PGDH inhibitors and methods of preparation and use

Abstract

Disclosed herein are compounds that can inhibit 15-hydroxyprostaglandin dehydrogenase. Such compounds can be administered to subjects who may benefit from regulation of prostaglandin levels.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 965,062, filed on January 23, 2020; U.S. Provisional Application No. 63 / 007,755, filed on April 9, 2020; U.S. Provisional Application No. 63 / 029,184, filed on May 22, 2020; U.S. Provisional Application No. 63 / 092,116, filed on October 15, 2020; U.S. Provisional Application No. 63 / 110,803, filed on November 6, 2020; and U.S. Provisional Application No. 63 / 133,965, filed on January 5, 2021, each of which is incorporated herein by reference. Background Art

[0003] Prostaglandins are a group of physiologically active lipid compounds with a wide variety of biological actions including vasodilation, inhibition of platelet aggregation, bronchial dilation, 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.

[0004] Treatment of a disease or illness may require activation of prostaglandins, or inhibition of the inactivation of prostaglandins. Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), are involved in the inactivation of prostaglandins. Therefore, the disease / illness associated with prostaglandins can be prevented, treated and / or managed using inhibitors of hydroxyprostaglandin dehydrogenases such as inhibitors of 15-PGDH. Summary of the invention

[0005] In one aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I:

[0006]

[0007] or a pharmaceutically acceptable salt thereof, wherein:

[0008] X is selected from –OCH 2 –, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH 2 –, –S(O)CH 2 –, –SO 2 CH 2 –

[0009] Each Y is independently selected from N and CR 11;

[0010] Each R 1 are independently 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 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0011] R 2 is H, and R 3 Yes – CF 3 ;or

[0012] R 2 and R 3 together to form an oxo group or a thio group;

[0013] Each R 4 are independently 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)R8 ,–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;

[0014] Each R 5 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0015] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0016] Each R 8 Independently selected from 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;

[0017] Each R 9 Independently selected from 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;

[0018] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0019] Each R 11 are 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 Aryl and 5- to 10-membered heteroaryl;

[0020] n is 0, 1, 2, 3, 4, or 5;

[0021] m is 0, 1, 2, 3 or 4; and

[0022] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0023] Provided that the compound of formula I is not

[0024] In some embodiments, the compound is a compound of Formula Ia:

[0025]

[0026] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compound is a compound of Formula Ib:

[0028]

[0029] or a pharmaceutically acceptable salt thereof.

[0030] In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula II:

[0031]

[0032] or a pharmaceutically acceptable salt thereof, wherein:

[0033] T, U, W, X and Y are independently selected from N and CR 5 ;

[0034] S, V and Z are independently selected from N and C;

[0035] R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 ,–SO 2R 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 and 5- to 10-membered heteroaryl;

[0036] R 2 is H, and R 3 Yes – CF 3 ;or

[0037] R 2 and R 3 together to form an oxo group or a thio group;

[0038] Each R 4 are independently 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, C3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0039] Two R's 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0040] Each R 5 are independently selected from 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 10C(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;

[0041] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0042] Each R 8 Independently selected from 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;

[0043] Each R 9 Independently selected from 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;

[0044] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; and

[0045] n is 1, 2, 3 or 4; and

[0046] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0047] Provided that the compound of formula II is not

[0048] In some embodiments, the compound is a compound of Formula IIa:

[0049]

[0050] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0051] In some embodiments, the compound is a compound of Formula IIb:

[0052]

[0053] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0054] In some embodiments, the compound is a compound of Formula IIc:

[0055]

[0056] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

[0057] In some embodiments, the compound is a compound of Formula IId:

[0058]

[0059] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0060] In some embodiments, the compound is a compound of Formula IIe:

[0061]

[0062] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0063] In some embodiments, the compound is a compound of Formula IIf:

[0064]

[0065] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0066] In some embodiments, the compound is a compound of Formula IIg:

[0067]

[0068] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0069] In some embodiments, the compound is a compound of Formula IIh:

[0070]

[0071] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0072] In some embodiments, the compound is a compound of Formula IIi:

[0073]

[0074] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0075] In some embodiments, the compound is a compound of Formula IIj:

[0076]

[0077] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0078] In some embodiments, the compound is a compound of Formula IIn:

[0079]

[0080] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0081] In some embodiments, the compound is a compound of Formula IIp:

[0082]

[0083] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0084] In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula III:

[0085]

[0086] or a pharmaceutically acceptable salt thereof, wherein:

[0087] Each X is independently selected from N and CR 7 ;

[0088] Y is selected from O, S, SO 2 and C(R 8 ) 2 ;

[0089] R 1 Selected from C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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;

[0090] R 2 is H, and R 3 Yes – CF 3 ;or

[0091] R 2 and R 3 together to form an oxo group or a thio group;

[0092] R 4 and R 5 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from the following: 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

[0093] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 R10 , 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;

[0094] Each R 6 are 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 aryl and 5- to 10-membered heteroaryl; or

[0095] Two R attached to the same carbon atom 6 Together they form an oxo group, a thio group or a C 3-10 cycloalkyl, and any remaining R 6 are 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 R10 ,–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;

[0096] Each R 7 are independently selected from 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;

[0097] Each R 8 are independently selected from 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

[0098] Two R's 8 may together form C optionally substituted by 1 to 3 substituents independently selected from the following 3-10 Cycloalkyl: halide, –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 1-6Haloalkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0099] R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0100] Each R 11 Independently selected from 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;

[0101] Each R 12 Independently selected from 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;

[0102] Each R 13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0103] m is 1 or 2; and

[0104] n is 0, 1, 2, 3 or 4.

[0105] In some embodiments, the compound is a compound of Formula IIIa:

[0106]

[0107] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound is a compound of Formula IIIb:

[0109]

[0110] or a pharmaceutically acceptable salt thereof, wherein:

[0111] Each R 14 are independently selected from halo, –NR 9 R 10 ,–OR11 , –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

[0112] p is 0, 1, 2 or 3.

[0113] In some embodiments, the compound is a compound of Formula IIIc:

[0114]

[0115] or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound is a compound of Formula IIId:

[0117]

[0118] or a pharmaceutically acceptable salt thereof, wherein:

[0119] Each R 14 are 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 2NR 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

[0120] p is 0, 1, 2 or 3.

[0121] In another aspect, provided herein is a compound of Formula IIk:

[0122]

[0123] or a pharmaceutically acceptable salt thereof, wherein:

[0124] T, U and Y are independently selected from N and CR 6 , provided that when U is N, at least one of T and Y is N;

[0125] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 R9 ,–NR 11 SO 2 NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 5- to 10-membered heteroaryl;

[0126] R 2 is H, and R 3 Yes – CF 3 ;or

[0127] R 2 and R 3 Together they form an oxo group;

[0128] Each R 4 are independently selected from H and halo;

[0129] R 5 Selected from halogen, –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;

[0130] R 6 Selected from H, halo, –NR 7 R 8 ,–OR9 , –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;

[0131] R 7 and R 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0132] Each R 9 Independently selected from 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;

[0133] Each R 10 Independently selected from 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;

[0134] Each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C3-6 cycloalkyl; and p is 0, 1 or 2.

[0135] In another aspect, provided herein is a compound of Formula IIm:

[0136]

[0137] or a pharmaceutically acceptable salt thereof, wherein:

[0138] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and 5- to 10-membered heteroaryl;

[0139] R 2 is H, and R 3 Yes – CF 3 ;or

[0140] R 2 and R 3 Together they form an oxo group;

[0141] Each R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R8 , –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

[0142] Two R's 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0143] R 5 Selected from halogen, –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;

[0144] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0145] Each R 8 Independently selected from 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;

[0146] Each R 9 Independently selected from C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0147] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0148] n is 1, 2, 3, or 4;

[0149] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0150] p is 0, 1, 2 or 3.

