Hz, 1H), 2.17 - 1.91 (m, 2H). ESI-MS (m / z): 417.1 [M+H] + 。

[0874]

[0875] Example 7A: 6-(2-Aminopyrimidin-5-yl)-2-chloro-4-(trifluoromethyl)nicotinonitrile. To a 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), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.019 mmol, 16 mg, 5 mol%) in degassed dioxane (1.0 mL) was added an aqueous solution of degassed 2 M sodium carbonate (0.5 mL) and the reaction mixture was stirred under nitrogen at 100 °C for 2.5 h. Once complete, 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 (51% isolated yield) (64 mg). ESI-MS (m / z): 300.0 [M+H] + 。

[0876]

[0877] 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 eq) and the reaction mixture was stirred at 100 °C for 20 min. The reaction progress was monitored by LCMS. Once complete (ca. 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] + 。

[0878] The reaction mixture was diluted with CH 3 CN (1.50 mL). Et 3 N (0.65 mmol, 65.6 mg, 90 μL, 3.0 eq) was added, followed by (chloromethyl)(2-methoxyethyl) sulfane (0.428 mmol, 60 mg, 2.0 eq). The reaction mixture was stirred at room temperature for 15 min. Once complete, 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 the product (28%). 1 1H NMR (400 MHz, chloroform-d) δ 9.03 (s, 2H), 7.59 (s, 1H), 5.52 (s, 2H), 4.55 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.38 (s, 3H), 2.90 (t, J = 6.0 Hz, 2H). ESI-MS (m / z): 402.1 [M+H] + 。

[0879]

[0880] Example 7C: Using the synthetic procedure described for the preparation of analogue example 1, 6-(2-Aminopyrimidin-5-yl)-2-((((2-methoxyethyl)sulfinyl)methyl)thio)-4-(trifluoromethyl)nicotinonitrile was prepared via standard oxidation with hydrogen peroxide (99% isolated yield). 11H NMR (400 MHz, chloroform-d) δ 9.03 (s, 2H), 7.65 (s, 1H), 6.15 (s, 2H), 4.78 (d, J = 13.2 Hz, 1H), 4.67 (d, J = 13.1 Hz, 1H), 3.98 (ddd, J = 10.7, 6.0, 3.6 Hz, 1H), 3.80 (ddd, J = 11.0, 8.4, 3.1 Hz, 1H), 3.40 (s, 3H), 3.18 (ddd, J = 13.8, 8.5, 3.7 Hz, 1H), 3.07 (ddd, J = 13.8, 6.0, 3.1 Hz, 1H). ESI-MS (m / z): 418.1 [M+H] + 。

[0881]

[0882] Example 7: Using 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 via a standard cyclization reaction with potassium hydroxide (71% isolated yield). 1 1H NMR (400 MHz, acetone-d 6 ) 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, 4.2 Hz, 1H), 3.70 (ddd, J = 10.5, 5.8, 4.5 Hz, 1H), 3.52 (ddd, J = 13.2, 5.9, 4.2 Hz, 1H), 3.35 (s, 3H), 3.33 - 3.27 (m, 1H). ESI-MS (m / z): 418.1 [M+H] + 。

[0883]

[0884] Example 8: Using the synthetic procedure described for the preparation of Analog Example 7, 6-(2-aminopyrimidin-5-yl)-2-((3-methoxypropyl)sulfinyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-3-amine was prepared. 1 1H NMR (400 MHz, methylene chloride-d 2) δ 9.06 (s, 2H), 7.93 (s, 1H), 5.46 (s, 2H), 5.20 (s, 2H), 3.52 (t, J = 5.9 Hz, 2H), 3.41 - 3.34 (m, 1H), 3.34 (s, 3H), 3.25 (ddd, J = 13.2, 8.3, 6.5 Hz, 1H), 2.16 - 1.88 (m, 2H). ESI-MS (m / z): 432.1 [M + H] + 。

[0885]

