Pgdh inhibitors and methods of making and using

Abstract

SOLUTION: There are disclosed herein compounds that can inhibit 15-hydroxyprostaglandin dehydrogenase. Such compounds may be administered to subjects that may benefit from modulation of prostaglandin levels.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 965,062, filed January 23, 2020, U.S. Provisional Patent Application No. 63 / 007,755, filed April 9, 2020, U.S. Provisional Patent Application No. 63 / 029,184, filed May 22, 2020, U.S. Provisional Patent Application No. 63 / 092,116, filed October 15, 2020, U.S. Provisional Patent Application No. 63 / 110,803, filed November 6, 2020, and U.S. Provisional Patent Application No. 63 / 133,965, filed January 5, 2021, each of which is incorporated herein by reference. [Background technology]

[0002] Prostaglandins are a group of physiologically active lipid compounds with diverse biological actions, including vasodilation, inhibition of platelet aggregation, bronchodilatation, bronchoconstriction, immune response, contraction and relaxation of gastrointestinal smooth muscle, gastric acid secretion, gastric mucus secretion, uterine contraction, inhibition of lipolysis, neurotransmission, coagulation, hyperalgesia, and fever.

[0003] Treatment of diseases or disorders may require the activation of prostaglandins or the inhibition of prostaglandin inactivation. Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), are involved in the inactivation of prostaglandins. Therefore, prostaglandin-related diseases / disorders can be prevented, treated, and / or managed using inhibitors of hydroxyprostaglandin dehydrogenase, such as inhibitors of 15-PGDH. Summary of the Invention

[0004] In one aspect herein, there is provided a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to said subject a compound of Formula I:

[0005] [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Y is independently N and R 11 is selected from Each R 1 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 together form an oxo or thio group, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8, -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 11 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of formula I is

[0006] [ka] A method is provided that assumes that

[0007] In some embodiments, the compound has Formula Ia:

[0008] [ka] or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound has Formula Ib:

[0010] [ka] or a pharmaceutically acceptable salt thereof.

[0011]

[0023] Another aspect herein provides a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to said subject a compound of formula II:

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently N and CR 5 is selected from S, V, and Z are independently selected from N and C; R 1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 together form an oxo or thio group, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10aryl, and 5- to 10-membered heteroaryl; Each R 5 are independently H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl, and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of formula II is

[0013] [ka]

[0014] [ka]

[0015] [ka] A method is provided that assumes that

[0016] In some embodiments, the compound has the formula IIa:

[0017] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0018] In some embodiments, the compound has the formula IIb:

[0019] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0020] In some embodiments, the compound has Formula IIc:

[0021] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0022] In some embodiments, the compound has Formula IId:

[0023] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0024] In some embodiments, the compound has Formula IIe:

[0025] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0026] In some embodiments, the compound has the formula IIf:

[0027] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0028] In some embodiments, the compound has formula IIg:

[0029] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0030] In some embodiments, the compound has formula IIh:

[0031] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0032] In some embodiments, the compound has the formula IIi:

[0033] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0034] In some embodiments, the compound has the formula IIj:

[0035] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0036] In some embodiments, the compound has the formula IIn:

[0037] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0038] In some embodiments, the compound has the formula IIp:

[0039] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0040]

[0023] Another aspect herein provides a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to a subject a compound of formula III:

[0041] [ka] or a pharmaceutically acceptable salt thereof, wherein: Each X is independently N and CR 7 is selected from Y is O, S, SO2, and C(R 8 )2 is selected, R 1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 together form an oxo or thio group, R 4 and R 5 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 forming a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; Each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; or Two Rs attached to the same carbon atom 6 can be united to form oxo, thio, or C 3-10 Form a cycloalkyl, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 7 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 8 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's 8 By uniting, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 C optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl 3-10 can form a cycloalkyl, R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 13 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; m is 1 or 2, and wherein n is 0, 1, 2, 3, or 4.

[0042] In some embodiments, the compound has Formula IIIa:

[0043] [ka] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the compound has Formula IIIb:

[0045] [ka] or a pharmaceutically acceptable salt thereof, wherein Each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0046] In some embodiments, the compound has formula IIIc:

[0047] [ka] or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the compound has formula IIId:

[0049] [ka] or a pharmaceutically acceptable salt thereof, wherein Each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0050] In another aspect herein, a compound of formula IIk:

[0051] [ka] or a pharmaceutically acceptable salt thereof, wherein T, U, and N are independently N and CR 6 provided that when U is N, then at least one of T and Y is N; R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, Each R 4 are independently selected from H and halo; R 5 Halo, -NR 7 R 8 , -OR 9 , -C(O)R9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R7 and R 8 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; Each R 9 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; and p is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

[0052] In another aspect herein, a compound of formula IIm:

[0053] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10aryl, and 5- to 10-membered heteroaryl; or The Two R's 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0054] In another aspect herein, a compound of formula IIq:

[0055] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7, -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0056] In another aspect herein, a compound of formula IIIc:

[0057] [ka] or a pharmaceutically acceptable salt thereof, wherein Each X is independently N and CR 7 is selected from Y is O, S, SO2, and C(R 8 )2 is selected, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, R 4 and R 5 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 forming a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; Each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; or Two Rs attached to the same carbon atom 6 combine to form an oxo, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 7 and R 8 are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11, -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; Each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 13 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; and n is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0058] In another aspect herein,

[0059] [ka] Compositions are provided that include a compound selected from the group consisting of:

[0060] In another aspect herein,

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] [ka]

[0069] [ka]

[0070] [ka] Compositions are provided that include a compound selected from the group consisting of:

[0071] In another aspect herein,

[0072] [ka] Compositions are provided that include a compound selected from the group consisting of:

[0073] In another aspect herein, there is provided a method of promoting and / or stimulating skin pigmentation, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0074] In another aspect herein, there is provided a method of inhibiting hair loss, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0075] Methods for treating and / or preventing skin inflammation and / or damage are provided, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0076] In another aspect herein, there is provided a method for preventing and / or treating vascular insufficiency, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0077] In another aspect herein, provided are methods for preventing, treating, minimizing, and / or ameliorating congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0078] In another aspect herein, there is provided a method of reducing cardiac ejection fraction, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0079] In another aspect herein, there is provided a method for preventing and / or treating gastrointestinal disorders, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0080] In another aspect herein, there is provided a method for preventing and / or treating renal dysfunction, the method comprising administering one or more of the compositions described herein to a subject in need of prevention and / or treatment.

[0081] In another aspect herein, there is provided a method of stimulating bone resorption and bone formation, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0082] In another aspect herein, there is provided a method of stimulating tissue regeneration by stimulation, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0083] In another aspect herein, there is provided a method of modulating cervical ripening, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0084] In another aspect herein, there is provided a method of promoting neuroprotection and / or stimulating neuroregeneration, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0085] In another aspect herein, there is provided a method for treating and / or preventing a neurological disorder, a neuropsychiatric disorder, nerve injury, a neurotoxic disorder, neuropathic pain, or a neurodegenerative disorder, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0086] In another aspect herein, there is provided a method of treating and / or preventing a fibrotic or adhesive disease, disorder, or condition, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0087] In another aspect herein, there is provided a method of reducing and / or preventing scar formation, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0088] In another aspect herein, there is provided a method for treating and / or preventing muscle disorders, muscle damage, and / or muscle atrophy, comprising administering to a subject in need thereof one or more of the compositions described herein.

[0089] In another aspect herein, there is provided a method of treating and / or preventing fibrosis, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0090] In another aspect herein, there is provided a method of treating and / or preventing idiopathic pulmonary fibrosis, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0091] In another aspect herein, there is provided a method of treating and / or preventing renal fibrosis, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0092] In another aspect herein, there is provided a method of stimulating muscle regeneration comprising administering to a subject in need thereof one or more of the compositions described herein.

[0093] In another aspect herein, there is provided a method of promoting organ adaptation, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0094] In another aspect herein, there is provided a method of promoting wound healing, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0095] In another aspect herein, there is provided a method of treating acute kidney injury, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0096] In another aspect herein, there is provided a method of treating sarcopenia, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0097] In another aspect herein, there is provided a method of treating a neuromuscular disease, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0098] Citation by reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0099] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention can be understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0100] [Figure 1] 1 shows the results of a cell-based assay for exemplary compounds. DETAILED DESCRIPTION OF THE INVENTION

[0101] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0102] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0103] "C x-y The term "alkyl," when used in combination with a chemical moiety such as alkyl, haloalkyl, or heteroalkyl, is intended to include groups containing x to y carbons in the chain. For example, "C 1-6 The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups, containing 1 to 6 carbons. x-y The term alkylene- refers to a substituted or unsubstituted alkylene chain containing x to y carbon atoms in the alkylene chain. For example, -C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0104] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups. An alkyl group is a group having 1 to 8 carbon atoms (C 1-8 alkyl) or 1 to 6 carbon atoms (C 1-6alkyl) and other 1-12 carbon atoms (e.g., C 1-12 The alkyl group may contain a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified herein, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0105] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0106] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group having one or more skeletal atoms selected from atoms other than carbon. Exemplary skeletal atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where nitrogen, phosphorus, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Where given, numerical ranges refer to the total chain length. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the remainder of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. Unless otherwise specified herein, heteroalkyl groups are optionally substituted with one or more substituents, such as those described herein.

[0107] "Aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise specified in this specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0108] "Heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, each heteroatom being independently selected from N, O, and S. As used herein, a heteroaryl ring is selected from monocyclic or bicyclic fused or bridged ring systems, in which at least one ring is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1 ,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxazolyl Sadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolyl thiazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydroquinolinyl Examples of heteroaryl include, but are not limited to, tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl is optionally substituted with one or more substituents, such as those described herein.

[0109] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, where each of the atoms forming the ring (skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). Cycloalkyl groups include groups with 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. Unless stated otherwise specifically in the specification, a cycloalkyl group may be optionally substituted.

[0110] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, a heterocycloalkyl radical can be a monocyclic or bicyclic ring system and can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atom in the heterocyclyl radical can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocycloalkyl can be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, 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, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 12 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise specified in this specification, heterocycloalkyl groups may be optionally substituted.

[0111] The term "substituted" refers to moieties having substituents replacing hydrogen on one or more carbon or heteroatoms of the structure. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution, subject to the permissible valences of the substituted atom and substituents, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocyclic and heterocyclic substituents, and aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents that satisfy the valences of the heteroatom and / or any permissible substituent of organic compounds described herein. Substituents may include any substituent described herein, for example, oxo, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocycle, heterocycle, cycloalkyl, heterocycloalkyl, aromatic moiety, heteroaromatic moiety.

[0112] It will be understood by those skilled in the art that the substituents themselves can be substituted, where appropriate. Unless specifically designated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0113] Substituents, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result by writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0114] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs and examples when it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups with no substitution.

[0115] The compounds of the present disclosure also include crystalline and amorphous forms of the compounds, and pharmaceutically acceptable salts and active metabolites of the foregoing compounds having the same type of activity, such as polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, as well as mixtures thereof.

[0116] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3 It has three naturally occurring isotopes, represented by H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment in deuteration may provide therapeutic benefits, such as increased in vivo half-life and / or exposure, or may result in compounds useful for studying in vivo pathways of drug excretion and metabolism. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0117] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to indicate a racemic mixture when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each asymmetric carbon can be specified as R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical compounds, pharmaceutical compositions, and methods are intended to encompass all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and mixtures of intermediates. Optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including, but not limited to, chiral chromatography and polarimetry, to determine the predominance of one stereoisomer over another.

[0118] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond may exist in the Z- or E-form (or cis- or trans-form). Additionally, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E-, and tautomeric forms as well.

[0119] Isolation and purification of the chemical entities and intermediates described herein, if desired, can be achieved by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, or a combination of these procedures. Specific examples of suitable separation and isolation procedures can be provided with reference to the examples below. However, other equivalent separation or isolation procedures can also be used.

[0120] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, small molecule isomers such as enantiomers, diastereomers, and mixtures of enantiomers (including racemates, diastereomeric mixtures, and other mixtures thereof), where possible, to the extent that routine experimentation will enable one of ordinary skill in the art. In such situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of racemic or diastereomeric mixtures. Resolution of racemic or diastereomeric mixtures, where possible, can be achieved by conventional methods such as crystallization in the presence of a resolving agent, i.e., chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, mixtures of two enantiomers enriched in one of the two can be purified to provide more optically enriched forms of the major enantiomer by recrystallization and / or trituration. In addition, such particular small molecules include the Z- and E-forms (or cis- and trans-forms) of the particular small molecule involving a carbon-carbon double bond or a carbon-nitrogen double bond. When a small molecule described herein exists in various tautomeric forms, the term "a small molecule" is intended to include all tautomeric forms of the small molecule.

[0121] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary amines, secondary amines, tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, etc., specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, etc. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0122] The phrases "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used herein, refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0123] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve its intended use, including but not limited to, the treatment of disease, as defined below. A therapeutically effective amount may vary depending on the intended treatment use (in vivo) or the subject and disease state being treated, e.g., the subject's weight and age, the severity of the disease state, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to administrations that can induce specific responses in target cells, such as reduced platelet adhesion and / or cell migration. Specific administrations may vary depending on the particular compound selected, the administration regimen followed, whether a particular compound is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system in which the compound is delivered.

[0124] As used herein, "treatment" or "treating" refers to an approach to obtaining a beneficial or desired result for a disease, disorder, or condition, including, but not limited to, therapeutic benefit and / or preventative benefit. Therapeutic benefit may include, for example, eradication or amelioration of the underlying disorder being treated. Further, therapeutic benefit may include, for example, eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be affected by the underlying disorder. In certain embodiments, for preventative benefit, the composition is administered to a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease, even if the disease has not been diagnosed.

[0125] The term "therapeutic effect," as used herein, encompasses therapeutic benefit and / or prophylactic benefit, as defined above. A prophylactic effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the appearance of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0126] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, include administration of two or more agents to an animal, including a human, such that the two agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which the two agents are present.

[0127] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Thus, the terms "antagonist" and "inhibitor" are defined in terms of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, while also specifically included within this definition are compounds that inhibit the biological activity of the target protein through interactions with other members of the signal transduction pathway in which the target protein is a member. A preferred biological activity inhibited by an antagonist is associated with tumor development, growth, or spread.

[0128] Whenever a protein is referred to herein, it is understood that one protein may be referred to by various names, for example, "15-PGDH," "PGDH," and "hPGDH" all refer to the same protein, namely, 15-hydroxyprostaglandin dehydrogenase.

[0129] Methods for inhibiting 15-PGDH Provided herein are methods for inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

[0130] In one aspect herein, there is provided a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to said subject a compound of Formula I:

[0131] [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, -SO2CH2-; Y is independently N and R 11 is selected from Each R 1 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 together form an oxo or thio group, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8, -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 11 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of formula I is

[0132] [ka] A method is provided that assumes that

[0133] In some embodiments, X is selected from -OCH2-, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH2-, -S(O)CH2-, and -SO2CH2-. In some embodiments, X is -OCH2-. In some embodiments, X is -C(O)NH-. In some embodiments, X is -NHC(O)-. In some embodiments, X is -C(O)NMe-. In some embodiments, X is -NMeC(O)-. In some embodiments, X is -SCH2-. In some embodiments, X is -S(O)CH2-. In some embodiments, X is -SO2CH2-.

[0134] In some embodiments, each Y is independently N and CR 11 In some embodiments, each Y is N. In some embodiments, each Y is CR 11 In some embodiments, one Y is N and the other Y is CR 11 is.

[0135] In some embodiments, each R 1 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8, -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 1 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 1 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -NR10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 1 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 is selected from.

[0136] In some embodiments, R 2 is H and R 3 is —CF. In some embodiments, R 2 and R 3 are taken together to form oxo. In some embodiments, R 2 and R 3 come together to form thio.

[0137] In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 is selected from.

[0138] In some embodiments, each R 5 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 5 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 5are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 5 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 is selected from.

[0139] In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 6 and R 7 are independently H and C in each occurrence. 1-6 alkyl.

[0140] In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 8 are independently H and C 1-6 alkyl.

[0141] In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 9 independently C 1-6 alkyl.

[0142] In some embodiments, each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10In some embodiments, each R 10 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 10 are independently H and C 1-6 alkyl.

[0143] In some embodiments, each R 11 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 11 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 11 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , and -C(O)OR 8 is selected from.

[0144] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0145] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0146] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0147] In some embodiments, the compound has Formula Ia:

[0148] [ka] or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the compound has Formula Ib:

[0150] [ka] or a pharmaceutically acceptable salt thereof.

[0151]

[0023] Another aspect herein provides a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to said subject a compound of formula II:

[0152] [ka] or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently N and CR 5 is selected from S, V, and Z are independently selected from N and C; R1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 together form an oxo or thio group, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 5are independently H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl, and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of formula II is

[0153] [ka]

[0154] [ka]

[0155] [ka] A method is provided that assumes that

[0156] In some embodiments, T, U, W, X, and Y are independently selected from N and CR 5 In some embodiments, at least one of T, U, W, X, and Y is N, and the rest are selected from CR 5 In some embodiments, at least two of T, U, W, X, and Y are N, and the rest are CR 5 In some embodiments, at least three of T, U, W, X, and Y are N, and the rest are CR 5 In some embodiments, at least four of T, U, W, X, and Y are N, and the remainder are CR. 5 In some embodiments, T, U, W, X, and Y are CR 5 In some embodiments, T, U, W, X, and Y are N.

[0157] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N and the remainder are C. In some embodiments, at least two of S, V, and Z are N and the remainder are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0158] In some embodiments, R 1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, aryl, or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is optionally substituted with 1 to 3 substituents independently selected from

[0159] In some embodiments, R 2 is H and R 3 is —CF. In some embodiments, R2 and R 3 are taken together to form oxo. In some embodiments, R 2 and R 3 come together to form thio.

[0160] In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 In some embodiments, each R 4 is halo. In some embodiments, each R 4 is fluoro.

[0161] In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C1-6 In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently selected from halo. 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R4 is fluoro.

[0162] In some embodiments, each R 5 are independently H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 5 are independently H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 5 are independently H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 5 are independently H, halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 In some embodiments, each R 5 is independently selected from H and halo.

[0163] In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, and C1-6 In some embodiments, R is selected from haloalkyl. 6 and R 7 are independently H and C in each occurrence. 1-6 alkyl.

[0164] In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 8 are independently H and C 1-6 alkyl.

[0165] In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6Heteroalkyl, and C 1-6 In some embodiments, each R 9 independently C 1-6 alkyl.

[0166] In some embodiments, each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 10 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 10 are independently H and C 1-6 alkyl.

[0167] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0168] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0169] In some embodiments, the compound has the formula IIa:

[0170] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0171] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0172] In some embodiments, the compound has the formula IIb:

[0173] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0174] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0175] In some embodiments, the compound has Formula IIc:

[0176] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0177] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0178] In some embodiments, the compound has Formula IId:

[0179] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0180] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0181] In some embodiments, the compound has Formula IIe:

[0182] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0183] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0184] In some embodiments, the compound has the formula IIf:

[0185] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0186] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0187] In some embodiments, the compound has formula IIg:

[0188] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0189] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0190] In some embodiments, the compound has formula IIh:

[0191] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0192] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0193] In some embodiments, the compound has the formula IIi:

[0194] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0195] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0196] In some embodiments, the compound has the formula IIj:

[0197] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0198] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0199] In some embodiments, the compound has the formula IIn:

[0200] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0201] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0202] In some embodiments, the compound has the formula IIp:

[0203] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0204] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0205]

[0023] Another aspect herein provides a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to a subject a compound of formula III:

[0206] [ka] or a pharmaceutically acceptable salt thereof, wherein: Each X is independently N and CR 7 is selected from Y is O, S, SO2, and C(R 8 )2 is selected, R 1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 together form an oxo or thio group, R 4 and R 5 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 forming a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; Each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or Two Rs attached to the same carbon atom 6 can be united to form oxo, thio, or C 3-10 Form a cycloalkyl, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 7 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 8 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's8 By uniting, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 C optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl 3-10 can form a cycloalkyl, R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 13 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; m is 1 or 2, and wherein n is 0, 1, 2, 3, or 4.