[0151] In another aspect, provided herein is a compound of formula IIq:

[0152]

[0153] or a pharmaceutically acceptable salt thereof, wherein:

[0154] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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, C3-10 Cycloalkyl and 5- to 10-membered heteroaryl;

[0155] R 2 is H, and R 3 Yes – CF 3 ;or

[0156] R 2 and R 3 Together they form an oxo group;

[0157] Each R 4 are independently 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 Cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0158] Two R's 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 R9 ,–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;

[0159] R 5 Selected from halogen, –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;

[0160] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0161] Each R 8 Independently selected from 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;

[0162] Each R 9 Independently selected from 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;

[0163] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0164] n is 1, 2, 3, or 4;

[0165] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0166] p is 0, 1, 2 or 3.

[0167] In another aspect, provided herein is a compound of formula IIIc:

[0168]

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

[0170] Each X is independently selected from N and CR 7 ;

[0171] Y is selected from O, S, SO 2 and C(R 8 ) 2 ;

[0172] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and 5- to 10-membered heteroaryl;

[0173] R 2 is H, and R 3 Yes – CF 3 ;or

[0174] R 2 and R 3 Together they form an oxo group;

[0175] R 4 and R 5 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from the following: 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

[0176] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 Aryl and 5- to 10-membered heteroaryl;

[0177] Each R 6 are 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 aryl and 5- to 10-membered heteroaryl; or

[0178] Two R attached to the same carbon atom 6 together to form an oxo group, and any remaining R 6 are 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 1-6Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0179] Each R 7 and R 8 are 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 Aryl and 5- to 10-membered heteroaryl;

[0180] R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0181] Each R 11 Independently selected from 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;

[0182] Each R 12 Independently selected from C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0183] Each R 13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

[0184] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0185]

[0186] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0197]

[0198] In another aspect, provided herein is a method of promoting and / or stimulating skin pigmentation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0199] In another aspect, provided herein is a method of inhibiting hair loss, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0200] A method of 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 thereof.

[0201] In another aspect, provided herein is a method for preventing and / or treating vascular insufficiency, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0202] In another aspect, provided herein is a method of preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0203] In another aspect, provided herein is a method of reducing cardiac ejection fraction, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0204] In another aspect, provided herein is a method for preventing and / or treating a gastrointestinal disease, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0205] In another aspect, provided herein is 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 thereof.

[0206] In another aspect, provided herein is a method of stimulating bone resorption and bone formation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0207] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0208] In another aspect, provided herein is a method of regulating cervical ripening, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0209] In another aspect, provided herein is a method of promoting neuroprotection and / or stimulating neuronal regeneration, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0210] In another aspect, provided herein is a method of treating and / or preventing a neurological disorder, a neuropsychiatric disorder, a neurological injury, a neurotoxic disorder, neuropathic pain, or a neurodegenerative disorder, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0211] In another aspect, provided herein is a method of treating and / or preventing a fibrotic or adhesion disease, disorder, or condition, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0212] In another aspect, provided herein is a method of reducing and / or preventing scarring, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0213] In another aspect, provided herein is a method of treating and / or preventing muscle disorders, muscle damage and / or muscle atrophy, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0214] In another aspect, provided herein is a method of treating and / or preventing fibrosis, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0215] In another aspect, provided herein is a method of treating and / or preventing idiopathic pulmonary fibrosis, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0216] In another aspect, provided herein is a method of treating and / or preventing renal fibrosis, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0217] In another aspect, provided herein is a method of stimulating muscle regeneration, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0218] In another aspect, provided herein is a method of promoting organ health, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0219] In another aspect, provided herein is a method of promoting wound healing, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0220] In another aspect, provided herein is a method of treating acute kidney injury, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0221] In another aspect, provided herein is a method of treating sarcopenia, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0222] In another aspect, provided herein is a method of treating a neuromuscular disease, the method comprising administering one or more of the compositions of any preceding claim to a subject in need thereof.

[0223] Incorporation by reference

[0224] 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 DESCRIPTION OF THE DRAWINGS

[0225] The novel features of the invention are particularly set forth in the appended claims. An understanding of the features and advantages of the invention may be obtained by reference to the following detailed description which sets forth illustrative embodiments in which the principles of the invention are utilized, and to the accompanying drawings, in which:

[0226] Figure 1 Results of cell-based assays for exemplary compounds are shown. DETAILED DESCRIPTION

[0227] definition

[0228] Unless defined otherwise, 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.

[0229] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0230] The term "C x-y " when used in conjunction with a chemical moiety such as alkyl, haloalkyl, or heteroalkyl is intended to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight-chain alkyl and branched-chain alkyl. The term -C x-y Alkylene - refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. For example, -C 1-6 Alkylene - may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which is optionally substituted.

[0231] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl. Alkyl groups may contain from one to twelve carbon atoms (e.g., C 1-12 Alkyl), such as one to eight carbon atoms (C 1-8 Alkyl) or one to six carbon atoms (C 1-6The alkyl group is optionally substituted with one or more substituents such as those described herein.

[0232] "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.

[0233] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon. Exemplary backbone chain atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or a combination thereof, wherein nitrogen, phosphorus and sulfur atoms may be optionally oxidized, and nitrogen heteroatoms may be optionally quaternized. If given, the numerical range refers to the overall chain length. For example, 3 to 8 yuan heteroalkyl groups have a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be carried out through heteroatoms or carbon in the heteroalkyl chain. Unless specifically stated otherwise in the specification, heteroalkyl groups are optionally substituted by one or more substituents such as those described herein.

[0234] "Aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl may be optionally substituted. Examples of aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, aryl may be a monovalent group or a divalent group (i.e., arylene). Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (such as in the case of "aralkyl") is intended to include optionally substituted aryl.

[0235] "Heteroaryl" refers to a 3 to 12 membered aromatic ring containing at least one heteroatom, wherein each heteroatom may be independently selected from N, O and S. As used herein, the heteroaryl ring may be selected from a monocyclic or bicyclic and fused or bridged ring system, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π electron system that conforms to the Hückel theory. One or more heteroatoms in the heteroaryl may be optionally oxidized. If present, one or more nitrogen atoms may be optionally quaternized. Where valence permits, the heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl.Examples of heteroaryl groups include, but are not limited to, azepine, 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, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazole, benzothienyl, benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazole, benzothienyl, benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazole, benzothiophenyl ... oxazolyl, 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] cycloheptatrienol[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyridazinyl, cyclooctatetraenol[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepine, oxazolyl, oxazolyl Cyclopropane, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[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-tetrahydro-5H-cycloheptatrienol[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 stated otherwise specifically in the specification, a heteroaryl group is optionally substituted with one or more substituents such as those described herein.

[0236] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, wherein each atom (i.e., skeleton atom) forming the ring is a carbon atom. In some embodiments, cycloalkyl is saturated or partially unsaturated. In some embodiments, cycloalkyl is a spirocyclic or bridged compound. In some embodiments, cycloalkyl is fused with an aromatic ring (in the case of the cycloalkyl being bonded by a non-aromatic ring carbon atom). Cycloalkyl includes a group with 3 to 10 ring atoms. Representative cycloalkyl includes but is not limited to a cycloalkyl with three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrahydronaphthyl, decahydronaphthyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. Unless specifically stated otherwise in the specification, cycloalkyl groups may be optionally substituted.

[0237] The term "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the specification, the heterocycloalkyl group may be a monocyclic or bicyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or a bridged ring system. The nitrogen, carbon or sulfur atoms in the heterocyclyl group may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl group may be partially or fully saturated. Examples of heterocycloalkyl include, but are not limited to, dioxolane, thienyl [1,3] dithiane, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiane, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 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 indicated, heterocycloalkyl has 2 to 12 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) constituting the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted.

[0238] The term "substituted" refers to a substituent of hydrogen on one or more carbons or heteroatoms with a partial replacement structure. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., this substitution meets the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, such as a stable compound that does not spontaneously undergo a transformation such as achieved by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is considered to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, permissible substituents may be one or more, and the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that meet the valence of heteroatoms. Substituents may include any of the substituents described herein, for example, oxo, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocyclic, heterocyclic, cycloalkyl, heterocycloalkyl, aromatic and heteroaromatic moieties.