[0886] 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 Analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 8.81 (s, 1H), 8.26 (dd, J = 8.7, 2.4 Hz, 1H), 7.96 (s, 1H), 6.66 (d, J = 9.0 Hz, 1H), 5.18 (s, 2H), 5.03 (s, 2H), 3.52 (t, J = 5.9 Hz, 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] + 。

[0887]

[0888] 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 Analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 8.82 (s, 1H), 8.26 (dd, J = 8.9, 2.3 Hz, 1H), 7.97 (s, 1H), 6.66 (d, J = 8.7 Hz, 1H), 5.14 (s, 2H), 4.97 (s, 2H), 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] + 。

[0889]

[0890] 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 Analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 9.35 (s, 2H), 8.06 (s, 1H), 5.25 (s, 2H), 3.52 (t, J = 5.9 Hz, 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] + .

[0891]

[0892] 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 Analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 9.35 (s, 2H), 8.06 (d, J = 1.2 Hz, 1H), 5.20 (s, 2H), 3.87 (ddd, J = 9.5, 7.6, 3.4 Hz, 1H), 3.73 - 3.58 (m, 2H), 3.39 (s, 3H), 3.32 (ddd, J = 12.9, 7.6, 3.6 Hz, 1H), 2.81 (s, 3H). ESI-MS (m / z): 417.0 [M+H] + .

[0893]

[0894] 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 Analog Example 7. 1 HNMR (500 MHz, methylene chloride-d 2) 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 = 5.5 Hz, 2H), 3.71 (td, J = 5.7, 3.0 Hz, 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] + 。

[0895]

[0896] 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 analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 9.03 (s, 2H), 7.89 (s, 1H), 6.01 (s, 1H), 5.19 (s, 2H), 3.95 - 3.79 (m, 2H), 3.68 (td, J = 5.7, 4.4 Hz, 2H), 3.52 (t, J = 5.9 Hz, 2H), 3.41 - 3.31 (m, 1H), 3.33 (s, 3H), 3.24 (ddd, J = 13.0, 8.2, 6.5 Hz, 1H), 3.00 (s, 1H), 2.18 - 1.86 (m, 2H). ESI-MS (m / z): 476.1 [M + H] + 。

[0897]

[0898] 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 analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2)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, 3.7 Hz, 1H). ESI-MS (m / z): 462.1 [M+H] + 。

[0899]

[0900] 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 (400 MHz, methylene chloride-d 2 )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 - 3.56 (m, 2H), 3.38 (s, 3H), 3.32 (s, 3H), 3.31 - 3.24 (m, 1H). ESI-MS (m / z): 476.1 [M+H] + 。

[0901]

[0902] 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. 1 H NMR (400 MHz, methylene chloride-d 2 )δ 9.06 (s, 2H), 7.90 (s, 1H), 5.19 (s, 2H), 3.89 (s, 4H), 3.51 (t, J=5.9 Hz, 2H), 3.40 - 3.34 (m, 1H), 3.33 (s, 3H), 3.32 (s, 3H), 3.24 (ddd, J=13.1, 8.3, 6.6 Hz, 1H), 2.18 - 1.86 (m, 2H). ESI-MS (m / z): 490.1 [M+H] + 。

[0903]

[0904] Example 18: 2-((5-(3-Amino-2-(cyclobutanesulfinyl)-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 Analog Example 7. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ 9.04 (s, 2H), 7.89 (s, 1H), 5.13 (s, 2H), 3.97 (p, J = 8.1 Hz, 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] + .

[0905]

[0906] 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 overnight at room temperature. The solvent was evaporated to give the desired product in quantitative yield.

[0907] 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. Once complete, the reaction mixture was filtered, the solid obtained was suspended in water, filtered 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]+.

[0908]

[0909] Example 19B: 4-Chloro-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile. The reaction mixture of 6-oxo-4-phenyl-2-(pyridin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile in POCl3 (1 mL) was stirred at 100 °C for 20 min. Once completed (monitored by LCMS), the reaction mixture was cooled to room temperature and Et2O was added. The formed 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]+.