[0207] In some embodiments, each X is independently N and CR 7 In some embodiments, at least one X is N and the rest are selected from CR 7 In some embodiments, at least two X are N and the rest are CR 7 In some embodiments, each X is N. In some embodiments, each X is CR 7 is.

[0208] In some embodiments, Y is selected from the group consisting of O, S, SO, and C(R 8 )2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R 8 )2.

[0209] In some embodiments, R 1 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl. 1 is C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein cycloalkyl, aryl, or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is optionally substituted with 1 to 3 substituents independently selected from

[0210] In some embodiments, R2 is H and R 3 is —CF. In some embodiments, R 2 and R 3 are taken together to form oxo. In some embodiments, R 2 and R 3 come together to form thio.

[0211] In some embodiments, R 4 and R 5 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. 4 and R 5 independently C 3-10cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. 4 and R 5 independently C 3-10 cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 4 and R 5 independently C 3-10 cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, R 4 and R 5 independently C 3-10 cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is optionally substituted with 1 to 3 substituents independently selected from

[0212] In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, R forms a 3- to 10-membered heterocycloalkyl optionally substituted with 1-3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl. 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C1-6 In some embodiments, R forms a 3-10 membered heterocycloalkyl optionally substituted with 1-3 substituents independently selected from haloalkyl. 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Forms a 3 to 10 membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from:

[0213] In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10, -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is selected from.

[0214] In some embodiments, two R 6 can be united to form oxo, thio, or C 3-10 Form a cycloalkyl, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 6 can be united to form oxo, thio, or C 3-10 Form a cycloalkyl, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, two R bonded to the same carbon atom are selected from haloalkyl. 6 can be united to form oxo, thio, or C 3-10 Form a cycloalkyl, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, two R attached to the same carbon atom are selected from 6 can be united to form oxo, thio, or C 3-10 Form a cycloalkyl, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is selected from.

[0215] In some embodiments, each R 7 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 7are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 7 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, each R 7 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR9 R 10 is selected from.

[0216] In some embodiments, each R 8 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 8 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, each R 8 are independently H, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is selected from.

[0217] In some embodiments, two R 8 By uniting, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 C optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl 3-10 In some embodiments, two R 8 By uniting, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from haloalkyl 3-10 In some embodiments, two R 8 By uniting, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 C optionally substituted with 1 to 3 substituents independently selected from 3-10 In some embodiments, two R 8 By uniting, halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 C optionally substituted with 1 to 3 substituents independently selected from 3-10 A cycloalkyl can be formed.

[0218] In some embodiments, R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 9 and R 10 are independently H and C in each occurrence. 1-6 alkyl.

[0219] In some embodiments, each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 11 are independently H and C 1-6 alkyl.

[0220] In some embodiments, each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 12 independently C 1-6 alkyl.

[0221] In some embodiments, each R 13 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 13 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 13 are independently H and C 1-6 alkyl.

[0222] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0223] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0224] In some embodiments, the compound has Formula IIIa:

[0225] [ka] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound has Formula IIIb:

[0227] [ka] or a pharmaceutically acceptable salt thereof, wherein Each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3

[0228] In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 In some embodiments, each R 4 is halo. In some embodiments, each R 4 is fluoro.

[0229] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0230] In some embodiments, the compound has formula IIIc:

[0231] [ka] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound has formula IIId:

[0233] [ka] or a pharmaceutically acceptable salt thereof, wherein Each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3

[0234] In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, each R 14 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 In some embodiments, each R 14 is independently halo. In some embodiments, each R 14 are independently fluoro.

[0235] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0236] compound In one aspect herein, a compound of formula IIk:

[0237] [ka] or a pharmaceutically acceptable salt thereof, wherein T, U, and N are independently N and CR 6 provided that when U is N, then at least one of T and Y is N; R 1 is C 6-10 aryl and 5-10 membered heteroaryl, wherein alkyl or heteroaryl is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, Each R 4 are independently selected from H and halo; R 5 Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 7 and R8 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; Each R 9 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; and p is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, T, U, and N are independently selected from N and CR 6 provided that when U is N, then at least one of T and Y is N. In some embodiments, one of T, U, and Y is N and the rest are CR 6 In some embodiments, two of T, U, and Y are N and the remaining are CR 6 In some embodiments, one of T, U, and Y is CR 6 and the remainder are N. In some embodiments, two of T, U, and Y are CR 6 and the remainder are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR6 is.

[0239] In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 is optionally substituted with 1 to 3 substituents independently selected from

[0240] In some embodiments, R 2is H and R 3 is —CF. In some embodiments, R 2 and R 3 together form an oxo.

[0241] In some embodiments, each R 4 is independently selected from H and halo. In some embodiments, each R 4 is independently selected from H and fluoro. In some embodiments, each R 4 is H. In some embodiments, each R 4 is fluoro. In some embodiments, one R 4 is H and one R 4 is fluoro.

[0242] In some embodiments, R 5 Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 5 Halo, -NR 7 R 8 , -OR9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 5 Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 In some embodiments, R 5 Halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 is selected from.

[0243] In some embodiments, R 6 H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 6 H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , -NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6In some embodiments, R is selected from haloalkyl. 6 H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 7 R 8 , -SOR 10 , -SO2R 10 , -SO2NR 7 R 8 , -NR 11 C(O)R 9 , -NR 11 C(O)NR 7 R 8 , -NR 11 SO2R 9 , and -NR 11 SO2NR 7 R 8 In some embodiments, R 6 H, halo, -NR 7 R 8 , -OR 9 , -C(O)R 9 , -C(O)OR 9 , and -C(O)NR 7 R 8 is selected from.

[0244] In some embodiments, R 7 and R 8 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 In some embodiments, R 7 and R 8 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 7 and R 8 are independently H and C in each occurrence. 1-6 alkyl.

[0245] In some embodiments, each R 9 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 9 are independently H and C 1-6 alkyl.

[0246] In some embodiments, each R 10 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 10 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 10 independently C 1-6 alkyl.

[0247] In some embodiments, each R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 In some embodiments, each R 11 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 11 are independently H and C1-6 alkyl.

[0248] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0249] In another aspect herein, a compound of formula IIm:

[0250] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R3 come together to form an oxo, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , and -NR 10 SO2NR 6 R 7 In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is optionally substituted with 1 to 3 substituents independently selected from

[0252] In some embodiments, R 2 is H and R 3 is —CF. In some embodiments, R 2 and R 3 together form an oxo.

[0253] In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 4 are independently halo, -NR 6 R7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 In some embodiments, each R 4 is independently selected from halo. 4 is fluoro.

[0254] In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is selected from.

[0255] In some embodiments, R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is selected from.

[0256] In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, R 6 and R 7are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, R is selected from haloalkyl. 6 and R 7 are independently H and C in each occurrence. 1-6 alkyl.

[0257] In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 8 are independently H and C 1-6 alkyl.

[0258] In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, each R 9 independently C 1-6 alkyl.

[0259] In some embodiments, each R 10 are independently H, C 1-6 Alkyl, C1-6 Haloalkyl, and C 3-10 In some embodiments, each R 10 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 10 are independently H and C 1-6 alkyl.

[0260] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0261] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0262] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0263] In another aspect herein, a compound of formula IIq:

[0264] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, Each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or The Two R's 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; Each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8, -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is optionally substituted with 1 to 3 substituents independently selected from

[0266] In some embodiments, R 2 is H and R 3 is —CF. In some embodiments, R 2 and R 3 together form an oxo.

[0267] In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7, -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, each R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 In some embodiments, each R 4 is independently selected from halo. 4 is fluoro.

[0268] In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, two R 4 are combined with the carbon atoms to which they are attached and any intervening atoms to form C 3-10 Form a cycloalkyl, and all remaining R 4 are independently halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is selected from.

[0269] In some embodiments, R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , -NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 , -SOR 9 , -SO2R 9 , -SO2NR6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO2R 8 , and -NR 10 SO2NR 6 R 7 In some embodiments, R 5 Halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , and -C(O)NR 6 R 7 is selected from.

[0270] In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, R 6 and R 7 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, R is selected from haloalkyl. 6 and R 7 are independently H and C in each occurrence. 1-6 alkyl.

[0271] In some embodiments, each R 8 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 8 are independently H and C 1-6 alkyl.

[0272] In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 9 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, each R 9 independently C 1-6 alkyl.

[0273] In some embodiments, each R 10 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 10 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 10 are independently H and C 1-6 alkyl.

[0274] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0275] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0276] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0277] In another aspect herein, a compound of formula IIIc:

[0278] [ka] or a pharmaceutically acceptable salt thereof, wherein Each X is independently N and CR 7 is selected from Y is O, S, SO2, and C(R 8 )2 is selected, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11, -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF3, or R 2 and R 3 come together to form an oxo, R 4 and R 5 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 forming a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; Each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or Two Rs attached to the same carbon atom 6 combine to form an oxo, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 7 and R 8 are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; Each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 13 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl; and n is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, each X is independently N and CR 7 In some embodiments, at least one X is N and the rest are selected from CR 7 In some embodiments, at least two X are N and the rest are CR 7 In some embodiments, each X is N. In some embodiments, each X is CR 7 is.

[0280] In some embodiments, Y is selected from the group consisting of O, S, SO, and C(R 8 )2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R 8 )2.

[0281] In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 3-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, cycloalkyl, and 5- to 10-membered heteroaryl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is optionally substituted with 1 to 3 substituents independently selected from

[0282] In some embodiments, R 2 is H and R 3 is —CF. In some embodiments, R 2 and R 3 together form an oxo.

[0283] In some embodiments, R 4 and R 5 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11, -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. 4 and R 5 independently C 3-10 cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. 4 and R 5 independently C 3-10cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is optionally substituted with 1 to 3 substituents independently selected from haloalkyl. 4 and R 5 independently C 3-10 cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10In some embodiments, R 4 and R 5 independently C 3-10 cycloalkyl, where each cycloalkyl is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is optionally substituted with 1 to 3 substituents independently selected from

[0284] In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, R forms a 3- to 10-membered heterocycloalkyl optionally substituted with 1-3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl. 4 and R 5together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R forms a 3-10 membered heterocycloalkyl optionally substituted with 1-3 substituents independently selected from haloalkyl. 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached to form halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 Forms a 3 to 10 membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from:

[0285] In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, each R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is selected from.

[0286] In some embodiments, two R 6 combine to form an oxo, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 6 combine to form an oxo, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, two R bonded to the same carbon atom are selected from haloalkyl. 6 combine to form an oxo, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, two R attached to the same carbon atom are selected from 6 combine to form an oxo, and all remaining R 6 are independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is selected from.

[0287] In some embodiments, R 7 and R 8 are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 7 and R 8 are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , -NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 7 and R 8 are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R11 , -C(O)OR 11 , -C(O)NR 9 R 10 , -SOR 12 , -SO2R 12 , -SO2NR 9 R 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 9 R 10 , -NR 13 SO2R 11 , and -NR 13 SO2NR 9 R 10 In some embodiments, R 7 and R 8 are each independently halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , and -C(O)NR 9 R 10 is selected from.

[0288] In some embodiments, R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, R 9 and R 10 are independently H and C when they occur. 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 9 and R 10 are independently H and C in each occurrence. 1-6 alkyl.

[0289] In some embodiments, each R 11 are independently H, C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 are independently H, C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 11 are independently H and C 1-6 alkyl.

[0290] In some embodiments, each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 12 independently C 1-6 Alkyl, C 1-6 Heteroalkyl, and C 1-6 In some embodiments, each R 12 independently C 1-6 alkyl.

[0291] In some embodiments, each R 13 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 In some embodiments, each R 13 are independently H, C 1-6 Alkyl, and C 1-6 In some embodiments, each R 13 are independently H and C 1-6 alkyl.

[0292] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0293] In another aspect herein,

[0294] [ka] Compositions are provided that include a compound selected from the group consisting of:

[0295] In another aspect herein,

[0296] [ka]

[0297] [ka]

[0298] [ka]

[0299] [ka]

[0300] [ka]

[0301] [ka]

[0302] [ka]

[0303] [ka]

[0304] [ka]

[0305] [ka] Compositions are provided that include a compound selected from the group consisting of:

[0306] In another aspect herein,

[0307] [ka] Compositions are provided that include a compound selected from the group consisting of:

[0308] Optionally, the solubility and hPGDH IC50 of the inhibitors are characterized as shown in Tables 1 and 2.

[0309] [Table 1-1]

[0310] [Table 1-2]

[0311] [Table 1-3]

[0312] [Table 1-4]

[0313] [Table 1-5]

[0314] [Table 1-6]

[0315] [Table 1-7]

[0316] [Table 2-1]

[0317] [Table 2-2]

[0318] Table 3 provides analytical data for some of the inhibitors described herein.

[0319] [Table 3-1]

[0320] [Table 3-2]

[0321] [Table 3-3]

[0322] [Table 3-4]

[0323] [Table 3-5]

[0324]

Table 3-6

[0325]

Table 3-7

[0326]

Table 3-8

[0327]

Table 3-9

[0328]

Table 3-10

[0329]

Table 3-11

[0330]

Table 3-12

[0331]

Table 3-13

[0332]

Table 3-14

[0333]

Table 3-15

[0334]

Table 3-16

[0335]

Table 3-17

[0336]

Table 3-18

[0337]

Table 3-19

[0338]

Table 3-20

[0339]

Table 3-21

[0340]

Table 3-22

[0341]

Table 3-23

[0342]

Table 3-24

[0343]

Table 3-25

[0344]

Table 3-26

[0345]

Table 3-27

[0346]

Table 3-28

[0347]

Table 3-29

[0348]

Table 3-30

[0349]

Table 3-31

[0350]

Table 3-32

[0351]

Table 3-33

[0352]

Table 3-34

[0353]

Table 3-35

[0354]

Table 3-36

[0355]

Table 3-37

[0356]

Table 3-38

[0357]

Table 3-39

[0358]

Table 3-40

[0359]

Table 3-41

[0360]

Table 3-42

[0361]

Table 3-43

[0362]

Table 3-44

[0363]

Table 3-45

[0364]

Table 3-46

[0365]

Table 3-47

[0366]

Table 3-48

[0367]

Table 3-49

[0368]

Table 3-50

[0369]

Table 3-51

[0370]

Table 3-52

[0371]

Table 3-53

[0372]

Table 3-54

[0373]

Table 3-55

[0374] How to use In one aspect of the present specification, there is provided a method for treating various disorders in a subject in need of treatment, comprising administering a compound described herein to the subject. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used for the prevention or treatment of diseases or disorders associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and / or low levels of prostaglandins. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used for the prevention or treatment of diseases or disorders in which it is desirable to increase the prostaglandin level in a subject suffering from the disease or disorder.

[0375] In some embodiments, a method of treating a disorder comprises administering to a subject a 15-PGDH inhibitor. In some embodiments, a compound described herein is a 15-PGDH inhibitor. In some embodiments, a compound having Formula I, Formula II, or Formula III is a 15-PGDH inhibitor. In some embodiments, the method comprises a therapeutically effective amount of a compound described herein. In some embodiments, the method comprises administering a therapeutically effective amount of a compound having Formula I, Formula II, or Formula III. In some embodiments, a compound described herein is a 15-PGDH inhibitor. In some embodiments, a compound having Formula I, Formula II, or Formula III is a 15-PGDH inhibitor. In some embodiments, the administering occurs in vitro. In some embodiments, the administering occurs in vivo.

[0376] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor refers to an amount sufficient to achieve the intended use, including but not limited to, the treatment of a disease, as defined herein, and the method contemplates the use of a sub-therapeutic amount of a 15-PGDH inhibitor to treat the intended disease state.

[0377] The amount of 15-PGDH administered may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, e.g., the weight and age of the subject, the severity of the disease state, the mode of administration, etc., and variations in the amount can be readily determined by one skilled in the art.

[0378] Measuring the inhibition of the biological effect of 15-PGDH can involve performing an assay on a biological sample, such as a sample obtained from a subject. Any of a variety of samples can be selected depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g., plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0379] Subjects treated with a 15-PGDH inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject's physiological response to treatment. For example, if the inhibition of the biological effect of 15-PGDH exceeds or falls below a threshold, the amount or frequency of administration may be reduced or increased, respectively. The method may further include continuing the treatment if the treatment is determined to be effective. The method may include maintaining, tapering, reducing, or stopping the dosage of the compound in the treatment if the treatment is determined to be effective. The method may include increasing the dosage of the compound in the treatment if the treatment is determined to be ineffective. Alternatively, the method may include stopping the treatment if the treatment is determined to be ineffective. In some embodiments, treatment with a 15-PGDH inhibitor is discontinued if the inhibition of the biological effect exceeds or falls below a threshold, such as in the absence of a response or side effect. The biological effect may be a change in any of various physiological indicators.

[0380] Generally, 15-PGDH inhibitors are compounds that inhibit one or more biological effects of 15-PGDH, which may be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.

[0381] In some other embodiments, the methods are useful for treating disease states associated with 15-PGDH, including any disease state resulting directly or indirectly from abnormal levels of 15-PGDH activity or expression.

[0382] In one aspect herein, a method for promoting and / or stimulating skin pigmentation is provided, comprising administering one or more of the compositions described herein to a subject in need thereof. 15-PGDH inhibitors are known to promote skin pigmentation (Markowitz et al., WO2015 / 065716). The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used as agents for promoting and / or inducing and / or stimulating pigmentation of the skin and / or skin appendages, and / or for preventing and / or limiting depigmentation and / or whitening of the skin and / or skin appendages, particularly for preventing and / or limiting canities. In some embodiments, the 15-PGDH inhibitors provided herein can be applied to a subject's skin, for example, topically, to promote and / or stimulate skin pigmentation and / or hair growth, inhibit hair loss, and / or treat skin disorders or inflammation, such as skin damage caused by physical or chemical irritation and / or UV exposure.

[0383] In another aspect herein, a method for inhibiting hair loss is provided, comprising administering one or more of the compositions described herein to a subject in need of hair loss inhibition. Prostaglandins are known to play an important role in hair growth. Prostaglandins such as prostaglandins A1, F2a, and E2 are stored in hair follicles or the adjacent skin environment and are known to be essential for maintaining and increasing hair density (Colombe L et al., 2007, Exp. Dermatol, 16(9), 762-9). 15-PGDH is involved in the degradation of prostaglandins present in the dermal papilla of hair follicles, and has been reported to inactivate prostaglandins, particularly PGF2a and PGE2, causing scalp damage and alopecia (Michelet JF et al., 2008, Exp. Dermatol, 17(10), 821-8). Therefore, the hydroxyprostaglandin dehydrogenase inhibitors described herein have sedative or inhibitory activity against 15-PGDH, and can improve scalp damage, prevent alopecia, promote hair growth, and can be used in pharmaceutical compositions for preventing alopecia and promoting hair growth.

[0384] In another aspect herein, there is provided a method for preventing and / or treating skin inflammation and / or damage, the method comprising administering one or more of the compositions described herein to a subject in need of prevention and / or treatment.

[0385] Another aspect of the present disclosure provides a method for preventing and / or treating vascular insufficiency, comprising administering one or more of the compositions described herein to a subject in need of such treatment. Prostaglandins, including endogenously produced prostaglandin homologs, are known to maintain the proper function of vascular walls, specifically contributing to vasodilation in the bloodstream, preventing platelet aggregation, and regulating the proliferation of smooth muscle cells surrounding the vascular walls (Yan Cheng et al., 2006, J. Clin., Invest). Additionally, inhibition of prostaglandin production or loss of prostaglandin activity can lead to endothelial degeneration in the vascular wall, platelet aggregation, and dysfunction of cellular mechanisms in smooth muscle cells. In particular, prostaglandin production in blood vessels has been shown to be reduced in patients with hypertension, including pulmonary arterial hypertension. The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention and / or treatment of cardiovascular diseases and / or conditions of vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary arterial hypertension.