[0239] Those skilled in the art will appreciate that substituents themselves may be substituted if appropriate. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein should be understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0240] When substituent groups are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.

[0241] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where 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 having no substitution.

[0242] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0243] The compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may have been artificially enriched to have a particular isotope with 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 has three naturally occurring isotopes, represented as 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature. Deuterium enrichment may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds useful for studying drug elimination and metabolic pathways in vivo. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0244] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way 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. When appropriate, the term "(±)" is used to specify a racemic mixture. "Diastereomers" 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 at each chiral carbon can be specified with R or S. The resolved compounds with unknown absolute configuration can be specified as (+) or (-) depending on the direction (right-handed or left-handed) of the rotation of plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers may be defined as (R)- or (S)- in terms of absolute stereochemistry. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and mixtures of intermediates. Optically active (R)-isomers and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds may be analyzed by any suitable method, including, but not limited to, chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over another may be determined.

[0245] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the chemical entities described herein are also intended to include all Z, E and tautomeric forms.

[0246] If desired, the separation and purification of the chemical entities and intermediates described herein can be achieved by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be obtained by reference to the examples below. However, other equivalent separation or isolation procedures may also be used.

[0247] When stereochemistry is not specified, some small molecules described herein include, but are not limited to, their isomers, such as enantiomers and diastereomers, when possible; mixtures of enantiomers, including racemates; mixtures of diastereomers; and other mixtures thereof, as long as they can be prepared by ordinary technicians in the art by routine experiments. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by splitting a mixture of racemates or diastereomers. If possible, the splitting of a mixture of a racemate or diastereomer can be achieved, for example, by conventional methods, such as crystallization in the presence of a splitting agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, a mixture of two enantiomers enriched in one of the two enantiomers can be purified by recrystallization and / or trituration to provide a further optically enriched form of the main enantiomer. In addition, some of these small molecules include Z and E forms (or cis and trans forms) of some small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. When certain small molecules described herein exist in various tautomeric forms, the term "certain small molecules" is intended to include all tautomeric forms of the certain small molecules.

[0248] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well 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, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium and magnesium salts.

[0249] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means 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 serve 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, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0250] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to achieve the intended application, including, but not limited to, disease treatment, as defined below. The therapeutically effective amount may vary depending on the intended therapeutic application (in vivo); or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition; the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that can induce a specific response in target cells, such as a decrease in platelet adhesion and / or cell migration. The specific dose may vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0251] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a preventive benefit. A therapeutic benefit may include, for example, the eradication or improvement of the underlying disorder being treated. In addition, a therapeutic benefit may include, for example, the eradication or improvement of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, although the subject may still be afflicted with the underlying disorder. In certain embodiments, for a preventive benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, although a diagnosis of the disease may not yet have been made.

[0252] "Therapeutic effect", as this term is used herein, encompasses therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0253] As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents encompass administration of two or more agents to animals, including humans, such that both 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 both agents are present.

[0254] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to compounds that are capable of inhibiting a 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 the context of the biological action of the target protein. Although preferred antagonists herein specifically interact with the target (e.g., bind to the target), compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also expressly included within this definition. Preferred biological activities inhibited by the antagonist are associated with the manifestation, growth, or spread of a tumor.

[0255] Whenever a protein is referred to herein, it is understood that a single protein may be referred to by different names. For example, "15-PGDH", "PGDH" and "hPGDH" all refer to the same protein, 15-hydroxyprostaglandin dehydrogenase.

[0256] Methods for inhibiting 15-PGDH

[0257] Provided herein are methods of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

[0258] In one aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I:

[0259]

[0260] or a pharmaceutically acceptable salt thereof, wherein:

[0261] X is selected from –OCH 2 –, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH 2 –, –S(O)CH 2 –, –SO 2 CH 2 –

[0262] Each Y is independently selected from N and CR 11 ;

[0263] Each R 1 are independently 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 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0264] R 2 is H, and R 3 Yes – CF 3 ;or

[0265] R 2 and R 3 together to form an oxo group or a thio group;

[0266] Each R 4 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0267] Each R 5 are independently 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 ,–NR10 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;

[0268] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0269] Each R 8 Independently selected from 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;

[0270] Each R 9 Independently selected from 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;

[0271] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0272] Each R 11 are independently 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 R7 ,–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;

[0273] n is 0, 1, 2, 3, 4, or 5;

[0274] m is 0, 1, 2, 3 or 4; and

[0275] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0276] Provided that the compound of formula I is not

[0277] In some embodiments, X is selected from -OCH 2 –, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH 2 –, –S(O)CH 2 – and –SO 2 CH 2 In some embodiments, X is -OCH 2 –. 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 –SCH 2 In some embodiments, X is -S(O)CH 2 In some embodiments, X is -SO 2 CH 2 –.

[0278] In some embodiments, each Y is independently selected from N and CR 11 In some embodiments, each Y is N. In some embodiments, each Y is CR 11In some embodiments, one Y is N and the other Y is CR 11 .

[0279] In some embodiments, each R 1 are independently 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 Cycloalkyl, C 6-10 In some embodiments, each R 1 are independently 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 and –NR10 SO 2 NR 6 R 7 In some embodiments, each R 1 are independently selected from 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 SO 2 R 8 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 1 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 and –C(O)OR 8 .

[0280] In some embodiments, R 2 is H, and R 3 Yes – CF 3 In some embodiments, R 2 and R 3 Together they form an oxo group. In some embodiments, R 2 and R 3 Together they form a thio group.

[0281] In some embodiments, each R 4 are independently 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 10C(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 In some embodiments, each R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 4 are independently selected from 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 SO 2R 8 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 and –C(O)OR 8 .

[0282] In some embodiments, each R 5 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 In some embodiments, each R 5 are independently 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 NR6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 SO 2 R 8 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 5 are independently selected from 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 SO 2 R 8 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 5 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 and –C(O)OR 8 .

[0283] In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, R 6 and R 7 is independently selected at each occurrence from H and C1-6 alkyl.

[0284] In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 8 Independently selected from H and C 1-6 alkyl.

[0285] In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 9 Independently selected from C 1-6 alkyl.

[0286] In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 10Independently selected from H and C 1-6 alkyl.

[0287] In some embodiments, each R 11 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 In some embodiments, each R 11 are independently 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 and –NR 10SO 2 NR 6 R 7 In some embodiments, each R 11 are independently selected from 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 SO 2 R 8 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 11 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 and –C(O)OR 8 .

[0288] 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.

[0289] 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.

[0290] 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.

[0291] In some embodiments, the compound is a compound of Formula Ia:

[0292]

[0293] or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compound is a compound of Formula Ib:

[0295]

[0296] or a pharmaceutically acceptable salt thereof.

[0297] In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula II:

[0298]

[0299] or a pharmaceutically acceptable salt thereof, wherein:

[0300] T, U, W, X and Y are independently selected from N and CR 5 ;

[0301] S, V and Z are independently selected from N and C;

[0302] R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 R7 ,–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 and 5- to 10-membered heteroaryl;

[0303] R 2 is H, and R 3 Yes – CF 3 ;or

[0304] R 2 and R 3 together to form an oxo group or a thio group;

[0305] Each R 4 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0306] Two R's 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10cycloalkyl, and any remaining R 4 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0307] Each R 5 are independently selected from 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 R7 , 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;

[0308] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0309] Each R 8 Independently selected from 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;

[0310] Each R 9 Independently selected from 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;

[0311] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; and

[0312] n is 1, 2, 3 or 4; and

[0313] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0314] Provided that the compound of formula II is not

[0315]

[0316] 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 CR 5In 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 rest 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.

[0317] 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 rest are C. In some embodiments, at least two of S, V, and Z are N, and the rest are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0318] In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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, C3-10 In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0319] In some embodiments, R 2 is H, and R3 Yes – CF 3 In some embodiments, R 2 and R 3 Together they form an oxo group. In some embodiments, R 2 and R 3 Together they form a thio group.