[0910]

[0911] Example 19C: 4-(((butylthio)methyl)thio)-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile. Sodium sulfide (85 mg, 1.09 mmol, 1.09 equiv) was added to crude 4-(((butylthio)methyl)thio)-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile (300 mg, 1.0 mmol) in DMF (1 mL) and the reaction mixture was stirred at 100 °C for 20 min. The reaction progress was followed by LCMS. Once completed, concentrated HCl was added and the reaction mixture was stirred in the hood for 10 min. ESI-MS (m / z): 291.0 [M+H]+.

[0912] 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. Once completed, 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 the product (62%). 1 1H NMR (400 MHz, chloroform-d) δ 9.83 (s, 1H), 9.43 (d, J = 8.8 Hz, 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 = 7.4 Hz, 2H), 1.64 (p, J = 7.4 Hz, 2H), 1.43 (h, J = 7.3 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). ESI-MS (m / z): 393.1 [M+H]+.

[0913]

[0914] Example 19D: 4-(((butylsulfinyl)methyl)thio)-6-phenyl-2-(pyridin-3-yl)pyrimidine-5-carbonitrile (98% isolated yield) was prepared via standard oxidation with hydrogen peroxide using the synthetic procedure described for the preparation of Analog Example 1. 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 = 6.9 Hz, 1H), 8.19 - 8.12 (m, 2H), 7.68 - 7.56 (m, 4H), 4.77 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 13.3 Hz, 1H), 3.05 - 2.85 (m, 2H), 1.95 - 1.74 (m, 2H), 1.64 - 1.43 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). ESI-MS (m / z): 409.1 [M+H]+.

[0915]

[0916] 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 eq, in 200 μl of water). The reaction mixture was stirred at room temperature for 20 min (monitoring the reaction by TLC). Once complete, the reaction was diluted with EtOAc and washed with 5% aqueous acetic acid. The organic phase was separated and the aqueous layer was extracted twice with EtOAc, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (48% isolated yield). 1 H NMR (400 MHz, methylene chloride-d2) δ 9.72 (s, 1H), 8.92 - 8.77 (m, 1H), 8.71 (d, J = 4.7 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.71 - 7.55 (m, 3H), 7.45 (dd, J = 8.0, 4.8 Hz, 1H), 4.83 (s, 2H), 3.28 (ddd, J = 12.7, 9.0, 6.1 Hz, 1H), 3.13 (ddd, J = 12.8, 9.1, 6.6 Hz, 1H), 1.85 - 1.59 (m, 2H), 1.59 - 1.38 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H). ESI-MS (m / z): 409.1 [M+H]+.

[0917] On a 1 cm Chiralpak AD-H column, the enantiomers of Example 19 were separated 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 at 5.5 min and the second peak was at 14.7 min.

[0918]

[0919] 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 the analogue Example 19. 1 H NMR (400 MHz, methylene chloride-d2) δ 9.72 (dd, J = 2.0, 1.0 Hz, 1H), 8.89 - 8.77 (m, 1H), 8.71 (dd, J = 4.7, 1.7 Hz, 1H), 7.83 - 7.70 (m, 2H), 7.70 - 7.57 (m, 3H), 7.45 (ddd, J = 8.0, 4.8, 1.0 Hz, 1H), 4.83 (s, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.38 - 3.28 (m, 1H), 3.32 (s, 3H), 3.22 (ddd, J = 12.8, 8.1, 6.4 Hz, 1H), 2.09 - 1.89 (m, 2H). ESI-MS (m / z): 425.1 [M+H]+.

[0920] On a 1 cm Chiralpak AD-H column, the enantiomers of Example 20 were separated 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 at 8.34 min and the second peak was at 27.5 min.

[0921]

[0922] 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 the analogue Example 19. 11H NMR (400 MHz, methylene chloride-d2) δ 9.73 (s, 1H), 8.80 (d, J = 8.0 Hz, 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 = 8.1 Hz, 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]+.