[0386] In another aspect herein, a method for preventing, treating, minimizing, and / or reversing congestive heart failure and cardiomyopathy is provided, the method comprising administering one or more of the compositions described herein to a subject in need thereof. In another aspect herein, a method for reducing cardiac ejection fraction is provided, the method comprising administering one or more of the compositions described herein to a subject in need thereof. Administration of a 15-PGDH inhibitor can be used to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and reduced cardiac ejection fraction (Markowitz et al., WO2018 / 187810). Therefore, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need thereof to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and reduced cardiac ejection fraction.

[0387] In another aspect herein, a method for preventing and / or treating gastrointestinal diseases is provided, comprising administering one or more of the compositions described herein to a subject in need of such prevention and / or treatment. Prostaglandins are essential for maintaining the protective and guarding mechanisms of the gastric mucosa (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65; SJ Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). The hydroxyprostaglandin dehydrogenase inhibitors described herein exhibit sedative or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect the gastric mucosa. Therefore, hydroxyprostaglandin dehydrogenase inhibitors may be effective in treating gastrointestinal diseases, particularly gastritis and gastric ulcers. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used to prevent and / or treat toxicity resulting from radiation therapy and / or chemotherapy, as well as other forms of intestinal damage, including chemotherapy-induced mucositis.

[0388] In addition, administration of 15-PGDH inhibitors, alone or in combination with corticosteroids and / or TNF inhibitors, can treat intestinal, gastrointestinal, or bowel disorders, such as oral ulcers, periodontal disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease (Markowitz et al., WO2018 / 102552). Thus, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat and / or prevent intestinal, gastrointestinal, or bowel disorders, such as oral ulcers, periodontal disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0389] In another aspect herein, a method for preventing and / or treating renal dysfunction is provided, comprising administering one or more of the compositions described herein to a subject in need of such prevention and / or treatment. In the kidney, prostaglandins may regulate renal blood flow and regulate urine formation through both renal vasoactivity and renal tubular activity. In clinical trials, prostaglandin inhibitors have been used to improve creatinine clearance in patients with chronic kidney disease, prevent transplant rejection and cyclosporine toxicity in renal transplant patients, and reduce urinary albumin excretion rates and N-acetyl-β-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64:22E-26E). Furthermore, because prostaglandins function as vasodilators in the kidney, inhibition of renal prostaglandin production has been reported to cause renal dysfunction (Hao, CM, 2008, Annu Rev Physiol, 70, 357.about.77). The hydroxyprostaglandin dehydrogenase inhibitors described herein have sedative or inhibitory activity against 15-PGDH, which degrades prostaglandins, and can be used to prevent and / or treat certain kidney diseases associated with impaired kidney function.

[0390] In another aspect herein, a method for stimulating bone resorption and bone formation is provided, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins have been shown to stimulate bone resorption and bone formation to increase bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore, inhibition of 15-PGDH increases callus size and mineralization after fracture. Given that 15-PGDH inhibits the activity of prostaglandins as described above, inhibition of 15-PGDH activity may result in the promotion of bone resorption and bone formation, which are inhibited by 15-PGDH. Therefore, inhibitors of hydroxyprostaglandin dehydrogenase described herein may be effective in promoting bone resorption and bone formation by inhibiting 15-PGDH activity. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can also be used to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and / or promote bone fusion to bone implants, artificial implants, dental implants, and bone grafts.

[0391] In another aspect herein, a method for stimulating tissue regeneration is provided, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin PGE2 supports the expansion of various types of tissue stem cells. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, enhances tissue regeneration in multiple organs. Studies have shown that inhibition of 15-PGDH increases prostaglandin PGE2 levels in bone marrow and other tissues, accelerates hematopoietic recovery after bone marrow transplantation, and promotes tissue regeneration in colon and liver injury (Zhang, Y. et al. Science 2015, 348(6240)). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the expansion of tissue stem cells.

[0392] Another aspect of the present disclosure provides a method for regulating cervical ripening, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates the EP2-receptor-signaling pathway in human cervical stromal cells, targeting its own synthesis by increasing the expression of COX-2 and PTGES and reducing its metabolism by the loss of its degradative enzyme, 15-PGDH (Word et al., WO2019010482). Downregulation of 15-PGDH has also been found to be important in PGE2-induced cervical ripening and preterm birth. Modulation of 15-PDGH activity can be used to regulate cervical ripening and induce or prevent preterm birth. Hydroxyprostaglandin dehydrogenase inhibitors can be used alone or in combination with other preterm birth inducers to induce cervical ripening and preterm birth.

[0393] In another aspect herein, a method for promoting neuroprotection and / or stimulating neuroregeneration is provided, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins exert various physiological functions in the central nervous system through their specific G protein-coupled receptors. The major prostaglandin, prostaglandin E2 (PGE2), can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4 receptors can regulate adenylate cyclase and the production of 3,5'-cyclic adenosine monophosphate (cAMP), while activation of EP1 and EP3 receptors can regulate Ca2+ signaling. Studies have shown that EP1 and EP2 receptors are expressed in neurons and microglia, as well as in neurons of the cerebral cortex, striatum, and hippocampus. Additionally, activation of EP2 receptors by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol. 1994 Feb;18(1):23-9; Yang et al., J Neurochem. 2009 Jan;108(1):295-304). Studies have further shown that, following activation, various PGE2 receptors can contribute to or prevent N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med. 2010 Jul 8;2(1):12). Another study showed that activation of EP2 receptors prevented neurons from amyloid beta-peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci. 2005 Nov;22(9):2199-206).Various studies have demonstrated that the mechanism by which PGE2 provides neuroprotection is via the EP2 or EP4 receptor, because both receptors increase cAMP, which in turn increases protein kinase A (PKA)-dependent pathways (Echeverria et al. Eur J Neurosci. 2005 Nov;22(9):2199-206; McCullough et al. J Neurosci. 2004 Jan 7;24(1):257-68). Stimulation of these receptors with PEG2 by administering compounds that inhibit, reduce, and / or antagonize 15-PGDH activity, such as the hydroxyprostaglandin dehydrogenase inhibitors capable of inhibiting 15-PGDH described herein, can promote neuroprotection in a subject from axonal degeneration, neuronal death, and / or glial cell damage following injury, enhance basic learning and memory through neural signaling, stimulate neuronal regeneration following injury, and / or treat nervous system diseases, disorders, and / or conditions.

[0394] In another aspect herein, methods are provided for treating and / or preventing neurological disorders, neuropsychiatric disorders, nerve injury, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders, the methods comprising administering one or more of the compositions described herein to a subject in need of such treatment and / or prevention. In some embodiments, the nervous system disease, disorder, and / or condition is treatable with the hydroxyprostaglandin dehydrogenase inhibitors provided herein and may include at least one of neurological disorders, neuropsychiatric disorders, nerve injury, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders. For example, the neurological disorder may include at least one of traumatic or toxic damage to the peripheral nerves, cranial nerves, spinal cord, or brain, such as traumatic brain injury, stroke, cerebral aneurysm, or spinal cord injury. The neurological disorder may also include at least one of Alzheimer's disease, Alzheimer's disease-related dementia, Parkinson's disease, diffuse Lewy body disease, senile dementia, Huntington's disease, Gilles de la Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Creutzfeldt-Jakob disease.

[0395] In some embodiments, the nerve damage may be caused by or associated with epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic nervous system disorder, bladder disorder, abnormal metabolic condition, muscular system disorder, infection, parasitic disease, neoplasm, endocrine disease, nutritional disease, metabolic disease, immune disease, blood disease, blood-forming organ disease, psychiatric disorder, nervous system disease, sensory organ disease, circulatory system disease, respiratory system disease, digestive system disease, genitourinary system disease, skin disease, subcutaneous tissue disease, musculoskeletal system disease, connective tissue disease, congenital abnormality, or perinatal disease.

[0396] In some embodiments, hydroxyprostaglandin dehydrogenase inhibitors can be administered to a subject or to the subject's neurons to promote the survival, growth, development, and / or function of neurons, particularly central nervous system (CNS), brain, brain neurons, and hippocampal neurons. In some embodiments, hydroxyprostaglandin dehydrogenase inhibitors can stimulate hippocampal neurogenesis and be used to treat neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neurostimulants such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine.

[0397] In another aspect herein, methods for treating and / or preventing fibrotic or adhesive diseases, disorders, or conditions are provided, comprising administering one or more of the compositions described herein to a subject in need of such treatment and / or prevention. Inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered to a subject in need thereof to reduce fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fibrillogenesis, inflammatory cytokine expression, and inflammatory cell infiltration, to treat and / or prevent a variety of fibrotic diseases, disorders, and conditions characterized in whole or in part by the overproduction of fibrous material, including the replacement of normal tissue elements with abnormal, non-functional, and / or excessive accumulation of matrix-associated components in the extracellular matrix (Markowitz et al., WO2016 / 144958).

[0398] Fibrotic diseases, disorders, and conditions characterized in whole or in part by the overproduction of fibrotic material include systemic sclerosis, connective tissue proliferation syndrome, nephrogenic systemic fibrosis, scleroderma (including morphea, systemic morphea, or linear scleroderma), sclerodermatous graft-versus-host disease, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive renal disease, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., pulmonary fibrosis, glomerulosclerotic pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation-induced fibrosis), oral fibrosis, endomyocardial fibrosis, triangular fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodule formation, eosinophilic fasciitis, and fibrotic syndromes characterized by varying degrees of replacement of normal muscle tissue with fibrous tissue. fibrosis syndrome, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug-induced ergotism, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ-specific fibrosis, etc. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders, or conditions.

[0399] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent renal fibrosis, including renal fibrosis resulting from dialysis after renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal failure, acute kidney injury, end-stage renal disease or renal failure, or a combination thereof.

[0400] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis resulting from chronic hepatitis, viral-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or nonalcoholic steatohepatitis (NASH), NASH-associated cirrhosis, obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions, exposure to toxins, or a combination thereof.

[0401] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent cardiac fibrosis, such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and renal fibrosis.

[0402] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis.

[0403] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders, or conditions resulting from post-surgical adhesion formation.

[0404] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce the intensity, severity, or frequency of, and / or delay the onset of, one or more symptoms or characteristics of a fibrotic disease, disorder, or condition, or other related disease, disorder, or condition.

[0405] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to decrease or reduce collagen secretion, collagen deposition, collagen fiber accumulation, or a combination thereof, in tissues or organs such as the lung, liver, intestine, colon, skin, heart, etc.

[0406] Studies have shown that 15-PGDH inhibition improves inflammatory symptoms and fibrosis in pulmonary fibrosis (Smith et.al., bioRxiv 2019.12.16.878215; Barnthaler et.al., J. Allergy Clin. Immunol. 2019,145(3),818-833). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent pulmonary fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal workers' pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of mineral dusts, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of toxic gases, aerosols, chemical dusts, odors, or vapors, drug-induced interstitial lung disease, pulmonary hypertension, and combinations thereof.

[0407] In another aspect herein, there is provided a method for reducing and / or preventing scar formation, the method comprising administering one or more of the compositions described herein to a subject in need thereof. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation in a subject. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent skin scar formation or scleroderma.

[0408] In another aspect herein, a method for treating and / or preventing muscle disorders, muscle damage, and / or muscle atrophy is provided, comprising administering one or more of the compositions described herein to a subject in need of such treatment and / or prevention. Studies have shown that inhibiting PGE2-degrading enzymes, such as 15-PGDH, can facilitate muscle regeneration and repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat muscle disorders, muscle damage, and / or muscle atrophy in a subject. In some cases, the subject suffering from muscle disorders, muscle damage, and / or muscle atrophy is a subject suffering from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), peripheral muscular dystrophy (DD), hereditary myopathy, myotonic muscular dystrophy (MMD), or other conditions. DD), oculopharyngeal muscular dystrophy, peripheral muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital tonicity, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyositis, dermatomyositis, cancer cachexia, AIDS cachexia, stress-induced urinary incontinence, urinary sphincter deficiency, sarcopenia, or a combination thereof.

[0409] In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat sarcopenia. In another embodiment, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy caused by the use of a ventilator. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat neuromuscular disorders such as genetic disorders and spinal muscular atrophy (SMA). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat ptosis, rotator cuff muscle atrophy, immobilization-related muscle atrophy, surgery-related muscle atrophy, sarcopenia, or a combination thereof.

[0410] Pharmaceutical Composition Inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions to treat the diseases and disorders described herein. In some embodiments, the pharmaceutical compositions may comprise one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein in a therapeutically effective amount.

[0411] The pharmaceutical compositions described herein may be administered in oral dosage forms such as tablets, capsules (each including sustained or extended release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syrups, emulsions, etc. In some embodiments, the pharmaceutical compositions may also be administered in the form of intravenous (bolus or infusion), subcutaneous injection, suppository, intraperitoneal, topical (e.g., epidermal, transdermal), intraocular such as eye drops, intranasal, subcutaneous, inhalation, intramuscular, transdermal (e.g., patch) forms, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0412] In some embodiments, a compound provided herein can be administered as part of a treatment regimen that includes administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents) simultaneously or sequentially with a compound provided herein. When administered sequentially, a compound provided herein can be administered before or after the one or more second agents. When administered simultaneously, a compound provided herein and one or more second agents can be administered by the same route (e.g., injection into the same location, taking tablets at the same time), by different routes (e.g., taking one tablet during an intravenous infusion), or as part of the same combination (e.g., a solution containing a compound provided herein and one or more second agents).

[0413] The combination treatments of the present disclosure may be effective over a wide dosage range. For example, in adult human treatment, dosages of 0.01-1000 mg / day, 0.5-100 mg / day, 1-50 mg / day, and 5-40 mg / day are exemplary dosages that may be used. The exact dosage will depend on the agent selected, the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician. [Example]

[0414] Example 1: Compound synthesis and characterization In another aspect, the present invention provides a method for producing the inhibitor described herein. Optionally, the inhibitor is isolated or extracted from one or more plants. Optionally, the inhibitor obtained from one or more plants can be further modified. Optionally, the inhibitor can be further purified after being isolated from one or more plants.

[0415] An exemplary synthetic scheme for inhibitors with a phenyl center described herein is:

[0416] [ka] Includes.

[0417] An exemplary synthetic scheme for inhibitors with a 6-5 ring center described herein is:

[0418] [ka]

[0419] [ka] Includes.

[0420] In some cases, the synthetic scheme may be a complete synthetic scheme for producing the inhibitors provided herein. In other cases, the synthetic scheme may be a partial scheme for producing the inhibitors provided herein.

[0421] Described herein are exemplary synthetic schemes that can be used to synthesize the inhibitors described herein. The following abbreviations are used:

[0422] [Table 4]

[0423] Synthesis of benzimidazole-5-carboxamide analogues with amide variations Provided below is an exemplary scheme for synthesizing benzimidazole-5-carboxamide analogs with amide variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0424] [ka]

[0425] Step 1: Synthesis of methyl 4-fluoro-3-nitrobenzoate (Int-2): To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 54.02 mmol) in DCM (100 mL) was added oxalyl chloride (9.42 mL, 108.04 mmol, 2 eq), followed by DMF (1 mL) at 0 °C. The RM was stirred at 0 °C for 1 h. The reaction was monitored by TLC, and upon completion, the mixture was quenched with methanol (20 mL) and stirred at room temperature for 1 h. The solvent was then evaporated under reduced pressure, diluted with ethyl acetate (100 mL), washed with saturated NaHCO solution (50 mL) and brine solution (50 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-fluoro-3-nitrobenzoate (10.4 g, 96.7%) as an off-white solid. LCMS: 75.82%, m / z=199.8 [M+H] + ; 1 H NMR (CDCl3,400MHz): δ8.75(dd,J=2.20,7.21Hz,1H),8.32(ddd,J=2.2,4.3,8.7Hz,1H),7.39(dd,J=8.7,10.2Hz,1H),3.97-3.99(m,3H).

[0426] Step 2: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (Int-3) (General procedure for SNAr reaction #1): In a sealed bomb, to a stirred solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1 eq) in EtOH (100 mL) was added 3-chloroaniline (7.68 g, 60.25 mmol, 1.2 eq) at room temperature. The steel bomb cap was tightly sealed, and the resulting reaction mixture was then warmed to 100 °C for 16 h. The reaction was monitored by LCMS / TLC, and upon completion, the reaction was cooled to room temperature, evaporated, quenched with saturated NH4Cl (100 mL), extracted with EtOAc (3 x 50 mL), the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was triturated with diethyl ether (100 mL) to give methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (8.2 g, 53.24%) as a yellow solid. LCMS: 95.95%, m / z = 307.1 [M+H] + ; 1 H NMR (CDCl 3, 400MHz):δ9.73(br s,1H),8.92(d,J=2.1Hz,1H),8.01(dd,J=1.8,8.9Hz,1H),7.36-7.41(m,1H),7.26-7.31(m,2H),7.19(d,J=8.9Hz,2H),3.92(s,3H).

[0427] Step 3: Synthesis of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (Int-4) (General procedure for aryl nitro reduction using Fe): To a stirred solution of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (8.2 g, 26.79 mmol, 1 eq) in EtOH / water (1:1, 160 mL) was added iron powder (10.47 g, 187.55 mmol, 7 eq) and NH4Cl (10.03 g, 187.55 mmol, 7 eq) at room temperature. The resulting reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by LCMS / TLC, and upon completion, the reaction mixture was filtered through a bed of Celite and washed with EtOAc (2 x 100 mL). Evaporation of the volatiles, quenching with saturated NaHCO3 (100 mL), extraction with EtOAc (3 x 50 mL), and washing the combined organic extracts with brine (100 mL), drying over sodium sulfate, filtering, and concentrating in vacuo gave the crude product. The crude was purified by gel column chromatography using 50% EtOAc / heptane to give methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (7.1 g, 96.07%) as a viscous liquid. LCMS: 67.71%, m / z = 277.1 [M+H] + ; 1 H NMR (CDCl 3, 400MHz): δ7.45-7.50(m,2H),7.14-7.19(m,2H),6.86-6.91(m,2H),6.77(td,J=1.2,8.8Hz,1H),5.55(br s,1H),3.88(s,3H).

[0428] Step 4: Synthesis of methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (Int-5): To a stirred solution of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (7.1 g, 25.72 mmol, 1 eq) and triethyl orthoformate (19.06 g, 128.62 mmol, 5 eq) in 1,4-dioxane (80 mL) was added PTSA (884 mg, 5.144 mmol, 0.2 eq) at room temperature. The resulting reaction mixture was warmed to 100 °C for 16 h until the SM was consumed as determined by crude LCMS / TLC. The reaction mixture was filtered through a Celite bed and washed with EtOAc (2 x 100 mL). The volatiles were evaporated, washed with saturated NaHCO3 (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to give methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (5.8 g, 78.6%) as a light brown solid. LCMS: 89.6%, m / z=287.2 [M+H] + ; 1 H NMR (CDCl 3, 400MHz): δ8.60(d,J=1.0Hz,1H),8.18(s,1H),8.08(dd,J=1.5,8.6Hz,1H),7.53-7.58(m,3H),7.42-7.51(m,2H),3.97(s,3H).

[0429] Step 5: Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-6). General procedure for ester hydrolysis using NaOH: To a stirred solution of methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (5.8 g, 20.23 mmol, 1 eq) in THF / water (8:2, 60 mL) or MeOH / water (8:2, 60 mL) was added NaOH (1.21 g, 30.34 mmol, 1.5 eq) at room temperature, followed by continued stirring for 16 h at room temperature. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the volatiles were evaporated and neutralized to pH = 7 with 1 N HCl. The solid was filtered, washed with EtO (200 mL), and dried under vacuum to give 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (4.5 g, 81.66%) as a light brown solid. LCMS: 99.58%, m / z = 273.1 [M+H] + ; 1 H NMR (DMSO-d 6, 500MHz): δ12.44-13.20(m,1H),8.73(s,1H),8.32(s,1H),7.96(br d,J=8.6Hz,1H),7.88(s,1H),7.65-7.73(m,3H),7.58-7.61(m,1H).

[0430] Step 6: General procedure for amide coupling using HATU: To a stirred solution of Int-6 (1 eq) in DMF (10 v) under an inert atmosphere, HATU (1.5 eq) was added, followed by the addition of an amine (1.2 eq) at 0 °C. To this stirred solution, N,N'-diisopropylethylamine (3 eq) was added at 0 °C, and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC. After consumption of the starting material, the reaction mixture was quenched with ice-water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with ice-water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 40% EtOAc / heptane followed by preparative HPLC to give the product shown in Scheme 1.