[0320] In some embodiments, each R 4 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 In some embodiments, each R 4 are independently 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 10C(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 and C 1-6 In some embodiments, each R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 4 are independently selected from 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 In some embodiments, each R 4 It is fluorine-based.

[0321] In some embodiments, both R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 , C1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently selected from 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 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 It is fluorine-based.

[0322] In some embodiments, each R 5are independently selected from 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 In some embodiments, each R 5 are independently selected from 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, C1-6 Heteroalkyl and C 1-6 In some embodiments, each R 5 are independently selected from 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 5 are independently selected from 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 are independently selected from H and halo.

[0323] In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, R 6 and R 7 is independently selected at each occurrence from H and C 1-6 alkyl.

[0324] In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 8 Independently selected from H and C 1-6 alkyl.

[0325] In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 9 Independently selected from C 1-6 alkyl.

[0326] In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 10 Independently selected from H and C1-6 alkyl.

[0327] 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.

[0328] 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.

[0329] In some embodiments, the compound is a compound of Formula IIa:

[0330]

[0331] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0332] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0.

[0333] In some embodiments, p is 1. In some embodiments, p is 2.

[0334] In some embodiments, the compound is a compound of Formula IIb:

[0335]

[0336] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0337] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0.

[0338] In some embodiments, p is 1. In some embodiments, p is 2.

[0339] In some embodiments, the compound is a compound of Formula IIc:

[0340]

[0341] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

[0342] 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.

[0343] In some embodiments, the compound is a compound of Formula IId:

[0344]

[0345] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0346] 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.

[0347] In some embodiments, the compound is a compound of Formula IIe:

[0348]

[0349] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0350] 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.

[0351] In some embodiments, the compound is a compound of Formula IIf:

[0352]

[0353] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0354] 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.

[0355] In some embodiments, the compound is a compound of Formula IIg:

[0356]

[0357] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0358] 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.

[0359] In some embodiments, the compound is a compound of Formula IIh:

[0360]

[0361] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0362] 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.

[0363] In some embodiments, the compound is a compound of Formula IIi:

[0364]

[0365] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0366] 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.

[0367] In some embodiments, the compound is a compound of Formula IIj:

[0368]

[0369] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0370] 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.

[0371] In some embodiments, the compound is a compound of Formula IIn:

[0372]

[0373] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0374] 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.

[0375] In some embodiments, the compound is a compound of Formula IIp:

[0376]

[0377] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0378] 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.

[0379] In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula III:

[0380]

[0381] or a pharmaceutically acceptable salt thereof, wherein:

[0382] Each X is independently selected from N and CR 7 ;

[0383] Y is selected from O, S, SO 2 and C(R 8 ) 2 ;

[0384] R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 2NR 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;

[0385] R 2 is H, and R 3 Yes – CF 3 ;or

[0386] R 2 and R 3 together to form an oxo group or a thio group;

[0387] R 4 and R 5 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from the following: 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 ,–NR13 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

[0388] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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;

[0389] Each R 6 are 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 aryl and 5- to 10-membered heteroaryl; or

[0390] Two R attached to the same carbon atom 6 Together they form an oxo group, a thio group or a C 3-10 cycloalkyl, and any remaining R 6 are 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 Aryl and 5- to 10-membered heteroaryl;

[0391] Each R 7 are independently selected from 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;

[0392] Each R 8 are independently selected from 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 R10 , 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

[0393] Two R's 8 may together form C optionally substituted by 1 to 3 substituents independently selected from the following 3-10 Cycloalkyl: halide, –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;

[0394] R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0395] Each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C6-10 Aryl and 5- to 10-membered heteroaryl;

[0396] Each R 12 Independently selected from 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;

[0397] Each R 13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0398] m is 1 or 2; and

[0399] n is 0, 1, 2, 3 or 4.

[0400] In some embodiments, each X is independently selected from N and CR 7 In some embodiments, at least one X is N, and the rest are 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 .

[0401] In some embodiments, Y is selected from O, S, SO 2 and C(R 8 ) 2 In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO 2 In some embodiments, Y is C(R 8 ) 2 .

[0402] In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR9 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 In some embodiments, R 1 Selected from C 3-10 Cycloalkyl, C 6-10 wherein the cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 3-10Cycloalkyl, C 6-10 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 R10 ,–NR 13 SO 2 R 11 ,–NR 13 SO 2 NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0403] In some embodiments, R 2 is H, and R 3 Yes – CF 3 In some embodiments, R 2 and R3 Together they form an oxo group. In some embodiments, R 2 and R 3 Together they form a thio group.

[0404] In some embodiments, R 4 and R 5 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from the following: 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 In some embodiments, R 4 and R 5 Independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR12 ,–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 In some embodiments, R 4 and R 5 Independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: 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 and C 1-6 In some embodiments, R 4 and R 5 Independently selected from C3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, R 4 and R 5 Independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0405] In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 R10 ,–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 In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and C 1-6 In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R11 , –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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0406] In some embodiments, each R 6 are 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 SO2 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 In some embodiments, each R 6 are 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 and C 1-6 In some embodiments, each R 6 are 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 13SO 2 R 11 and –NR 13 SO 2 NR 9 R 10 In some embodiments, each R 6 are 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 .

[0407] In some embodiments, two R 6 Together they form an oxo group, a thio group or a C 3-10 cycloalkyl, and any remaining R 6 are 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 In some embodiments, two R groups attached to the same carbon atom are 6 Together they form an oxo group, a thio group or a C 3-10 cycloalkyl, and any remaining R 6 are independently selected from halo, –NR 9 R10 ,–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 and C 1-6 In some embodiments, two R 6 Together they form an oxo group, a thio group or a C 3-10 cycloalkyl, and any remaining R 6 are 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, two R 6 Together they form an oxo group, a thio group or a C3-10 cycloalkyl, and any remaining R 6 are 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 .

[0408] In some embodiments, each R 7 are independently selected from 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 In some embodiments, each R 7 are independently selected from 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 and C 1-6 In some embodiments, each R 7 are independently selected from 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, each R 7 are independently selected from H, halo, –NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0409] In some embodiments, each R 8 are independently selected from 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 In some embodiments, each R 8 are independently selected from 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 and C 1-6 In some embodiments, each R 8 are independently selected from H, halo, –NR 9 R 10 ,–OR11 , –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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, each R 8 are independently selected from H, halo, –NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0410] In some embodiments, both R 8 may together form C optionally substituted by 1 to 3 substituents independently selected from the following 3-10 Cycloalkyl: halide, –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 SO2 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 In some embodiments, two R 8 may together form C optionally substituted by 1 to 3 substituents independently selected from the following 3-10 Cycloalkyl: halide, –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 and C 1-6 In some embodiments, two R 8 may together form C optionally substituted by 1 to 3 substituents independently selected from the following 3-10 Cycloalkyl: halide, –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)R11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 SO 2 R 11 and –NR 13 SO 2 NR 9 R 10 In some embodiments, two R 8 may together form C optionally substituted by 1 to 3 substituents independently selected from the following 3-10 Cycloalkyl: halide, –NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0411] In some embodiments, R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, R 9 and R 10 is independently selected at each occurrence from H and C 1-6 alkyl.

[0412] In some embodiments, each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 11 Independently selected from H and C 1-6 alkyl.

[0413] In some embodiments, each R 12 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 12 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 12 Independently selected from C 1-6 alkyl.

[0414] In some embodiments, each R 13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 13 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 13 Independently selected from H and C 1-6 alkyl.

[0415] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0416] 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.

[0417] In some embodiments, the compound is a compound of Formula IIIa:

[0418]

[0419] or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the compound is a compound of Formula IIIb:

[0421]

[0422] or a pharmaceutically acceptable salt thereof, wherein:

[0423] Each R 14 are independently selected from halo, –NR 9 R10 ,–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

[0424] p is 0, 1, 2 or 3.

[0425] In some embodiments, each R 14 are 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 , C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 14 are 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 and C 1-6 In some embodiments, each R 14 are 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 and –NR 13 SO2 NR 9 R 10 In some embodiments, each R 14 are 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 In some embodiments, each R 14 In some embodiments, each R 14 are independently fluoro.

