Compositions and methods of modulating short-chain dehydrogenase activity

Abstract

Compounds having a structure of formula (IA): [Image disponible dans le document PDF, Image available in the PDF document] and pharmaceutically acceptable salts, tautomers, and solvates thereof, and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and / or prostaglandin levels include 15-PGDH inhibitors described herein.

Description

DEMANDE OU BREVET VOLUMINEUX LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND PLUS D'UN TOME. CECI EST LE TOME 1 DE 2 CONTENANT LES PAGES 1 À 315 NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS / PATENTS THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE THAN ONE VOLUME THIS IS VOLUME 1 OF 2 CONTAINING PAGES 1 TO 315 NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME : NOTE POUR LE TOME / VOLUME NOTE: COMPOSITIONS AND METHODS OF MODULATING SHORT-CHAIN DEHYDROGENASE ACTIVITY CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 770,571, filed November 21, 2018. GOVERNMENT FUNDING

[0002] 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 United States government has certain rights to the invention. BACKGROUND

[0003] Short-chain dehydrogenases (SCDs) are a family of dehydrogenases that share only 15% to 30% sequence identity, with similarity predominantly in the coenzyme binding domain and the substrate binding domain. In addition to their role in detoxification of ethanol, SCDs are involved in synthesis and degradation of fatty acids, steroids, and some prostaglandins, and are therefore implicated in a variety of disorders such as lipid storage disease, myopathy, SCD deficiency, and certain genetic disorders.

[0004] The SCD, 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), (hydroxyprostaglandin dehydrogenase 15-(nicotinamide adeninedinucleotide); 15-PGDH; Enzyme Commission number 1.1.1.141; encoded by the HPGD gene), represents the key enzyme in the inactivation of a number of active prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs) (e.g., by catalyzing oxidation of PGE<com:Sub>2< / com:Sub> to 15-keto- prostaglandin E2, 15k-PGE). The human enzyme is encoded by the HPGD gene and consists of a homodimer with subunits of a size of 29 kDa. The enzyme belongs to the evolutionarily conserved superfamily of short-chain dehydrogenase / reductase enzymes (SDRs), and according to the recently approved nomenclature for human enzymes, it is named SDR36C1. Thus far, two forms of 15-PGDH enzyme activity have been identified, NAD+-dependent type I 15-PGDH that is encoded by the HPGD gene, and the 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 prostaglandin suggest that the majority of the in vivo activity can be attributed to type I 15-PGDH encoded by the HPGD gene, that hereafter, and throughout all following text, simply denoted as 15-PGDH.

[0005] Recent studies suggest that inhibitors of 15-PGDH and activators of 15-PGDH could be therapeutically valuable. It has been shown that there is an increase in the incidence of colon tumors in 15-PGDH knockout mouse models. A more recent study implicates increased 15-PGDH expression in the protection of thrombin-mediated cell death. It is well known that 15-PGDH is responsible for the inactivation of prostaglandin E2 (PGE<com:Sub>2< / com:Sub>), which is a downstream product of COX-2 metabolism. PGE<com:Sub>2< / com:Sub> has been shown to be beneficial in a variety of biological processes, such as hair density, dermal wound healing, and bone formation. SUMMARY

[0006] Embodiments described herein relate to compounds and methods of modulating short chain dehydrogenase (SCD) (e.g., 15-PGDH) activities, modulating tissue prostaglandin levels, and / or treating diseases, disorders, or conditions in which it is desired to modulate SCD (e.g., 15-PGDH) activity and / or prostaglandin levels.

[0007] In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to tissue or blood of a subject at an amount effective to inhibit the activity of a short chain dehydrogenase enzyme. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to tissue or blood of a subject at an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor can include a compound having a structure of formula (IA): [Image disponible dans le document PDF, Image available in the PDF document] (IA) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -N(R<com:Sup>5< / com:Sup>)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>- alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math>; R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; R<com:Sup>10< / com:Sup> is –OH, halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2; n is 0, 1, or 2; and t is 0, 1, or 2.

[0008] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered cycloalkyl), -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkoxy), 3- to 6-membered heterocyclyl, or -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered heterocyclyl).

[0009] In other embodiments, R<com:Sup>1< / com:Sup> is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopropyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclobutyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopentyl, or -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclohexyl; wherein p is 1, 2, or 3.

[0010] In still other embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>.

[0011] In some embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0012] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0013] In still other embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0014] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−C(O)NR5(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)NR^5(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0015] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0016] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0017] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6)<annotation encoding="application / x-tex">-O-(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)(C1−C6)<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)N(R5)2<annotation encoding="application / x-tex">-C(O)N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)N(R5)(C1−C6)<annotation encoding="application / x-tex">-C(O)N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl), <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>.

[0018] In other embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl)OH, -NH<com:Sub>2< / com:Sub>, -N(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl)<com:Sub>2< / com:Sub>, -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, N(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH)<com:Sub>2< / com:Sub>, -NHCH<com:Sub>2< / com:Sub>CH(CH<com:Sub>2< / com:Sub>OH)<com:Sub>2< / com:Sub>, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)CH<com:Sub>2< / com:Sub>CH(CH<com:Sub>2< / com:Sub>OH)<com:Sub>2< / com:Sub>, -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl), -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)<com:Sub>2< / com:Sub>, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl), -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)<com:Sub>2< / com:Sub>, -NHSO<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)SO<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl), or -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)<com:Sub>2< / com:Sub>.

[0019] In still other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[0020] In some embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is halogen, -CN, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -OH, -O-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- OH, <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)−(3− to 6-membered cycloalkyl)<annotation encoding="application / x-tex">-C(O)-(3-\text{ to 6-membered cycloalkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−C6<annotation encoding="application / x-tex">C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[0021] In some embodiments, n is 1.

[0022] In other embodiments, the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(Π)<annotation encoding="application / x-tex">(\Pi)< / annotation>< / semantics>< / com:Math> or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is 3- to 6-membered cycloalkyl, -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)-(3- to 6-membered cycloalkyl), 3-to 6-membered heterocyclyl, or -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered heterocyclyl); [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is oxo, <com:Math><semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-alkylene-<com:Math><semantics>N(R5)2<annotation encoding="application / x-tex">N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)<annotation encoding="application / x-tex">-N(R^5)< / annotation>< / semantics>< / com:Math>(alkylene-<com:Math><semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>< / com:Math>), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; X is N or CH; m is 0, 1, or 2; and t is 0, 1, or 2.

[0023] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is 3- to 5-membered cycloalkyl or -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- (3- to 5-membered cycloalkyl).

[0024] In other embodiments, R<com:Sup>1< / com:Sup> is cyclobutyl.

[0025] In still other embodiments, R<com:Sup>1< / com:Sup> is a bicyclic 4- to 6-membered cycloalkyl.

[0026] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−C(O)NR5(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)NR^5(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0027] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>.

[0028] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ3<annotation encoding="application / x-tex">\mathbb{C}_3< / annotation>< / semantics>< / com:Math> haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0029] In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>. In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. 」 F、∕◎

[0030] In some embodiments, R<com:Sup>7< / com:Sup> is –CF<com:Sub>3< / com:Sub>, isopropyl, <com:Math><semantics>N=N−N−N−N−N−N−N−N−N−<annotation encoding="application / x-tex">N = N - N - N - N - N - N - N - N - N -< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document]

[0031] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>, isopropyl, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0032] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>, [Image disponible dans le document PDF, Image available in the PDF document] .

[0033] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is -O-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene-OH), -C(O)N(<com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math>)2, -C(O)N(<com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math>)(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene-OH), -C(O)(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl), - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0035] In still other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[0036] In other embodiments, the compound has the structure of formula (III): [Image disponible dans le document PDF, Image available in the PDF document] (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>; [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternative, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>4< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; and m is 0, 1, or 2.

[0037] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is cyclobutyl. In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-<com:Math><semantics>(C1−C3 alkoxy)<annotation encoding="application / x-tex">(C_1-C_3 \text{ alkoxy})< / annotation>< / semantics>< / com:Math>.

[0038] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>, pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>.

[0039] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>, pyridyl, fluorophenyl, or a triazole optionally substitued with one or more halogen or methyl. [Image disponible dans le document PDF, Image available in the PDF document]

[0040] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>, [Image disponible dans le document PDF, Image available in the PDF document]

[0041] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document]

[0042] In still other embodiments, <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is [Image disponible dans le document PDF, Image available in the PDF document]

[0043] In some embodiments, R<com:Sup>7< / com:Sup> is *

[0044] In other embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0045] In othere embodiments, the compound has the structure of formula (IV): [Image disponible dans le document PDF, Image available in the PDF document] (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is 3- to 6-membered cycloalkyl, optionally substituted with one or more R<com:Sup>4< / com:Sup>; [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, [Image disponible dans le document PDF, Image available in the PDF document] or alternative, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2.

[0046] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is cyclopropyl.

[0047] In other embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is 3- to 6-membered cycloalkyl, -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)-(3- to 6-membered cycloalkyl), -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkoxy), 3- to 6-membered heterocyclyl, or <com:Math><semantics>−(C1−C6 alkylene)<annotation encoding="application / x-tex">-(C_1-C_6 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-(3- to 6-membered heterocyclyl).

[0048] In some embodiments, R<com:Sup>1< / com:Sup> is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopropyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclobutyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopentyl, or -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclohexyl; wherein p is 1, 2, or 3.

[0049] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is cyclobutyl. In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-<com:Math><semantics>(C1−C3 alkoxy)<annotation encoding="application / x-tex">(C_1-C_3 \text{ alkoxy})< / annotation>< / semantics>< / com:Math>.

[0050] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6)<annotation encoding="application / x-tex">-O-(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)(C1−C6)<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)N(R5)2<annotation encoding="application / x-tex">-C(O)N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)N(R5)(C1−C6)<annotation encoding="application / x-tex">-C(O)N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0053] In other embodiments, the compound has the structure of formula (V): [Image disponible dans le document PDF, Image available in the PDF document] (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently H, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(R<com:Sup>9< / com:Sup>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH<com:Sub>2< / com:Sub>, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, alkylene-COOH, or <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub> alkyl); or alternative, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; [Image disponible dans le document PDF, Image available in the PDF document]

[0054] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is cyclobutyl. In some embodiments, <com:Math><semantics>−(C1−C4)<annotation encoding="application / x-tex">-(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene)-<com:Math><semantics>(C1−C3 alkoxy)<annotation encoding="application / x-tex">(C_1-C_3 \text{ alkoxy})< / annotation>< / semantics>< / com:Math>.

[0055] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6<annotation encoding="application / x-tex">-O-(C_1-C_6< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−N(R5)(C1−C6)2<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)_2< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub> alkylene-OH).

[0056] In other embodiments, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)-OH, or -S(O)<com:Sub>2< / com:Sub>(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>- C<com:Sub>3< / com:Sub> alkyl). [Image disponible dans le document PDF, Image available in the PDF document]

[0058] In other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[0059] In still other embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NHCH2CH2OH<annotation encoding="application / x-tex">-NHCH_2CH_2OH< / annotation>< / semantics>< / com:Math>.

[0060] In some embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0061] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0062] In some embodiments, R<com:Sup>6< / com:Sup> is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isooxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0063] In other embodiments, R<com:Sup>6< / com:Sup> is thiazole, imidazole, oxazole, pyridine, or pyrimidine.

[0064] In some embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[0065] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclyl, optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>, selected from morpholine, pyridine-one, or piperidine.

[0066] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0067] In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, cyclopropyl, phenyl, pyrzole, pyridyl, or triazole, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>. In still other [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0068] In some embodiments, the compound has the structure of formula (VI): [Image disponible dans le document PDF, Image available in the PDF document] (VI) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is fused bicyclic heterocyclyl or fused bicyclic heteroaryl, each of which is optionally substituted with one or more R<com:Sup>3< / com:Sup>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>-alkyl; R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_{m}< / annotation>< / semantics>< / com:Math>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; and m is 0, 1, or 2.

[0069] In some embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more R<com:Sup>3< / com:Sup>.

[0070] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−C(O)NR5(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)NR^5(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0071] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0072] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0073] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[0074] In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>. In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted [Image disponible dans le document PDF, Image available in the PDF document] with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>. In further embodiments, <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is isopropyl, [Image disponible dans le document PDF, Image available in the PDF document]

[0075] In further embodiments, R<com:Sup>7< / com:Sup> is [Image disponible dans le document PDF, Image available in the PDF document]

[0076] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered cycloalkyl), -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkoxy), 3- to 6-membered heterocyclyl, or -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered heterocyclyl).

[0077] In other embodiments, R<com:Sup>1< / com:Sup> is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopropyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclobutyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopentyl, or -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclohexyl; wherein p is 1, 2, or 3. In some embodiments, R<com:Sup>1< / com:Sup> is cyclobutyl. In some embodiments, <com:Math><semantics>−(C1−C4 alkylene)−(C1−C3 alkoxy).<annotation encoding="application / x-tex">-(C_1-C_4 \text{ alkylene})-(C_1-C_3 \text{ alkoxy}).< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0080] In some embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[0081] In other embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is halogen, -CN, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -OH, -O-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- OH, <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)−(3− to 6-membered cycloalkyl)<annotation encoding="application / x-tex">-C(O)-(3-\text{ to 6-membered cycloalkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−C6<annotation encoding="application / x-tex">C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[0082] In some embodiments, the compound has the structure of formula (VII): [Image disponible dans le document PDF, Image available in the PDF document] (VII) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is cyclobutyl or -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkoxy); [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] -N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -N(R<com:Sup>5< / com:Sup>)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>- alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; R<com:Sup>10< / com:Sup> is –OH, halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2; p is 0 or 1; and t is 0, 1, or 2.

[0083] In some embodiments, the compound has the structure of formula (VIII): [Image disponible dans le document PDF, Image available in the PDF document] (VIII) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is cyclobutyl or -(<com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ4<annotation encoding="application / x-tex">\mathbb{C}_4< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ3<annotation encoding="application / x-tex">\mathbb{C}_3< / annotation>< / semantics>< / com:Math> alkoxy); <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CN<annotation encoding="application / x-tex">CN< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−NHC(O)<annotation encoding="application / x-tex">-NHC(O)< / annotation>< / semantics>< / com:Math>alkyl; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>7< / com:Sup> is –CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, cyclobutyl, [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl; and X is N or CH.

[0084] In some embodiments, the compound or 15-PGDH inhibitor can inhibit the enzymatic activity of recombinant 15-PGDH at an IC<com:Sub>50< / com:Sub> of less than 1 μM, at an IC<com:Sub>50< / com:Sub> of less than 250 nM, at an IC<com:Sub>50< / com:Sub> of less than 50 nM, at an IC<com:Sub>50< / com:Sub> of less than 10 nM, at an IC<com:Sub>50< / com:Sub> of less than 5 nM at a recombinant, at an IC<com:Sub>50< / com:Sub> of about 2.5 nM to about 10 nM, or less than about 2.5 nM at a 15-PGDH concentration of about 5 nM to about 10 nM.

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

[0086] 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 a tissue graft.

[0087] In one embodiment, the 15-PGDH inhibitor can be administered to a subject to treat at least one of oral ulcers, gum disease, colitis, ulcerative colitis, gastrointestinal ulcers, inflammatory bowel disease, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary artery hypertension, cardiovascular disease, and renal disease.