[0431] Synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone Provided below is an exemplary scheme for synthesizing (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0432] [ka]

[0433] Step 1: Synthesis of tert-butyl (1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate (Int-7): Using the general procedure for amide coupling with HATU described above, Int-6 (400 mg, 1.47 mmol) was reacted with 3-Boc aminopyrrolidine (326 mg, 1.76 mmol, 1.2 eq) to afford tert-butyl (1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate (280 mg, 43%) as a pale yellow liquid. LCMS: 81.8%, m / z=441.2 [M+H] + ; 1 H NMR (DMSO-d 6, 400MHz):δ8.76(s,1H),7.85-7.98(m,2H),7.49-7.74(m,4H),7.20-7.29(m,1H),3.87-4.12(m,1H),3.59-3.68(m,2H) ),3.08-3.35(m,2H),2.81-2.89(m,1H),2.65-2.73(m,1H),1.94-2.09(m,1H),1.69-1.89(m,1H),1.30-1.40(m,9H).

[0434] Step 2: Synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone (MF-PGDH-051): To a stirred solution of Int-7 (280 mg, 0.63 mmol, 1 eq) in DCM (5 mL) cooled to 0 °C was added 4 N HCl in 1,4-dioxane (5 mL), warmed to room temperature, and then stirring was continued at room temperature for 16 h. The reaction was monitored by LCMS / TLC, and after consumption of the starting material, the reaction mixture was concentrated, dissolved in water, and washed with EtOAc (20 mL). The aqueous layer was then basified with saturated NaHCO3 solution and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated under vacuum to give (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone (120 mg, 57% yield) as an off-white solid. LCMS: m / z=341.2 [M+H] + .

[0435] Synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-064): Provided below is an exemplary scheme for synthesizing 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0436] [ka]

[0437] Step 1: Synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-064): A stirred solution of 1-(3-chlorophenyl)-N-cyclopropyl-1H-benzo[d]imidazole-5-carboxamide (200 mg, 0.641 mmol, 1 eq) in DMF (3 mL) was cooled to 0 °C and NaH (60% in mineral oil) (24 mg, 0.96 mmol, 1.5 eq) was added. After stirring at 0 °C for 20 min, methyl iodide (136.05 mg, 0.961 mmol, 1.5 eq) was added at 0 °C, warmed to room temperature, and stirred for 6 h. The reaction was monitored by LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane, followed by preparative HPLC purification to give 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (14.31 mg, 6.84% yield) as a brown liquid. LCMS: m / z = 326.1 [M+H] + .

[0438] Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090) Provided below is an exemplary scheme for synthesizing 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0439] [ka]

[0440] Steps 1 and 2: Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090): A stirred solution of Int-6 (100 mg, 0.367 mmol, 1 eq) in DCM (2 mL) was cooled to 0 °C, to which oxalyl chloride (92.73 mg, 0.735 mmol, 2.0 eq) and DMF (0.1 mL) were added, followed by stirring at 0 °C for 30 min. The reaction was monitored by TLC, and after consumption of the starting material, the reaction mixture was concentrated and carried on to the next step. The crude material was dissolved in DCM (2 mL), cooled to 0 °C, pyrrolidone (53.60 mg, 121.5 mmol, 1.2 eq) was added, allowed to warm to room temperature, and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090, 4.8 mg, 3.85% yield) as a brown liquid.

[0441] Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102) Provided below is an exemplary scheme for synthesizing 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0442] [ka]

[0443] Step 1: Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102): To a stirred solution of Int-6 (200 mg, 0.733 mmol, 1 eq) in DMF (5 mL) under an inert atmosphere, HATU (416 mg, 1.093 mmol, 1.5 eq) and NHCl (196.33 mg, 3.669 mmol, 5.0 eq) were added at 0 °C. N,N'-Diisopropylethylamine (282 mg, 2.177 mmol, 3.0 eq) was added to the stirred solution at 0 °C, and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with ice water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (138.52 mg, 69.51%) as an off-white solid. LCMS: m / z = 272.1 [M+H] + .

[0444] Synthesis of 2-substituted benzimidazole analogues Provided below are exemplary schemes for synthesizing benzimidazole analogs with 2-substituents that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0445] [ka]

[0446] Step 1: Synthesis of 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (Int-1): To a stirred solution of 4-fluoro-3-nitrobenzoic acid (5 g, 27.02 mmol, 1 eq) in ethanol (100 mL) at room temperature in a sealed pressure vessel, metachloroaniline (4.18 g, 32.96 mmol, 1.22 eq) was added followed by potassium carbonate (1.86 g, 13.51 mmol, 0.5 eq), and the mixture was then heated to 80 °C for 16 h. The reaction was monitored by TLC, and upon completion, the mixture was cooled to room temperature, filtered, and the solid was washed with ethanol and dried to give 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (5.2 g, 65.8% yield) as an off-white solid. LCMS: m / z = 293.0 [M+H] + .

[0447] Step 2: Synthesis of (4-((3-chlorophenyl)amino)-3-nitrophenyl)(piperidin-1-yl)methanone (Int-2): To a stirred solution of Int-1 (4.5 g, 15.41 mmol, 1 eq) in DCM (45 mL), oxalyl chloride (5.83 g, 46.23 mmol, 3 eq) was added dropwise at 0° C., and stirring was continued at 0° C. for 1 h, and the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and the volatiles were evaporated. This was dissolved in DCM (45 mL), and to this stirred solution was added piperidine (1.57 g, 18.49 mmol, 1.2 eq), stirred at room temperature for 5 h, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 5% MeOH / DCM to give (4-((3-chlorophenyl)amino)-3-nitrophenyl)(piperidin-1-yl)methanone (5.7 g, 89% yield) as a yellow solid. LCMS: 87.89%, m / z=360.0 [M+H] + .

[0448] Step 3: Synthesis of (3-amino-4-((3-chlorophenyl)amino)phenyl)(piperidin-1-yl)methanone (Int-3): To a stirred solution of Int-2 (7 g, 19.44 mmol, 1 eq) in EtOH:water (1:1, 120 mL), iron powder (7.6 g, 136.11 mmol, 7 eq) and NH4Cl (7.4 g, 136.11 mmol, 7 eq) were added at room temperature. The resulting reaction mixture was warmed to 90 °C for 16 h. The reaction was monitored by TLC, and after consumption of the starting material, the reaction mixture was filtered through a celite bed and washed with EtOAc (2 x 50 mL). The volatiles were evaporated, quenched with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was triturated with diethyl ether (20 mL) to give (3-amino-4-((3-chlorophenyl)amino)phenyl)(piperidin-1-yl)methanone (5 g, 77.60%) as a viscous liquid. LCMS: m / z=330.0 [M+H] + .

[0449] Step 4A: Synthesis of ethyl 1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazole-2-carboxylate (MF-PGDH-027): In a sealed tube, a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq), ethyl glyoxylate (186.2 mg, 1.823 mmol, 3 eq), and PTSA (20 mg, 0.116 mmol, 0.2 eq) was added at room temperature. The resulting reaction mixture was warmed to 70 °C for 16 h. The reaction was monitored by TLC, and after complete consumption of the starting material, it was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane, followed by preparative HPLC purification to give MF-PGDH-027 (18.82 mg, 7.55% yield) as an off-white solid.

[0450] Step 4B: Synthesis of ethyl 2-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)acetate (MF-PGDH-030): To a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq) in DMF (3 mL) was added ethyl (E)-3-amino-3-ethoxyacrylate (355 mg, 1.818 mmol, 3 eq) at room temperature. The resulting reaction mixture was warmed to 100° C. for 16 h. The reaction was monitored by TLC, and after complete consumption of the starting material, it was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane, followed by preparative HPLC purification to give MF-PGDH-030 (35.4 mg, 13.7%) as an off-white solid.

[0451] Step 4C: Synthesis of MF-PGDH-091 (General procedure for ester hydrolysis with LiOH): To a stirred solution of MF-PGDH-30 (1 g, 2.35 mmol, 1 eq) in THF:water (1:1, 10 mL) at 0 °C, LiOH.HO (235 mg, 4.7 mmol, 2 eq) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC, and after complete consumption of the starting material, it was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane, followed by preparative HPLC purification to give MF-PGDH-091 (20.38 mg, 2.9%) as an off-white solid. LCMS: m / z = 354.2 [M+H] + .

[0452] Step 4D: Synthesis of methyl 4-((2-((3-chlorophenyl)amino)-5-(piperidine-1-carbonyl)phenyl)amino)-4-oxobutanoate (Int-4): Int-3 (500 mg, 1.51 mmol, 1 eq) was subjected to the general procedure for amide coupling using HATU to afford methyl 4-((2-((3-chlorophenyl)amino)-5-(piperidine-1-carbonyl)phenyl)amino)-4-oxobutanoate (600 mg, 89.1%) as an off-white solid. LCMS: m / z=444.1 [M+H] + .

[0453] Step 4E: Synthesis of ethyl 3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanoate (MF-PGDH-033) and 3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propionic acid (MF-PGDH-034): To a stirred solution of Int-4 (1 g, 2.252 mmol, 1 eq) in DCE (20 mL) was added TFA (10 mL) under an inert atmosphere at 0 °C. This was allowed to warm slowly to room temperature and then to 80 °C over 16 h. The reaction was monitored by TLC, and after consumption of the starting material, the reaction mixture was cooled to room temperature and diluted with ice water (20 mL). The mixture was neutralized with 10% NaHCO3 solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with ice water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give MF-PGDH-033 (68.36 mg) and MF-PGDH-034 (33.41 mg) as an off-white solid.

[0454] Step 4F: Synthesis of 3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanamide (MF-PGDH-035): To a stirred solution of MF-PGDH-034 (200 mg, 2.252 mmol, 1 eq) in a steel bomb was added aqueous ammonia (10 mL) in MeOH at 0 °C. The resulting reaction mixture was slowly warmed to room temperature and then heated to 80 °C for 16 h. The reaction was monitored by TLC, and after consumption of the starting material, the reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC purification to give MF-PGDH-035 (33.27 mg, 17.3% yield) as an off-white solid.

[0455] Synthesis of benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations Provided below are exemplary schemes for synthesizing benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0456] [ka]

[0457] The synthesis of Int-1 is described in Scheme 1, 1a above.

[0458] Step 2: Synthesis of methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate (Int-2): Methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1 eq) in EtOH (100 mL) was converted to Int-2 using the general procedure for SNAr reaction #1 with p-anisidine (7.68 g, 60.25 mmol, 1.2 eq) to give methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate (8.2 g, 53.24%) as a yellow solid. LCMS: 96.47%, m / z = 303.1 [M+H]+ .

[0459] Step 3: Synthesis of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (Int-3): Using the general procedure for aryl nitro reduction with Fe, methyl-(4-methoxyphenyl)amino)-3-nitrobenzoate (8.09 g, 26.79 mmol) was converted to methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (7.1 g, 96.07%) to afford Int-3 as a viscous liquid. LCMS: 91.32%, m / z = 273.2 [M+H] + .

[0460] Step 4: Synthesis of methyl 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate / methyl 2-cyclopropyl-1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (Int-4a / 4b): To a stirred solution of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (7.02 g, 25.72 mmol, 1 eq) and triethyl orthoformate / cyclopropynealdehyde (128.62 mmol, 5 eq) in 1,4-dioxane (80 mL) / DMF was added PTSA (884 mg, 5.144 mmol, 0.2 eq) / NaSO (1 eq) at room temperature. The resulting reaction mixture was warmed to 90 °C for 16 h until the SM was consumed as determined by crude LCMS / TLC. The reaction mixture was filtered through a celite bed and washed with EtOAc (2 x 100 mL). The volatiles were evaporated, washed with saturated NaHCO3 (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude was purified by silica gel column chromatography using 40% EtOAc / heptane to give methyl 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate, Int-4a (78.6% yield, m / z = 283.3 [M+H]). +), and methyl 2-cyclopropyl-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-4b) (yield 53.40%, m / z = 323.33 [M+H] + ) was obtained.

[0461] Step 5: Synthesis of 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-5a) / 2-cyclopropyl-1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-5b): Int-5a (4.5 g, 81.66% yield, LCMS: m / z = 269.2 [M+H]) was obtained by hydrolysis of Int-4a / 4b (1 eq) using the general procedure for ester hydrolysis with NaOH. + ), and Int-5b (230 mg, yield 64.5%, LCMS: m / z = 309.0 [M+H] + ) was obtained as a light brown solid.

[0462] Step 6: Synthesis of MF-DH-008, MF-DH-009, and MF-DH-021: Int-5a / 5b were subjected to the general procedure of amide coupling using HATU to give MF-DH-008, MF-DH-009, and MF-DH-021.

[0463] Synthesis of benzimidazole-5-carboxamide analogues with aryl / amide variation Provided below are exemplary schemes for synthesizing benzimidazole-5-carboxyamide analogs with aryl / amide variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0464] [ka]

[0465] The synthesis of Int-1 is described in Scheme 1.

[0466] Step 2: Synthesis of Int-2; General procedure for SNAr reaction #2: To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 12.51 mmol, 1 eq) in EtOH (100 mL) in a sealed pressure vessel, 5-methoxypyridin-2-amine / 3-chloro-4-methoxyaniline (1.2 eq) and K2CO3 (1.726 g, 1 eq) were added at room temperature. The steel pressure vessel was tightly sealed and the reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by LCMS / TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The residue was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was triturated with diethyl ether (100 mL) to give Int-2a (50.5% yield, LCMS: m / z = 304.1 [M+H]) for MF-PGDH-22 and MF-DH-141. + ) was obtained as a yellow solid.

[0467] Int-1 was synthesized using MF-PGDH-24 and MF-PGDH-61 as Int-2b (yield 51.0%, m / z = 337.2 [M+H] + ) was converted to

[0468] Int-1 was synthesized using the general procedure in SNAr#1 with MF-PGDH-62 to give Int-2c (yield 59.0%, LCMS: m / z = 317.1 [M+H] + ) was converted to

[0469] Step 3: Using the general procedure for aryl nitro reduction, synthesis of Int-3a, Int-3b, and Int-3c was achieved to give Int-3a (82.3% yield, LCMS: m / z = 274.1 [M+H] + ), Int-3b (yield 79.2%, LCMS: m / z=307.1[M+H] + ), and Int-3c (yield 80.0%, LCMS: m / z = 287.2 [M+H] + ) was obtained as a viscous liquid.

[0470] Step 4: Synthesis of Int-4a, Int-4b, and Int-4c: To a stirred solution of Int-3a / Int-3b / Int-3c (1 eq) and triethyl orthoformate (19.06 g, 128.62 mmol, 5 eq) in 1,4-dioxane (80 mL) / DMF, PTSA (884 mg, 0.2 eq) was added at room temperature. The resulting reaction mixture was warmed to 90 °C for 16 h until the SM was consumed as determined by crude LCMS / TLC. The reaction mixture was filtered through a Celite bed and washed with EtOAc (2 x 50 mL). The volatiles were evaporated, washed with saturated NaHCO3 (20 mL), extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with brine (30 mL). The crude product was obtained after drying over sodium sulfate, filtration, and concentration in vacuo. The crude material was purified by silica gel column chromatography using 40% EtOAc / heptane to give Int-4a (yield 32.7%, LCMS: m / z = 287.2 [M+H] + ), Int-4b (yield 73.0%, LCMS: m / z=317.1[M+H] + ), and Int-4c (yield 83.0%, LCMS: m / z = 297.0 [M+H] + ) was obtained as a light brown solid.

[0471] Step 5: Synthesis of Int-5a, Int-5b, and Int-5c: Using the general procedure of ester hydrolysis with NaOH, Int-4a, Int-4b, and Int-4c were each prepared into Int-5a (65.2% yield, LCMS: m / z = 270.1 [M+H]). + ), Int-5b (yield 70.5%, LCMS: m / z=303.2[M+H] + ), and Int-5c (yield 81.4%, LCMS: m / z = 282.1 [M+H] + ), all of which were obtained as light brown solids.

[0472] Step 6: Int-5 was coupled with the appropriate amine using the general procedure for amide coupling with HATU to give MF-PGDH-022, MF-PGDH-024, MF-PGDH-062, and MF-DH-141.

[0473] Step 7: Synthesis of (1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone: To a stirred solution of (1-(3-chloro-4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone, MF-PGDH-024 (200 mg, 0.54 mmol, 1 eq) in CHCl (10 mL) under inert atmosphere, BBr (1.62 mL, 1.62 mmol, 3.0 eq, 1 M in CHCl) was added at 0 °C and stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with MeOH (10 mL), evaporated to dryness, and then quenched with saturated NaHCO solution (5 mL). This was extracted with EtOAc (2 x 15 mL), and the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give crude material, which was purified by preparative HPLC to give 1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-061 (120 mg, 63%) as an off-white solid.

[0474] Synthesis of pyrrolopyridine-5-carboxamide analogues with amide / aryl / heteroaryl variation Provided below are exemplary schemes for the synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0475] [ka]

[0476] Scheme 9, Step 1: As shown in Scheme 9, Int-1 underwent amide coupling with an appropriate amine using HATU as previously described to give Int-2.

[0477] Piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (950 mg, yield: 79%); LCMS: m / z=230.2 [M+H,] + ; 1 H NMR(400MHz,DMSO-d6)δ=11.84(s,1H),8.23(s,1H),7.98(s,1H),7.56(d,J =1.83Hz,1H),6.51(d,J=1.89Hz,1H),3.67-3.38(m,4H),1.68-1.43(m,6H).

[0478] (4-Fluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (2.17 g, yield: 69%); LCMS: 88.5%, m / z=248.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ=11.83(s,1H),8.25(s,1H),8.01(s,1H),7.65(d,J =1.84Hz,1H),6.78(d,J=1.86Hz,1H),3.76-3.35(m,4H),1.98-1.54(m,4H).

[0479] (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone: (1.15 g, yield: 69%); LCMS: 85.2%) m / z = 282 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ=13.11(br s,1H),12.35(s,1H),8.84(s,1H),8.46(s,1H),7.80(s,1H),5.03-4.80(m,1H),3.82-3.33(m,4H),2.04-1.64(m,4H).

[0480] Scheme 9, Step 2: General Buchwald procedure for the synthesis of (MF-PGDH-071 and MF-DH-123, 124): To a stirred solution of piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone / (4-fluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-2) (0.65 mmol, 1 eq) in dioxane (15 mL) under inert atmosphere in a sealed tube was added CsCO (422 mg, 1.3 mmol, 2.0 eq) and the corresponding chloro / bromo arene (1.2 eq) at room temperature. Argon gas was purged for 15 minutes, and then Xantphos (75.14 mg, 0.13 mmol, 0.2 eq) and Pd(dba) (59.47 mg, 0.065 mmol, 0.1 eq) were added under an argon atmosphere. The sealed tube was tightly capped and the resulting reaction mixture was warmed to 100 °C for 16 hours. The reaction was monitored by crude LCMS / TLC. Upon completion, the reaction mixture was quenched with saturated NHCl (10 mL), filtered through a celite bed, and washed with EtOAc (10 mL). The mixture was extracted with EtOAc (2 x 10 mL), and the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 70% EtOAc / heptane followed by preparative HPLC purification to give MF-PGDH-071 and MF-DH-123, 124.

[0481] Scheme 10, Step 1: General procedure for chlorination using NCS. Synthesis of 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-2, Scheme 10): To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-1) (1 g, 6.17 mmol) in DMF (10 v) under an inert atmosphere was added NCS (906 mg, 6.68 mmol) at 40 °C. The resulting reaction mixture was warmed to 60 °C over 4 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with ice water (20 mL), and the solid was filtered and washed with diethyl ether (3 x 10 mL). The crude product was azeotropically dried with toluene (2 x 10 mL) and then dried for 2 h to give 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-2) as a light brown solid (850 mg, 70% yield). LCMS: 88.2%) m / z = 195.0 [M−H]. - ; 1 H NMR (500MHz, DMSO-d6) δ = 13.18 (br s, 1H), 12.37 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.82 (s, 1H).