[0426] 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.

[0427] In some embodiments, the compound is a compound of Formula IIIc:

[0428]

[0429] or a pharmaceutically acceptable salt thereof.

[0430] In some embodiments, the compound is a compound of Formula IIId:

[0431]

[0432] or a pharmaceutically acceptable salt thereof, wherein:

[0433] Each R 14 are 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 R11 ,–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

[0434] p is 0, 1, 2 or 3.

[0435] In some embodiments, each R 14 are 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, C 6-10 In some embodiments, each R 14 are 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 NR9 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 and C 1-6 In some embodiments, each R 14 are 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, each R 14 are 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 In some embodiments, each R 14 In some embodiments, each R 14 are independently fluoro.

[0436] 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.

[0437] Compound

[0438] In one aspect, provided herein is a compound of formula IIk:

[0439]

[0440] or a pharmaceutically acceptable salt thereof, wherein:

[0441] T, U and Y are independently selected from N and CR 6 , provided that when U is N, at least one of T and Y is N;

[0442] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and 5- to 10-membered heteroaryl;

[0443] R 2 is H, and R 3 Yes – CF 3 ;or

[0444] R2 and R 3 Together they form an oxo group;

[0445] Each R 4 are independently selected from H and halo;

[0446] R 5 Selected from halogen, –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;

[0447] R 6 Selected from 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;

[0448] R 7 and R 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0449] Each R 9 Independently selected from 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;

[0450] Each R 10 Independently selected from 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;

[0451] Each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; and p is 0, 1 or 2.

[0452] In some embodiments, T, U and Y are independently selected from N and CR 6 , provided that when U is N, 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 rest are CR 6 In some embodiments, one of T, U, and Y is CR 6 , and the rest are N. In some embodiments, two of T, U, and Y are CR6 , and the rest are N. In some embodiments, T, U and Y are N. In some embodiments, T, U and Y are CR 6 .

[0453] In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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)R9 ,–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 and C 1-6 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 11 SO 2 NR 7 R 8 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 7 R 8 ,–OR 9 , –C(O)R 9 , –C(O)OR 9 and –C(O)NR 7 R 8 .

[0454] In some embodiments, R 2 is H, and R 3Yes – CF 3 In some embodiments, R 2 and R 3 Together they form an oxo group.

[0455] In some embodiments, each R 4 is independently selected from H and halo. 4 is independently selected from H and fluoro. 4 is H. In some embodiments, each R 4 In some embodiments, one R 4 is H, and an R 4 It is fluorine-based.

[0456] In some embodiments, R 5 Selected from halogen, –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 In some embodiments, R 5 Selected from halogen, –NR 7 R 8 ,–OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR10 ,–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 and C 1-6 In some embodiments, R 5 Selected from halogen, –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 and –NR 11 SO 2 NR 7 R 8 In some embodiments, R 5 Selected from halogen, –NR 7 R 8 ,–OR 9 , –C(O)R 9 , –C(O)OR 9 and –C(O)NR 7 R 8 .

[0457] In some embodiments, R 6 Selected from H, halo, –NR 7 R8 ,–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 In some embodiments, R 6 Selected from 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 and C 1-6In some embodiments, R 6 Selected from 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 and –NR 11 SO 2 NR 7 R 8 In some embodiments, R 6 Selected from H, halo, –NR 7 R 8 ,–OR 9 , –C(O)R 9 , –C(O)OR 9 and –C(O)NR 7 R 8 .

[0458] In some embodiments, R 7 and R 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 In some embodiments, R 7 and R 8 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, R 7 and R 8 is independently selected at each occurrence from H and C 1-6 alkyl.

[0459] In some embodiments, each R 9 Independently selected from H, C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 In some embodiments, each R 9 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 9 Independently selected from H and C 1-6 alkyl.

[0460] In some embodiments, each R 10 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 In some embodiments, each R 10 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 10 Independently selected from C 1-6 alkyl.

[0461] In some embodiments, each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 In some embodiments, each R 11 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 11 Independently selected from H and C 1-6 alkyl.

[0462] 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.

[0463] In another aspect, provided herein is a compound of Formula IIm:

[0464]

[0465] or a pharmaceutically acceptable salt thereof, wherein:

[0466] R 1 Selected from C 6-10aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and 5- to 10-membered heteroaryl;

[0467] R 2 is H, and R 3 Yes – CF 3 ;or

[0468] R 2 and R 3 Together they form an oxo group;

[0469] Each R 4 are independently 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 10C(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

[0470] Two R's 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0471] R 5 Selected from halogen, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR6 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;

[0472] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0473] Each R 8 Independently selected from 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;

[0474] Each R 9 Independently selected from 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;

[0475] Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0476] n is 1, 2, 3, or 4;

[0477] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0478] p is 0, 1, 2 or 3.

[0479] In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 ,–NR10 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 and C 1-6 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0480] In some embodiments, R 2is H, and R 3 Yes – CF 3 In some embodiments, R 2 and R 3 Together they form an oxo group.

[0481] In some embodiments, each R 4 are independently 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 Cycloalkyl, C 6-10 In some embodiments, each R 4 are independently 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 ,–NR10 SO 2 R 8 ,–NR 10 SO 2 NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 4 are independently selected from 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 In some embodiments, each R 4 It is fluorine-based.

[0482] In some embodiments, both R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R8 , –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 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 and C1-6 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0483] In some embodiments, R 5 Selected from halogen, –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 R7 ,–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 In some embodiments, R 5 Selected from halogen, –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 and C 1-6 In some embodiments, R 5 Selected from halogen, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 ,–SO 2 R9 ,–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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, R 5 Selected from halogen, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0484] In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, R 6 and R 7 is independently selected at each occurrence from H and C 1-6 alkyl.

[0485] In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 8 Independently selected from H and C1-6 alkyl.

[0486] In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, each R 9 Independently selected from C 1-6 alkyl.

[0487] In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 10 Independently selected from H and C 1-6 alkyl.

[0488] 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.

[0489] 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.

[0490] 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.

[0491] In another aspect, provided herein is a compound of formula IIq:

[0492]

[0493] or a pharmaceutically acceptable salt thereof, wherein:

[0494] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and 5- to 10-membered heteroaryl;

[0495] R 2 is H, and R 3 Yes – CF 3 ;or

[0496] R 2 and R 3 Together they form an oxo group;

[0497] Each R 4 are independently 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 R9 ,–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

[0498] Two R's 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 Cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl;

[0499] R5 Selected from halogen, –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;

[0500] R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0501] Each R 8 Independently selected from 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;

[0502] Each R 9 Independently selected from 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;

[0503] Each R10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl;

[0504] n is 1, 2, 3, or 4;

[0505] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0506] p is 0, 1, 2 or 3.

[0507] In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R7 , –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 and C 1-6 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8, –C(O)OR 8 and –C(O)NR 6 R 7 .

[0508] In some embodiments, R 2 is H, and R 3 Yes – CF 3 In some embodiments, R 2 and R 3 Together they form an oxo group.

[0509] In some embodiments, each R 4 are independently 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 Cycloalkyl, C 6-10 In some embodiments, each R 4 are independently 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 R7 ,–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 and C 1-6 In some embodiments, each R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, each R 4 are independently selected from 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 In some embodiments, each R 4 It is fluorine-based.

[0510] In some embodiments, both R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C3-10 cycloalkyl, and any remaining R 4 are independently 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 Cycloalkyl, C 6-10 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 ,–NR10 SO 2 NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently 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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, two R 4 Together with the carbon atom to which they are attached and any intervening atoms, they form the C 3-10 cycloalkyl, and any remaining R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0511] In some embodiments, R 5 Selected from halogen, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R7 , –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 In some embodiments, R 5 Selected from halogen, –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 and C 1-6 In some embodiments, R 5 Selected from halogen, –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 and –NR 10 SO 2 NR 6 R 7 In some embodiments, R 5 Selected from halogen, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0512] In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, R 6 and R 7 is independently selected at each occurrence from H and C 1-6 alkyl.