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

[0089] In other embodiments, the 15-PGDH inhibitor can be administered to a subject and / or tissue of the subject to increase tissue stem cells. For example, the 15-PGDH inhibitor can be administered to bone marrow of a subject to increase stem cells in the subject.

[0090] In still other embodiments, the 15-PGDH inhibitor can be administered to a tissue graft donor, 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 increase the fitness of a donor tissue graft, a donor bone marrow graft, and / or a 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 bone marrow of a subject to increase the fitness of the marrow as a donor graft, and / or to a preparation of hematopoietic stem cells of a subject to increase the fitness of the stem cell preparation as a donor graft, and / or to a preparation of peripheral blood hematopoietic stem cells of a subject to increase the fitness of the stem cell preparation as a donor graft, and / or to a preparation of umbilical cord blood stem cells to increase the fitness of the stem cell preparation as a donor graft, and / or to a preparation of umbilical cord blood stem cells to decrease the number of units of umbilical cord blood required for transplantation.

[0091] In other embodiments, the 15-PGDH inhibitor can be administered to a subject to mitigate tissue graft rejection, to enhance tissue and / or bone marrow graft engraftment, to enhance bone marrow graft engraftment, following treatment of the subject or the marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy, to enhance engraftment of a progenitor stem cell graft, hematopoietic stem cell graft, or an umbilical cord blood stem cell graft, to enhance engraftment of a hematopoietic stem cell graft, or an umbilical cord stem cell graft, following treatment of the subject or the marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy, and / or in order to decrease the number of units of umbilical cord blood required for transplantation into the subject.

[0092] In other embodiments, the 15-PGDH inhibitor can be administered to a recipient of a tissue graft transplant, bone marrow transplant, and / or hematopoietic stem cell transplant, or of an umbilical cord stem cell transplant, in order to decrease the administration of other treatments or growth factors.

[0093] In some embodiments, the 15-PGDH inhibitor can be administered to a subject or to a tissue graft of a subject to mitigate graft rejection, to enhance graft engraftment, and / or to enhance graft engraftment following treatment of the subject or the marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy.

[0094] In other embodiments, the 15-PGDH inhibitor can be administered to a subject or to the bone marrow of a subject to confer resistance to toxic or lethal effects of exposure to radiation, to confer resistance to the toxic effect of Cytoxan, the toxic effect of fludarabine, the toxic effect of chemotherapy, or the toxic effect of immunosuppressive therapy, to decrease pulmonary toxicity from radiation, and / or to decrease infection.

[0095] In still other embodiments, the 15-PGDH inhibitor can be administered to a subject to increase neutrophil counts following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase neutrophil counts in a subject with neutropia following 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 following viral infections, to increase neutrophil counts in a subject with neutropia, to increase platelet counts following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase platelet counts in a subject with thrombocytopenia following 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 following viral infections, to increase platelet counts in a subject with thrombocytopenia, to increase red blood cell counts, or hematocrit, or hemoglobin level, following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase red blood cell counts, or hematocrit, or hemoglobin level in a subject with anemia following 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 disorder of bone marrow, drug induced anemia, immune mediated anemias, anemia of chronic disease, anemia following viral infections, or anemia of unknown cause, to increase red blood cell counts, or hematocrit, or hemoglobin level in a subject with anemia, to increase bone marrow stem cells, following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase bone marrow stem cells in a subject following chemotherapy administration or radiation therapy, and / or to increase bone marrow stem cells in a subject with aplastic anemia, myelodysplasia, myelofibrosis, other disorder of bone marrow, drug induced cytopenias, immune cytopenias, cytopenias following viral infections, or cytopenias.

[0096] In other embodiments, the 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 a cytokine to a subject in need thereof to increase and / or mobilize hematopoiectic stem cells and / or neutrophils in the blood, marrow, and / or tissue of the subject.

[0097] In some embodiments, the administration of a 15-PGDH inhibitor can be in combination with G-CSF for the purpose of increasing neutrophils.

[0098] In other embodiments, the administration of a 15-PGDH inhibitor can be in combination with a hematopoietic cytokine for the purpose of increasing neutrophils.

[0099] In still other embodiments, the administration of a 15-PGDH inhibitor can be in combination with G-CSF for the purpose of increasing numbers of and / or of mobilizing peripheral blood hematopoietic stem cells.

[00100] In other embodiments, the administration of a 15-PGDH inhibitor can be in combination with a hemopoietic cytokine for the purpose of increasing numbers of and / or of mobilizing peripheral blood hematopoietic stem cells.

[00101] In some embodiments, the administration of a 15-PGDH inhibitor can be in combination with a second agent, including, for example, Plerixafor, for the purpose of increasing numbers of and / or of mobilizing peripheral blood hematopoietic stem cells.

[00102] In other embodiments, the administration of a 15-PGDH inhibitor can be in combination with G-CSF for the purpose of increasing numbers of and / or of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[00103] In still other embodiments, the administration of a 15-PGDH inhibitor can be in combination with a hemopoietic cytokine for the purpose of increasing numbers of and / or of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[00104] In other embodiments, the administration of a 15-PGDH inhibitor can be in combination with a second agent, including Plerixafor, for the purpose of increasing numbers of and / or of mobilizing peripheral blood hematopoietic stem cells for use in hematopoietic stem cell transplantation.

[00105] In still other embodiments, the administration of a 15-PGDH inhibitor can be in combination with G-CSF for the purpose of increasing numbers of hematopoietic stem cells in blood or bone marrow.

[00106] In other embodiments, the administration of a 15-PGDH inhibitor can be in combination with a hemopoietic cytokine for the purpose of increasing numbers of hematopoietic stem cells in blood or bone marrow.

[00107] In other embodiments, the 15-PGDH inhibitor can be administered to a subject and / or tissue of the subject to increase tissue stem cells. For example, the 15-PGDH inhibitor can be administered to bone marrow of a subject to increase stem cells in the subject.

[00108] In other embodiments, the 15-PGDH inhibitor can be administered to a recipient of a tissue graft transplant, bone marrow transplant, and / or hematopoietic stem cell transplant, or of an umbilical cord stem cell transplant, in order to decrease the administration of other treatments or growth factors.

[00109] In still other embodiments, the 15-PGDH inhibitor can be administered to a subject to increase neutrophil counts following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase neutrophil counts in a subject with neutropia following 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 following viral infections, to increase neutrophil counts in a subject with neutropia, to increase platelet counts following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase platelet counts in a subject with thrombocytopenia following 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 following viral infections, to increase platelet counts in a subject with thrombocytopenia, to increase red blood cell counts, or hematocrit, or hemoglobin level, following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase red blood cell counts, or hematocrit, or hemoglobin level in a subject with anemia following 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 disorder of bone marrow, drug induced anemia, immune mediated anemias, anemia of chronic disease, anemia following viral infections, or anemia of unknown cause, to increase red blood cell counts, or hematocrit, or hemoglobin level in a subject with anemia, to increase bone marrow stem cells, following a hematopoetic cell transplant with bone marrow, hematopoetic stem cells, or umbilical cord blood, to increase bone marrow stem cells in a subject following chemotherapy administration or radiation therapy, and / or to increase bone marrow stem cells in a subject with aplastic anemia, myelodysplasia, myelofibrosis, other disorder of bone marrow, drug induced cytopenias, immune cytopenias, cytopenias following viral infections, or cytopenias.

[00110] In other embodiments, the 15-PGDH inhibitor can be administered to a subject to increase responsiveness to cytokines in the presence of cytopenias, with cytopenias including any of: neutropenia, thrombocytopenia, lymphocytopenia and anemia; and with cytokines having increased responsiveness potentiated by the 15-PGDH inhibitor including any of: G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, TPO-RA (thrombopoietin receptor agonist), and SCF.

[00111] In some embodiments, the 15-PGDH inhibitor can be administered to a subject to increase bone density, treat osteoporosis, promote healing of fractures, or promote healing after bone surgery or joint replacement and / or to promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[00112] In other embodiments, the 15-PGDH inhibitor can be administered to a subject or to the intestine of a subject to increase stem cells or cell proliferation in the intestine and / or and confer resistance to toxic or lethal effects of exposure to radiation or the toxic, lethal, or mucositis effects resultant from treatment with chemotherapy.

[00113] In some embodiments, the 15-PGDH inhibitor can be administered to a subject or to intestine of a subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

[00114] In other embodiments, the 15-PGDH inhibitor can be administered to a subject to increase liver regeneration following liver surgery, following live liver donation, following liver transplantation, or following liver injury by toxins and / or to promote recovery from or resistance to liver toxins, including acetaminophen and related compounds.

[00115] In still other embodiments, the 15-PGDH inhibitor can be administered to a subject to treat erectile dysfunction.

[00116] In yet other embodiments, the 15-PGDH inhibitor can be administered to inhibit at least one of the growth, proliferation, or metastasis of 15-PGDH expressing cancers.

[00117] Still other embodiments described herein relate to a method of treating a subject in need of cell therapy. The method includes administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cell administered a 15-PGDH inhibitor described herein and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

[00118] In some embodiments, the subject has received human hematopoietic stem cells and / or has received the preparation and / or the therapeutic composition.

[00119] In other embodiments, the subject has acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, severe aplastic anemia, Fanconi's anemia, paroxysmal nocturnal hemoglobinuria (PNH), pure red cell aplasia, amegakaryocytosis / congenital thrombocytopenia, severe combined immunodeficiency syndrome (SCID), Wiskott-Aldrich syndrome, beta-thalassemia major, sickle cell disease, Hurler's syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia, familial erythrophagocytic lymphohistiocytosis, solid tumors, chronic granulomatous disease, mucopolysaccharidoses, or Diamond Blackfan anemia.

[00120] Other embodiments relate to a method of treating a subject having at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia. The method includes administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells administered a 15-PGDH inhibitor described herein and / or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

[00121] In some embodiments, the ischemia can be associated with at least one of acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, brain edema, brain hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarct, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound- healing, diabetes (type I and type II), diabetic neuropathy, diabetes induced ischemia, disseminated intravascular coagulation (DIC), embolic brain ischemia, graft- versus-host disease, hereditary hemorrhagic telengiectasiaischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral-bone cyst, thrombosis, thrombotic brain ischemia, tissue ischemia, transient isc hemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[00122] Other embodiments relate to methods for treating and / or preventing fibrosis and various fibrotic diseases, disorders or conditions by administration of 15-PGDH inhibitors. In some embodiments, a 15-PGDH inhibitor described herein can be administered to a subject in need thereof to decrease fibrotic symptoms, such as collagen deposition, inflammatory cytokine expression, and inflammatory cell infiltration, and treat and / or prevent various fibrotic diseases, disorders, and conditions characterized, in whole or in part, by the excess production of fibrous material, including excess production of fibrotic material within the extracellular matrix, or the replacement of normal tissue elements by abnormal, non- functional, and / or excessive accumulation of matrix-associated components.

[00123] Fibrotic diseases, disorders and conditions characterized, in whole or in part, by excess production of fibrotic material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), sclerodermatous graft-vs-host-disease,, kidney fibrosis (including glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulomanry 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, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myleoid leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myeloproferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, collagenous colitis, acute fibrosis, organ specific fibrosis, and the like.

[00124] In some embodiments, a method of treating or preventing a fibrotic disease, disorder or condition includes administering to a subject in need thereof a therapeutically effect amount of a 15-PGDH inhibitor.

[00125] In some embodiments, the 15-PGDH inhibitors can be used to treat or prevent lung fibrosis. Lung fibrosis, which can be treated, can be selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[00126] In other embodiments, the 15-PGDH inhibitors can be used to treat or prevent kidney fibrosis. The kidney fibrosis can result from dialysis following kidney failure, catheter placement, a nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end stage renal disease or renal failure, or combinations thereof.

[00127] In other embodiments, the 15-PGDH inhibitors can be used to treat or prevent liver fibrosis. The liver fibrosis can result from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or combinations thereof.

[00128] In some embodiments, the 15-PGDH inhibitors can be used to treat or prevent heart fibrosis, for example, cardiac fibrosis and endomyocardial fibrosis.

[00129] In some embodiments, the 15-PGDH inhibitors can be used to treat or prevent systemic sclerosis.

[00130] In some embodiments, the 15-PGDH inhibitors can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

[00131] In some embodiments, the 15-PGDH inhibitors can be used for reducing or preventing scar formation in a subject.

[00132] In other embodiments, the 15-PGDH inhibitors can be used to reduce or prevent scar formation on skin or scleroderma.

[00133] In various embodiments, the 15-PGDH inhibitors can be administered at a therapeutically effective amount such that at least one symptom or feature of a fibrotic disease, disorder or condition, or other related diseases, disorders or conditions, is reduced in intensity, severity, or frequency, or has delayed onset.

[00134] In other embodiments, the 15-PGDH inhibitors can be used in a method for decreasing or reducing collagen secretion or collagen deposition in a tissue or organ, such as the lung, the liver, the intestines, the colon, the skin or the heart, of a subject. The method can include administering a therapeutically effective amount of the 15-PGDH inhibitors to the subject in need thereof. The subject can have or be at risk of an excessive collagen secretion or collagen deposition in the tissue or organ, such as the kidney, the lung, the liver, the intestines, the colon, the skin or the heart. Usually, the excessive collagen secretion or collagen deposition in an organ results from an injury or an insult. Such injury and insult can be organ-specific. The 15-PGDH inhibitors can be administered over a sufficient period of time to decrease or reduce the level of collagen deposition in the tissue or organ, completely or partially. A sufficient period of time can be during one week, or between 1 week to 1 month, or between 1 to 2 months, or 2 months or more. For chronic condition, the 15-PGDH inhibitors can be advantageously administered for life time period.

[00135] Other embodiments described herein relate to the use of 15-PGDH inhibitors in combination with corticosteroids or TNF inhibitors to treat inflammation, reduce aberrant activity of the immune system, and / or promote wound healing in a subject in need thereof. It was found that corticosteroids administered to a subject can induce 15-PGDH expression in tissue of the subject. Administration of a 15-PGDH inhibitor in combination with a corticosteroid was found to enhance anti-inflammatory and / or immunosuppressive effects of the corticosteroid while attenuating corticosteroid induced adverse and / or cytotoxic effects. Treatment of inflammatory, disorders, immune disorders, and / or wounds by administration of 15-PGDH inhibitors in combination with corticosteroids can increase therapeutic efficacy and can allow the corticosteroids to be administered, in some instances, at lower dosages to achieve similar effects, and, in other instances, at higher dosages and for prolonged periods of times with attenuated and / or reduced adverse or cytotoxic effects.

[00136] In some embodiments, the inflammatory and / or immune disease or disorder treated with the combination of 15-PGDH inhibitor and a corticosteroid or TNF inhibitor can include intestinal, gastrointestinal, or bowel disorders. As described below, it was found that inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered to a subject in need thereof alone or in combination with corticosteroids and tumor necrosis factor (TNF)-alpha antagonists 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.

[00137] In other embodiments, the 15-PGDH inhibitor can be used as a glucocorticoid sensitizer to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse the glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticoid resistance or unresponsiveness or intolerance to corticosteroids. For example, the 15-PGDH inhibitor can be administered to a subject in combination with the corticosteroid to treat glucocorticoid insensitivity, restore corticosteroid sensitivity, enhance glucocorticoid sensitivity, and / or reverse the glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticoid resistance or unresponsiveness or intolerance to corticosteroids.