[0482] Step 2 of Scheme 9 and Step 3 of Scheme 10: General Ullmann Coupling Procedure: To a stirred solution of Int-2 (Scheme 9) / Int-3 (Scheme 10) (0.7 mmol, 1 eq) in dioxane (100 mL) was added heteroaryl bromide (1.2 eq), 2.0 eq KPO, 0.2 eq CuI, and 0.2 eq trans-dimethylcyclohexane-1,2-diamine at room temperature. The reaction mixture was purged with argon gas for 15 minutes and then allowed to react at 100 °C for 16 hours. The reaction was monitored by TLC. Upon completion, the reaction was quenched with saturated NHCl solution (10 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, diluted with ethyl acetate (10 mL), washed with saturated NaHCO solution (50 mL) and brine solution (50 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude products were further purified by preparative HPLC to give the final products MF-PGDH-014, MF-PGDH-067, MF-PGDH-069, MF-PGDH-070, MF-PGDH-073, MF-PGDH-074, MF-PGDH-075, MF-PGDH-076, MF-DH-128, MF-DH-129, MF-DH-131, MF-DH-132, MF-DH-133, MF-DH-134, MF-DH-135, MF-DH-139, MF-DH-140, MF-DH-145, and MF-DH-157.

[0483] Synthesis of azabenzimidazole analogues Provided below are exemplary schemes for synthesizing azabenzimidazole analogs that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0484] [ka]

[0485] Step 1: Synthesis of Int-1: 6-chloro-5-nitronicotinate (7 g, 32.31 mmol, 1 eq) and 3-Cl / 4-methoxyaniline (1 eq) were subjected to SNAr#2 conditions to give Int-1a (Ar = 3-Cl phenyl, 95.2% yield, LCMS: m / z = 308.2 [M+H]). + ) as a yellow solid, Int-1b (Ar = 4-OMe phenyl, yield 87.6%, LCMS: 96.0%, m / z = 304.2 [M+H] + ) as a pale yellow solid.

[0486] Step 2: Synthesis of Int-2: Methyl-6-((4-methoxyphenyl)amino)-5-nitronicotinate / methyl-6-((3-chlorophenyl)amino)-5-nitronicotinate (Int-1) was subjected to the general procedure of aryl nitro reduction using Fe. The crude material was purified by silica gel column chromatography using 60% EtOAc / heptane to give Int-2a (Ar = 3-Cl phenyl, 97% yield, LCMS: m / z = 278.2 [M+H]). + ) as a yellow solid, Int-2b (Ar = 4-OMe phenyl, 77% yield, LCMS: m / z = 272.4 [M+H] + ) was obtained as a pale yellow solid.

[0487] Step 3: Synthesis of Int-3 (General Procedure for PTSA-Catalyzed Ring Closure to Form Imidazoles): To a stirred solution of methyl-5-amino-6-((4-methoxyphenyl)amino)nicotinate / methyl-5-amino-6-((3-chlorophenyl)amino)nicotinate (Int-2) (1 g, 1 eq) and triethyl orthoformate (5 eq) in dioxane (20 mL) was added PTSA (0.2 eq) at room temperature. The resulting reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was filtered through a celite bed and washed with EtOAc (2 x 50 mL). The volatiles were evaporated, quenched with saturated NaHCO3 solution (20 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane to give Int-3a (Ar = 3-Cl phenyl, 83% yield, LCMS: m / z = 288.2 [M+H]). + ) as a yellow solid, Int-3b (Ar = 4-OMe phenyl, 71% yield, LCMS: m / z = 284.2 [M+H] + ) was obtained as a pale yellow solid.

[0488] Step 4: Synthesis of Int-4, general procedure for ester hydrolysis using LiOH: To a stirred solution of methyl 3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate / methyl 3-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-3) (1 g, 1 eq) in THF / water (1:1, 20 mL) or MeOH / water (1:1, 20 mL) was added LiOH (2.5 eq) at room temperature, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by crude LCMS / TLC, and upon completion, the reaction mixture was concentrated and neutralized with 1N HCl. The resulting solid was filtered, washed with EtO (50 mL), and dried under vacuum to give Int-4a (Ar = 3-Cl phenyl, 65% yield, LCMS: m / z = 274.2 [M+H] + ) as an off-white solid, Int-4b (Ar = 4-OMe phenyl, 90.5% yield, LCMS: m / z = 270.1 [M+H] + ) was obtained as an off-white solid.

[0489] Step 5: Synthesis of MF-PGDH-020, MF-PGDH-077, MF-PGDH-078, MF-PGDH-079, and MF-PGDH-138: Int-4 was subjected to amide coupling with the appropriate amine using HATU as described above to give the crude material, which was purified by silica gel column chromatography using 40% EtOAc:heptane / 5% MeOH:CHCl, followed by preparative HPLC purification to give MF-PGDH-020, MF-PGDH-077, MF-PGDH-078, MF-PGDH-079, and MF-PGDH-138 as off-white solids. The compounds in Scheme 11 above were synthesized by this procedure.

[0490] Synthesis of 2-substituted azabenzimidazole analogues MF-DH-115 and MF-DH-116 Provided below are exemplary schemes for synthesizing 2-substituted azabenzimidazole analogs that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0491] [ka]

[0492] Step 1: Synthesis of methyl 2-amino-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-3): To a stirred solution of methyl 5-amino-6-((4-methoxyphenyl)amino)nicotinate (1 g, 3.54 mmol, 1 eq) in MeOH / water (1:1, 40 mL) was added cyanogen bromide (1.1 g, 10.63 mmol, 3 eq) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and then to 80° C. over 16 h. The reaction was monitored by crude LCMS / TLC, and upon completion, the reaction was cooled to room temperature, quenched with water (10 mL), extracted with EtOAc (3 x 50 mL), and the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl 2-amino-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (1.08 g, 99%) as a viscous liquid. LCMS: 80.63%, m / z = 299.2 [M+H] + .

[0493] Step 2: Synthesis of methyl 2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-4): To a stirred solution of Int-3 (800 mg, 2.68 mmol, 1 eq) in DCM (8 mL) was added triethylamine (829 mg, 8.05 mmol, 3 eq) at 0 °C. This was stirred at 0 °C for 10 min, followed by the addition of acetic anhydride (821 mg, 8.05 mmol, 3 eq). The reaction mixture was warmed to room temperature and then stirred for 16 h. The reaction was monitored by crude LCMS / TLC. Upon completion, the reaction was quenched with ice-water (10 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and dried under vacuum to give the crude product. The crude material was purified by silica gel column chromatography using 20% EtOAc / heptane to give methyl 2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (550 mg, 60.3%) as an off-white solid. LCMS: m / z=341.0 [M+H] + .

[0494] Step 3: Synthesis of 2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (Int-5): Int-4 (450 mg, 1.32 mmol, 1 eq) was subjected to the general procedure of ester hydrolysis using NaOH to give 2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (400 mg, 96%) as a light brown solid. LCMS: m / z=327.0 [M+H] + .

[0495] Step 4: Synthesis of MF-DH-116: Int-5 (470 mg, 1.44 mmol, 1 eq) was subjected to amide coupling with 4-fluoropiperidine (241 mg, 1.73 mmol, 1.2 eq) using HATU as described above. The crude material was purified by silica gel column chromatography using 5% MeOH / DCM followed by preparative HPLC purification to give MF-DH-116 (12.57 mg, 2.12%) as an off-white solid.

[0496] Step 5: Synthesis of MF-DH-115: To a stirred solution of MF-DH-116 (350 mg, 0.85 mmol, 1 eq) in methanol (5 mL) under an inert atmosphere, KCO (235 mg, 1.70 mmol, 2.0 eq) was added at room temperature, and stirring was continued for 16 h at room temperature. The reaction was monitored by crude LCMS / TLC. After consumption of the starting material, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 5% MeOH / DCM, followed by preparative HPLC purification to give MF-DH-115 (12.46 mg, 3.96%) as an off-white solid.

[0497] Synthesis of benzamide analogues Provided below are exemplary schemes for synthesizing benzamide analogs that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0498] [ka]

[0499] Step 1: Synthesis of (4-(hydroxymethyl)phenyl)(piperidin-1-yl)methanone (Int-1): To a stirred solution of 4-(hydroxymethyl)benzoic acid (2 g, 13.15 mmol, 1 eq) and piperidine (1.12 g, 13.5 mol, 1 eq) in CHCl (20 mL) under an inert atmosphere, EDCI (3.82 g, 19.72 mol, 1.2 eq) and HOBt (2.13 g, 15.78 mol, 1.2 eq) were added at 0 °C. To this stirred solution, N,N'-diisopropylethylamine (373 mL, 2.14 mol, 3 eq) was added at 0 °C, and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with ice water (20 mL x 2) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to give Int-1 (1.6 g, 57.1%) as a pale yellow solid. LCMS: m / z = 220.1 [M+H] + .

[0500] Step 2: Synthesis of MF-PGDH-036, MF-PGDH-037, and MF-PGDH-039: To a stirred solution of Int-1 (250 mg, 1.13 mmol, 1 eq) and 2-bromophenol / 2-chlorophenol / 2-chlorothiophenol (1.1 eq) in THF (10 mL) under an inert atmosphere, TPP (446 mg, 1.7 mol, 1.5 eq) was added sequentially, followed by DIAD (460 mg, 1.07 mmol, 1.5 eq) in THF (5 mL), and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 40% EtOAc / heptane, followed by preparative HPLC purification to give MF-PGDH-036 (yield: 2.05%), MF-PGDH-037 (yield: 2.1%), and MF-PGDH-039 (yield: 2.2%) as off-white solids.

[0501] Synthesis of (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-040) Provided below is an exemplary scheme for synthesizing (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0502] [ka]

[0503] To a stirred solution of MF-PGDH-39 (from Scheme 13) (200 mg, 0.578 mmol, 1 eq) in CHCl (15 mL) was added m-CPBA (196.1 mg, 1.15 mmol, 2 eq), and stirring was continued at room temperature for 16 h. An additional aliquot of m-CPBA was added (1 eq). The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with ice-water (10 mL) and extracted with CHCl (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 40% EtOAc / heptane followed by preparative HPLC purification to give (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-040) (21.1 mg, 9.6%) as a brown liquid.

[0504] Synthesis of (4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-045) Provided below is an exemplary scheme for synthesizing (4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanone, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0505] [ka]

[0506] To a stirred solution of MF-PGDH-39 (50 mg, 0.144 mmol, 1 eq) in CHCN:water, NaIO (61.99 mg, 0.289 mmol, 2 eq) was added and stirring was continued for 4 h at room temperature. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with ice-water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane, followed by preparative HPLC purification to give 35.8 mg of MF-PGDH-045 as a brown liquid.

[0507] Synthesis of MF-PGDH-38, MF-PGDH-098, MF-DH-118, and MF-DH-121 Provided below are exemplary schemes for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase, labeled as MF-PGDH-38, MF-PGDH-098, MF-DH-118, and MF-DH-121 in Scheme 16 below.

[0508] [ka]

[0509] Scheme 16A, Step 1: Synthesis of methyl 4-(bromomethyl)-3-methoxybenzoate (Int-1): To a stirred solution of methyl 3-methoxy-4-methylbenzoate / methyl 5-methylpicolinate (2.5 g, 13.87 mmol, 1 eq) in CHCl (20 mL) under an inert atmosphere, NBS (2.96 g, 16.66 mol, 1.2 eq) and AIBN (0.45 g, 2.74 mol, 0.2 eq) were added at room temperature, and the resulting reaction mixture was heated to reflux for 16 h. The reaction was monitored by crude LCMS / TLC. After consumption of the starting material, the reaction mixture was quenched with saturated NaSO (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with ice water (2 x 30 mL) and brine (20 mL), dried over sodium sulfate, filtered, and dried under vacuum to give the crude product. The crude material was purified by silica gel column chromatography using 30% EtOAc / heptane to give methyl 4-(bromomethyl)-3-methoxybenzoate (Int-1) (2.0 g, 55.7%) as an off-white solid. MS: m / z=261.1 [M+2] + .

[0510] Scheme 16A, Step 2: Synthesis of Int-2: To a stirred solution of Int-1 (500 mg, 1.93 mmol, 1 eq) and 2-chlorophenol (1 eq) in DMF (10 mL) under an inert atmosphere, K2CO3 (1.5 eq) was added at room temperature and then heated to reflux for 16 h. The reaction was monitored by crude LCMS / TLC. After consumption of the starting material, the reaction mixture was quenched with ice-water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with ice-water (2 x 10 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 15% EtOAc / heptane to give Int-2 (430 mg, 71.83% yield) as an off-white solid. LCMS: 91.35%: m / z = 307.3 [M+H] + .

[0511] Scheme 16A, Step 3: Synthesis of Int-3: Using the general procedure for ester hydrolysis with LiOH, Int-2 was hydrolyzed to give Int-3 (yield: 58.7%) as a light brown solid. LCMS: m / z = 293.2 [M+H] + .

[0512] Scheme 16A, Step 4: Synthesis of MF-PGDH-038, MF-DH-118: Int-3 (200 mg, 1 eq) was coupled with piperidine / 4-fluoropiperidine (1.2 eq) using HATU as the coupling agent as described above to give MF-PGDH-038, MF-DH-118 as an off-white solid.

[0513] Scheme 16B, Step 1: Methyl 5-(bromomethyl)picolinate (Int-1): Methyl 5-methylpicolinate was brominated using the general bromination procedure described above with NBS to give Int-1 (52% yield) as an off-white solid. LCMS: m / z=232.9 [M+2H] + .

[0514] Scheme 16B, Step 2: Synthesis of methyl 5-((2-chlorophenoxy)methyl)picolinate (Int-2): Int-1 was converted to Int-2 using the previously described substitution reaction procedure with 2-chlorophenol (Scheme 16A) to afford Int-2 (66% yield) as a pale yellow solid. LCMS: m / z = 278.1 [M+H] + .

[0515] Scheme 16B, Step 3: Synthesis of 4-((2-chlorophenoxy)methyl)benzoic acid (Int-3): Using the general procedure for ester hydrolysis with LiOH, Int-2 was hydrolyzed to give Int-3 (84% yield) as an off-white solid. LCMS: m / z=264.1 [M+H] + .

[0516] Scheme 16B, Step 4: Synthesis of (5-((2-chlorophenoxy)methyl)pyridin-2-yl)(4-fluoropiperidin-1-yl)methanone (MF-DH-121): Int-3 was coupled with 4-fluoropiperidine using HATU as the coupling agent as described above to give MF-DH-121 (yield: 61%) as an off-white solid. LCMS: 99.96%, MS: m / z = 349.0 [M+H] + .

[0517] Synthesis of MF-PGDH-095, MF-PGDH-096, and MF-PGDH-097 Provided below are exemplary schemes for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase, labeled as MF-PGDH-095, MF-PGDH-096, and MF-DH-097 in Scheme 17 below.

[0518] [ka]

[0519] Step 1: To a stirred solution of bromo compound MF-PGDH-036 (5 g, 0.013 mol, 1 eq.) and the corresponding bis(pinacolato)diboron (5.1 g, 0.02 mol, 1.5 eq.) in 1,4-dioxane (5 V, 50 mL / mmol), KOAc (3.82 g, 0.04 mmol, 3 eq.) was added and purged with argon for 15 minutes. To this solution, PdCl(dppf).DCM (1 g, 0.0013 mmol, 0.1 eq.) was added and purged with argon for another 10 minutes. The resulting reaction mixture was stirred at 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water followed by brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography to give 2.82 g (51%) of Int-1. LCMS: m / z=422.2 [M+H] + ,340.2[M+H] +.

[0520] Step 2: To a stirred solution of aryl / heteroaryl bromide (2.1 mmol, 1 eq.) and Int-1 (2.52 mmol, 1.2 eq.) in 1,4-dioxane:water (3:1, 4.96 mL / mmol), Na2CO3 (6.5 mmol, 3 eq.) was added and purged with argon for 15 minutes. To this solution, Pd(PPh3)4 (0.21 mmol, 0.1 eq.) was added and purged with argon for another 10 minutes. The resulting reaction mixture was stirred at 90 °C for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was filtered through Celite and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water followed by brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude products were purified by column chromatography followed by preparative HPLC to give MF-PGDH-095, MF-PGDH-096, and MF-PGDH-097 as off-white solids.

[0521] Synthesis of MF-PGDH-041, MF-PGDH-042, MF-PGDH-087, MF-PGDH-088, and MF-PGDH-089 Provided below are exemplary schemes for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase, labeled as MF-PGDH-041, MF-PGDH-042, and MF-DH-087 in Scheme 18 below.

[0522] [ka]

[0523] Step 1: Synthesis of Int-1: Int-1a (X, X' = F, 85% yield, LCMS: m / z = 271.1 [M+H]) was obtained by coupling 4-nitrobenzoic acid (2 g, 1 eq) with piperidine / 4,4-difluoropiperidine (1.5 eq) using HATU as previously described. + ) and Int-1b (X, X' = H, yield 91%, LCMS: m / z = 235.1 [M + H] +) was obtained.

[0524] Step 2: Synthesis of Int-2: Using the general procedure for reduction of aryl nitro with Fe as described above, Int-1 (1 eq) was converted to Int-2 to give Int-2a (X, X' = F, 51.7% yield, LCMS: m / z = 240.1 [M+H]). + ) and Int-2b: (X, X' = H, yield 53.5%, LCMS: m / z = 205.2 [M + H] + ) was obtained.

[0525] Step 3: Synthesis of Int-3: Coupling of Int-2 (1 eq) with 2-methoxyphenyl / 2-chlorophenyl / 3-methoxyphenyl carboxylic acid (0.7 eq) using HATU as previously described gave MF-PGDH-041, MF-PGDH-087, MF-PGDH-088, and MF-PGDH-089 as off-white solids.

[0526] Step 4: MF-PGDH-042 (General procedure for N-methylation of amides): To a stirred solution of MF-PGDH-041 (140 mg, 0.414 mmol, 1 eq) in THF (5 mL) was added NaH (60% in mineral oil) (30 mg, 0.625 mmol, 1.5 eq) over 1 h from 0 °C to room temperature. To this stirred suspension was added MeI (88.18 mg, 0.625 mmol, 1.5 eq), and the resulting reaction mixture was stirred for 6 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 50% EtOAc / heptane followed by preparative HPLC purification to give MF-PGDH-042 (24.42 mg, 16.71%) as a light brown solid.

[0527] Synthesis of MF-PGDH-043 and MF-PGDH-044 Provided below are exemplary schemes for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase, labeled as MF-PGDH-043 and MF-DH-044 in Scheme 19 below.

[0528] [ka]

[0529] Step 1: Synthesis of methyl 4-(piperidine-1-carbonyl)benzoate (Int-1): 4-(Methoxycarbonyl)benzoic acid (2 g, 11.09 mmol, 1 eq) and piperidine (1.3 mL, 13.31 mmol, 1.5 eq) in DMF (20 mL) were coupled using HATU as described above to give Int-1 (2.6 g, 92% yield) as a pale yellow solid. MS: m / z = 248.1 [M+H] + .

[0530] Step 2: Synthesis of 4-(piperidine-1-carbonyl)benzoic acid (Int-2): Using the general procedure for ester hydrolysis with NaOH, Int-1 (2.8 g) was hydrolyzed to give Int-2 (1.8 g, 58% yield) as an off-white solid. MS: m / z = 234.0 [M+H] + .

[0531] Step 3: Synthesis of N-(2-methoxyphenyl)-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-043): 4-(piperidine-1-carbonyl)benzoic acid (800 mg, 3.43 mmol, 1 eq) was coupled with 2-methoxyaniline (0.5 mL, 4.12 mol, 1.2 eq) using HATU (2 g, 5.14 mol, 1.5 eq) as described above to give MF-PGDH-043 (1 g, 90% yield) as a pale yellow solid.

[0532] Step 4: N-(2-Methoxyphenyl)-N-methyl-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-044): Using the general procedure for N-methylation of amides, MF-PGDH-043 (300 mg) was methylated with MeI to give MF-PGDH-044 (64.44 mg, 23.69%) as a light brown solid.