[0513] In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 8Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 8 Independently selected from H and C 1-6 alkyl.

[0514] In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In some embodiments, each R 9 Independently selected from C 1-6 alkyl.

[0515] In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 10 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 10 Independently selected from H and C 1-6 alkyl.

[0516] 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.

[0517] 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.

[0518] 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.

[0519] In another aspect, provided herein is a compound of formula IIIc:

[0520]

[0521] or a pharmaceutically acceptable salt thereof, wherein:

[0522] Each X is independently selected from N and CR 7 ;

[0523] Y is selected from O, S, SO 2 and C(R 8 ) 2 ;

[0524] R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and 5- to 10-membered heteroaryl;

[0525] R 2 is H, and R 3 Yes – CF 3;or

[0526] R 2 and R 3 Together they form an oxo group;

[0527] R 4 and R 5 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from the following: 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

[0528] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR12 ,–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 Aryl and 5- to 10-membered heteroaryl;

[0529] Each R 6 are 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 aryl and 5- to 10-membered heteroaryl; or

[0530] Two R attached to the same carbon atom 6together to form an oxo group, and any remaining R 6 are 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 Aryl and 5- to 10-membered heteroaryl;

[0531] Each R 7 and R 8 are 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 2NR 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;

[0532] R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0533] Each R 11 Independently selected from 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;

[0534] Each R 12 Independently selected from 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;

[0535] Each R 13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; and n is 0, 1, 2, 3 or 4.

[0536] In some embodiments, each X is independently selected from N and CR 7 In some embodiments, at least one X is N, and the rest are 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 .

[0537] In some embodiments, Y is selected from O, S, SO 2 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 .

[0538] In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 ,–NR13 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 and C 1-6 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, R 1 Selected from C 6-10 aryl and 5 to 10 membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0539] In some embodiments, R 2 is H, and R 3 Yes – CF 3In some embodiments, R 2 and R 3 Together they form an oxo group.

[0540] In some embodiments, R 4 and R 5 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from the following: 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 In some embodiments, R 4 and R 5 Independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 ,–SO2 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 In some embodiments, R 4 and R 5 Independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: 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 and C 1-6 In some embodiments, R 4 and R 5 Independently selected from C 3-10Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, R 4 and R 5 Independently selected from C 3-10 Cycloalkyl; wherein each cycloalkyl is independently optionally substituted by 1 to 3 substituents independently selected from the following: halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0541] In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and C 1-6 In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 9 R 10 ,–OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0542] In some embodiments, each R 6 are 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 NR9 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 In some embodiments, each R 6 are 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 and C 1-6 In some embodiments, each R 6 are 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 R11 and –NR 13 SO 2 NR 9 R 10 In some embodiments, each R 6 are 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 .

[0543] In some embodiments, two R 6 together to form an oxo group, and any remaining R 6 are 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 In some embodiments, two R groups attached to the same carbon atom are 6 together to form an oxo group, and any remaining R 6 are 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 and C 1-6 In some embodiments, two R 6 together to form an oxo group, and any remaining R 6 are 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, two R 6 together to form an oxo group, and any remaining R 6 are 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 .

[0544] In some embodiments, each R 7 and R 8 are 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 In some embodiments, each R 7 and R 8 are 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 and C 1-6 In some embodiments, each R 7 and R 8 are 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 and –NR 13 SO 2 NR 9 R 10 In some embodiments, each R 7 and R 8 are 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 .

[0545] In some embodiments, R 9 and R 10 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, R 9 and R 10 independently selected at each occurrence from H, C1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, R 9 and R 10 is independently selected at each occurrence from H and C 1-6 alkyl.

[0546] In some embodiments, each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 11 Independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 11 Independently selected from H and C 1-6 alkyl.

[0547] In some embodiments, each R 12 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 In some embodiments, each R 12 Independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 12 Independently selected from C 1-6 alkyl.

[0548] In some embodiments, each R 13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 In some embodiments, each R 13 Independently selected from H, C 1-6 Alkyl and C 1-6 In some embodiments, each R 13 Independently selected from H and C 1-6 alkyl.

[0549] 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.

[0550] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0551]

[0552] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0564]

[0565]

[0566] In some cases, the solubility and hPGDH IC50 characteristics of the inhibitors are shown in Tables 1 and 2.

[0567] Table 1: Characteristics of PGDH inhibitors with a 6-5 ring core.

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] Table 2: Characteristics of PGDH inhibitors with a phenyl core.

[0576]

[0577]

[0578] Analytical data for some of the inhibitors described herein are provided in Table 3.

[0579] Table 3: Analytical data of selected inhibitors

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

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[0672] How to use

[0673] In one aspect, provided herein is a method for treating the various diseases of an object in need, the method comprising administering a compound as described herein to the object. In some embodiments, provided herein is an inhibitor of hydroxyprostaglandin dehydrogenase that can be used for preventing or treating a disease or illness associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and / or with prostaglandin levels. In some embodiments, provided herein is an inhibitor of hydroxyprostaglandin dehydrogenase that can be used for preventing or treating a disease or illness in which it is desired to increase the prostaglandin level in the object suffering from a disease or illness.

[0674] In some embodiments, the method for treating a disorder includes administering a 15-PGDH inhibitor to the subject. In some embodiments, the compound described herein is a 15-PGDH inhibitor. In some embodiments, a compound of formula I, formula II, or formula III is a 15-PGDH inhibitor. In some embodiments, the method includes administering a therapeutically effective amount of a compound described herein. In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula I, formula II, or formula III. In some embodiments, the compound described herein is a 15-PGDH inhibitor. In some embodiments, a compound of formula I, formula II, or formula III is a 15-PGDH inhibitor. In some embodiments, administration occurs in vitro. In other embodiments, administration occurs in vivo.

[0675] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor refers to an amount sufficient to achieve the intended application including, but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of subtherapeutic amounts of a 15-PGDH inhibitor to treat a predetermined disease condition.

[0676] The amount of 15-PGDH inhibitor administered may vary depending on the intended application (in vitro or in vivo); or the subject and disease condition being treated, e.g., weight and age of the subject, severity of the disease condition; mode of administration, etc., which can be readily determined by one of ordinary skill in the art.

[0677] Measuring the inhibition of the biological effect of 15-PGDH may include measuring a biological sample such as a sample from a subject. Depending on the assay, any one of a variety of samples may be selected. Examples of samples include, but are not limited to, blood samples (e.g., plasma or serum), breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0678] The object being treated with 15-PGDH inhibitor can be monitored to determine the effectiveness of treatment, and the treatment regimen can be adjusted based on the physiological response of the object to treatment. For example, if the inhibition of the biological effect of 15-PGDH is higher or lower than a threshold value, the dosage or frequency of administration can be reduced or increased respectively. The method may also include continuing the therapy if the therapy is determined to be effective. The method may include maintaining, gradually reducing, reducing or stopping the dosage of the compound in the therapy if the therapy is determined to be effective. The method may include increasing the dosage of the compound in the therapy if the therapy is determined to be not effective. Alternatively, the method may include stopping the therapy if the therapy is determined to be not effective. In some embodiments, if the inhibition of the biological effect is higher or lower than a threshold value, such as in the absence of a response or in the presence of an adverse reaction, the treatment performed with the 15-PGDH inhibitor is terminated. The biological effect can be a change in any one of a variety of physiological indicators.

[0679] In general, a 15-PGDH inhibitor is a compound that inhibits one or more biological effects of 15-PGDH. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0680] In some other embodiments, the subject methods can be used to treat disease conditions associated with 15-PGDH.Any disease condition that is directly or indirectly caused by abnormal activity or expression levels of 15-PGDH can be a predetermined disease condition.