[00138] The 15-PGDH inhibitor can also be administered in combination with a corticosteroid or TNF inhibitor to a subject to promote wound healing, tissue repair, and / or tissue regeneration and / or engraftment or regeneration of a tissue graft.

[00139] In some embodiments, the 15-PGDH inhibitor can be administered to a subject at an amount effective to increase prostaglandin levels in the subject and attenuate corticosteroid induced adverse and / or cytotoxic effects. DETAILED DESCRIPTION

[00140] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[00141] As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably "comprise", "consist of", or "consist essentially of", the steps, elements, and / or reagents described in the claims.

[00142] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[00143] The term "pharmaceutically acceptable" means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use within the scope of sound medical judgment.

[00144] The term "pharmaceutically acceptable salts" include those obtained by reacting the active compound functioning 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 may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. The term "pharmaceutically acceptable salts" also includes those obtained by reacting the active compound functioning 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, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and the like. Non limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like.

[00145] Additionally, the salts of the compounds described herein, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[00146] The term "solvates" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math>, such combination being able to form one or more hydrate.

[00147] The compounds and salts described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the present compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

[00148] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.

[00149] Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.

[00150] The terms below, as used herein, have the following meanings, unless indicated otherwise: "Amino" refers to the -NH<com:Sub>2< / com:Sub> radical. "Cyano" refers to the -CN radical. "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo radical. "Hydroxy" or "hydroxyl" refers to the -OH radical. "Imino" refers to the =NH substituent. "Nitro" refers to the -NO<com:Sub>2< / com:Sub> radical. "Oxo" refers to the =O substituent. "Thioxo" refers to the =S substituent.

[00151] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkyl, an alkyl comprising up to 10 carbon atoms is a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkyl, an alkyl comprising up to 6 carbon atoms is a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl and an alkyl comprising up to 5 carbon atoms is a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C5<annotation encoding="application / x-tex">C_5< / annotation>< / semantics>< / com:Math> alkyl. A <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>- C<com:Sub>5< / com:Sub> alkyl includes C<com:Sub>5< / com:Sub> alkyls, C<com:Sub>4< / com:Sub> alkyls, C<com:Sub>3< / com:Sub> alkyls, C<com:Sub>2< / com:Sub> alkyls and C<com:Sub>1< / com:Sub> alkyl (i.e., methyl). A C<com:Sub>1< / com:Sub>- <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl includes all moieties described above for <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C5<annotation encoding="application / x-tex">C_5< / annotation>< / semantics>< / com:Math> alkyls but also includes <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyls. A <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkyl includes all moieties described above for <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C5<annotation encoding="application / x-tex">C_5< / annotation>< / semantics>< / com:Math> alkyls and <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyls, but also includes <com:Math><semantics>C7<annotation encoding="application / x-tex">C_7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C9<annotation encoding="application / x-tex">C_9< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkyls. Similarly, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkyl includes all the foregoing moieties, but also includes <com:Math><semantics>C11<annotation encoding="application / x-tex">C_{11}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkyls. Non-limiting examples of <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t- amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[00152] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non- limiting examples of <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[00153] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkenyl, an alkenyl comprising up to 10 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkenyl, an alkenyl group comprising up to 6 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkenyl and an alkenyl comprising up to 5 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C5<annotation encoding="application / x-tex">C_5< / annotation>< / semantics>< / com:Math> alkenyl. A C<com:Sub>2< / com:Sub>-C<com:Sub>5< / com:Sub> alkenyl includes C<com:Sub>5< / com:Sub> alkenyls, C<com:Sub>4< / com:Sub> alkenyls, C<com:Sub>3< / com:Sub> alkenyls, and C<com:Sub>2< / com:Sub> alkenyls. A C<com:Sub>2< / com:Sub>-C<com:Sub>6< / com:Sub> alkenyl includes all moieties described above for C<com:Sub>2< / com:Sub>-C<com:Sub>5< / com:Sub> alkenyls but also includes C<com:Sub>6< / com:Sub> alkenyls. A C<com:Sub>2< / com:Sub>-C<com:Sub>10< / com:Sub> alkenyl includes all moieties described above for C<com:Sub>2< / com:Sub>-C<com:Sub>5< / com:Sub> alkenyls and <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkenyls, but also includes <com:Math><semantics>C7<annotation encoding="application / x-tex">C_7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C9<annotation encoding="application / x-tex">C_9< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkenyls. Similarly, a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkenyl includes all the foregoing moieties, but also includes <com:Math><semantics>C11<annotation encoding="application / x-tex">C_{11}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkenyls. Non-limiting examples of C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub> alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11- dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[00154] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[00155] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkynyl, an alkynyl comprising up to 10 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkynyl, an alkynyl group comprising up to 6 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkynyl and an alkynyl comprising up to 5 carbon atoms is a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C5<annotation encoding="application / x-tex">C_5< / annotation>< / semantics>< / com:Math> alkynyl. A <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C5<annotation encoding="application / x-tex">C_5< / annotation>< / semantics>< / com:Math> alkynyl includes C<com:Sub>5< / com:Sub> alkynyls, C<com:Sub>4< / com:Sub> alkynyls, C<com:Sub>3< / com:Sub> alkynyls, and C<com:Sub>2< / com:Sub> alkynyls. A C<com:Sub>2< / com:Sub>-C<com:Sub>6< / com:Sub> alkynyl includes all moieties described above for C<com:Sub>2< / com:Sub>-C<com:Sub>5< / com:Sub> alkynyls but also includes C<com:Sub>6< / com:Sub> alkynyls. A C<com:Sub>2< / com:Sub>-C<com:Sub>10< / com:Sub> alkynyl includes all moieties described above for C<com:Sub>2< / com:Sub>-C<com:Sub>5< / com:Sub> alkynyls and C<com:Sub>2< / com:Sub>-C<com:Sub>6< / com:Sub> alkynyls, but also includes <com:Math><semantics>C7<annotation encoding="application / x-tex">C_7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C9<annotation encoding="application / x-tex">C_9< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkynyls. Similarly, a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkynyl includes all the foregoing moieties, but also includes <com:Math><semantics>C11<annotation encoding="application / x-tex">C_{11}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkynyls. Non-limiting examples of <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[00156] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[00157] "Alkoxy" refers to a radical of the formula -OR<com:Sub>a< / com:Sub> where R<com:Sub>a< / com:Sub> is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[00158] "Alkylamino" refers to a radical of the formula -NHR<com:Sub>a< / com:Sub> or -NR<com:Sub>a< / com:Sub>R<com:Sub>a< / com:Sub> where each R<com:Sub>a< / com:Sub> is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[00159] "Alkylcarbonyl" refers to the <com:Math><semantics>−C(=O)Ra<annotation encoding="application / x-tex">-C(=O)R_a< / annotation>< / semantics>< / com:Math> moiety, wherein <com:Math><semantics>Ra<annotation encoding="application / x-tex">R_a< / annotation>< / semantics>< / com:Math> is an alkyl, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl ("acetal") moiety. Alkylcarbonyl groups can also be referred to as "C<com:Sub>w< / com:Sub>-C<com:Sub>z< / com:Sub> acyl" where w and z depicts the range of the number of carbon in R<com:Sub>a< / com:Sub>, as defined above. For example, "<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> acyl" refers to alkylcarbonyl group as defined above, where <com:Math><semantics>Ra<annotation encoding="application / x-tex">R_a< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkenyl, or <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.

[00160] "Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" is meant to include aryl radicals that are optionally substituted.

[00161] "Aralkyl" or "arylalkyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>c< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkylene group as defined above and R<com:Sub>c< / com:Sub> is one or more aryl radicals as defined above. Aralkyl radicals include, but are not limited to, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[00162] "Aralkenyl" or "arylalkenyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>c< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkenylene group as defined above and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.

[00163] "Aralkynyl" or "arylalkynyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>c< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkynylene group as defined above and <com:Math><semantics>Rc<annotation encoding="application / x-tex">R_c< / annotation>< / semantics>< / com:Math> is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.

[00164] "Carbocyclyl," "carbocyclic ring" or "carbocycle" refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. Cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[00165] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[00166] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[00167] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[00168] "Cycloalkylalkyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>d< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkylene, alkenylene, or alkynylene group as defined above and R<com:Sub>d< / com:Sub> is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.

[00169] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[00170] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[00171] "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[00172] "Heterocyclyl," "heterocyclic ring" or "heterocycle" refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, aziridinyl, oextanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyridine-one, and the like. The point of attachment of the heterocyclyl, heterocyclic ring, or heterocycle to the rest of the molecule by a single bond is through a ring member atom, which can be carbon or nitrogen. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[00173] "Heterocyclylalkyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>e< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkylene group as defined above and R<com:Sub>e< / com:Sub> is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.

[00174] "Heterocyclylalkenyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>e< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkenylene group as defined above and R<com:Sub>e< / com:Sub> is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group can be optionally substituted.

[00175] "Heterocyclylalkynyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>e< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkynylene group as defined above and R<com:Sub>e< / com:Sub> is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group can be optionally substituted.

[00176] "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.

[00177] "Heteroaryl" refers to a 5- to 20-membered ring system radical one to thirteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, as the ring member. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring containing a heteroatom ring member is aromatic. The nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzimidolyl, benzimidolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[00178] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.

[00179] "Heteroarylalkyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>f< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkylene chain as defined above and R<com:Sub>f< / com:Sub> is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[00180] "Heteroarylalkenyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>f< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkenylene, chain as defined above and <com:Math><semantics>Rf<annotation encoding="application / x-tex">R_f< / annotation>< / semantics>< / com:Math> is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyl group can be optionally substituted.

[00181] "Heteroarylalkynyl" refers to a radical of the formula -R<com:Sub>b< / com:Sub>-R<com:Sub>f< / com:Sub> where R<com:Sub>b< / com:Sub> is an alkynylene chain as defined above and R<com:Sub>f< / com:Sub> is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted.

[00182] "Thioalkyl" refers to a radical of the formula -SR<com:Sub>a< / com:Sub> where R<com:Sub>a< / com:Sub> is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.

[00183] The term "substituted" used herein means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, <com:Math><semantics>−NRgC(=O)Rh<annotation encoding="application / x-tex">-NR_gC(=O)R_h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRgC(=O)NRgRh<annotation encoding="application / x-tex">-NR_gC(=O)NR_gR_h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRgC(=O)ORh<annotation encoding="application / x-tex">-NR_gC(=O)OR_h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRgSO2Rh<annotation encoding="application / x-tex">-NR_gSO_2R_h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR_gR_h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−ORg<annotation encoding="application / x-tex">-OR_g< / annotation>< / semantics>< / com:Math>, -SR<com:Sub>g< / com:Sub>, -SO<com:Sub>2< / com:Sub>R<com:Sub>g< / com:Sub>, -SO<com:Sub>2< / com:Sub>R<com:Sub>g< / com:Sub>, -OSO<com:Sub>2< / com:Sub>R<com:Sub>g< / com:Sub>, -SO<com:Sub>2< / com:Sub>OR<com:Sub>g< / com:Sub>, =NSO<com:Sub>2< / com:Sub>R<com:Sub>g< / com:Sub>, and -SO<com:Sub>2< / com:Sub>NR<com:Sub>g< / com:Sub>R<com:Sub>h< / com:Sub>. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)R<com:Sub>g< / com:Sub>, -C(=O)OR<com:Sub>g< / com:Sub>, -C(=O)NR<com:Sub>g< / com:Sub>R<com:Sub>h< / com:Sub>, -CH<com:Sub>2< / com:Sub>SO<com:Sub>2< / com:Sub>R<com:Sub>g< / com:Sub>, -CH<com:Sub>2< / com:Sub>SO<com:Sub>2< / com:Sub>NR<com:Sub>g< / com:Sub>R<com:Sub>h< / com:Sub>. In the foregoing, R<com:Sub>g< / com:Sub> and <com:Math><semantics>Rh<annotation encoding="application / x-tex">R_h< / annotation>< / semantics>< / com:Math> are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents. [Image disponible dans le document PDF, Image available in the PDF document]

[00184] As used herein, the symbol ' " (hereinafter can be referred to as "a point of attachment bond") denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For [Image disponible dans le document PDF, Image available in the PDF document] example, 'indicates that the chemical entity "A" is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , wherein 'infers that the point of attachment bond is the bond by which X is depicted as being attached to the phenyl ring at the ortho position relative to fluorine.

[00185] The phrases "parenteral administration" and "administered parenterally" are art- recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[00186] The term "treating" is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[00187] The term "preventing" is art-recognized and includes stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and / or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.

[00188] A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder.

[00189] The terms "prophylactic" or "therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[00190] The terms "therapeutic agent", "drug", "medicament" and "bioactive substance" are art-recognized and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition. The terms include without limitation pharmaceutically acceptable salts thereof and prodrugs. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.

[00191] The phrase "therapeutically effective amount" or "pharmaceutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the rate of release of an agent from a polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the agent.

[00192] The term "ED50" is art-recognized. In certain embodiments, ED50 means the dose of a drug, which produces 50% of its maximum response or effect, or alternatively, the dose, which produces a pre-determined response in 50% of test subjects or preparations. The term "LD50" is art-recognized. In certain embodiments, LD50 means the dose of a drug, which is lethal in 50% of test subjects. The term "therapeutic index" is an art-recognized term, which refers to the therapeutic index of a drug, defined as LD50 / ED50.

[00193] The terms "IC<com:Sub>50< / com:Sub>," or "half maximal inhibitory concentration" is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.

[00194] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.

[00195] Throughout the description, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[00196] All percentages and ratios used herein, unless otherwise indicated, are by weight.

[00197] The term "neoplasm" refers to any abnormal mass of cells or tissue as a result of neoplasia. The neoplasm may be benign, potentially malignant (precancerous), or malignant (cancerous). An adenoma is an example of a neoplasm.

[00198] The terms "adenoma", "colon adenoma" and "polyp" are used herein to describe any precancerous neoplasm of the colon.

[00199] The term "colon" as used herein is intended to encompass the right colon (including the cecum), the transverse colon, the left colon and the rectum.

[00200] The terms "colorectal cancer" and "colon cancer" are used interchangeably herein to refer to any cancerous neoplasia of the colon (including the rectum, as defined above).

[00201] The terms "gene expression" or "protein expression" includes any information pertaining to the amount of gene transcript or protein present in a sample, as well as information about the rate at which genes or proteins are produced or are accumulating or being degraded (e.g., reporter gene data, data from nuclear runoff experiments, pulse-chase data etc.). Certain kinds of data might be viewed as relating to both gene and protein expression. For example, protein levels in a cell are reflective of the level of protein as well as the level of transcription, and such data is intended to be included by the phrase "gene or protein expression information". Such information may be given in the form of amounts per cell, amounts relative to a control gene or protein, in unitless measures, etc.; the term "information" is not to be limited to any particular means of representation and is intended to mean any representation that provides relevant information. The term "expression levels" refers to a quantity reflected in or derivable from the gene or protein expression data, whether the data is directed to gene transcript accumulation or protein accumulation or protein synthesis rates, etc.

[00202] The terms "healthy" and "normal" are used interchangeably herein to refer to a subject or particular cell or tissue that is devoid (at least to the limit of detection) of a disease condition.

[00203] 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 analogues of either RNA or DNA made from nucleotide analogues, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double-stranded polynucleotides. In some embodiments, "nucleic acid" refers to inhibitory nucleic acids. Some categories of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such categories of nucleic acids are well-known in the art.