[0923]

[0924] 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 Analog Example 19. 1 1H NMR (400 MHz, methylene chloride-d2) δ 9.70 - 9.57 (m, 1H), 8.71 (dt, J = 8.0, 2.0 Hz, 1H), 8.68 (dd, J = 4.9, 1.7 Hz, 1H), 7.47 - 7.35 (m, 1H), 5.26 (s, 2H), 3.92 (p, J = 8.0 Hz, 1H), 2.88 - 2.73 (m, 1H), 2.68 (tt, J = 8.1, 4.7 Hz, 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]+.

[0925]

[0926] 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 Analog Example 19. 11H NMR (400 MHz, methylene chloride-d2) δ 9.63 (dd, J = 2.2, 0.9 Hz, 1H), 8.71 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 7.42 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.25 (s, 2H), 3.86 (ddd, J = 10.5, 7.6, 4.0 Hz, 1H), 3.68 (ddd, J = 10.5, 6.3, 4.3 Hz, 1H), 3.58 (ddd, J = 13.0, 6.3, 4.0 Hz, 1H), 3.39 (s, 3H), 3.27 (ddd, J = 13.1, 7.5, 4.3 Hz, 1H), 2.66 (tt, J = 8.0, 4.7 Hz, 1H), 1.59 - 1.54 (m, 2H), 1.30 - 1.25 (m, 2H). ESI-MS (m / z): 375.1 [M+H]+.

[0927]

[0928] 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 Analog Example 19. 1 1H NMR (400 MHz, methylene chloride-d2) δ 9.63 (dd, J = 2.2, 0.9 Hz, 1H), 8.71 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 7.41 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.30 (s, 2H), 3.52 (t, J = 5.9 Hz, 2H), 3.37 - 3.28 (m, 1H), 3.34 (s, 3H), 3.22 (ddd, J = 13...

Claims

1. A compound having the formula (IA): or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 3- to 6-membered cycloalkyl or -(C 1 -C 6 -alkylene)-(C 1 -C 6 -alkoxy); R 2 is -NH 2 or -NHC(O)-C 1 -C 6 alkyl; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C3-C6 cycloalkyl or 5-10 membered heteroaryl, each optionally substituted with one or more R 4 substituents; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 alkylene)-OH; R 4 is a halogen, C 1 -C 6 -alkyl, -(C 1 -C 6 -alkylene)-O-(C 1 -C 6 -alkyl) or a 3- to 10-membered cycloalkyl; X is N or CH; and n is 1.

2. The compound or salt according to claim 1, wherein R 1 is a 3- to 6-membered cycloalkyl group.

3. The compound or salt according to claim 1, wherein R 1 is -(C 1 -C 6 -alkylene)-(C 1 -C 6 -alkoxy).

4. The compound or salt according to claim 1, wherein R 2 is -NH 2 .

5. The compound or salt according to claim 1, wherein R 6 is substituted by one or more R 3 substituents 6. The compound or salt according to claim 5, wherein R 7 is C 1 -C 6 alkyl or C3-C6 cycloalkyl.

7. The compound or salt according to claim 1, wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl or a 5- to 10-membered heteroaryl, each of which is substituted by one or more R 4 substituents.

8. The compound or salt according to claim 1, wherein R 7 is C 1 -C 6 haloalkyl, C3-C6 cycloalkyl, C5-C10 heteroaryl, each of which is optionally substituted by one or more R 4 substituents.

9. The compound or salt according to claim 1, wherein R 3 is -(C 1 -C 6 -alkylene)-OH.

10. The compound or salt according to claim 1, wherein R 3 is C 1 -C 6 alkyl.

11. The compound or salt according to claim 5, wherein R 3 is C 1 -C 3 alkyl.

12. The compound or salt according to claim 1, wherein R 4 is C 1 -C 6 alkyl.

13. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is a 3- to 6-membered cycloalkyl group; R 2 is -NH 2 ; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a 3- to 6-membered cycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted by one or more R 4 substituents; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 alkylene)-OH; R 4 is halogen, C 1 -C 6 -alkyl, -(C 1 -C 6 -alkylene)-O-(C 1 -C 6 -alkyl) or a 3- to 10-membered cycloalkyl; X is N or CH.