[0681] In one aspect, there is provided herein a method for promoting and / or stimulating skin pigmentation, the method comprising applying one or more of the compositions described herein to an object in need. It is known that the inhibitor of 15-PGDH promotes skin pigmentation (Markowitz et al., WO 2015 / 065716). Hydroxyprostaglandin dehydrogenase inhibitors as described herein can be used for promoting and / or inducing and / or stimulating the pigmentation of skin and / or skin appendages, and / or as an agent for preventing and / or limiting the depigmentation and / or bleaching of skin and / or skin appendages, particularly as an agent for preventing and / or limiting gray hair disease. In some embodiments, the 15-PGDH inhibitor provided herein can be applied to the skin of the object, for example, in local application, to promote and / or stimulate the pigmentation and / or hair growth of the skin, suppress alopecia, and / or treat skin damage or inflammation, such as the skin damage caused by physical or chemical irritants and / or ultraviolet exposure.

[0682] On the other hand, a method for suppressing hair loss is provided herein, the method comprising applying one or more of the compositions described herein to an object in need. It is known that prostaglandins play an important role in hair growth. Prostaglandins such as prostaglandins A1, F2a and E2 are stored in hair follicles or adjacent skin environments, and have been shown to be necessary in terms of maintaining and increasing hair density (Colombe L et al., 2007, Exp. Dermatol, 16 (9), 762-9). It has been reported that 15-PGDH involved in the degradation of prostaglandins is present in the dermal papilla of the hair follicle, inactivating prostaglandins, especially PGF2a and PGE2, to cause scalp damage and hair loss (Michelet JF et al., 2008, Exp. Dermatol, 17 (10), 821-8). Therefore, hydroxyprostaglandin dehydrogenase inhibitors described herein that have a containment or inhibition activity for 15-PGDH can improve scalp damage, prevent hair loss and promote hair growth, and can be used in pharmaceutical compositions to prevent hair loss and promote hair growth.

[0683] In another aspect, provided herein is a method of 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 thereof.

[0684] On the other hand, a method for preventing and / or treating vascular insufficiency is provided herein, the method comprising administering one or more of the compositions described herein to an object in need. It is known that the prostaglandins produced in the body, including prostaglandin homologues, can maintain the appropriate effect of the vascular wall, especially can contribute to vasodilation to achieve blood flow, thereby preventing platelet aggregation and regulating the hyperplasia of the smooth muscle around the vascular wall (Yan.Cheng et al., 2006, J.Clin., Invest). In addition, the inhibition of prostaglandin production or the loss of their activity can cause the dysfunction of the cell mechanism in the degeneration, platelet aggregation and smooth muscle of the endothelium in the vascular wall. Among other aspects, it is also presented in hypertensive patients (including pulmonary hypertension), and the generation of prostaglandins in blood vessels is reduced. 15-PGDH inhibitors as described herein can be used in pharmaceutical compositions to prevent or treat cardiovascular diseases and / or vascular insufficiency diseases, such as Raynaud's disease, Buerger's disease, diabetic neuropathy and pulmonary hypertension.

[0685] On the other hand, there is provided herein a method for preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, the method comprising applying one or more of the compositions described herein to an object in need. On the other hand, there is provided herein a method for reducing cardiac ejection fraction, the method comprising applying one or more of the compositions described herein to an object in need. It has been shown that the use of 15-PGDH inhibitors can be used for treating, preventing, minimizing and / or reversing congestive heart failure, cardiomyopathy and / or cardiac ejection fraction reduction (Markowitz et al., WO2018 / 187810). Therefore, hydroxyprostaglandin dehydrogenase inhibitors as described herein can be applied to an object in need to treat, prevent, minimize and / or reverse congestive heart failure, cardiomyopathy and / or cardiac ejection fraction reduction.

[0686] On the other hand, a method for preventing and / or treating gastrointestinal diseases is provided herein, the method comprising administering one or more of the compositions described herein to an object in need. Prostaglandins are necessary for maintaining a mechanism for protecting and maintaining 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 inhibitor of hydroxyprostaglandin dehydrogenase described herein shows containment or inhibition activity for the 15-PGDH of prostaglandins that degrade and protect gastric mucosa. Therefore, hydroxyprostaglandin dehydrogenase inhibitors can be effectively used for preventing or treating gastrointestinal diseases, especially gastritis and gastric ulcers. In addition, hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for preventing and / or treating other forms of intestinal damage, including toxicity caused by radiation and / or chemotherapy, and mucositis induced by chemotherapy.

[0687] In addition, it has been shown that 15-PGDH inhibitors can be used alone or in combination with corticosteroids and / or TNF inhibitors to treat intestines, gastrointestinal or intestinal disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcer, inflammatory bowel disease and Crohn's disease (Markowitz et al., WO 2018 / 102552). Therefore, hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for treating and / or preventing and treating intestines, gastrointestinal or intestinal disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcer, inflammatory bowel disease and Crohn's disease.

[0688] On the other hand, a method for preventing and / or treating renal dysfunction is provided herein, and the method includes applying one or more of the compositions described herein to an object in need. In kidney, prostaglandins regulate renal blood flow, and can regulate urine formation by producing renal vascular influence and renal tubule influence. In clinical studies, the inhibitor of prostaglandins has been used to improve the creatinine clearance in the patient with chronic kidney disease, prevent graft rejection and cyclosporin toxicity in renal transplant patients, reduce urine albumin excretion rate and N-acetyl-β-D-glucosaminidase level (Porter, Am., 1989, J.Cardiol., 64: 22E-26E) in the patient with diabetic nephropathy. In addition, it has been reported that prostaglandins act as vasodilators in kidney, and therefore, the inhibition of prostaglandin production in kidney can cause renal dysfunction (Hao.CM, 2008, Annu Rev Physiol, 70, 357-77). The hydroxyprostaglandin dehydrogenase inhibitors described herein have suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins, and can be used to prevent and / or treat renal diseases associated with renal dysfunction.

[0689] On the other hand, there is provided herein a method for stimulating bone resorption and bone formation, the method comprising applying one or more of the compositions described herein to an object in need. It has been shown that prostaglandins can stimulate bone resorption and bone formation to increase the volume and strength of bone (H. Kawaguchi et al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). In addition, suppressing 15-PGDH will increase callus size and mineralization after fracture (Collier et al., ORS 2017 Annual Meeting Paper No. 0190). Considering that 15-PGDH suppresses the activity of prostaglandins as mentioned above, suppressing 15-PGDH activity can lead to promoting bone resorption and bone formation suppressed by 15-PGDH. Therefore, by suppressing 15-PGDH activity, the inhibitor of hydroxyprostaglandin dehydrogenase described herein can be effectively used to promote bone resorption and bone formation. 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 healing between bone and bone implants, bone and artificial implants, dental implants and bone grafts.

[0690] On the other hand, a method for stimulating tissue regeneration by stimulation is provided herein, and the method includes applying one or more of the compositions described herein to an object in need. Prostaglandin PGE2 supports the expansion of several types of tissue stem cells. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as a prostaglandin degrading enzyme can enhance tissue regeneration in multiple organs. Studies have shown that inhibition of 15-PGDH can increase prostaglandin PGE2 levels in bone marrow and other tissues; accelerate hematopoietic recovery after bone marrow transplantation; promote tissue regeneration of colon and liver damage (Zhang, Y. et al. Science 2015, 348 (6240)). Hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to achieve tissue regeneration by supporting the expansion of tissue stem cells.

[0691] On the other hand, there is provided herein a method for regulating cervical ripening, the method comprising administering one or more of the compositions described herein to an object in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates the EP2 receptor signaling pathway in human cervical stromal cells; its own synthesis is targeted by increasing COX-2 and PTGES expression; and its metabolism is reduced by causing its degradation enzyme 15-PGDH loss (Word et al., WO2019010482). It is also found that the downregulation of 15-PGDH is essential for the cervical ripening and premature birth induced by PGE2. The regulation of 15-PDGH activity can be used to regulate cervical ripening; and induce or prevent premature birth. The hydroxyprostaglandin dehydrogenase inhibitor provided herein can be used to induce cervical ripening and delivery alone or in combination with another labor inducing agent.