[00204] Embodiments described herein relate to compounds and methods of modulating SCD activity (e.g., 15-PGDH activity), modulating tissue prostaglandin levels, and / or treating diseases, disorders, or conditions in which it is desired to modulate 15-PGDH activity and / or prostaglandin levels.

[00205] "Inhibitors," "activators," and "modulators" of 15-PGDH expression or of 15-PGDH activity are used to refer to inhibitory, activating, or modulating molecules, respectively, identified using in vitro and in vivo assays for 15-PGDH expression or 15-PGDH activity, e.g., ligands, agonists, antagonists, and their homologs and mimetics. The term "modulator" includes inhibitors and activators. Inhibitors are agents that, e.g., inhibit expression of 15-PGDH or bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of 15-PGDH, e.g., antagonists. Activators are agents that, e.g., induce or activate the expression of a 15-PGDH or bind to, stimulate, stabilize, increase, open, activate, facilitate, or enhance activation, sensitize or up regulate the activity of 15-PGDH, e.g., agonists. Modulators include naturally occurring and synthetic ligands, small chemical molecules, and the like.

[00206] 15-PGDH inhibitors described herein can provide a pharmacologic method for elevating prostaglandin levels in tissue. Known activities of prostaglandins include promoting hair growth, promoting skin pigmentation, and promoting skin darkening or the appearance of skin tanning. Known activities of prostaglandins also include ameliorating pulmonary artery hypertension. 15-PGDH inhibitors described herein may also be utilized to increase tissue stem cell numbers for purposes that would include increasing resistance to tissue damage by radiation, increasing resistance to environmental exposures to radiation, increasing stem cell numbers to increase fitness of bone marrow or other types of transplantation (through either in vivo exposure to 15-PGDH inhibitors described herein to increase stem cell numbers prior to harvest of a transplanted tissue, or through ex vivo exposure of a harvested tissue prior to transplant into a recipient host, or through treatment of the graft recipient). 15-PGDH inhibitors described herein may also be utilized for purposes that would include promoting liver regeneration, including liver regeneration after liver resection, and liver regeneration after toxic insults, which for example may be the toxic insult of acetaminophen overdose. Prostaglandin signaling is also known to promote wound healing, protect the stomach from ulceration, and promote healing of ulcers of stomach and intestines. Additionally, 15-PGDH inhibitors described herein can promote activity of human keratinocytes in "healing" scratches across cultures of keratinocyte cells. Hence, 15-PGDH inhibitors described herein may be utilized to also heal ulcers of other tissues, including, but not limited to skin, and including but not limited to diabetic ulcers. Further, 15-PGDH inhibitors described herein may be utilized for the treatment of erectile dysfunction.

[00207] 15-PGDH inhibitors described herein can be identified using assays in which putative modulator compounds are applied to cells expressing 15-PGDH and then the functional effects on 15-PGDH activity are determined. Samples or assays comprising 15- PGDH that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.

[00208] Agents tested as modulators of SCD (e.g., 15-PGDH) can be any small chemical molecule or compound. Typically, test compounds will be small chemical molecules, natural products, or peptides. The assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays). Modulators also include agents designed to increase the level of 15-PGDH mRNA or the level of translation from an mRNA.

[00209] In some embodiments, the modulator of SCD can be an SCD inhibitor that can be administered to tissue or blood of a subject at an amount effective to inhibit the activity of a short chain dehydrogenase enzyme. The SCD inhibitor can be a 15-PGDH inhibitor that can be administered to tissue or blood of a subject at an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor can include a compound having a structure of formula (IA): [Image disponible dans le document PDF, Image available in the PDF document] (IA) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] -N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -N(R<com:Sup>5< / com:Sup>)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>- alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math>; R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; R<com:Sup>10< / com:Sup> is –OH, halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2; n is 0, 1, or 2; and t is 0, 1, or 2.

[00210] In some embodiment, the 15-PGDH inhibitor can include a compound having a structure of formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclycl or heteroaryl, each of which is optionally substituted with one or more R<com:Sup>3< / com:Sup>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is oxo, halogen, -CN, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(R<com:Sup>9< / com:Sup>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; X is N or CH; m is 0, 1, or 2; n is 0, 1, or 2; and t is 0, 1, or 2.

[00211] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered cycloalkyl), -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkoxy), 3- to 6-membered heterocyclyl, or -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered heterocyclyl).

[00212] In other embodiments, R<com:Sup>1< / com:Sup> is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopropyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclobutyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopentyl, or -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclohexyl; wherein p is 1, 2, or 3.

[00213] In still other embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>.

[00214] In some embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclycl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R<com:Sup>3< / com:Sup>.

[00215] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00216] In still other embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00217] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−C(O)NR5(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)NR^5(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00218] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00219] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00222] In other embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is -NH<com:Sub>2< / com:Sub>, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl)<com:Sub>2< / com:Sub>, -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, -N(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00224] In some embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is halogen, -CN, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -OH, -O-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- OH, <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)−(3− to 6-membered cycloalkyl)<annotation encoding="application / x-tex">-C(O)-(3-\text{ to 6-membered cycloalkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−C6<annotation encoding="application / x-tex">C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[00225] In some embodiments, n is 1.

[00226] In other embodiments, the 15-PGDH inhibitor can include a compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] . , [Image disponible dans le document PDF, Image available in the PDF document] • • [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • 9 H , , [Image disponible dans le document PDF, Image available in the PDF document] į , [Image disponible dans le document PDF, Image available in the PDF document] 5 -57- [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] • , [Image disponible dans le document PDF, Image available in the PDF document] , , , [Image disponible dans le document PDF, Image available in the PDF document] 9 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] ŧ g with ittoivenies iteritores in the till incie is of pharmaceutically acceptable salts thereof, a tautomoer sthereof, and a solvates thereof.

[00227] In other emodiments, the 15-PGDH inhibitor is selected from compounds disclosed in any one of Examples 1-323, or pharmaceutically acceptable salts thereof, a tautomoer sthereof, and a solvates thereof.

[00228] In some embodiments, the 15-PGDH inhibitor having formula I, IA, II, III, IV, V, VI, VII, or VIII (i.e., formula I-VIII) is not a compound having the following formula: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , -70- [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] . b [Image disponible dans le document PDF, Image available in the PDF document] 4 [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document] -76- [Image disponible dans le document PDF, Image available in the PDF document] • -77- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ••• [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] . , [Image disponible dans le document PDF, Image available in the PDF document] , -83- [Image disponible dans le document PDF, Image available in the PDF document]

[00229] In some embodiments and without being limited by theory, Applicants unexpectedly and surprisingly discovered that carbocyclyl groups at the R<com:Sup>1< / com:Sup> position increase the half-life of the compound. Half-life is an important parameter of a therapeutic agent because it determines that duration of action of the agent – the longer the half-life, the longer the agent is able to exert a therapeutic effect in the subject. In some embodiments, 3- to 6- membered cycloalkyls, particularly 3- to 5-membered cycloalkyls such as cyclobutyl, were observed to have desirable half-lives.

[00230] In other embodiments, the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is 3- to 6-membered cycloalkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered cycloalkyl), 3-to 6-membered heterocyclyl, or -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered heterocyclyl); [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is oxo, -OH, -O-alkylene-N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, - <com:Math><semantics>C(O)O<annotation encoding="application / x-tex">C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl, R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; X is N or CH; m is 0, 1, or 2; and t is 0, 1, or 2.

[00231] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is 3- to 5-membered cycloalkyl or -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- (3- to 5-membered cycloalkyl).

[00232] In other embodiments, R<com:Sup>1< / com:Sup> is cyclobutyl.

[00233] In still other embodiments, R<com:Sup>1< / com:Sup> is a bicyclic 4- to 6-membered cycloalkyl.

[00234] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−C(O)NR5(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)NR^5(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00235] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00236] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ3<annotation encoding="application / x-tex">\mathbb{C}_3< / annotation>< / semantics>< / com:Math> haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>.

[00237] In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>. In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00238] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6<annotation encoding="application / x-tex">-O-(C_1-C_6< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)(C1−C6)2<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)_2< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)N(R5)2<annotation encoding="application / x-tex">-C(O)N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)N(R5)(C1−C6)<annotation encoding="application / x-tex">-C(O)N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl), [Image disponible dans le document PDF, Image available in the PDF document]

[00239] In other embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C3<annotation encoding="application / x-tex">-N(C_1-C_3< / annotation>< / semantics>< / com:Math> alkyl)<com:Sub>2< / com:Sub>, <com:Math><semantics>−NHCH2CH2OH<annotation encoding="application / x-tex">-NHCH_2CH_2OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C3)<annotation encoding="application / x-tex">-N(C_1-C_3)< / annotation>< / semantics>< / com:Math> alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00240] In still other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[00241] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that substituents at the R<com:Sup>7< / com:Sup> position could be modified to improve hERG activity, including hERG inhibition (IC<com:Sub>50< / com:Sub>), blockade, and efflux ratio. For example, in some embodiments, certain 6- to 10-membered aryls (e.g., optionally substituted phenyl) and 5- to 10-membered heteroaryls (e.g., optionally substituted pyridyls, pyrazoles, and triazoles) were observed to have beneficial hERG properties. In some embodiments, certain C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> haloalkyls (e.g., -CF<com:Sub>3< / com:Sub>) exhibited improved hERG inhibition (IC50), while also improving half-life and solubility.

[00242] In other embodiments, the compound has the structure of formula (III): [Image disponible dans le document PDF, Image available in the PDF document] (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is oxo, <com:Math><semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-alkylene-<com:Math><semantics>N(R5)2<annotation encoding="application / x-tex">N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)<annotation encoding="application / x-tex">-N(R^5)< / annotation>< / semantics>< / com:Math>(alkylene-<com:Math><semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>< / com:Math>), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, - <com:Math><semantics>C(O)O<annotation encoding="application / x-tex">C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)<com:Math><semantics>m<annotation encoding="application / x-tex">_{m}< / annotation>< / semantics>< / com:Math>-alkyl; or alternative, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>4< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; and m is 0, 1, or 2.

[00243] In some embodiments, R<com:Sup>7< / com:Sup> is –CF<com:Sub>3< / com:Sub>, pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with R<com:Sup>4< / com:Sup>.

[00244] In other embodiments, R<com:Sup>7< / com:Sup> is –CF<com:Sub>3< / com:Sub>, pyridyl, fluorophenyl, or a triazole optionally substitued with halogen or methyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00246] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>< / com:Math>.

[00247] In still other embodiments, R<com:Sup>7< / com:Sup> is F [Image disponible dans le document PDF, Image available in the PDF document]

[00248] In some embodiments, R<com:Sup>7< / com:Sup> is [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00249] In some embodiments, R<com:Sup>7< / com:Sup> is ٠

[00250] In other embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00251] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that 3- to 6-membered cycloalkyls at the R<com:Sup>7< / com:Sup> position can improve solublity while maintaining PDGH activity.

[00252] In other embodiments, the compound has the structure of formula (IV): [Image disponible dans le document PDF, Image available in the PDF document] (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is 3- to 6-membered cycloalkyl, optionally substituted with one or more R<com:Sup>4< / com:Sup>; [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is halogen, -CN, -NH<com:Sub>2< / com:Sub>, -OH, or C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternative, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2.

[00253] In some embodiments, R<com:Sup>7< / com:Sup> is cyclopropyl.

[00254] In other embodiments, R<com:Sup>1< / com:Sup> is 3- to 6-membered cycloalkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered cycloalkyl), -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkoxy), 3- to 6-membered heterocyclyl, or <com:Math><semantics>−(C1−C6 alkylene)<annotation encoding="application / x-tex">-(C_1-C_6 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-(3- to 6-membered heterocyclyl).

[00255] In some embodiments, R<com:Sup>1< / com:Sup> is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopropyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclobutyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopentyl, or -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclohexyl; wherein p is 1, 2, or 3.

[00256] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6)<annotation encoding="application / x-tex">-O-(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)(C1−C6)<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)N(R5)2<annotation encoding="application / x-tex">-C(O)N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)N(R5)(C1−C6)<annotation encoding="application / x-tex">-C(O)N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl), <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00258] In other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[00259] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that the R<com:Sup>6< / com:Sup> position can be substituted with certain R<com:Sup>3< / com:Sup> groups to improve solubility and activity.

[00260] In other embodiments, the compound has the structure of formula (V): [Image disponible dans le document PDF, Image available in the PDF document] (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>; R<com:Sup>7< / com:Sup> is haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently H, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(R<com:Sup>9< / com:Sup>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl), -C(O)O(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl), alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>(C<com:Sub>1< / com:Sub>- C<com:Sub>6< / com:Sub> alkyl); or alternative, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2.

[00261] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6<annotation encoding="application / x-tex">-O-(C_1-C_6< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−N(R5)(C1−C6)2<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)_2< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub> alkylene-OH).

[00262] In other embodiments, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)-OH, or -S(O)<com:Sub>2< / com:Sub>(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl).

[00263] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C3 alkyl)2<annotation encoding="application / x-tex">-N(C_1-C_3 \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHCH2CH2OH<annotation encoding="application / x-tex">-NHCH_2CH_2OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C3 alkyl)2<annotation encoding="application / x-tex">-N(C_1-C_3 \text{ alkyl})_2< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>−OCH2CH2NH2<annotation encoding="application / x-tex">-OCH_2CH_2NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OCH2CH2NH(C1−C3 alkyl)<annotation encoding="application / x-tex">-OCH_2CH_2NH(C_1-C_3 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−OCH2CH2N(C1−C3 alkyl)2<annotation encoding="application / x-tex">-OCH_2CH_2N(C_1-C_3 \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>.

[00264] In other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[00265] In still other embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NHCH2CH2OH<annotation encoding="application / x-tex">-NHCH_2CH_2OH< / annotation>< / semantics>< / com:Math>.

[00266] In some embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00267] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00268] In some embodiments, R<com:Sup>6< / com:Sup> is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isooxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00269] In other embodiments, R<com:Sup>6< / com:Sup> is thiazole, imidazole, oxazole, pyridine, or pyrimidine.

[00270] In some embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00271] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclyl, optionally substituted with one or more R<com:Sup>3< / com:Sup>, selected from morpholine, pyridine-one, or piperidine.

[00272] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>.

[00273] In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, cyclopropyl, phenyl, pyrzole, pyridyl, or triazole, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>.

[00274] In some embodiments, the compound has the structure of formula (VI): [Image disponible dans le document PDF, Image available in the PDF document] (VI) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R<com:Sup>1< / com:Sup> is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is fused bicyclic heterocyclyl or fused bicyclic heteroaryl, each of which is optionally substituted with one or more R<com:Sup>3< / com:Sup>; R<com:Sup>7< / com:Sup> is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR<com:Sup>5< / com:Sup>-alkyl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, cycloalkyl, heterocyclyl, <com:Math><semantics>−C(O)N(R5)2<annotation encoding="application / x-tex">-C(O)N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-alkyl, or <com:Math><semantics>−S(O)m<annotation encoding="application / x-tex">-S(O)_m< / annotation>< / semantics>< / com:Math>-alkyl; R<com:Sup>4< / com:Sup> is oxo, halogen, -CN, -N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -OH, -O-alkylene-OH, -S(O)<com:Sub>m< / com:Sub>-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R<com:Sup>8< / com:Sup>; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, or - <com:Math><semantics>S(O)m<annotation encoding="application / x-tex">S(O)_{m}< / annotation>< / semantics>< / com:Math>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; X is N or CH; and m is 0, 1, or 2.