14. The compound or salt according to claim 13, wherein R 1 is a 3- to 5-membered cycloalkyl group.

15. The compound or salt according to claim 13, wherein R 1 is cyclobutyl.

16. The compound or salt according to claim 13, wherein R 1 is bicyclic C4-C6 cycloalkyl.

17. The compound or salt according to claim 13, wherein R 7 is C 1 -C 6 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with one or more R 4 substituents.

18. The compound or salt according to claim 13, wherein R 7 is C 1 -C 4 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with one or more R 4 substituents.

19. The compound or salt according to claim 13, wherein R 7 is C 1 -C 3 alkyl or cycloalkyl having 3 members, each of which is optionally substituted with one or more R 4 substituents.

20. The compound or salt according to claim 13, wherein R 7 is isopropyl or cyclopropyl, each optionally substituted by one or more R 4 substituents.

21. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is a 3- to 6-membered cycloalkyl group or -(C 1 -C 6 -alkylene)-(C 1 -C 6 -alkoxy); R 2 is -NH 2 or -NHC(O)-C 1 -C 6 alkyl; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is C 1 -C 6 a haloalkyl or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one or more R 4 substituents; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 -alkylene)-OH, R 4 is a halogen or a C 1 -C 6 alkyl; and X is N or CH.

22. The compound or salt according to claim 21, wherein R 7 is -CF 3 , pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with one or more R 4 substituents.

23. The compound or salt according to claim 21, wherein R 7 is -CF 3 , pyridyl, pyrazole, fluorophenyl, or triazole, which is optionally substituted by halogen or methyl.

24. The compound or salt according to claim 21, wherein R 7 is -CF 3 、 25. The compound or salt according to claim 21, wherein R 7 is -CF 3 .

26. The compound or salt according to claim 21, wherein R 7 is 27. The compound or salt according to claim 21, wherein R 7 is 28. The compound or salt according to claim 21, wherein R 6 is substituted by one or more R 3 groups.

29. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is a 3- to 6-membered cycloalkyl or -(C 1 -C 6 -alkylene)-(C 1 -C 6 -alkoxy); R 2 is -NH 2 or -NHC(O)-C 1 -C 6 alkyl; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is an optionally 3- to 6-membered cycloalkyl group substituted with one or more R 4 groups; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 alkylene)-OH, R 4 is a halogen, C 1 -C 6 -alkyl, -(C 1 -C 6 -alkylene)-O-(C 1 -C 6 -alkyl) or a 3- to 10-membered cycloalkyl; and X is N or CH.

30. The compound or salt according to claim 29, wherein R 7 is cyclopropyl.

31. The compound or salt according to claim 29, wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

32. The compound or salt according to claim 29, wherein R 3 is C 1 -C 6 alkyl.

33. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is a 3- to 6-membered cycloalkyl group or -(C 1 -C 6 -alkylene)-(C 1 -C 6 -alkoxy); R 2 is -NH 2 ; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is C 1 -C 6 haloalkyl, C3-C6 cycloalkyl or 5-10 membered heteroaryl, each optionally substituted by one or more R 4 substituents; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 -alkylene)-OH; R 4 is a halogen, C 1 -C 6 -alkyl, -(C 1 -C 6 -alkylene)-O-(C 1 -C 6 -alkyl) or a C3-C10 cycloalkyl; and X is N.

34. The compound or salt according to claim 33, wherein R 3 is C 1 -C 6 alkyl.

35. The compound or salt according to claim 33, wherein R 7 is C 1 -C 3 haloalkyl, 3-membered cycloalkyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 substituents.

36. The compound or salt according to claim 33, wherein R 7 is -CF 3 , cyclopropyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted by one or more R 4 substituents.

37. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is a 3- to 6-membered cycloalkyl or -(C 1 -C 6 -alkylene)-(C 1 -C 6 -alkoxy); R 2 is -NH 2 ; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is C 1 -C 6 alkyl or C3-C6 cycloalkyl; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 -alkylene)-OH, R 4 is C 1 -C 6 alkyl; and X is N.

38. The compound or salt according to claim 37, wherein R 6 is substituted by one or more R 3 groups.

39. The compound or salt according to claim 37, wherein R 7 is C 1 -C 4 alkyl or 3- to 6-membered cycloalkyl, each of which is optionally substituted with one or more R 4 substituents.

40. The compound or salt according to claim 37, wherein R 7 is C 1 -C 3 alkyl or 3- to 6-membered cycloalkyl, each of which is optionally substituted by one or more R 4 substituents.

41. The compound or salt according to claim 37, wherein R 7 is C 1 -C 3 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with one or more R 4 substituents.

42. The compound or salt according to claim 37, wherein R 7 is isopropyl or cyclopropyl.

43. The compound or salt according to claim 37, wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

44. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is cyclobutyl or -(C 1 -C 4 -alkylene)-(C 1 -C 3 -alkoxy); R 2 is -NH 2 or -NHC(O)-C 1 -C 6 alkyl; R 6 is each optionally substituted by one or more R 3 substituents; R 7 is -CF 3 , isopropyl, where p is 0 or 1; R 3 is C 1 -C 6 alkyl or -(C 1 -C 6 alkylene)-OH; R 4 is C 1 -C 3 alkyl; and X is N or CH.

45. The compound or salt according to claim 1, wherein the compound has the structure of formula (II): wherein: R 1 is cyclobutyl or -(C 1 -C 4 -alkylene)-(C 1 -C 3 -alkoxy); R 2 is -NH 2 or -NHC(O)-C 1 -C 6 alkyl; R 6 is each optionally substituted with one or more R 3 substituents; R 7 is -CF 3 , isopropyl, cyclopropyl, cyclobutyl, each of which is optionally substituted by one or more R 4 substituents; R 3 is -NH 2 、-NH(C 1 -C 3 -alkyl), -NH(C 1 -C 4 -alkylene)-OH, or C 1 -C 3 -alkyl; R 4 is C 1 -C 3 alkyl; and X is N or CH.

46. The compound or salt according to claim 1, wherein R 3 is C 1 -C 6 alkyl.

47. The compound or salt according to claim 5, wherein R 3 is methyl.

48. The compound or salt according to claim 1, wherein the compound is selected from the group consisting of:

49. The compound according to claim 1, wherein the compound is:

50. The compound according to claim 1, wherein the compound is:

51. The compound according to claim 1, wherein the compound is:

52. The compound according to claim 1, wherein the compound is:

53. The compound according to claim 1, wherein the compound is:

54. The compound according to claim 1, wherein the compound is:

55. The compound according to claim 1, wherein the compound is:

56. The compound according to claim 1, wherein the compound is:

57. The salt according to claim 1, wherein the compound is:

58. The salt according to claim 1, wherein the compound is:

59. The salt according to claim 1, wherein the compound is:

60. The salt according to claim 1, wherein the compound is:

61. The salt according to claim 1, wherein the compound is:

62. The salt according to claim 1, wherein the compound is:

63. The salt according to claim 1, wherein the compound is:

64. The salt according to claim 1, wherein the compound is:

65. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 64 and a pharmaceutically acceptable excipient or carrier.

66. Use of the compound or salt according to any one of claims 1 to 64 as a 15 - PGDH inhibitor in the preparation of a medicament for the treatment of colitis.

67. Use of the compound or salt according to any one of claims 1 to 64 as a 15 - PGDH inhibitor in the preparation of a medicament for the treatment of ulcerative colitis.

68. Use of the compound or salt according to any one of claims 1 to 64 as a 15 - PGDH inhibitor in the preparation of a medicament for the treatment of inflammatory bowel disease. Use of a compound or a salt according to any one of claims 1 to 64 as a 15-PGDH inhibitor in the manufacture of a medicament for the treatment of Crohn's disease.

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