[0533] Synthesis of indoles MF-PGDH-004 and MF-PGDH-005 Provided below are exemplary schemes for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase, labeled as MF-PGDH-004 and MF-DH-005 in Scheme 20 below.

[0534] [ka]

[0535] Step 1: Synthesis of Int-1: Using the general procedure for chlorination with NCS in Scheme 1 above, where R = Cl, 1H-indole-5-carboxylic acid (2 g) was converted to Int-1 (2.3 g, 95% yield). MS: m / z = 196.01 [M+H] + .

[0536] Step 2: Synthesis of Int-2: Using the general procedure for amide coupling with HATU, Int-1 / 1H-indole-5-carboxylic acid was coupled with piperidine to give Int-2a (R = H, 71% yield, MS: m / z = 229.1 [M+H]). + ) and Int-2b (R = Cl, yield 68%, MS: m / z = 263.6 [M + H] + ) was obtained.

[0537] Step 3: Synthesis of MF-PGDH-004 and MF-PGDH-005: To a stirred solution of Int-2a / Int-2b (1 eq) in DMF (10 mL) was added 3-chloroiodobenzene (1.2 eq) and K2CO3 (2 eq) at room temperature. The reaction mixture was purged with argon gas for 15 minutes. To this stirred solution, CuI (0.2 eq) and trans-dimethylcyclohexane-1,2-diamine (0.2 eq) were added, followed by stirring at 100 °C for 16 hours. The reaction was monitored by TLC, and after complete consumption of the starting material, it was quenched with saturated NH4Cl solution (10 mL), filtered, and washed with EtOAc. After an extractive workup with EtOAc and washing with ice water (2 x 30 mL) and brine solution (50 mL), the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude products which were further purified by preparative HPLC to give MF-PGDH-004 and MF-PGDH-005 as off-white solids.

[0538] Synthesis of MF-PGDH-053 and MF-PGDH-054 Provided below are exemplary schemes for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase, labeled as MF-PGDH-053 and MF-DH-054 in Scheme 21 below.

[0539] [ka]

[0540] Step 1: Synthesis of methyl 3-bromo-1H-indole-6-carboxylate (Int-1): To a stirred solution of methyl 1H-indole-6-carboxylate (2 g, 11.42 mmol, 1 eq) in DMF (40 mL), NBS (3.04 g, 17.14 mmol, 1.5 eq) was added and stirred at room temperature for 2 h. The reaction was monitored by crude LCMS / TLC. Upon completion, the mixture was quenched with ice-water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with ice-water (2 x 30 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to give Int-1 (1.51 g, 53%) as a light brown solid. MS: m / z=256.1[M+2] + .

[0541] Step 2: Synthesis of methyl 3-(3-chlorophenyl)-1H-indole-6-carboxylate (Int-2), general procedure for Suzuki coupling: To a stirred solution of methyl 3-bromo-1H-indole-6-carboxylate (2.3 g, 9.05 mmol, 1 eq.), (3-chlorophenyl)boronic acid (2.11 g, 13.58 mmol, 1.5 eq.) in 1,4-dioxane:water (3:1, 20 mL), NaCO (2.39 g, 22.63 mmol, 2.5 eq.) was added, and the mixture was purged with argon for 15 min. To this solution, Pd(PPh) (1.04 g, 0.90 mmol, 0.1 eq.) was added under argon. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water, then brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography using 40% EtOAc / heptane to give Int-2 (550 mg, 22%) as a brown solid. MS: m / z=287.1 [M+2] + .

[0542] Step 3: Synthesis of 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (Int-3): Using the general procedure for ester hydrolysis with LiOH, methyl 3-(3-chlorophenyl)-1H-indole-6-carboxylate (550 mg) was converted to Int-3 (500 mg, 95.7%) as a light brown solid. MS: m / z = 270.1 [M−H] + .

[0543] Step 4: Synthesis of (3-(3-chlorophenyl)-1H-indol-6-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-053: Using the general procedure for amide coupling with HATU, 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (500 mg) was converted to MF-PGDH-053 as an off-white solid.

[0544] Step 5: Synthesis of (3-(3-chlorophenyl)-1-methyl-1H-indol-6-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-054: To a stirred solution of MF-PGDH-053 (20 mg, 0.059 mmol, 1 eq) in THF (0.2 mL) was added NaH (60% in mineral oil) (3 mg, 0.11 mmol, 2 eq) over 1 h from 0 °C to room temperature. To this stirred suspension was added MeI (16 mg, 0.11 mmol, 2 eq) and the resulting reaction mixture was stirred for 2 h. The reaction was monitored by crude LCMS / TLC, and after consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 50% EtOAc / heptane followed by preparative HPLC purification to give MF-PGDH-054 (16.94 mg, 81.4%) as an off-white solid.

[0545] Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-057 Provided below is an exemplary scheme for synthesizing (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone, or MF-PGDH-057, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0546] [ka]

[0547] Step 1: Synthesis of 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (Int-1): Using the general procedure of ester hydrolysis with NaOH, methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (1 g) was converted to Int-1 (800 mg, 86.9%) as a brown solid. MS: m / z = 178.1 [M+H] + .

[0548] Step 2: Synthesis of piperidin-1-yl(1,2,3,4-tetrahydroquinolin-6-yl)methanone (Int-2): Using the general procedure for amide coupling with HATU, 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (800 mg) was converted to Int-2 (309 mg, 48%) as a brown solid. MS: m / z = 245.2 [M+H] + .

[0549] Step 3: Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-057: To a stirred solution of piperidin-1-yl(1,2,3,4-tetrahydroquinolin-6-yl)methanone (200 mg, 0.819 mmol, 1 eq.), 1-chloro-3-iodobenzene (234 mg, 0.983 mmol, 1.2 eq.) in 1,4-dioxane (4 mL) was added CsCO (800 mg, 2.45 mmol, 3 eq.) and then purged with argon for 15 min. To this solution, Pd2(dba)3 (37.5 mg, 0.0409 mmol, 0.1 eq) and xantphos (47.37 mg, 0.0819 mmol, 0.1 eq) were added and purged with argon for an additional 10 min. The resulting reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by LCMS / TLC. After completion of the reaction, the mixture was filtered through Celite and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water followed by brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give MF-PGDH-057 (20.4 mg, 7.0%) as an off-white solid.

[0550] Synthesis of 1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one, i.e., MF-PGDH-058 Provided below is an exemplary scheme for synthesizing 1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one, or MF-PGDH-058, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0551] [ka]

[0552] Step 1: Synthesis of 6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (Int-1): Using the general procedure for amide coupling with HATU, 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (1.5 g) was coupled with piperidine (806 mg, 9.46 mmol, 1.2 eq) to give Int-1 (1.7 g, 84.1%) as a brown solid. MS: m / z = 259.1 [M+H] + .

[0553] Step 2: Synthesis of 1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one, i.e., MF-PGDH-058: 6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.775 mmol, 1 eq.) and 1-chloro-3-iodobenzene (277 mg, 1.162 mmol, 1.5 eq.) were subjected to the general Ullmann coupling procedure. The crude product was purified by preparative HPLC to give MF-PGDH-058 (23.5 mg, 8.2%) as an off-white solid.

[0554] Synthesis of (1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-006 Provided below is an exemplary scheme for synthesizing (1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone, or MF-PGDH-006, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0555] [ka]

[0556] Step 1: Synthesis of (1H-indazol-5-yl)(piperidin-1-yl)methanone (Int-1): Using the general procedure for amide coupling with HATU, 1H-indazole-5-carboxylic acid (500 mg) was converted to Int-1 (610 mg, 86.28%) to afford the title compound as a brown solid. MS: m / z=230.1 [M+H] + .

[0557] Step 2: Synthesis of MF-PGDH-006: To a stirred solution of (1H-indazol-5-yl)(piperidin-1-yl)methanone (610 mg, 2.66 mmol, 1 eq.) and 1-chloro-3-iodobenzene (623 mg, 2.66 mmol, 1 eq.) in DMF (5 mL), KCO (734 mg, 5.32 mmol, 2 eq.) was added and purged with argon for 15 min. To this solution, copper iodide (101 mg, 0.532 mmol, 0.2 eq.) and trans-N,N'-dimethylcyclohexane-1,2-diamine (126 mg, 0.532 mmol, 0.2 eq.) were added under argon and purged for an additional 10 min. The resulting reaction mixture was heated at 90 °C for 16 h. The reaction progress was monitored by LCMS / TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water and then brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain MF-PGDH-006 (40 mg, 4.41%) as a viscous liquid.

[0558] Synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-007 Provided below is an exemplary scheme for the synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone, or MF-PGDH-007, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0559] [ka]

[0560] Step 1: Synthesis of methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-1): To a stirred solution of methyl imidazo[1,2-a]pyridine-7-carboxylate (1 g, 5.68 mmol, 1 eq) in ethanol (10 mL) was added sodium acetate (931 mg, 11.36 mol, 2 eq), KBr (675 mg, 5.68 mmol, 1 eq), followed by bromide (897 mg, 11.36 mmol, 2 eq) at 0 °C, and the mixture was allowed to warm to room temperature over 1 h. The reaction was monitored by crude LCMS / TLC, and upon completion, the mixture was quenched with saturated NaSO (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with ice water (2 x 30 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give Int-1 (900 mg, 62%) as a light brown solid. MS: m / z = 256.1 [M+H] + .

[0561] Step 2: Synthesis of 3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (Int-2): Using the general Suzuki coupling procedure, methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate (600 mg, 2.38 mmol, 1 eq.) was coupled with (3-chlorophenyl)boronic acid (371 mg, 2.38 mmol, 1 eq.) to give Int-2 (150 mg, 23%) as a brown solid. MS: m / z = 273.1 [M+H] + .

[0562] Step 3: Synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-007: Using the general procedure for amide coupling with HATU, 3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (150 mg) was converted to MF-PGDH-007 (29.28 mg, 15.7%) as an off-white solid.

[0563] Synthesis of (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-011 Provided below is an exemplary scheme for synthesizing (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone, or MF-PGDH-011, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0564] [ka]

[0565] Step 1: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (Int-1): To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 13.50 mmol, 1 eq) in ethanol (25 mL) was added 4-methoxyaniline (1.72 g, 13.50 mol, 1 eq) at room temperature and then heated to 80 °C for 16 h. The reaction was monitored by crude LCMS / TLC, and upon completion, the mixture was filtered to give Int-1 (2.10 g, 56.5%) as a light brown solid. MS: m / z = 307.1 [M+H] + .

[0566] Step 2: Synthesis of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (Int-2): Using the general procedure for aryl nitro reduction with Fe, Int-1 (2g) was converted to Int-2 (1.20g, 66.6%), which was obtained as a viscous liquid. MS: m / z = 277.2 [M+H] + .

[0567] Step 3: Synthesis of methyl 1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (Int-3): To a stirred solution of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (700 mg, 2.545 mmol, 1 eq) and NaNO (175 mg, 2,545 mmol, 1 eq) in THF:water (1:1, 10 mL) under inert atmosphere, 6N HSO (2 mL) was added slowly at 0 °C over 15 min, then gradually warmed to room temperature and heated to reflux for 12 h. The reaction was monitored by crude TLC, and upon completion, the mixture was quenched with saturated NaHCO (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with ice water (2 x 30 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to give Int-3 (300 mg, yield: 41.26%) as an off-white solid. MS: m / z = 288.1 [M+H] + .

[0568] Step 4: Synthesis of (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone or MF-PGDH-011: To a stirred solution of methyl 1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (300 mg, 1.045 mmol, 1 eq) in toluene (7 mL) was slowly added piperidine (107 mg, 1.256 mmol, 1.2 eq) followed by trimethylaluminum (1.5 mL, 5.22 mmol, 5 eq) at 0 °C and then slowly warmed to 60 °C over 16 h. The reaction was monitored by TLC, and upon completion, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with ice water (2 x 30 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give MF-PGDH-011 (161.2 mg, 45.29%) as an off-white solid.

[0569] Synthesis of (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-012 Provided below is an exemplary scheme for synthesizing (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone, or MF-PGDH-012, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0570] [ka]

[0571] Step 1: Synthesis of (3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (Int-1): Using the general procedure for amide coupling with HATU, 3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (500 mg) was coupled with piperidine (212 mg, 2.49 mmol, 1.2 eq) to give Int-1 (309 mg, 48%) as a brown solid. MS: m / z = 310.1 [M+2H] + .

[0572] Step 2: Synthesis of (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone, i.e., MF-PGDH-012: Using the general Suzuki coupling procedure, (3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (300 mg, 0.97 mmol, 1 eq.) was coupled with (3-chlorophenyl)boronic acid (227 mg, 1.455 mmol, 1.5 eq.) to afford MF-PGDH-012 (32.78 mg, 9.9%) as an off-white solid.

[0573] Synthesis of (4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, i.e., MF-DH-150, and (3-chloro-4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-151 Provided below are exemplary schemes for synthesizing the hydroxyprostaglandin dehydrogenase inhibitors (4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, i.e., MF-DH-150, and (3-chloro-4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-151.

[0574] [ka]

[0575] Step 1: Synthesis of Int-1: Using the general procedure for chlorination with NCS, a solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (500 mg, 2.83 mmol, 1 eq) in DMF (15 mL) was converted to Int-1 (450 mg, 75.37% yield) as a viscous liquid. MS: m / z = 212.2 [M+H] + .

[0576] Step 2: Synthesis of Int-2: Int-1 (300 mg, 1.43 mmol, 1 eq) was subjected to the general procedure for amide coupling using HATU to give Int-2 (250 mg, 62%) as a brown liquid. MS: m / z = 278.1 [M+H] + .

[0577] Step 3: Synthesis of MF-DH-150 and MF-DH-151: Using the general Ullmann coupling procedure, Int-2 (1 eq) and 2-bromopyrazine (1.2 eq) were converted to MF-DH-150 (35.7% yield) and MF-DH-151 (6.1% yield), which were isolated as off-white solids.

[0578] Synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone, i.e., MF-DH-161 Provided below is an exemplary scheme for synthesizing (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone, or MF-PGDH-012, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0579] [ka]

[0580] Step 1: Synthesis of methyl 1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (Int-1): In a sealed tube, to a stirred solution of methyl 2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (SM) (300 mg, 1.16 mmol, 1 eq) in dioxane (15 mL) under inert atmosphere was added CsCO (1.130 g, 3.47 mmol, 3.0 eq) and 2-bromopyrazine (220 mg, 1.38 mmol, 1.2 eq) at room temperature. Argon gas was purged for 15 minutes, and then Xantphos (133.7 mg, 0.234 mmol, 0.2 eq) and Pd2(dba)3 (105.8 mg, 0.115 mmol, 0.1 eq) were added under an argon atmosphere. The sealed tube was tightly capped and the resulting reaction mixture was warmed to 100 °C for 16 hours. The reaction was monitored by crude LCMS / TLC. Upon completion, the mixture was quenched with saturated NH4Cl (10 mL), filtered through a celite bed, and washed with EtOAc (10 mL). The mixture was extracted with EtOAc (2 x 10 mL), and the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography using 70% EtOAc / heptane to give Int-1 (220 mg, 56.4%). MS: m / z=338.1 [M+H] + .

[0581] Step 2: Synthesis of 1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (Int-2): Int-1 (220 mg, 0.652 mmol, 1 eq) in methanol:water (1:1, 10 mL) was subjected to the general procedure for ester hydrolysis using NaOH to give Int-2 (120 mg, 57.1%) as a brown solid. MS: m / z = 324.2 [M+H] + .

[0582] Step 3: Synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone (MF-DH-161): A stirred solution of Int-2 (120 mg, 0.372 mmol, 1 eq) in DMF (5 v) was subjected to the general procedure for amide coupling using HATU to give MF-DH-161 (17.0% yield) as a semi-solid.

[0583] Synthesis of (4,4-dimethyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-160, ((4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone, i.e., MF-DH-162, and ((4-fluoropiperidin-1-yl)(1-(pyrimidin-5-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone, i.e., MF-DH-164 Provided below are exemplary schemes for synthesizing the hydroxyprostaglandin dehydrogenase inhibitors (4,4-dimethyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)(4-fluoropiperidin-1-yl)methanone (MF-DH-160), ((4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone (MF-DH-162), and ((4-fluoropiperidin-1-yl)(1-(pyrimidin-5-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone (MF-DH-164).

[0584] [ka]

[0585] Step 1: Synthesis of Int-1: SM (1 g, 5.00 mmol, 1 eq) in methanol:water (1:1, 10 mL) was subjected to the general procedure of ester hydrolysis using NaOH to give Int-1a (R, R' = CH, 86.9% yield, MS: 206.1 [M+H]). + ), Int-1b(R=H, R'=CH3, yield 74.0%, MS:192.1[M+H] + ), and Int-1c (R,R' = H, yield 73.4%, MS: 176.1 [M−H] - obtained.

[0586] Step 2: Synthesis of (Int-2): A stirred solution of Int-1 (1.563 mmol, 1 eq) in DMF (10 mL) was subjected to the general procedure for amide coupling using HATU to give Int-2a (R, R' = CH, 800 mg, 86.9% yield, MS: 291.1 [M+H]). + ), Int-2b (R = H, R' = CH, 650 mg, yield 75.9%, MS: 277.1 [M + H] + ), and Int-2c (R,R' = H, yield 73.4%, MS: 263.1 [MH] - ) was obtained as a colorless liquid.

[0587] Step 3: Synthesis of MF-DH-160, MF-DH-162, and MF-DH-164 (General Procedure for Buchwald Coupling): To a stirred solution of Int-2a / 2b / 2c (1.26 mmol, 1 eq.), 2-bromopyrazine / 5-bromopyridine (1.2 eq.) in 1,4-dioxane (4 mL), CsCO (3 eq.) was added and the mixture was purged with argon for 15 min. To this solution, Pd(dba) (0.1 eq.) and xantphos (0.1 eq.) were added and the mixture was purged with argon for an additional 10 min. The resulting reaction mixture was stirred at 90 °C for 16 h. Extractive workup gave crude materials that were purified by column chromatography followed by preparative HPLC to give MF-DH-160 (16.7% yield), MF-DH-162 (7.5% yield), and MF-DH-164 (18.6% yield) as off-white solids / semi-solids.

[0588] Synthesis of (3-chloro-1-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-167, (3-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-168, and (3-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-191 Provided below are exemplary schemes for synthesizing the hydroxyprostaglandin dehydrogenase inhibitors (3-chloro-1-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-167, (3-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-168, and (3-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone, i.e., MF-DH-191.

[0589] [ka]

[0590] Step 1: Synthesis of Int-1: Using the general procedure for chlorination with NCS, 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1 g, 6.16 mmol, 1 eq) was converted to Int-1 (850 mg, 70.1% yield) to give a pale yellow solid. MS: m / z = 197.01 [M+H] + .

[0591] Step 2: Synthesis of Int-2: A stirred solution of SM / Int-1 (1 g, 5.12 mmol, 1 eq) in DMF (10 mL) was subjected to the general procedure for amide coupling using HATU to give Int-2 (1.1 g, 76%) as a brown solid. MS: m / z = 282.2 [M+H] + .

[0592] Step 3: General procedure for the synthesis of MF-DH-167, MF-DH-168, and MF-DH-191: To a stirred solution of Int-2 (1 eq) in dioxane (10 mL), 5-methyl-2-bromopyrazine / 3-methyl-2-bromopyrazine / 4-bromoanisole (1.2 mmol, 1.2 eq) and KPO (630 mg, 3 mmol, 3 eq) were added at room temperature. The reaction mixture was purged with argon gas for 15 min. To this stirred solution, CuI (38.1 mg, 0.2 mmol, 0.2 eq) and trans-dimethylcyclohexane-1,2-diamine (28.44 mg, 0.2 mmol, 0.2 eq) were added, and stirring was continued at 100 °C for 16 h. The reaction was monitored by TLC, and after complete consumption of the starting material, it was quenched with saturated NH4Cl solution (10 mL), filtered, and washed with EtOAc. This was extracted with EtOAc and washed with ice water (2 x 30 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude material was further purified by preparative HPLC to give MF-DH-167 (16.5% yield), MF-DH-168 (9.5% yield), and MF-DH-191 (16.9% yield) as off-white solids.