[00275] In some embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00276] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)O(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−C(O)NR5(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)NR^5(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>.

[00277] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>.

[00278] In still other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00279] In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>. In other embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00280] In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>. In other embodiments, R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>.

[00281] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> haloalkyl, 3- to 6-membered cycloalkyl, -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered cycloalkyl), -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkoxy), 3- to 6-membered heterocyclyl, or -(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkylene)-(3- to 6-membered heterocyclyl).

[00282] In other embodiments, R<com:Sup>1< / com:Sup> is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopropyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclobutyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclopentyl, or -(CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>-cyclohexyl; wherein p is 1, 2, or 3. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00286] In other embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is halogen, -CN, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -OH, -O-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- OH, <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)−(3− to 6-membered cycloalkyl)<annotation encoding="application / x-tex">-C(O)-(3-\text{ to 6-membered cycloalkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−C6 alkyl<annotation encoding="application / x-tex">C_1-C_6 \text{ alkyl}< / annotation>< / semantics>< / com:Math> alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[00287] In some embodiments, the compound has the structure of formula (VII): [Image disponible dans le document PDF, Image available in the PDF document] (VII) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is cyclobutyl or -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkoxy); [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>6< / com:Sup> is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>; N F F <com:Math><semantics>(R4)p−r1UN<annotation encoding="application / x-tex">(R^4)_p - \frac{r_1}{U} N< / annotation>< / semantics>< / com:Math> R<com:Sup>7< / com:Sup> is –CF<com:Sub>3< / com:Sub>, isopropyl, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -N(R<com:Sup>5< / com:Sup>)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, -C(O)N(R<com:Sup>5< / com:Sup>)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)<com:Sub>m< / com:Sub>- alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>5< / com:Sup> is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH<com:Sub>2< / com:Sub>, -alkylene-N(<com:Math><semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH<com:Sub>2< / com:Sub>, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)<com:Sub>m< / com:Sub>-alkyl; or alternatively, two R<com:Sup>5< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R<com:Sup>8< / com:Sup>; R<com:Sup>8< / com:Sup> is halogen, alkyl, or alkoxy; R<com:Sup>9< / com:Sup> is H or alkyl, or two R<com:Sup>9< / com:Sup> together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, <com:Math><semantics>S(O)t<annotation encoding="application / x-tex">S(O)_t< / annotation>< / semantics>< / com:Math>, or N; R<com:Sup>10< / com:Sup> is –OH, halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2; p is 0 or 1; and t is 0, 1, or 2.

[00288] In still other embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>.

[00289] In some embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heterocyclycl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00290] In other embodiments, R<com:Sup>6< / com:Sup> is 5- to 6-membered heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00291] In still other embodiments, R<com:Sup>6< / com:Sup> is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>.

[00292] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−O−(C1−C6)<annotation encoding="application / x-tex">-O-(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene)<com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)2<annotation encoding="application / x-tex">-N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)(C1−C6)<annotation encoding="application / x-tex">-N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)N(R5)2<annotation encoding="application / x-tex">-C(O)N(R^5)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)N(R5)(C1−C6)<annotation encoding="application / x-tex">-C(O)N(R^5)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkylene-OH), <com:Math><semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl), [Image disponible dans le document PDF, Image available in the PDF document]

[00293] In other embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl)OH, -NH<com:Sub>2< / com:Sub>, -N(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl)<com:Sub>2< / com:Sub>, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00294] In still other embodiments, R<com:Sup>3< / com:Sup> is -NHCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or -N(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH.

[00295] In some embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is halogen, -CN, -N(<com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>, -OH, -O-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkylene)- OH, <com:Math><semantics>−S(O)m(C1−C6 alkyl)<annotation encoding="application / x-tex">-S(O)_m(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)(C1−C6 alkyl)<annotation encoding="application / x-tex">-C(O)(C_1-C_6 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)−(3− to 6-membered cycloalkyl)<annotation encoding="application / x-tex">-C(O)-(3-\text{ to 6-membered cycloalkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−C6<annotation encoding="application / x-tex">C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[00296] In some embodiments, n is 1.

[00297] In some embodiments, the compound has the structure of formula (VIII): [Image disponible dans le document PDF, Image available in the PDF document] (VIII) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is cyclobutyl or -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkoxy); <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CN<annotation encoding="application / x-tex">CN< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−NHC(O)<annotation encoding="application / x-tex">-NHC(O)< / annotation>< / semantics>< / com:Math>alkyl; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with one or more <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>7< / com:Sup> is –CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, cyclobutyl, [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with one or more <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is -NH<com:Sub>2< / com:Sub>, -NH(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl), -NH(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkylene)-OH, or C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl; and X is N or CH.

[00298] In some embodiments of Formula (VIII), R<com:Sup>1< / com:Sup> is cyclobutyl. In some embodiments of Formula (VIII), <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkoxy). In some embodiments of Formula (VIII), the <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> -(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkoxy) is -(<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkylene)-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math> alkoxy).

[00299] In some embodiments of Formula (VIII), <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document]

[00300] In some embodiments of Formula (VIII), R<com:Sup>6< / com:Sup> is [Image disponible dans le document PDF, Image available in the PDF document]

[00301] In some embodiments of Formula (VIII), R<com:Sup>3< / com:Sup> is -NH<com:Sub>2< / com:Sub>. In some embodiments of Formula (VIII), R<com:Sup>3< / com:Sup> is -NH(C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub> alkyl). In some embodiments of Formula (VIII), R<com:Sup>3< / com:Sup> is - <com:Math><semantics>NH(C1−C4 alkylene)−OH<annotation encoding="application / x-tex">NH(C_1-C_4 \text{ alkylene})-OH< / annotation>< / semantics>< / com:Math> (e.g., <com:Math><semantics>−NH(C2−C4 alkylene)−OH<annotation encoding="application / x-tex">-NH(C_2-C_4 \text{ alkylene})-OH< / annotation>< / semantics>< / com:Math>). In some embodiments of Formula (VIII), <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math> alkyl (e.g., methyl or ethyl).

[00302] In some embodiments, of Formula (VIII), R<com:Sup>7< / com:Sup> is -CF<com:Sub>3< / com:Sub>, isopropyl, cyclopropyl, or cyclobutyl. In some embodiments, of Formula (VIII), R<com:Sup>7< / com:Sup> is isopropyl. In some [Image disponible dans le document PDF, Image available in the PDF document] embodiments of Formula (VII), R<com:Sup>7< / com:Sup> is , each of which is optionally substituted with one or more R<com:Sup>4< / com:Sup>. In some embodiments, each R<com:Sup>4< / com:Sup> is idependently selected from methyl or ethyl.

[00303] In some embodiments of Formula (VIII), X is –CH.

[00304] In some embodiments, the compounds of Formula (VIII) are provided in Table 2.

[00305] In one embodiment, the compounds of Formula (VIII) excludes: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] F [Image disponible dans le document PDF, Image available in the PDF document] •

[00306] In some embodiments, the 15-PGDH inhibitor of the present disclosure inhibit colon 15-PGDH activity in a range of 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 subranges therein. Colon 15-PGDH inhibition can be measured (e.g., with the assay described in this present exmples) using an approporiate dose of the compounds of the present disclosure, 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 after administration, including all times between these values. In some embodiments, colon 15-PGDH inhibition is measured at 30 minutes after adminstration. In particular embodiments, colon 15-PGDH inhibition is measured at 4 hours. In some embodiments, the appropriate dose is 1 2, 3, 4, 5, 6, 7, 8, 9, 0 15, 20, 30, 40, 50, or more mg / kg, including all values and ranges in between these values.

[00307] In one embodiment, lung, liver, intestines, the skin, heart (or any other organ disclosed herein) 15-PGDH inhibition can be measured using an approportate dose of the compounds of the present disclosure, 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, including all times and ranges in between these values. In some embodiments, lung 15-PGDH inhibition is measured at 30 minutes. In particular embodiments, lung 15-PGDH inhibition is measured at 4 hours. In some embodiments, the appropriate dose is 1 2, 3, 4, 5, 6, 7, 8, 9, 0 15, 20, 30, 40, 50, or more mg / kg, including all values and ranges in between these values. In some embodiments, the 15-PGDH inhibitor of the present disclosure inhibit lung 15-PGDH activity in a range of 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 subranges therein.

[00308] In some embodiments, the 15-PGDH inhibitor of the present disclosure (e.g., having formula I-VIII), is administered at 10 mg / kg in a mammal and inhibits colon 15- PGDH activity at 30 minutes in a range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 30 minutes in a range of about 65% to <com:Math><semantics>100%<annotation encoding="application / x-tex">100\%< / annotation>< / semantics>< / com:Math> (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges therein. In some embodiments, the compounds of the present disclosure when administered at 10 mg / kg in a mammal can inhibit colon 15-PGDH activity at 30 minutes in a range of about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 30 minutes in a range of about 80% to 100%, and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 30 minutes in a range of about 90% to 100%, and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 30 minutes in a range of about 95% to 100%, and any subranges therein. This is a unexpected and surprising result, as previously synthesized 15-PGDH inhibitors, such as Reference Compound C (Example B), when given orally at 10 mpk was not sufficiently potent to inhibit colon 15-PGDH activity at 30 minutes. In fact, Reference Compound C actually increased activity colon 15-PGDH activity, as indicated by the -55.2% inhibition.

[00309] In some embodiments, the 15-PGDH inhibitor of the present disclosure (e.g., having formula I-VIII), is administered at 10 mg / kg in a mammal and inhibits colon 15- PGDH activity at 4 hours in a range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 4 hours in a range of about 65% to 100% (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges therein. In some embodiments, the compounds of the present disclosure when administered at 10 mg / kg in a mammal can inhibit colon 15-PGDH activity at 4 hours in a range of about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 4 hours in a range of about 80% to 100%, and any subranges therein. In some embodiments, the compounds of the present disclosure, when administered at 10 mg / kg in a mammal, inhibit colon 15-PGDH activity at 4 hours in a range of about 80% to 98%, and any subranges therein.

[00310] In some embodiments, the 15-PGDH inhibitor of the present disclosure (e.g., having formula I-VIII), is administered at 10 mg / kg in a mammal and inhibits lung, liver, intestines, the skin, heart (or any other organ disclosed herein) 15-PGDH activity at 30 minutes in a range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges 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 a range of about 65% to 100% (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges 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 a range of about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges 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 a range of about 80% to 100%, and any subranges therein.

[00311] In some embodiments, the 15-PGDH inhibitor of the present disclosure (e.g., having formula I-VIII), is administered at 10 mg / kg in a mammal and inhibits lung, liver, intestines, the skin, heart (or any other organ disclosed herein) 15-PGDH activity at 4 hours in a range of about 25% to 100%, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, and any subranges 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 4 hours in a range of about 65% to 100% (e.g., about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges 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 4 hours in a range of about 70% to 100% (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%), and any subranges 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 4 hours in a range of about 80% to 100%, and any subranges therein.

[00312] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 50 minutes. In some embodiments, the compounds of the present disclosure has a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 60 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 70 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 80 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 90 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 100 minutes. In some embodiments, the compounds of the present disclosure has a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 110 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 120 minutes. In some embodiments, the 15- PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 130 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 145 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> ranging from 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).

[00313] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) have better human microsome stability compared to previously disclosed 15-PGDH inhibitors. See WO 2013 / 158649, WO 2015 / 065716, WO 2016 / 144958, WO 2016 / 168472, WO 2018 / 017582, WO 2018 / 102552, WO 2018 / 145080, WO 2018 / 187810, and WO 2018 / 218251. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 15 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 25 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 35 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 45 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 55 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 65 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 75 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 85 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 95 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 100 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 110 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 120 minutes longer than previously disclosed 15-PGDH inhibitors. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> ranging that is from 15 minutes to about 120 minutes longer than the microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of previously disclosed 15- PGDH inhibitors.

[00314] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 40 minutes longer than Reference Compound C (Example B). In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 70 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 80 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 90 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 100 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 110 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 120 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a human microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> ranging that is from 70 minutes to about 120 minutes longer than Reference Compound C.

[00315] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 10 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 50 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 60 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 70 minutes. In some embodiments, the 15- PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 80 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 90 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 100 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 110 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 120 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 130 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 140 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> of greater than 145 minutes. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> ranging from 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).

[00316] In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 10 minutes longer than Reference Compound C (Example B). In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 20 minutes longer than Reference Compound C. In some embodiments, the 15- PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 30 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 40 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 50 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 60 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 70 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 80 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 90 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 100 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 110 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 120 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 130 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> which is at least 140 minutes longer than Reference Compound C. In some embodiments, the 15-PGDH inhibitors of the present disclosure have a mouse microsome stability <com:Math><semantics>T1 / 2<annotation encoding="application / x-tex">T_{1 / 2}< / annotation>< / semantics>< / com:Math> that is from 65 to at least 145 longer than Reference Compound C (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).

[00317] The EC<com:Sub>50< / com:Sub> for induction of PGE2 is determined using A549 cells that have been treated with IL1-β 24 hours. In some embodiments, the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) have an EC<com:Sub>50< / com:Sub> for induction of PGE2 that is less than or equal to 10 nM. In some embodiments, the EC<com:Sub>50< / com:Sub> is less than or equal to 5 nM. In some embodiments, the EC<com:Sub>50< / com:Sub> is less than or equal to 4 nM. In some embodiments, the EC<com:Sub>50< / com:Sub> is less than or equal to 3 nM. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is less than or equal to 2 nM. In some embodiments, the EC<com:Sub>50< / com:Sub> is less than or equal to 1 nM. In some embodiments, the EC<com:Sub>50< / com:Sub> is from 10 nM to about 0.01 nM including all values and subranges in between these values). In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 4 times less than the previously disclosed 15-PGDH inhibitors, such as those disclosed in the publications referenced above. In some embodiments, the EC<com:Sub>50< / com:Sub> is at least 8 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 10 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the EC<com:Sub>50< / com:Sub> is at least 15 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the EC<com:Sub>50< / com:Sub> is at least 20 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the EC<com:Sub>50< / com:Sub> is at least 30 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the EC<com:Sub>50< / com:Sub> is at least 40 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 50 times less than the previously disclosed 15-PGDH inhibitors. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is 10 times to 50 times less than the previously disclosed 15-PGDH inhibitors.

[00318] In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> of the 15-PGDH inhibitors of the present disclosure (e.g., formula I-VIII) is at least 5 times less than Reference Compound C (Example B). In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 10 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 15 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 20 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 25 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 30 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 35 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 40 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 45 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is at least 50 times less than Reference Compound C. In some embodiments, the <com:Math><semantics>EC50<annotation encoding="application / x-tex">EC_{50}< / annotation>< / semantics>< / com:Math> is 5 times to 50 times less than Reference Compound C.

[00319] In certain embodiments, the 15-PGDH inhibitor having formula (I-VIII), can be selected that can ia) at 2.5 µM concentration, stimulate a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70 (using a scale on which a value of 100 indicates a doubling of reporter output over baseline); iia) at 2.5 µM concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 75; iiia) at 7.5 µM concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70; and iva) at 7.5 µM concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a level greater than 20; and va) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC<com:Sub>50< / com:Sub> of less than 1 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>M.

[00320] In other embodiments, the 15-PGDH inhibitor can ib) at 2.5 µM concentration, stimulate a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iib) at 2.5 µM concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iiib) at 7.5 µM concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; ivb) at 7.5 µM concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a luciferase level greater than 20% above background; and vb) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC<com:Sub>50< / com:Sub> of less than 1 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>M.

[00321] In some embodiments, the compound or 15-PGDH inhibitor can inhibit the enzymatic activity of recombinant 15-PGDH at an IC<com:Sub>50< / com:Sub> of less than 1 µM, at an IC<com:Sub>50< / com:Sub> of less than 250 nM, at an IC<com:Sub>50< / com:Sub> of less than 50 nM, at an IC<com:Sub>50< / com:Sub> of less than 10 nM, at an IC<com:Sub>50< / com:Sub> of less than 5 nM at a recombinant, at an IC<com:Sub>50< / com:Sub> of about 2.5 nM to about 10 nM, or less than about 2.5 nM at a 15-PGDH concentration of about 5 nM to about 10 nM.

[00322] The 15-PGDH inhibitors described herein can be used for the prevention or the treatment of diseases that are associated with 15-PGDH and / or decreased prostaglandin levels and / or where it desirable to increase prostaglandin levels in the subject. For example, as discussed above, it is known that prostaglandins play an important role in hair growth. Specifically, internal storage of various types <com:Math><semantics>(A2,F2a,E2)<annotation encoding="application / x-tex">(A_2, F_{2a}, E_2)< / annotation>< / semantics>< / com:Math> of prostaglandins in the various compartments of hair follicles or their adjacent skin environments has been shown to be essential in maintaining and increasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9), 762-9). It has been reported that 15-PGDH, which is involved in the degradation of prostaglandins is present in the hair follicle dermal papillae, inactivates prostaglandins, especially, PGF<com:Sub>2a< / com:Sub> and PGE<com:Sub>2< / com:Sub>, to cause scalp damage and alopecia (Michelet J F et. al., 2008, Exp. Dermatol, 17(10), 821-8). Thus, the compounds described herein, which have a suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins, can improve scalp damage, prevent alopecia and promote hair growth and be used in a pharmaceutical composition for the prevention of alopecia and the promotion of hair growth.

[00323] In other embodiments, the 15-PGDH inhibitors described herein can be used in a pharmaceutical composition for promoting and / or inducing and / or stimulating pigmentation of the skin and / or skin appendages, and / or as an agent for preventing and / or limiting depigmentation and / or whitening of the skin and / or skin appendages, in particular as an agent for preventing and / or limiting canities.

[00324] In some embodiments, the 15-PGDH inhibitor can be applied to skin of a subject, e.g., in a topical application, to promote and / or stimulate 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.

[00325] In still other embodiments, the 15-PGDH inhibitors described herein can be used in a pharmaceutical composition for the prevention or the treatment of cardiovascular disease and / or diseases of vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary artery hypertension. Prostaglandins including prostaglandin homologues produced in the body have been known to maintain the proper action of the blood vessel wall, especially to contribute to vasodilation for blood flow, preventing platelet aggregation and modulating the proliferation of smooth muscle that surrounds blood vessel walls (Yan. Cheng et. al., 2006, J. Clin., Invest). In addition, the inhibition of prostaglandins production or the loss of their activity causes the degeneration of the endothelium in the blood vessel walls, platelet aggregation and the dysfunction of cellular mechanism in the smooth muscle. Among others, the production of prostaglandins in blood vessels was shown to be decreased in hypertension patients, including pulmonary artery hypertension.

[00326] In other embodiments, the 15-PGDH inhibitors described herein can be used in a pharmaceutical composition for the prevention or the treatment of oral, intestinal, and / or gastrointestinal injury or diseases, or inflammatory bowel disease, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, and gastric ulcers. Gastritis and gastric ulcer, representatives of the gastrointestinal diseases, are defined as the conditions where gastrointestinal mucus membrane is digested by gastric acid to form ulcer. In stomach walls generally consisting of mucosa, submucosa, muscle layer and serosa, gastric ulcer even damages submucosa and muscle layer, while gastritis damages mucosa only. Although the morbidity rates of gastritis and gastric ulcer are relatively high, the causes thereof have not been clarified yet. Until now, they are known to be caused by an imbalance between aggressive factors and defensive factors, i.e., the increase in aggressive factors such as the increase in gastric acid or pepsin secretion, or the decrease in defensive factors such as structural or morphological deficit of the gastric mucus membrane, the decrease in mucus and bicarbonate ion secretion, the decrease in prostaglandin production, or the like.

[00327] Currently available therapeutic agents for gastritis and gastric ulcer comprise various drugs for strengthening the defensive factors such as an antacid, which does not affect, gastric acid secretion but neutralizes gastric acid that has been already produced, an inhibitor of gastric acid secretion, a promoter of prostaglandin secretion, and a coating agent for stomach walls. Especially, prostaglandins are known to be essential in maintaining the mechanism for protecting and defending gastric mucus membrane (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65, S. J. Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). In view of the above, since the 15-PGDH inhibitors described herein show a suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect gastric mucus membrane, they can be effective for the prevention or the treatment of gastrointestinal diseases, inter alia, gastritis and gastric ulcer.

[00328] Moreover, 15-PGDH inhibitors would also be expected to protect from other forms of intestinal injury, such as toxicity from radiation, toxicity from chemotherapy, and chemotherapy induced mucositis.

[00329] In the kidney, prostaglandins modulate renal blood flow and may serve to regulate urine formation by both renovascular and tubular effects. In clinical studies, PGE<com:Sub>1< / com:Sub> has been used to improve creatinine clearance in patients with chronic renal disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, to reduce the urinary albumin excretion rate and N-acetyl-beta-D-glucosaminidase levels in patients with diabetic nephropathy (see Porter, Am., 1989, J. Cardiol., 64: 22E-26E). In addition, U.S. Pat. No. 5,807,895 discloses a method of preventing renal dysfunction by intravenous administration of prostaglandins such as PGE<com:Sub>1< / com:Sub>, PGE<com:Sub>2< / com:Sub> and PGI<com:Sub>2< / com:Sub>. Furthermore, it has been reported that prostaglandins serve as vasodilators in the kidney, and, thus, the inhibition of prostaglandin production in the kidney results in renal dysfunction (Hao. C M, 2008, Annu Rev Physiol, 70, 357.about.77).

[00330] Thus, the 15-PGDH inhibitors described herein, which have a suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins, may be effective in the prevention or the treatment of renal diseases that are associated with renal dysfunction.

[00331] The term "renal dysfunction" as used herein includes such manifestations as follows: lower than normal creatinine clearance, lower than normal free water clearance, higher than normal blood urea, nitrogen, potassium and / or creatinine levels, altered activity of kidney enzymes such as gamma glutamyl synthetase, alanine phosphatidase, N-acetyl-β-D- glucosaminidase, or <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-w-microglobulin; and increase over normal levels of macroalbuminuria.

[00332] Prostaglandins including PGE<com:Sub>1< / com:Sub>, PGE<com:Sub>...

Claims

1. A compound of formula (IA): [Image disponible dans le document PDF, Image available in the PDF document] (IA) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 R^1 is C 1 C_1 - C 12 C_{12} alkyl, C 1 C_1 - C 12 C_{12} haloalkyl, 3- to 10-membered cycloalkyl, -( C 1 C_1 - C 12 C_{12} alkylene)-(3- to 10-membered membered cycloalkyl), -(C 1 -C 12 alkylene)-(C 1 -C 12 alkoxy), 3- to 20- membered heterocyclyl, or − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) -(3- to 20-membered heterocyclyl); R 2 R^2 is − N H 2 -NH_2 or C N CN ; R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 R^3 ; R 7 is C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 6- to 18-membered aryl, 3- to 20-membered heterocyclyl, 5- to 20-membered heteroaryl, -C(O)-(C 1 -C 12 alkyl), - C ( O ) O − ( C 1 − C 12 alkyl ) C(O)O-(C_1-C_{12} \text{ alkyl}) , or − C ( O ) N R 5 − ( C 1 − C 12 alkyl ) -C(O)NR^5-(C_1-C_{12} \text{ alkyl}) , each of which is optionally substituted with one or more R 4 ; R 3 R^3 is oxo, -OH, -O-(C 1 -C 12 alkylene)-OH, -O-(C 1 -C 12 alkylene)-N( R 5 R^5 ) 2 , -N( R 5 R^5 ) 2 , -N( R 5 R^5 )(C 1 - C 12 C_{12} alkylene-OH), − N ( R 5 ) ( C 1 − C 12 -N(R^5)(C_1-C_{12} alkylene-O-alkyl), C 1 − C 12 C_1-C_{12} alkyl, − ( C 1 − C 12 -(C_1-C_{12} alkylene)- OH, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, - C ( O ) N ( R 5 ) 2 C(O)N(R^5)_2 , − C ( O ) N ( R 5 ) ( C 1 − C 12 alkylene-OH ) -C(O)N(R^5)(C_1-C_{12} \text{ alkylene-OH}) , − C ( O ) − ( C 1 − C 12 alkyl ) -C(O)-(C_1-C_{12} \text{ alkyl}) , − C ( O ) O − ( C 1 − C 12 alkyl ) -C(O)O-(C_1-C_{12} \text{ alkyl}) alkyl), or -S(O) m -(C 1 -C 12 alkyl), wherein each of the 3- to 10-membered cycloalkyl and the 3- to 20-membered heterocyclyl is optionally substituted with R 10 ; R 4 R^4 is oxo, halogen, -CN, -N( R 5 R^5 ) 2 , -OH, -O-( C 1 C_1 - C 12 C_{12} alkylene)-OH, -S(O) m -( C 1 C_1 - C 12 C_{12} alkyl), - C ( O ) C(O) - ( C 1 (C_1 - C 12 C_{12} alkyl), − C ( O ) -C(O) - ( 3 (3 - to 10-membered cycloalkyl), C 1 C_1 - C 12 C_{12} alkyl, − ( C 1 -(C_1 - C 12 C_{12} alkylene)-O-(C 1 -C 12 alkyl), C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, or -(C 1 -C 12 alkylene)-(6- to 18-membered aryl) optionally substituted with R 8 ; each R 5 is independently, H, C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, -(C 1 -C 12 alkylene)-NH 2 , - ( C 1 − C 12 alkylene ) − N ( R 9 ) 2 (C_1-C_{12} \text{ alkylene})-N(R^9)_2 , − ( C 1 − C 12 alkylene ) − O − ( C 1 − C 12 alkylene ) − O H -(C_1-C_{12} \text{ alkylene})-O-(C_1-C_{12} \text{ alkylene})-OH , − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) alkylene)-O-(C 1 -C 12 alkylene)-NH 2 , -C(O)-(C 1 -C 12 alkyl), -C(O)O-(C 1 -C 12 alkyl), -(C 1 - C 12 C_{12} alkylene)-COOH, or -S(O) m -( C 1 C_1 - C 12 C_{12} alkyl), wherein the -( C 1 C_1 - C 12 C_{12} alkylene)-OH is optionally substituted with -OH; or alternatively, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 8 R^8 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; R 9 is H or C 1 -C 12 alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O O , S ( O ) t S(O)_t , or N N ; R 10 R^{10} is –OH, halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; X is N or CH; m is 0, 1, or 2; n is 0, 1, or 2; and t is 0, 1, or 2.

2. The compound, salt, or solvate of claim 1, wherein R 1 R^1 is C 1 C_1 - C 6 C_6 alkyl, C 1 C_1 - C 6 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 heterocyclyl, or -(C 1 -C 6 alkylene)-(3- to 6- membered heterocyclyl).

3. The compound, salt, or solvate of claim 1 or 2, wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or − ( C H 2 ) p -(CH_2)_p -cyclohexyl; wherein p is 1, 2, or 3.

4. The compound, salt, or solvate of any one of claims 1-3, wherein R 2 R^2 is − N H 2 -NH_2 .

5. The compound, salt, or solvate of any one of claims 1-4, wherein R 6 is substituted with one ℝ 3 \mathbb{R}^3 .

6. The compound, salt, or solvate of any one of claims 1-5, wherein R 7 R^7 is C 1 C_1 - C 6 C_6 alkyl, C 1 C_1 - C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ alkyl}) , − C ( O ) O ( C 1 − C 6 alkyl ) -C(O)O(C_1-C_6 \text{ alkyl}) , or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .

7. The compound, salt, or solvate of any one of claims 1-6, wherein R 7 R^7 is C 1 C_1 - C 6 C_6 alkyl, C 1 C_1 - C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 R^4 .

8. The compound, salt, or solvate of any one of claims 1-7, wherein R 7 R^7 is C 1 C_1 - C 6 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 .

9. The compound, salt, or solvate of any one of claims 1-8, wherein R 3 R^3 is -O-( C 1 C_1 - C 6 C_6 alkylene)- N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) ( C 1 − C 6 ) N(R^5)(C_1-C_6) alkylene-OH), - C ( O ) N ( R 5 ) 2 C(O)N(R^5)_2 , - C ( O ) N ( R 5 ) ( C 1 − C 6 ) C(O)N(R^5)(C_1-C_6) C 6 C_6 alkylene-OH), − C ( O ) ( C 1 − C 6 -C(O)(C_1-C_6 alkyl), − C ( O ) O ( C 1 − C 6 -C(O)O(C_1-C_6 alkyl), or − S ( O ) m ( C 1 − C 6 -S(O)_m(C_1-C_6 alkyl).

10. The compound, salt, or solvate of any one of claims 1-8, wherein R 3 R^3 is -( C 1 C_1 - C 3 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 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, - O C H 2 C H 2 N H 2 OCH_2CH_2NH_2 , − O C H 2 C H 2 N H ( C 1 − C 3 alkyl ) -OCH_2CH_2NH(C_1-C_3 \text{ alkyl}) , or − O C H 2 C H 2 N ( C 1 − C 3 alkyl ) 2 -OCH_2CH_2N(C_1-C_3 \text{ alkyl})_2 .

11. The compound, salt, or solvate of claim 10, wherein R 3 is -NHCH 2 CH 2 OH or - N ( C H 3 ) C H 2 C H 2 O H N(CH_3)CH_2CH_2OH .

12. The compound, salt, or solvate of any one of claims 1-11, wherein R 4 is halogen, -CN, - N ( R 5 ) 2 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 heterocyclyl.