[0593] Synthesis of (4-fluoropiperidin-1-yl)(4-(pyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone, i.e., MF-DH-159, (4-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone, i.e., MF-DH-207, and (4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone, i.e., MF-DH-209 Provided below are exemplary schemes for synthesizing the hydroxyprostaglandin dehydrogenase inhibitors (4-fluoropiperidin-1-yl)(4-(pyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone, i.e., MF-DH-159; (4-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone, i.e., MF-DH-207; and (4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone, i.e., MF-DH-209.

[0594] [ka]

[0595] Step 1: Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (Int-1): Methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (500 mg, 2.59 mmol, 1 eq) in THF:water (1:1, 10 mL) was subjected to the general procedure for ester hydrolysis using NaOH to give Int-1 (300 mg, 64.7%) as a brown solid. The same reaction was repeated on a 500 mg scale to give 310 mg of Int-1. MS: m / z = 179.9 [M+H] + .

[0596] Step 2: Synthesis of (3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone / (3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(4-fluoropiperidin-1-yl)methanone (Int-2): A stirred solution of Int-1 (1.67 mmol, 1 eq) in DMF (10 mL) was subjected to the general procedure for amide coupling using HATU to give the crude product. The crude product was purified by silica gel column chromatography to give Int-2a (X = H, 95% yield, MS: m / z = 247.1 [M+H]). + ) and Int-2b (X = F, yield 63.3%, MS; m / z = 265.1 [M+H] + ) was obtained.

[0597] Step 3: Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone, i.e., MF-DH-159, MF-DH-207, and MF-DH-209: Using the general Buchwald coupling procedure, Int-2 (0.56 mmol, 1 eq.) and 2-bromopyrazine / 5-bromobenzo[d][1,3]dioxole / 4-bromoanisole (1.2 eq.) were converted to MF-DH-159 (5.48% yield), MF-DH-207 (30.3% yield), and MF-DH-209 (2.2% yield), which were isolated as off-white solids after purification.

[0598] Synthesis of (1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone (MF-DH-203) Provided below is an exemplary scheme for synthesizing (1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone, or MF-DH-203, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0599] [ka]

[0600] Step 1: Synthesis of methyl 4-(tert-butylamino)-3-nitrobenzoate (Int-1): To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 12.56 mmol, 1 eq) in EtOH (100 mL) was added t-butylamine (918 mg, 12.56 mmol, 1 eq) in a sealed pressure vessel at room temperature. The vessel was tightly capped and the resulting reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by LCMS / TLC, and upon completion, the reaction was cooled to room temperature. The volatiles were evaporated, quenched with saturated NH4Cl (100 mL), extracted with EtOAc (3 x 50 mL), and the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Trituration with diethyl ether (100 mL) gave methyl 4-(tert-butylamino)-3-nitrobenzoate (Int-1, 1.2 g, 38.10%) as a yellow solid. MS: m / z=253.1 [M+H] + .

[0601] Step 2: Synthesis of methyl 3-amino-4-(tert-butylamino)benzoate (Int-2): To a stirred solution of Int-1 (1.2 g, 4.70 mmol, 1 eq) in EtOH / water (1:1, 50 mL), iron powder (1.33 g, 23.8 mmol, 5 eq) and NH4Cl (1.27 g, 23.8 mmol, 5 eq) were added at room temperature. The resulting reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by LCMS / TLC. Upon completion, the mixture was filtered through a Celite bed and washed with EtOAc (1 x 30 mL). The volatiles were evaporated, quenched with saturated NaHCO3 (20 mL), and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 50% EtOAc / heptane to give methyl 3-amino-4-(tert-butylamino)benzoate (Int-2, 1.0 g, 95.07%) as a viscous liquid. MS: m / z=223.1 [M+H] + .

[0602] Step 3: Synthesis of methyl 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylate (Int-3): To a stirred solution of Int-2 (1 g, 4.23 mmol, 1 eq) and triethyl orthoformate (3.1 g, 21.18 mmol, 5 eq) in 1,4-dioxane (80 mL) was added PTSA (145 mg, 0.84 mmol, 0.2 eq) at room temperature. The resulting reaction mixture was warmed to 100 °C for 16 h until SM was consumed as determined by crude LCMS / TLC. The volatiles were evaporated, washed with saturated NaHCO3 (50 mL), and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 50% EtOAc / heptane to give methyl 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylate (Int-3, 600 mg, 61.1% yield, MS: m / z = 233.1 [M+H]). + ) was obtained as a light brown solid.

[0603] Step 4: Synthesis of 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-4): Int-3 (600 mg, 2.43 mmol, 1 eq) in THF / water (8:2, 20 mL) was subjected to the general procedure of ester hydrolysis with NaOH to give 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-4, 320 mg, 60.2%, MS: m / z = 219.2 [M+H]). + ) was obtained as a light brown sticky solid.

[0604] Step 5: Synthesis of (1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone (MF-DH-203): A stirred solution of 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylic acid (320 mg, 1.46 mmol, 1 eq) in DMF (10 v) was subjected to the general procedure for amide coupling using HATU to give MF-DH-203 (20.4% yield) as an off-white solid.

[0605] Synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone, i.e., MF-DH-165 Provided below is an exemplary scheme for synthesizing (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone, or MF-DH-165, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0606] [ka]

[0607] Step 1: Synthesis of methyl indoline-5-carboxylate (Int-1): To a stirred solution of SM (2 g, 11.42 mmol, 1 eq) in acetic acid (20 mL) was added NaCNBH (2.15 g, 34.27 mmol, 3 eq) over 15 min at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated and neutralized with NaHCO to pH = 7. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give methyl indoline-5-carboxylate, Int-1 (1.65 g, 81.6%) as a brown solid. LCMS: 97.65%, m / z = 178.2 [M+H] + .

[0608] Step 2: Synthesis of methyl 1-(pyrazin-2-yl)indoline-5-carboxylate (Int-2): Using the general procedure for Buchwald coupling, methyl indoline-5-carboxylate (Int-1) (500 mg, 2.83 mmol, 1 eq) and 2-chloropyrazine (355 mg, 3.10 mmol, 1.2 eq) were converted to Int-2 (310 mg, 42.9%). LCMS: 95.10%, m / z = 257.1 [M+H]. + .

[0609] Step 3: Synthesis of 1-(pyrazin-2-yl)indoline-5-carboxylic acid (Int-3): Methyl 1-(pyrazin-2-yl)indoline-5-carboxylate (110 mg, 0.43 mmol, 1 eq) in MeOH / water (8:2, 10 mL) was subjected to the general procedure for ester hydrolysis with NaOH to give 1-(pyrazin-2-yl)indoline-5-carboxylic acid (80 mg, 77.2%) as a light brown sticky solid. MS: m / z = 242.2 [M+H] + .

[0610] Step 4: Synthesis of ((4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone (MF-DH-165) (General procedure for amide coupling using EDCI): To a stirred solution of 1-(pyrazin-2-yl)indoline-5-carboxylic acid (80 mg, 0.32 mmol, 1 eq) in DCM (10 v) under an inert atmosphere were added EDCI (92 mg, 0.48 mmol, 1.5 eq) and HOBt (52 mg, 0.38 mmol, 1.2 eq). The mixture was cooled to 0 °C and 4-fluoropiperidine (44 mg, 0.32 mmol, 1.0 eq) was added. To this stirred solution To the solution, N,N'-diisopropylethylamine (0.13 mL, 0.96 mmol, 3 eq) and DMAP (5 mg) were added at 0 °C, and the mixture was then warmed and stirred at room temperature for 16 h. The reaction mixture was quenched with ice-water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with ice-water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography followed by preparative HPLC to give MF-DH-165 (7.2% yield) as an off-white solid.

[0611] Synthesis of pyrrolopyridine-5-carboxamide analogues with amide / aryl variation Provided below are exemplary schemes for synthesizing pyrrolopyridine-5-carboxamide analogs with amide / aryl variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0612] [ka]

[0613] Step 1: Synthesis of Int-1a (X=H) and Int-1b (X=F): The synthesis of Int-1a and Int-1b is described in Schemes 9 and 10.

[0614] Step 2: General procedure for Ullmann reaction: Synthesis of MF-DH-239, 285, 294, 295, 296, 297, 298, 300, 302, 305, 306, 309, 310, 317, 321, 322, and MF-DH-336: Int-1a and Int-1b were subjected to the general procedure for Ullmann coupling using the appropriate aryl bromide. The crude products were purified by flash chromatography to give MF-DH-285, MF-DH-294, MF-DH-295, MF-DH-296, MF-DH-297, MF-DH-298, MF-DH-300, MF-DH-302, MF-DH-305, MF-DH-306, MF-DH-309, MF-DH-310, MF-DH-317, MF-DH-321, MF-DH-322, and MF-DH-336.

[0615] Synthesis of pyrrolopyridine-5-carboxamide analogues with N-aryl variation Provided below is an exemplary scheme for synthesizing pyrrolopyridine-5-carboxamide analogs with N-aryl variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0616] [ka]

[0617] General Procedure for Oxidation of Nitriles (MF-DH-299 and MF-DH-301) To a stirred solution of Int-2 (0.5 mmol, 1 eq) in DMSO (10 mL) was added KCO (2.0 eq) and HO (2 eq) at room temperature under aerobic conditions. The reaction mixture was warmed to 80 °C for 16 h. The reaction was monitored by LCMS / TLC. Upon completion, the reaction was quenched with ice-water (20 mL), filtered through a Celite® bed, and washed with EtOAc (20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and purified under reduced pressure to give the crude product, which was further purified by flash chromatography to give MF-DH-299 and MF-DH-301.

[0618] General Procedure for the Reduction of Nitriles (MF-DH-303 and MF-DH-304) To a stirred solution of nitrile Int-2 (0.5 mmol, 1 eq) in MeOH (15 mL) was added Ra-Ni (20 mol%) under a nitrogen atmosphere at room temperature. The reaction mixture was stirred under a hydrogen balloon atmosphere for 16 h. The reaction was monitored by LCMS / TLC. Upon completion, the solid was filtered through a Celite® bed, washed with EtOAc (20 mL), and the volatiles were evaporated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the combined organic extracts were washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give MF-DH-303 and MF-DH-304.

[0619] General Procedure for Reduction of Aldehydes (MF-DH-307 and MF-DH-308) To a stirred solution of aldehyde Int-2 (0.5 mmol, 1 eq) in MeOH (15 mL) was added NaBH4 (5 eq) portionwise over 15 min at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by LCMS / TLC. Upon completion, the reaction mixture was quenched with saturated NH4Cl (20 mL) and the volatiles were evaporated. The aqueous phase was extracted with ethyl acetate (2 x 20 mL), and the combined organic extracts were washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by flash chromatography to give MF-DH-307 and MF-DH-308.

[0620] Synthesis of 3-chloro-pyrrolopyridine-5-carboxamide analogues with amide / aryl / heteroaryl variation Provided below are exemplary schemes for synthesizing 3-chloro-pyrrolopyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0621] [ka]

[0622] The synthesis of Int-1a (X=H) is described in Scheme 9. The synthesis of Int-1b (X=F) is described in Scheme 31.

[0623] Step 1: Synthesis of MF-DH-191, MF-DH-250, MF-DH-251, MF-DH-273, MF-DH-274, and MF-DH-273: Int-1 was converted according to the general procedure for Ullmann coupling with the appropriate aryl bromide to give the title compounds.

[0624] Synthesis of MF-DH-146 Provided below is an exemplary scheme for synthesizing MF-DH-146, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0625] [ka]

[0626] Step 1: Using the general procedure for HATU coupling, SM 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was converted to Int-1 to give Int-1 (70%) as a brown solid. MS: m / z=282.2 [M+H] + .

[0627] Step 2: Int-2 was converted to MF-DH-146 using the general procedure for Buchwald coupling to afford MF-DH-146 as an off-white solid.

[0628] Synthesis of MF-DH-147 Provided below is an exemplary scheme for synthesizing MF-DH-147, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0629] [ka]

[0630] Step 1: Using the general procedure for chlorination with NCS, SM was converted to Int-1 to give Int-1 (334 mg, yield: 70.1%) as a pale yellow solid. MS: m / z = 231.10 [M+H] + .

[0631] Step 2: Int-1 was converted to Int-2 using the general procedure for HATU coupling to give Int-2 (323 mg, 76%) as a brown solid. MS: m / z=299.2 [M+2H] + .

[0632] Step 3: Int-2 was converted to MF-DH-147 using the general procedure for Buchwald coupling to afford MF-DH-147 as an off-white solid.

[0633] Synthesis of MF-DH-148 Provided below is an exemplary scheme for synthesizing MF-DH-148, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0634] [ka]

[0635] Step 1: Using the general procedure for HATU coupling, SM 6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was converted to Int-1 to give Int-1 (60%) as a brown liquid. MS: m / z=262.1 [M+H] + .

[0636] Step 2: Synthesis of MF-DH-148: Using the general procedure for Buchwald coupling, Int-1 (0.95 mmol, 1 eq) was reacted with 2-bromopyrazine (183 mg, 1.14 mmol, 1.2 eq) to give the crude product, which was purified by silica gel column chromatography with 70% EtOAc / heptane followed by preparative HPLC purification to give MF-DH-148.

[0637] Synthesis of MF-DH-149 Provided below is an exemplary scheme for synthesizing MF-DH-149, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0638] [ka]

[0639] Step 1: 6-Methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (SM) was converted to Int-1 using the general procedure for chlorination with NCS to give Int-1 (300 mg, yield: 84.2%) as a viscous liquid. MS: m / z = 211.2 [M+H] + ,212.2[M+2H]+ .

[0640] Step 2: Int-1 was converted to Int-2 using the general procedure for HATU coupling to give Int-2 (259 mg / 168 mg, 63%) as a brown liquid. MS: m / z=278.1 [M+H] + .

[0641] Step 3: Synthesis of MF-DH-149: Using the general procedure for Buchwald coupling, Int-2 (0.95 mmol, 1 eq) was reacted with 2-bromopyrazine to give the crude product, which was purified by silica gel column chromatography with 70% EtOAc / heptane, followed by preparative HPLC purification to give MF-DH-149.

[0642] Synthesis of (1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-311) and piperidin-1-yl(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (MF-DH-312) Provided below are exemplary schemes for synthesizing (1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone, or MF-DH-311, and piperidin-1-yl(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, or MF-DH-312, which are inhibitors of hydroxyprostaglandin dehydrogenase.

[0643] [ka]

[0644] The synthesis of Int-1 is described in Scheme 9.

[0645] Step 1: Synthesis of MF-DH-311 and MF-DH-312: Sodium hydride (60% in mineral oil) (100 mg, 1.5 mmol, 1.52 eq) was added to a stirred solution of piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (230 mg, 1 mmol) in DMF (15 mL) at 0 °C, and the resulting suspension was warmed to room temperature and stirred for 1 h. Difluorocyclohexyl 4-methylbenzenesulfonate, tosyl chloride, and mesyl chloride (1.2 eq each) were added, and the resulting reaction mixture was stirred for 6 h. The reaction was monitored by crude LCMS / TLC, and after complete consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography using 60% EtOAc / heptane to give (1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-311) and piperidin-1-yl(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (MF-DH-312) as off-white solids.

[0646] Synthesis of pyrrolopyridine-5-carboxamide analogues with amide / aryl variation Provided below are exemplary schemes for synthesizing MF-DH-318, MF-DH-320, MF-DH-322, MF-DH-342, MF-DH-344, MF-DH-346, MF-DH-366, MF-DH-389, and MF-DH-397, which are inhibitors of hydroxyprostaglandin dehydrogenase.

[0647] [ka]

[0648] Step 1: Synthesis of Int-1a (X=H) and Int-1b (X=F): The synthesis of Int-1a and Int-1b is described in Scheme 9.

[0649] Int-1a was converted to MF-DH-318 using the general procedure for Ullmann coupling with 7-bromoimidazo[1,2-a]pyridine to give MF-DH-318 as a sticky solid.

[0650] Int-1a was converted to MF-DH-320 using the general procedure for Ullmann coupling using 3-bromo-5-methylpyridine with Int-1 to give MF-DH-320 as an off-white solid.

[0651] Int-1a was converted to MF-DH-322 using the general procedure for Ullmann coupling with 5-bromopyridin-3-amine to afford MF-DH-322 as an off-white solid.

[0652] Int-1b was converted to MF-DH-342 using the general procedure for Ullmann coupling with 4-bromobenzonitrile to afford MF-DH-342 as an off-white solid.

[0653] Int-1b was converted to MF-DH-344 using the general procedure for Ullmann coupling with 3-bromobenzonitrile to afford MF-DH-344 as an off-white solid.

[0654] Int-1b was converted to MF-DH-346 using the general procedure for Ullmann coupling with 4-bromo-N,N-dimethylaniline to afford MF-DH-346 as an off-white solid.

[0655] Int-1a was converted to MF-DH-366 using the general procedure for Ullmann coupling with 5-bromo-N,N-dimethylpyridin-2-amine to give MF-DH-346 as an off-white solid.

[0656] Int-1a was converted to MF-DH-389 using the general procedure for Ullmann coupling with 5-bromopicolinonitrile to afford MF-DH-389 as an off-white solid.

[0657] Int-1a was converted to MF-DH-397 using the general procedure for Ullmann coupling with 5-bromopyrimidine-2-carbonitrile to afford MF-DH-397 as an off-white solid.

[0658] Synthesis of (1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-319) Provided below is an exemplary scheme for synthesizing (1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone, or MF-DH-319, an inhibitor of hydroxyprostaglandin dehydrogenase.

[0659] [ka]

[0660] Step A: Synthesis of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (Int-A) and 5-bromo-1-(4-methoxybenzyl)-2H-indazole (Int-A'): To a stirred solution of 6-bromoindazole (1 g, 5.07 mmol, 1 eq) in DMF (15 mL), NaH (60% in mineral oil) (0.24 g, 6.08 mmol, 1.2 eq) was added over 1 h from 0 °C to RT. To this stirred suspension was added PMBCl (1.18 g, 7.60 mmol, 1.5 eq), and the resulting reaction mixture was stirred for 4 h. The reaction was monitored by crude LCMS / TLC, and after complete consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 40% EtOAc / heptane to give 5-bromo-1-(4-methoxybenzyl)-1H-indazole, Int-A (0.81 g, 50.06%), and 5-bromo-1-(4-methoxybenzyl)-2H-indazole, Int-A' (0.55 g, 34.3%) as off-white solids. LCMS: 98.3%, m / z=318.1 [M+2H] + .

[0661] Step 1: The synthesis of Int-1 is described in Scheme 9. Using the general procedure for Ullmann coupling using 5-bromo-1-(4-methoxybenzyl)-1H-indazole (Int-A) with Int-1, Int-1 was converted to MF-DH-337 to give MF-DH-337 as a sticky solid.

[0662] Step 3: Using the general procedure for Ullmann coupling using 5-bromo-1-(4-methoxybenzyl)-2H-indazole (Int-A′) with Int-1, Int-1 was converted to MF-DH-340 to give MF-DH-340 as an off-white solid.

[0663] Step 2: Synthesis of 5(1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-319): To a stirred solution of MF-DH-337 (120 mg, 0.257 mmol, 1 eq) in DCE (15 mL) was added TFA (4 mL) at 0 °C and stirred at room temperature for 1 h, then warmed to 80 °C for 16 h. The reaction was monitored by crude LCMS / TLC, and after complete consumption of the starting material, the reaction mixture was quenched with saturated NaHCO (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography using 40% EtOAc / heptane to give 5(1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-319) as a viscous liquid.

[0664] Synthesis of pyrrolopyridine-5-carboxamide analogues with amide / aryl variation Provided below are exemplary schemes for synthesizing pyrrolopyridine-5-carboxamide analogs with amide / aryl variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0665] [ka]

[0666] The synthesis of Int-1a (X, X' = H) and Int-1b (X = H, X' = F) is described in Scheme 9.