13. The compound, salt, or solvate of any one of claims 1-12, wherein n is 1.

14. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: R 1 is 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), 3-to 6- membered heterocyclyl, -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), or -(C 1 -C 6 alkylene)-(3- to 6- membered heterocyclyl); R 2 R^2 is − N H 2 -NH_2 or C N CN : R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 R^3 ; R 7 is C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 6- to 18-membered aryl, 3- to 20-membered heterocyclyl, 5- to 20-membered heteroaryl, -C(O)-(C 1 -C 12 alkyl), - C(O)O-(C 1 -C 12 alkyl), or -C(O)NR 5 -(C 1 -C 12 alkyl), each of which is optionally substituted with one or more R 4 ; R 3 R^3 is oxo, − O H -OH , − O − ( C 1 − C 12 -O-(C_1-C_{12} alkylene)- N ( R 5 ) 2 N(R^5)_2 , − N ( R 5 ) 2 -N(R^5)_2 , − N ( R 5 ) ( C 1 − C 12 -N(R^5)(C_1-C_{12} alkylene- O H OH ), C 1 − C 12 C_1-C_{12} alkyl, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, -C(O)N(R 5 ) 2 , -C(O)N(R 5 )(C 1 -C 12 alkylene-OH), -C(O)-(C 1 -C 12 alkyl), -C(O)O-(C 1 -C 12 alkyl), or − S ( O ) m -S(O)_m -(C 1 -C 12 alkyl); R 4 R^4 is oxo, halogen, -CN, -N( R 5 R^5 ) 2 , -OH, -O-( C 1 C_1 - C 12 C_{12} alkylene)-OH,-S(O) m -( C 1 C_1 - C 12 C_{12} alkyl), - C ( O ) C(O) - ( C 1 (C_1 - C 12 C_{12} alkyl), − C ( O ) -C(O) - ( 3 (3 - to 10-membered cycloalkyl), C 1 C_1 - C 12 C_{12} alkyl, C 1 C_1 - C 12 C_{12} haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, or -(C 1 -C 12 alkylene)-aryl optionally substituted with R 8 ; each R 5 is independently, H, C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, -(C 1 -C 12 alkylene)-NH 2 , - ( C 1 − C 12 alkylene ) − N ( R 9 ) 2 (C_1-C_{12} \text{ alkylene})-N(R^9)_2 , − ( C 1 − C 12 alkylene ) − O − ( C 1 − C 12 alkylene ) − O H -(C_1-C_{12} \text{ alkylene})-O-(C_1-C_{12} \text{ alkylene})-OH , − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) alkylene)-O-(C 1 -C 12 alkylene)-NH 2 , -C(O)-(C 1 -C 12 alkyl), -C(O)O-(C 1 -C 12 alkyl), -(C 1 - C 12 C_{12} alkylene)-COOH, or -S(O) m -( C 1 C_1 - C 12 C_{12} alkyl), wherein the -( C 1 C_1 - C 12 C_{12} alkylene)-OH is optionally substituted with -OH; or alternatively, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 8 R^8 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; R 9 is H or C 1 -C 12 alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S ( O ) t S(O)_t , or N; X is N or CH; m is 0, 1, or 2; and t is 0, 1, or 2.

15. The compound, salt, or solvate of claim 14, wherein R 1 is 3- to 5-membered cycloalkyl or − ( C 1 − C 6 alkylene ) − ( 3 − to 5 − membered cycloalkyl ) . -(C_1-C_6 \text{ alkylene})-(3-\text{ to }5-\text{membered cycloalkyl}).

16. The compound, salt, or solvate of claim 14 or 15, wherein R 1 is cyclobutyl.

17. The compound, salt, or solvate of claim 14, wherein R 1 is a bicyclic 4- to 6-membered cycloalkyl.

18. The compound, salt, or solvate of any one of claims 14-17, wherein R 7 R^7 is C 1 C_1 - C 6 C_6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6- membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 - C 6 alkyl), or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more ℝ 4 \mathbb{R}^4 .

19. The compound, salt, or solvate of any one of claims 14-18, wherein R 7 R^7 is C 1 C_1 - C 4 C_4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more ℝ 4 \mathbb{R}^4 .

20. The compound, salt, or solvate of any one of claims 14-19, wherein R 7 R^7 is C 1 C_1 - C 3 C_3 alkyl, C 1 -C 3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6- membered heteroaryl, each of which is optionally substituted with one or more R 4 .

21. The compound, salt, or solvate of any one of claims 14-20, wherein R 7 R^7 is -CF 3 , isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R 4 .

22. The compound, salt, or solvate of any one of claims 14-21, wherein ℝ 3 \mathbb{R}^3 is -O-( ℂ 1 \mathbb{C}_1 - ℂ 6 \mathbb{C}_6 alkylene)- N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) ( C 1 − C 6 ) N(R^5)(C_1-C_6) alkylene-OH), - C ( O ) N ( R 5 ) 2 C(O)N(R^5)_2 , - C ( O ) N ( R 5 ) ( C 1 − C 6 ) C(O)N(R^5)(C_1-C_6) C 6 C_6 alkylene-OH), − C ( O ) ( C 1 − C 6 -C(O)(C_1-C_6 alkyl), − C ( O ) O ( C 1 − C 6 -C(O)O(C_1-C_6 alkyl), or − S ( O ) m ( C 1 − C 6 -S(O)_m(C_1-C_6 alkyl).

23. The compound, salt, or solvate of any one of claims 14-22, wherein R 3 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 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 , - O C H 2 C H 2 N H ( C 1 − C 3 alkyl ) OCH_2CH_2NH(C_1-C_3 \text{ alkyl}) , or − O C H 2 C H 2 N ( C 1 − C 3 alkyl ) 2 -OCH_2CH_2N(C_1-C_3 \text{ alkyl})_2 .

24. The compound, salt, or solvate of claim 23, wherein R 3 is -NHCH 2 CH 2 OH or - N ( C H 3 ) C H 2 C H 2 O H N(CH_3)CH_2CH_2OH .

25. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: R 1 R^1 is 3- to 10-membered cycloalkyl, -( C 1 C_1 - C 12 C_{12} alkylene)-(3- to 10-membered cycloalkyl), -( C 1 C_1 - C 12 alkylene)-(C 1 -C 12 alkoxy), 3- to 20-membered heterocyclyl, or –(C 1 -C 12 alkylene)- (3- to 20-membered heterocyclyl); R 2 R^2 is − N H 2 -NH_2 or C N CN ; R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 R^3 ; R 7 is C 1 -C 6 haloalkyl, 6- to 18-membered aryl or 5- to 20-membered heteroaryl, each of which is optionally substituted with one or more R 4 ; R 3 R^3 is oxo, − O H -OH , − O − ( C 1 − C 12 -O-(C_1-C_{12} alkylene)- N ( R 5 ) 2 N(R^5)_2 , − N ( R 5 ) 2 -N(R^5)_2 , − N ( R 5 ) ( C 1 − C 12 -N(R^5)(C_1-C_{12} alkylene- O H OH ), C 1 − C 12 C_1-C_{12} alkyl, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, − C ( O ) N ( R 5 ) 2 -C(O)N(R^5)_2 , − C ( O ) N ( R 5 ) ( C 1 − C 12 alkylene-OH ) -C(O)N(R^5)(C_1-C_{12} \text{ alkylene-OH}) , − C ( O ) − ( C 1 − C 12 alkyl ) -C(O)-(C_1-C_{12} \text{ alkyl}) , − C ( O ) O − ( C 1 − C 12 alkyl ) -C(O)O-(C_1-C_{12} \text{ alkyl}) alkyl), or − S ( O ) m -S(O)_m - ( C 1 (C_1 - C 12 C_{12} alkyl), each R 5 is independently, H, C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, -(C 1 -C 12 alkylene)-NH 2 , - ( C 1 − C 12 alkylene ) − N ( R 9 ) 2 (C_1-C_{12} \text{ alkylene})-N(R^9)_2 , − ( C 1 − C 12 alkylene ) − O − ( C 1 − C 12 alkylene ) − O H -(C_1-C_{12} \text{ alkylene})-O-(C_1-C_{12} \text{ alkylene})-OH , − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) alkylene)-O-( C 1 C_1 - C 12 C_{12} alkylene)-NH 2 , -C(O)- ( C 1 C_1 - C 12 C_{12} alkyl), -( C 1 C_1 - C 12 C_{12} alkylene)-COOH, - C ( O ) O − ( C 1 − C 12 alkyl ) C(O)O-(C_1-C_{12} \text{ alkyl}) , or − S ( O ) m − ( C 1 − C 12 alkyl ) -S(O)_m-(C_1-C_{12} \text{ alkyl}) , wherein the − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) -OH is optionally substituted with -OH; or alternative, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 4 R^4 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; X is N or CH; and m is 0, 1, or 2.

26. The compound, salt, or solvate of any one of claims 14-25, wherein R 7 is -CF 3 , pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with one or more R 4 R^4 .

27. The compound, salt, or solvate of any one of claims 14-26, wherein R 7 is -CF 3 , pyridyl, pyrazole, fluorophenyl, or a triazole optionally substituted with halogen or methyl.

28. The compound, salt, or solvate of any one of claims 14-20 and 22-26, wherein ℝ 7 \mathbb{R}^7 is: [Image disponible dans le document PDF, Image available in the PDF document]29. The compound, salt, or solvate of claim 26, wherein R 7 R^7 is − C F 3 -CF_3 . [Image disponible dans le document PDF, Image available in the PDF document]30. The compound, salt, or solvate of claim 26, wherein R 7 is [Image disponible dans le document PDF, Image available in the PDF document]31. The compound, salt, or solvate of claim 26, wherein R 7 is , [Image disponible dans le document PDF, Image available in the PDF document]32. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: R 1 is 3- to 10-membered cycloalkyl, -(C 1 -C 12 alkylene)-(3- to 10-membered membered cycloalkyl), -(C 1 -C 12 alkylene)-(C 1 -C 12 alkoxy), 3- to 20-membered heterocyclyl, or - ( C 1 − C 12 alkylene ) (C_1-C_{12} \text{ alkylene}) - ( 3 − to 20 − membered heterocyclyl ) ; (3-\text{ to } 20-\text{membered heterocyclyl}); R 2 R^2 is − N H 2 -NH_2 or C N CN ; R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 R^3 ; R 7 is 3- to 6-membered cycloalkyl, optionally substituted with one or more R 4 ; R 3 R^3 is oxo, − O H -OH , − O − ( C 1 − C 12 -O-(C_1-C_{12} alkylene)- N ( R 5 ) 2 N(R^5)_2 , − N ( R 5 ) 2 -N(R^5)_2 , − N ( R 5 ) ( C 1 − C 12 -N(R^5)(C_1-C_{12} alkylene- O H OH ), C 1 − C 12 C_1-C_{12} alkyl, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, − C ( O ) N ( R 5 ) 2 -C(O)N(R^5)_2 , − C ( O ) N ( R 5 ) ( C 1 − C 12 alkylene-OH ) -C(O)N(R^5)(C_1-C_{12} \text{ alkylene-OH}) , − C ( O ) − ( C 1 − C 12 alkyl ) -C(O)-(C_1-C_{12} \text{ alkyl}) , − C ( O ) O − ( C 1 − C 12 alkyl ) -C(O)O-(C_1-C_{12} \text{ alkyl}) alkyl), or − S ( O ) m -S(O)_m -( C 1 C_1 - C 12 C_{12} alkyl); R 4 R^4 is halogen, -CN, -NH 2 , -OH, or C 1 -C 3 alkyl; each R 5 is independently, H, C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, -(C 1 -C 12 alkylene)-NH 2 , - ( C 1 − C 12 alkylene ) − N ( R 9 ) 2 (C_1-C_{12} \text{ alkylene})-N(R^9)_2 , − ( C 1 − C 12 alkylene ) − O − ( C 1 − C 12 alkylene ) − O H -(C_1-C_{12} \text{ alkylene})-O-(C_1-C_{12} \text{ alkylene})-OH , − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) alkylene)-O-( C 1 C_1 - C 12 C_{12} alkylene)-NH 2 , -C(O)-( C 1 C_1 - C 12 C_{12} alkyl), -( C 1 C_1 - C 12 C_{12} alkylene)-COOH, - C ( O ) O − ( C 1 − C 12 alkyl ) C(O)O-(C_1-C_{12} \text{ alkyl}) , or − S ( O ) m − ( C 1 − C 12 alkyl ) -S(O)_m-(C_1-C_{12} \text{ alkyl}) , wherein the − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) -OH is optionally substituted with -OH; or alternative, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 8 R^8 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; X is N or CH; m is 0, 1, or 2.

33. The compound, salt, or solvate of claim 32, wherein ℝ 7 \mathbb{R}^7 is cyclopropyl.

34. The compound, salt, or solvate of any one of claims 29-33, wherein R 1 is, 3- to 6- membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), 3- to 6- membered heterocyclyl, or − ( C 1 − C 6 alkylene ) -(C_1-C_6 \text{ alkylene}) -(3- to 6-membered heterocyclyl).

35. The compound, salt, or solvate of any one of claims 29-34, wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p - cyclopentyl, or − ( C H 2 ) p -(CH_2)_p -cyclohexyl; wherein p is 1, 2, or 3.

36. The compound, salt, or solvate of any one of claims 29-35, wherein R 3 R^3 is -O-( C 1 C_1 - C 6 C_6 alkylene)- N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) ( C 1 − C 6 ) N(R^5)(C_1-C_6) alkylene-OH), - C ( O ) N ( R 5 ) 2 C(O)N(R^5)_2 , - C ( O ) N ( R 5 ) ( C 1 − C 6 ) C(O)N(R^5)(C_1-C_6) C 6 C_6 alkylene-OH), − C ( O ) ( C 1 − C 6 -C(O)(C_1-C_6 alkyl), − C ( O ) O ( C 1 − C 6 -C(O)O(C_1-C_6 alkyl), or − S ( O ) m ( C 1 − C 6 -S(O)_m(C_1-C_6 alkyl).

37. The compound, salt, or solvate of any one of claims 29-36, wherein R 3 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 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 C_3 alkyl) C H 2 C H 2 N H ( C 1 − C 3 CH_2CH_2NH(C_1-C_3 alkyl), − N ( C 1 − C 3 -N(C_1-C_3 alkyl) C H 2 C H 2 N ( C 1 − C 3 CH_2CH_2N(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 , - O C H 2 C H 2 N H ( C 1 − C 3 alkyl ) OCH_2CH_2NH(C_1-C_3 \text{ alkyl}) , or − O C H 2 C H 2 N ( C 1 − C 3 alkyl ) 2 -OCH_2CH_2N(C_1-C_3 \text{ alkyl})_2 .

38. The compound, salt, or solvate of claim 37, wherein R 3 is -NHCH 2 CH 2 OH or - N ( C H 3 ) C H 2 C H 2 O H N(CH_3)CH_2CH_2OH .

39. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: [Image disponible dans le document PDF, Image available in the PDF document] R 2 R^2 is − N H 2 -NH_2 or C N CN ; R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 ; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or alternative, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 8 R^8 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; X is N or CH; m is 0, 1, or 2.

40. The compound, salt, or solvate of claim 39, wherein R 3 R^3 is -O-( C 1 C_1 - C 6 C_6 alkylene)-N( R 5 R^5 ) 2 , - N ( R 5 ) 2 N(R^5)_2 or − N ( R 5 ) ( C 1 − C 6 -N(R^5)(C_1-C_6 alkylene-OH).

41. The compound, salt, or solvate of claim 39 or 40, wherein R 5 is H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-OH, or − S ( O ) 2 ( C 1 − C 3 alkyl ) -S(O)_2(C_1-C_3 \text{ alkyl}) .

42. The compound, salt, or solvate of claim 39, wherein R 3 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 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 C_3 alkyl) C H 2 C H 2 N H ( C 1 − C 3 CH_2CH_2NH(C_1-C_3 alkyl), − N ( C 1 − C 3 -N(C_1-C_3 alkyl) C H 2 C H 2 N ( C 1 − C 3 CH_2CH_2N(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 , - O C H 2 C H 2 N H ( C 1 − C 3 alkyl ) , or − O C H 2 C H 2 N ( C 1 − C 3 alkyl ) 2 . OCH_2CH_2NH(C_1-C_3 \text{ alkyl}), \text{ or } -OCH_2CH_2N(C_1-C_3 \text{ alkyl})_2.

43. The compound, salt, or solvate of claim 42, wherein R 3 is -NHCH 2 CH 2 OH or - N ( C H 3 ) C H 2 C H 2 O H N(CH_3)CH_2CH_2OH .

44. The compound, salt, or solvate of claim 42 or 43, wherein R 3 is –NHCH 2 CH 2 OH.

45. The compound, salt, or solvate of any one of claims 14-31 or 32-44, wherein R 6 is substituted with one R 3 R^3 .

46. The compound, salt, or solvate of any one of claims 39-45, wherein R 7 R^7 is C 1 C_1 - C 3 C_3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6- membered heteroaryl, each of which is optionally substituted with one or more R 4 .

47. The compound, salt, or solvate of any one of claims 39-45, wherein R 7 R^7 is -CF 3 , cyclopropyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .

48. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: R 1 R^1 is 3- to 10-membered cycloalkyl, -( C 1 C_1 - C 12 C_{12} alkylene)-(3- to 10-membered cycloalkyl), -( C 1 C_1 - C 12 alkylene)-(C 1 -C 12 alkoxy), 3- to 20-membered heterocyclyl, or -(C 1 -C 12 alkylene)- (3- to 20-membered heterocyclyl); R 2 R^2 is − N H 2 -NH_2 or C N CN ; R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 R^3 ; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] R 4 R^4 is oxo, halogen, -CN, -N( R 5 R^5 ) 2 , -OH, -O-( C 1 C_1 - C 12 C_{12} alkylene)-OH, -S(O) m -( C 1 C_1 - C 12 C_{12} alkyl), - [Image disponible dans le document PDF, Image available in the PDF document] haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, or -(C 1 -C 12 alkylene)-(6- to 18-membered aryl) optionally substituted with R 8 ; each R 5 is independently, H, C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, -(C 1 -C 12 alkylene)-O-(C 1 - [Image disponible dans le document PDF, Image available in the PDF document] C ( O ) O − ( C 1 − C 12 alkyl ) C(O)O-(C_1-C_{12} \text{ alkyl}) , or − S ( O ) m − ( C 1 − C 12 alkyl ) -S(O)_m-(C_1-C_{12} \text{ alkyl}) , wherein the − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) -OH is optionally substituted with -OH; or alternatively, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 8 R^8 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; X is N or CH; and m is 0, 1, or 2.

49. The compound, salt, or solvate of claim 48, wherein R 6 R^6 is substituted with one R 3 R^3 .

50. The compound, salt, or solvate of claim 48 or 49, wherein R 7 R^7 is C 1 C_1 - C 6 C_6 alkyl, C 1 C_1 - C 6 C_6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ alkyl}) , − C ( O ) O ( C 1 − C 6 alkyl ) -C(O)O(C_1-C_6 \text{ alkyl}) , or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .

51. The compound, salt, or solvate of any one of claims 48-50, wherein R 7 R^7 is C 1 C_1 - C 4 C_4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .

52. The compound, salt, or solvate of any one of claims 48-51, wherein R 7 R^7 is C 1 C_1 - C 3 C_3 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more ℝ 4 \mathbb{R}^4 .

53. The compound, salt, or solvate of any one of claims 48-52, wherein R 7 R^7 is C 1 C_1 - C 3 C_3 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R 4 .

54. The compound, salt, or solvate of any one of claims 48-53, wherein R 7 R^7 is -CF 3 , isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R 455. The compound, salt, or solvate of any one of claims 48-54, wherein R 1 is 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 heterocyclyl, or -(C 1 -C 6 alkylene)-(3- to 6- membered heterocyclyl).

56. The compound, salt, or solvate of any one of claims 48-55, wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p - cyclopentyl, or − ( C H 2 ) p -(CH_2)_p -cyclohexyl; wherein p is 1, 2, or 3.

57. The compound, salt, or solvate of any one of claims 48-56, wherein ℝ 3 \mathbb{R}^3 is -O-( ℂ 1 \mathbb{C}_1 - ℂ 6 \mathbb{C}_6 alkylene)- N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) 2 N(R^5)_2 , - N ( R 5 ) ( C 1 − C 6 ) N(R^5)(C_1-C_6) alkylene-OH), - C ( O ) N ( R 5 ) 2 C(O)N(R^5)_2 , - C ( O ) N ( R 5 ) ( C 1 − C 6 ) C(O)N(R^5)(C_1-C_6) C 6 C_6 alkylene-OH), − C ( O ) ( C 1 − C 6 -C(O)(C_1-C_6 alkyl), − C ( O ) O ( C 1 − C 6 -C(O)O(C_1-C_6 alkyl), or − S ( O ) m ( C 1 − C 6 -S(O)_m(C_1-C_6 alkyl).

58. The compound, salt, or solvate of any one of claims 48-57, wherein R 3 R^3 is -NH 2 , -N(C 1 - C 3 alkyl) 2 , -NHCH 2 CH 2 OH, or N(CH 3 )CH 2 CH 2 OH.

59. The compound, salt, or solvate of claim 58, wherein R 3 is -NHCH 2 CH 2 OH or - N ( C H 3 ) C H 2 C H 2 O H N(CH_3)CH_2CH_2OH .

60. The compound, salt, or solvate of any one of claims 48-59, wherein R 4 is halogen, -CN, − N ( R 5 ) 2 -N(R^5)_2 , − O H -OH , − O − ( C 1 − C 6 alkylene ) − O H -O-(C_1-C_6 \text{ alkylene})-OH , − S ( O ) m ( C 1 − C 6 alkyl ) -S(O)_m(C_1-C_6 \text{ alkyl}) , − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ alkyl}) , − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ alkyl}) , − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ alkyl}) , − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ alkyl}) , − C ( O ) ( C 1 − C 6 alkyl ) -C(O)(C_1-C_6 \text{ 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 heterocyclyl.

61. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 R^1 is cyclobutyl or -( C 1 C_1 - C 4 C_4 alkylene)-( C 1 C_1 - C 3 C_3 alkoxy); R 2 R^2 is − N H 2 -NH_2 or C N CN ; R 6 is 8- to 10-membered fused bicyclic heteroaryl, which is optionally substituted with one or more R 3 R^3 ; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] R 3 R^3 is oxo, -OH, -O-(C 1 -C 12 alkylene)-OH, -O-(C 1 -C 12 alkylene)-N( R 5 R^5 ) 2 , -N( R 5 R^5 ) 2 , -N( R 5 R^5 )(C 1 - C 12 C_{12} alkylene-OH), -N(R 5 )(C 1 -C 12 alkylene)-O-(C 1 -C 12 alkyl), C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, C 1 -C 12 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, − C ( O ) N ( R 5 ) 2 -C(O)N(R^5)_2 , − C ( O ) N ( R 5 ) ( C 1 − C 12 alkylene-OH ) -C(O)N(R^5)(C_1-C_{12} \text{ alkylene-OH}) , − C ( O ) − ( C 1 − C 12 alkyl ) -C(O)-(C_1-C_{12} \text{ alkyl}) , − - C ( O ) O − ( C 1 − C 12 alkyl ) C(O)O-(C_1-C_{12} \text{ alkyl}) , or − S ( O ) m − ( C 1 − C 12 alkyl ) -S(O)_m-(C_1-C_{12} \text{ alkyl}) , wherein the cycloalkyl and the heterocyclyl is each optionally substituted with R 10 R^{10} ; R 4 R^4 is C 1 C_1 - C 3 C_3 alkyl; each R 5 is independently, H, C 1 -C 12 alkyl, -(C 1 -C 12 alkylene)-OH, -(C 1 -C 12 alkylene)-NH 2 , - ( C 1 − C 12 alkylene ) − N ( R 9 ) 2 (C_1-C_{12} \text{ alkylene})-N(R^9)_2 , − ( C 1 − C 12 alkylene ) − O − ( C 1 − C 12 alkylene ) − O H -(C_1-C_{12} \text{ alkylene})-O-(C_1-C_{12} \text{ alkylene})-OH , − ( C 1 − C 12 alkylene ) -(C_1-C_{12} \text{ alkylene}) alkylene)-O-(C 1 -C 12 alkylene)-NH 2 , -C(O)-(C 1 -C 12 alkyl), -C(O)O-(C 1 -C 12 alkyl), -(C 1 - C 12 C_{12} alkylene)-COOH, or -S(O) m -( C 1 C_1 - C 12 C_{12} alkyl), wherein the -( C 1 C_1 - C 12 C_{12} alkylene)-OH is optionally substituted with -OH; or alternatively, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R 8 ; R 8 R^8 is halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; R 9 is H or C 1 -C 12 alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O O , S ( O ) t S(O)_t , or N N ; R 10 R^{10} is -OH, halogen, C 1 C_1 - C 12 C_{12} alkyl, or C 1 C_1 - C 12 C_{12} alkoxy; X is N or CH; m is 0, 1, or 2; p is 0 or 1; and t is 0, 1, or 2.

62. The compound, salt, or solvate of claim 1, wherein the compound has the structure of formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: R 1 R^1 is cyclobutyl or -( C 1 C_1 - C 4 C_4 alkylene)-( C 1 C_1 - C 3 C_3 alkoxy); R 2 R^2 is − N H 2 -NH_2 or C N CN ; [Image disponible dans le document PDF, Image available in the PDF document] , each of which is optionally substituted with one or more R 3 R^3 ; [Image disponible dans le document PDF, Image available in the PDF document] R 7 is –CF 3 , isopropyl, cyclopropyl, cyclobutyl, , each of which is optionally substituted with one or more R 4 ; 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 R^4 is C 1 C_1 - C 3 C_3 alkyl; and X is N or CH.

63. The compound, salt, or solvate of claim 1, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • • [Image disponible dans le document PDF, Image available in the PDF document] _ , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] - , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , - 380 - [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] - 385 - [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] - 387 - [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document]64. The compound: [Image disponible dans le document PDF, Image available in the PDF document]65. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] ___66. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document]67. The compound: [Image disponible dans le document PDF, Image available in the PDF document]68. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document]69. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document]70. The compound: [Image disponible dans le document PDF, Image available in the PDF document] ٠71. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •72. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •73. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •74. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document]75. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document]76. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •77. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •78. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document]79. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •80. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •81. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •82. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •83. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •84. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document] . •85. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •86. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •87. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •88. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •89. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •90. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •91. The compound: [Image disponible dans le document PDF, Image available in the PDF document] •92. A pharmaceutically acceptable salt of the compound: [Image disponible dans le document PDF, Image available in the PDF document] •93. A solvate of the compound: [Image disponible dans le document PDF, Image available in the PDF document]94. A compound having the following structure: [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] 0 , [Image disponible dans le document PDF, Image available in the PDF document] - - 1 - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] T. [Image disponible dans le document PDF, Image available in the PDF document] , , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] K 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] _ [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , 1 • [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] . [Image disponible dans le document PDF, Image available in the PDF document] - , [Image disponible dans le document PDF, Image available in the PDF document] _ [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pharmaceutically acceptable salt thereof, or a solvate thereof.

95. The compound of any one of claims 1 to 63 and 94.

96. The pharmaceutically acceptable salt of any one of claims 1 to 63 and 94.

97. The solvate of any one of claims 1 to 63 and 94.

98. A pharmaceutical composition comprising the compound, salt, or solvate of any one of claims 1 to 97 and a pharmaceutically acceptable excipient or a carrier.

99. Use of the compound, salt, or solvate of any one of claims 1 to 97 for the treatment of a 15-prostaglandin dehydrogenase mediated disease or condition.

100. The use of claim 99, wherein the 15-prostaglandin dehydrogenase mediated disease or condition is oral ulcers, gum disease, colitis, ulcerative colitis, gastrointestinal ulcers, inflammatory bowel disease, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary artery hypertension, cardiovascular disease, or renal disease.

101. The use of claim 99 or 100, wherein the 15-prostaglandin dehydrogenase mediated disease or condition is osteoporosis.

102. The use of claim 99 or 100, wherein the 15-prostaglandin dehydrogenase mediated disease or condition is colitis, ulcerative colitis, or inflammatory bowel disease.

103. Use of the compound, salt, or solvate of any one of claims 1 to 97 for treating a subject having at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia.

104. The use of claim 103, wherein the ischemia is associated with at least one of acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, bone fracture, brain edema, brain hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarct, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound-healing, type I diabetes, (type II diabetes, diabetic neuropathy, diabetes induced ischemia, disseminated intravascular coagulation (DIC), embolic brain ischemia, graft- versus-host disease, hereditary hemorrhagic telengiectasiaischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral-bone cyst, thrombosis, thrombotic brain ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

105. Use of the compound, salt, or solvate of any one of claims 1 to 97 for treating or preventing a fibrotic disease, disorder or condition in a subject in need thereof.

106. The use of claim 105, wherein the fibrotic disease, disorder or condition is characterized, in whole or in part, by the excess production of fibrous material.

107. The use of claim 105, wherein the fibrotic disease, disorder, or condition is selected from the group consisting of systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma, sclerodermatous graft-vs-host-disease, kidney fibrosis, glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy, cardiac fibrosis, pulomanry fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, chemotherapy / radiation induced pulmonary fibrosis, oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fascilitis, eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis, bone marrow fibrosis, drug induced ergotism, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myleoid leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myeloproferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, collagenous colitis, acute fibrosis, and organ specific fibrosis.

108. The use of claim 105, wherein the fibrotic disease, disorder, or condition comprises lung fibrosis.

109. The use of claim 108, wherein the lung fibrosis is selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

110. The use of claim 109, wherein the lung fibrosis is cystic fibrosis.

111. The use of claim 105, wherein the fibrotic disease, disorder or condition comprises kidney fibrosis.

112. The use of claim 105, wherein the fibrotic disease, disorder or condition comprises liver fibrosis.

113. The use of claim 112, wherein the fibrotic disease, disorder or condition comprises liver fibrosis and wherein the liver fibrosis results from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non- alcoholic steatohepatitis (NASH), NASH associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha-1- antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or combinations thereof.

114. The use of claim 105, wherein the fibrotic disease, disorder or condition comprises heart fibrosis.

115. The use of claim 105, wherein the fibrotic disease, disorder or condition is systemic sclerosis.

116. The use of claim 105, wherein the fibrotic disease, disorder or condition is caused by post-surgical adhesion formation.

117. Use of the compound, salt, or solvate of any one of claims 1 to 97 in treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof.

118. The use of claim 117, wherein compound, salt, or solvate of any one of claims 1 to 76 is for use in combination with a corticosteroid and / or a tumor necrosis factor α \alpha (TNF α \alpha ) inhibitor.

119. The use of claim 117 or 118, wherein the disorder comprises at least one of oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

120. The use of claim 117 or 118, wherein the disease is inflammatory bowel disease.

121. The use of claim 117 or 120, wherein the disease is ulcerative colitis.

122. The use of claim 117 or 120, wherein the disease is Crohn's disease.

123. A compound, salt, or solvate of any one of claims 1 to 97 in combination with a corticosteroid for use in treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof.

124. The combination of claim 123, wherein the disorder comprises at least one of oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

125. The combination of claim 123, wherein the disorder comprises inflammation of the esophagus, inflammation of the glottis, inflammation of the epiglottis, inflammation of the tonsils, inflammation of the oropharynx, eosinophilic esophagitis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), erosive esophagitis, Barrett's esophagus, eosinophilic gastroenteritis, hypereosinophilic syndrome, corrosive (caustic) chemical esophagitis, radiation-induced esophagitis, chemotherapy-induced esophagitis, transient drug-induced esophagitis, persistent drug-induced esophagitis, Crohn's disease of the esophagus, and pseudomembranous esophagitis.