[0667] Synthesis of Int-1c (X,X' = F): To a stirred solution of 11H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (30 g, 185.1 mmol, 1 eq) in DMF (5 v) under an inert atmosphere, HATU (84.44 g, 222.2 mmol, 1.3 eq) was added, and 4,4-difluoropiperidine (31.98 g, 203.7 mmol, 1.1 eq) was added at 0 °C. N,N'-diisopropylethylamine (119.6 g, 925.9 mmol, 5 eq) was added to the stirred solution at 0 °C, followed by stirring at room temperature for 16 h. The reaction mixture was quenched with ice water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with ice water (2 x 100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography to give 32.5 g of Int-1c (66.2% yield). 1 HNMR(400MHz,DMSO-d6):δ11.89(s,1H),8.31(d,J=2.0Hz,1H),8.08(d,J=1.6Hz,1H),7.56(t,J=2.8H z,1H),6.52(dd,J=1.6,3.2Hz,1H),3.64-3.58(m,4H),2.09-2.01(m,4H).LCMS:97.17%;MS:266[M+H] + .

[0668] Step 1: Int-1a, Int-1b, and Int-1c were combined to give Int-2a: (Ar1 = pyridine-2-CN, X, X' = H) yield 30%, MS: m / z = 332.2 [M + H] + Int-2b: (Ar1 = pyrazine-2-CN, X, X' = H) Yield 68%, MS: m / z = 333.2 [M + H] + ;Int-2c:(Ar1=4-CHO-Ph,X,X'=H)Yield 83%,MS:m / z=334.1[M+H] + ;Int-2d:(Ar1=3-CHO-Ph, X,X'=H) Yield 53%, MS: m / z=334.1[M+H] +;Int-2e:(Ar1=4-CH3C=O-Ph, X,X'=H) Yield 62%, MS: m / z=348.1[M+H] + ;Int-2f:(Ar1=3-CH3C=O-Ph, X,X'=H) yield 60%, MS: m / z=348.1[M+H] + ;Int-2g:(Ar1=4-CHO-Ph, X=H,X'=F) Yield 58%, MS: m / z=353.1[M+H] + ;Int-2h:(Ar1=3-CHO-Ph,X=H,X'=F)Yield 78%,MS:m / z=353.1[M+H] + and Int-2i: (Ar1 = 4-CN-Ph, X = H, X' = F) Yield 43%, MS: m / z = 349.2 [M + H] + was converted to.

[0669] Step 2: Using the general procedure for oxidation of nitriles, MF-DH-342 (synthesis described in Scheme 43), MF-DH-344 (synthesis described in Scheme 43), Int-2a, Int-2b, and Int-2i were converted to MF-DH-343, MF-DH-345, MF-DH-365, MF-DH-384, and MF-DH-394, which were isolated as off-white solids.

[0670] Using the general procedure for reduction of aldehydes / ketones, MF-DH-347, MF-DH-348, MF-DH-347, and MF-DH-348 were obtained as viscous liquids.

[0671] General Procedure for Aldehyde / Ketone Alkylation To a stirred solution of aldehydes / ketones Int-2c, Int-2e, Int-2d, and Int-2f (0.5 mmol, 1 eq) in THF (15 mL) was added MeMgBr (2 M in THF, 2 eq) in small portions over 15 min at 0 °C. The reaction mixture was stirred at room temperature for 5 min. The reaction was monitored by LCMS / TLC. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude products, which were purified by flash chromatography to give MF-DH-370, MF-DH-374, MF-DH-371, and MF-DH-375 as off-white solids and sticky liquids.

[0672] General procedure for aldehyde reduction: To a stirred solution of aldehyde / ketone Int-2g / Int-2h (0.5 mmol, 1 eq) in MeOH (15 mL) was added NaBH4 (4 eq.) in small portions over 15 min at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated in vacuo, diluted with water, and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude products, which were purified by flash chromatography to give MF-DH-347 and MF-DH-348 as off-white solids.

[0673] Synthesis of pyrrolopyridine-5-carboxamide analogs (MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327, MF-DH-328, MF-DH-329) with amide / aryl variation Provided below are exemplary schemes for synthesizing pyrrolopyridine-5-carboxamide analogs with amide / aryl variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0674] [ka]

[0675] Step 1: Synthesis of methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Int-1): To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (5 g, 30.08 mmol, 1 eq) in DCM (100 mL) was added oxalyl chloride (5.3 mL, 61.60 mmol, 2 eq) followed by DMF (0.5 mL) over 30 min at 0° C. and then stirred at room temperature for 1 h. The reaction was monitored by TLC, and upon completion, it was quenched with methanol (20 mL) and stirred at room temperature for 12 h. The solvent was then evaporated under reduced pressure, diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (50 mL) and brine (50 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-1 (5.38 g, 99%) as an off-white solid. LCMS: 96.42%, m / z = 177.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.08 (br s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.56 (s, 1H), 6.57 (s, 1H), 3.81 (s, 3H).

[0676] Step 2: Synthesis of methyl 1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Int-2): Using the general procedure for the Ullmann reaction, Int-1 (2.5 g, 14.1 mmol) was converted to Int-2 (2.51 g, 62.5%), which was isolated as an off-white solid. LCMS: 99.12%, m / z = 283.1 [M+H] + .

[0677] Step 3: Synthesis of 1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-3): Methyl 1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.5 g, 8 mmol, 1 eq) in MeOH:water (8:2, 30 mL) was subjected to the general procedure for ester hydrolysis using NaOH to give Int-3 (1.5 g, 65.21%) as a light brown sticky solid. LCMS: 96.35 m / z = 269.1 [M+H] + .

[0678] Step 4: Synthesis of MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327, MF-DH-328, and MF-DH-329: Using the general procedure for HATU coupling, Int-3 was converted to MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327, MF-DH-328, and MF-DH-329, which were isolated as off-white / sticky solids after purification.

[0679] Synthesis of pyrrolopyridine-5-carboxamide analogues with amide / aryl variation Provided below are exemplary schemes for synthesizing pyrrolopyridine-5-carboxamide analogs with amide / aryl variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0680] [ka]

[0681] The synthesis of Int-1a (X=H) and Int-1b (X=F) is described in Scheme 9.

[0682] Step 1: Using the general procedure for Ullmann coupling with 4-bromobenzoate, Int-1a / 1b was converted to Int-2a / 2b to give Int-2a (X = H, 55% yield, MS: m / z = 364.1 [M+1]). +) and Int-2b (X = F, yield 60.74%, MS: m / z = 382.1 [M+1] + ) was obtained as an off-white solid.

[0683] Step 2: Using the general procedure for ester hydrolysis with NaOH, Int-2 was converted to Int-3a (X = H, 86% yield, m / z = 350.1 [M+1] + ) and Int-3b (X = F, yield 89%, MS: m / z = 366.1 [M−H] - The crude product was carried on to the next step without further purification.

[0684] Step 3: Int-3 was subjected to the general procedure for amide coupling using HATU to give MF-DH-357, MF-DH-367, MF-DH-358, MF-DH-368, MF-DH-359, and MF-DH-360.

[0685] Synthesis of azabenzimidazole analogues with aryl / amide variation: Provided below are exemplary schemes for synthesizing azabenzimidazole analogs with aryl / amide variations that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0686] [ka]

[0687] Step 1: General procedure for the synthesis of Int-1: In a sealed pressure vessel, methyl 6-chloro-5-nitronicotinate (7 g, 32.31 mmol, 1 eq), arylamine (Ar-NH, 1 eq) were dissolved in EtOH (70 mL). To this stirred solution, KCO (1 eq) was added at room temperature. The steel pressure vessel was tightly capped and the resulting reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC. Upon completion, the reaction was cooled to room temperature, then filtered and washed with EtOAc (50 mL). The volatiles were evaporated, quenched with saturated NHCl (100 mL), extracted with EtOAc (3 x 50 mL), and the combined organic extracts were washed with brine (50 mL). Drying over sodium sulfate, filtration, and concentration in vacuo gave a yellow solid, which was triturated with DEE (100 mL) to give Int-1a (Ar = 3-Cl phenyl, 64% yield, MS: m / z = 307.2 [M+H] + ); Int-1b (Ar = 4-OMePh, yield 87%, MS: m / z = 318.2 [M + H] + ); Int-1c (Ar = 4-F-Ph, yield 70%, MS: [M + H] + Int-1d (Ar = 3,4-difluoroPh, 96% yield); Int-1e (Ar = 4-OCHF3Ph, 96% yield, MS: m / z = 328.2); Int-1f (Ar = 4-OCHF2Ph, 66% yield, MS: m / z = 338.2 [M+H] + );Int-1g(Ar=4-OEtPh, 62% yield, MS: m / z=317.2[M+H] + ); Int-1h (Ar = 3-OCF3Ph, yield 72%, MS: m / z = 326.2 [M + H] + );Int-1i(Ar=3-OCHF2Ph, yield 62%, MS: m / z=309.2[M+H] + ); Int-1j (Ar = 3-pentyl, yield 83%, MS: m / z = 254.1 [M + H] + ); Int-1k (Ar = 4-OHPh, yield 76%, MS: m / z = 290.1 [M + H] + ); and Int-1l (Ar = 4-CNPh, crude, m / z = 299.1 [M+H] +) was obtained.

[0688] Step 2: Synthesis of Int-2: Int-1 (2 g, 1 eq) was subjected to the general procedure for aryl nitro reduction using Fe. The crude material was purified by silica gel column chromatography using 60%-70% EtOAc / heptane to give Int-2a (Ar = 3-ClPh, 20% yield, MS: m / z = 291.0 [M+H]). + );Int-2b(Ar=4-OMePh, crude, MS:m / z=288.2[M+H] + );Int-2c(Ar=4-FPh, crude, MS:m / z=261.2[M+H] + ); Int-2d (Ar = 3,4-difluoroPh, yield 96%, MS: m / z = 280.2 [M + H] + ); Int-2e (Ar = 4-OCHF3Ph, yield 96%, MS: m / z = 328.2); Int-2f (Ar = 4-OCHF2Ph, yield 71.4%, MS: m / z = 324.2 [M+1] + );Int-2g(Ar=4-OEtPh, yield 93%, MS: m / z=286.2[M+H] + );Int-2h(Ar=3-OCF3Ph, yield 68%, MS: m / z=338.1[M+H] + ); Int-2i (Ar = 3-OCHF2Ph, yield 57%, MS: m / z = 310.2 [M + 1H] + ); Int-2j (Ar = 3-pentyl, yield 84%, MS: m / z = 252.1 [M + H] + );Int 2k(Ar=4-OHPh, yield 76%, MS:m / z=290.1[M+H] + ); and Int-2l (Ar = 4-CNPh, crude, MS: m / z = 269.2 [M+H] + ) was obtained.

[0689] Step 3: General procedure for the synthesis of Int-3: To a stirred solution of Int-2 (1.5 g, 1 eq) and triethyl orthoformate (5 eq) in dioxane (20 mL) was added PTSA (0.2 eq) at room temperature. The resulting reaction mixture was warmed to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC, and after complete consumption of the starting material, the reaction mixture was quenched with saturated NaHCO3 solution (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane to give Int-3a (Ar = 3-ClPh, ...

Claims

1. 1. A method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to said subject a compound of Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: X is -OCH ２ -, -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, -SCH ２ -, -S(O)CH ２ -, -SO ２ CH ２ - is selected from, Y is independently N or R １１ is selected from Each R １ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ and R ２ and R ３ together form an oxo or thio group, Each R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ５ is halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ６ and R ７ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; Each R ８ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ９ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １０ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; Each R １１ is halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of formula I is 【Chemistry 2】 A method that assumes that this is not the case.

2. The compound has the formula Ia: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

3. The compound has the formula Ib: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

4. 1. A method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to said subject a compound of formula II: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently N and CR ５ is selected from S, V, and Z are independently selected from N and C; R １ is C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, —NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ and R ２ and R ３ together form an oxo or thio group, Each R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or Two R's ４ are C together with the carbon atom to which they are attached and any intervening atoms. ３－１０ form a cycloalkyl, and all remaining R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ５ are independently H, halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ６ and R ７ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; Each R ８ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ９ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １０ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl, and n is 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of formula II is 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 A method that assumes that this is not the case.

5. The compound has the formula IIa: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

6. The compound has the formula IIb: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

7. The compound has the formula IIc: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

8. The compound has the formula IId: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

9. The compound has the formula IIe: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

10. The compound has the formula IIf: 【Chemistry 14】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

11. The compound has the formula IIg: 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

12. The compound has the formula IIh: 【Chemistry 16】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

13. The compound has the formula IIi: 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

14. The compound has the formula IIj: 【Chemistry 18】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

15. The compound has the formula IIn: 【Chemistry 19】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

16. The compound has the formula IIp: 【Chemistry 20】 or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

17. 1. A method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising: 【Chemical 21】 or a pharmaceutically acceptable salt thereof, wherein: Each X is independently N and CR ７ is selected from Y is O, S, SO ２ , and C(R ８ ) ２ is selected from R １ is C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halo, —NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ and R ２ and R ３ together form an oxo or thio group, R ４ and R ５ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R ４ and R ５ together with the nitrogen atom to which they are attached form halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ forming a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; Each R ６ are independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or Two R bonded to the same carbon atom ６ are united to form oxo, thio, or C ３－１０ form a cycloalkyl, and all remaining R ６ are independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ７ are independently H, halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ８ are independently H, halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or Two R's ８ are united to form halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ C optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl ３－１０ can form a cycloalkyl, R ９ and R １０ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; Each R １１ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １２ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; m is 1 or 2, and The method wherein n is 0, 1, 2, 3, or 4.

18. The compound has the formula IIIa: 【Chemical 22】 or a pharmaceutically acceptable salt thereof.

19. The compound has the formula IIIb: 【Chemical 23】 or a pharmaceutically acceptable salt thereof, wherein Each R １４ are independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; and 18. The method of claim 17, wherein p is 0, 1, 2, or 3.

20. The compound has the formula IIIc: 【Chemistry 24】 or a pharmaceutically acceptable salt thereof.

21. The compound has the formula IIId: 【Chemistry 25】 or a pharmaceutically acceptable salt thereof, wherein Each R １４ are independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; and 18. The method of claim 17, wherein p is 0, 1, 2, or 3.

22. Formula IIk: 【Chemical Formula 26】 or a pharmaceutically acceptable salt thereof, wherein T, U, and N are independently N and CR ６ provided that when U is N, then at least one of T and Y is N; R １ is C ６－１０ aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, —NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , —C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ or R ２ and R ３ come together to form an oxo, Each R ４ is independently selected from H and halo; R ５ is halo, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , —C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ６ is H, halo, -NR ７ R ８ , -OR ９ , -C(O)R ９ , -C(O)OR ９ , —C(O)NR ７ R ８ , -SOR １０ , -SO ２ R １０ , -SO ２ NR ７ R ８ , -NR １１ C(O)R ９ , -NR １１ C(O)NR ７ R ８ , -NR １１ SO ２ R ９ , -NR １１ SO ２ NR ７ R ８ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ７ and R ８ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; Each R ９ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １０ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; and p is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

23. Formula IIm: 【Chemical 27】 or a pharmaceutically acceptable salt thereof, wherein R １ is C ６－１０ aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, —NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ or R ２ and R ３ come together to form an oxo, Each R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or Two R's ４ are C together with the carbon atom to which they are attached and any intervening atoms. ３－１０ form a cycloalkyl, and all remaining R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ５ is halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ６ and R ７ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; Each R ８ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ９ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １０ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

24. Formula IIq: 【Chemical Formula 28】 or a pharmaceutically acceptable salt thereof, wherein R １ is C ６－１０ aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, —NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ or R ２ and R ３ come together to form an oxo, Each R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or Two R's ４ are C together with the carbon atom to which they are attached and any intervening atoms. ３－１０ form a cycloalkyl, and all remaining R ４ are independently halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ５ is halo, -NR ６ R ７ , -OR ８ , -C(O)R ８ , -C(O)OR ８ , —C(O)NR ６ R ７ , -SOR ９ , -SO ２ R ９ , -SO ２ NR ６ R ７ , -NR １０ C(O)R ８ , -NR １０ C(O)NR ６ R ７ , -NR １０ SO ２ R ８ , -NR １０ SO ２ NR ６ R ７ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ６ and R ７ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; Each R ８ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R ９ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １０ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－１０ cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

25. Formula IIIc: 【Chemical 29】 or a pharmaceutically acceptable salt thereof, wherein Each X is independently N and CR ７ is selected from Y is O, S, SO ２ , and C(R ８ ) ２ is selected from R １ is C ６－１０ aryl and 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from halo, —NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, and 5- to 10-membered heteroaryl; R ２ is H and R ３ Ha-CF ３ or R ２ and R ３ come together to form an oxo, R ４ and R ５ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl, wherein alkyl, heteroalkyl, haloalkyl, and cycloalkyl are each independently selected from halo, —NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; R ４ and R ５ together with the nitrogen atom to which they are attached form halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ forming a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from aryl, and 5- to 10-membered heteroaryl; Each R ６ are independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or Two R bonded to the same carbon atom ６ are united to form oxo, and all remaining R ６ are independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ７ and R ８ are each independently halo, -NR ９ R １０ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , —C(O)NR ９ R １０ , -SOR １２ , -SO ２ R １２ , -SO ２ NR ９ R １０ , -NR １３ C(O)R １１ , -NR １３ C(O)NR ９ R １０ , -NR １３ SO ２ R １１ , -NR １３ SO ２ NR ９ R １０ , C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ９ and R １０ are independently H and C when they occur. １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; Each R １１ are independently H, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １２ is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; Each R １３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; and n is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

26.

30. A composition comprising a compound selected from the group consisting of:

27.

31. 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 A composition comprising a compound selected from the group consisting of:

28.

42. A composition comprising a compound selected from the group consisting of:

29. 30. A method for promoting and / or stimulating skin pigmentation, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

30. 30. A method of inhibiting hair loss, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

31. 30. A method for treating and / or preventing skin inflammation and / or damage, comprising administering one or more of the compositions of any one of claims 26 to 28 to a subject in need of such treatment and / or prevention.

32. 30. A method for preventing and / or treating vascular insufficiency, comprising administering one or more of the compositions described in any one of claims 26 to 28 to a subject in need of prevention and / or treatment.

33. A method for preventing, treating, minimizing, and / or ameliorating congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described in any one of claims 26 to 28 to a subject in need thereof.

34. 30. A method of reducing cardiac ejection fraction, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

35. 30. A method for preventing and / or treating gastrointestinal disorders, comprising administering one or more of the compositions of any one of claims 26 to 28 to a subject in need of prevention and / or treatment.

36. 30. A method for preventing and / or treating renal dysfunction, comprising administering one or more of the compositions described in any one of claims 26 to 28 to a subject in need of prevention and / or treatment.

37. 30. A method for stimulating bone resorption and bone formation, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

38. 30. A method for stimulating tissue regeneration by stimulation, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

39. 30. A method of modulating cervical ripening, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

40. 30. A method for promoting neuroprotection and / or stimulating neuroregeneration, comprising administering one or more of the compositions described in claims 26 to 28 to a subject in need thereof.

41. 30. A method for treating and / or preventing a neurological disorder, a neuropsychiatric disorder, nerve injury, a neurotoxic disorder, neuropathic pain, or a neurodegenerative disorder, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

42. 30. A method for treating and / or preventing a fibrotic or adhesive disease, disorder, or condition, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

43. 30. A method for reducing and / or preventing scar formation, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

44. 30. A method for treating and / or preventing muscle disorders, muscle damage, and / or muscle atrophy, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

45. 30. A method for treating and / or preventing fibrosis, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

46. 30. A method for treating and / or preventing idiopathic pulmonary fibrosis, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

47. 30. A method for treating and / or preventing renal fibrosis, comprising administering to a subject in need thereof one or more of the compositions described in any one of claims 26 to 28.

48. 30. A method of stimulating muscle regeneration, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

49. 30. A method of promoting organ adaptation, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

50. 30. A method of promoting wound healing, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

51. 30. A method of treating acute kidney injury, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

52. 30. A method of treating sarcopenia, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

53. 30. A method of treating a neuromuscular disease, comprising administering to a subject in need thereof one or more of the compositions of any one of claims 26 to 28.

Images