[0692] On the other hand, a method for promoting neuroprotection and / or stimulating neuronal regeneration is provided herein, the method comprising administering one or more of the compositions described herein to an object in need. Prostaglandins have a variety of physiological functions in the central nervous system through their specific G protein-coupled receptors. Prostaglandin E2 (PGE2) as the main prostaglandin can activate receptor types EP1, EP2, EP3 and EP4. The activation of EP2 and EP4 receptors can regulate the production of adenylate cyclase and 3,5'-cyclic adenosine monophosphate (cAMP), while the 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 neurons of the cerebral cortex, striatum and hippocampus. In addition, activation of EP2 receptors by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol. 1994 February; 18 (1): 23-9; Yang et al., J Neurochem. 2009 January; 108 (1): 295-304). Studies have also shown that after activation, different PGE2 receptors can promote or prevent N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med. 2010 July 8; 2 (1): 12). Other studies have shown that activation of EP2 receptors protects neurons from beta-amyloid peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci. 2005 November; 22 (9): 2199-206). Several studies have shown that the mechanism by which PGE2 provides neuroprotection is achieved through EP2 or EP4 receptors (because they both increase cAMP) and protein kinase A (PKA)-dependent pathways in sequence (Echeverria et al. Eur J Neurosci. 2005 November; 22 (9): 2199-206; McCullough et al., J Neurosci. 2004 January 7; 24 (1): 257-68). Stimulation of these receptors with PGE2 by administering compounds that inhibit, reduce and / or antagonize 15-PGDH activity (such as hydroxyprostaglandin dehydrogenase inhibitors described herein that can inhibit 15-PGDH) can promote neuroprotection in subjects from axonal degeneration, neuronal cell death and / or glial cell damage after injury, enhance neuronal signaling that underlies learning and memory, stimulate neuronal regeneration after injury, and / or treat diseases, disorders and / or conditions of the nervous system.

[0693] On the other hand, a method for treating and / or preventing neurological disorders, neuropsychiatric disorders, nerve damage, neurotoxic disorders, neuropathic pain or neurodegenerative disorders is provided herein, and the method includes applying one or more of the compositions described herein to an object in need. In some embodiments, the diseases, disorders and / or conditions of the nervous system that can be treated with hydroxyprostaglandin dehydrogenase inhibitors provided herein may include at least one of neurological disorders, neuropsychiatric disorders, nerve damage, neurotoxic disorders, neuropathic pain or neurodegenerative disorders. For example, neurological disorders may include at least one of traumatic or toxic damage to peripheral nerves or cranial nerves such as traumatic brain injury, stroke, cerebral aneurysm and spinal cord injury. Neurological disorders can also include at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, diffuse Lewy body disease, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfieldt disease.

[0694] In some embodiments, the nerve damage may be caused by or be associated with at least one of the following: epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic nervous system disorder, bladder disorder, abnormal metabolic state, muscular system disorder, infectious and parasitic disease, neoplasm, endocrine disease, nutritional and metabolic disease, immune disease, blood and hematopoietic organ disease, psychological disorder, nervous system disease, sense organ disease, circulatory system disease, respiratory system disease, digestive system disease, genitourinary system disease, skin and subcutaneous tissue disease, musculoskeletal system and connective tissue disease, congenital anomaly or condition originating in the perinatal period.

[0695] In certain embodiments, hydroxyprostaglandin dehydrogenase inhibitors can be administered to an object or to the object's neurons to promote the survival, growth, development and / or function of neurons, particularly central nervous system (CNS), brain, cerebrum and hippocampal neurons. In certain embodiments, hydroxyprostaglandin dehydrogenase inhibitors can be used to stimulate hippocampal neurogenesis 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 syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiotherapy, chronic stress and neuroactive drugs such as alcohol, opiates, methamphetamine, phencyclidine and cocaine abuse.

[0696] On the other hand, there is provided herein a method for treating and / or preventing fibrosis or adhesion disease, illness or the patient's condition, the method comprising administering one or more of the compositions described herein to an object in need. It has been shown that an inhibitor of short-chain dehydrogenase activity such as a 15-PGDH inhibitor can be administered to an object in need to alleviate fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression and inflammatory cell infiltration, and treat and / or prevent various fibrotic diseases, illness and the patient's condition, which is characterized in that overproduction of fibrous material is entirely or partially, including overproduction of fibrotic material in an extracellular matrix, or normal tissue components are replaced due to abnormal, non-functional and / or excessive accumulation of matrix-related components (Markowitz et al., WO2016 / 144958).

[0697] Fibrotic diseases, disorders and conditions characterized in whole or in part by excessive production of fibrotic substances may include systemic sclerosis, multifocal fibrosing sclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea or linear scleroderma), scleroderma-like 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 pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, generalized fibrosis syndrome characterized by replacement of normal muscle tissue with fibrous tissue to varying degrees, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis (myelofibrosis), drug-induced ergot poisoning, 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.

[0698] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent renal fibrosis, including renal fibrosis caused by dialysis, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute renal injury, end-stage renal disease or renal failure, or a combination thereof.

[0699] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis caused by chronic liver disease, viral-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins, or a combination thereof.

[0700] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent heart fibrosis, such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and renal fibrosis.

[0701] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis.

[0702] The hydroxyprostaglandin dehydrogenase inhibitors provided herein are useful for treating or preventing fibrotic diseases, disorders, or conditions resulting from post-surgical adhesion formation.

[0703] The hydroxyprostaglandin dehydrogenase inhibitors provided herein are useful for reducing the intensity, severity, or frequency of, and / or delaying the onset of, one or more symptoms or characteristics of a fibrotic disease, disorder, or condition, or other related diseases, disorders, or conditions.

[0704] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or decrease collagen secretion or collagen deposition or collagen fiber accumulation in a tissue or organ, such as the lung, liver, intestine, colon, skin, or heart, or a combination thereof.

[0705] Studies have shown that 15-PGDH inhibition improves inflammatory lesions 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 lung fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal miner pneumoconiosis, carbonyl pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[0706] In another aspect, a method of reducing and / or preventing scarring is provided herein, 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 scarring in a subject. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scarring or scleroderma on the skin.

[0707] On the other hand, there is provided herein a method for treating and / or preventing muscle disorders, muscle damage and / or amyotrophy, the method comprising applying one or more of the compositions described herein to an object in need. Studies have shown that inhibition of PGE2 degradation enzymes such as 15-PGDH enables muscle regeneration and muscle repair (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020) to be achieved after damage. The inhibitor of hydroxyprostaglandin dehydrogenase provided herein can be used for treating muscle disorders, muscle damage and / or amyotrophy of an object. In some cases, the subject suffering from a muscle disorder, muscle damage and / or muscle atrophy may have 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), distal muscular dystrophy (DD), hereditary myopathy, myotonic dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress-induced urinary incontinence, urinary sphincter defect, sarcopenia, or a combination thereof.

[0708] In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat sarcopenia. In another embodiment, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy due to the use of a mechanical ventilator. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat genetic disorders or neuromuscular disorders such as spinal muscular atrophy (SMA). In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat sarcopenia, rotator cuff muscle atrophy, muscle atrophy associated with fixation, muscle atrophy associated with surgical procedures, sarcopenia, or a combination thereof.

[0709] Pharmaceutical composition

[0710] Inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions to treat the diseases and conditions described herein. In some embodiments, pharmaceutical compositions can include a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein.

[0711] The pharmaceutical compositions described herein can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, inhalants, liposomal particles, nanoparticles, syrups, and emulsions. In some embodiments, the pharmaceutical compositions can also be administered intravenously (bolus or infusion), subcutaneously, by suppository, intraperitoneally, topically (e.g., transdermally, transepidermally, transdermally), ocularly such as eye drops, intranasally, subcutaneously, by inhalation, intramuscularly, or transdermally (e.g., by patch), all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0712] In some embodiments, the compounds provided herein can be administered as part of a treatment regimen that includes administering one or more second doses (e.g., 1, 2, 3, 4, 5 or more second doses) simultaneously or sequentially with the compounds provided herein. When administered sequentially, the compounds provided herein can be administered before or after one or more second doses. When administered simultaneously, the compounds provided herein and one or more second doses can be administered by the same route (e.g., injection to the same location; oral tablets at the same time), by different routes (e.g., oral tablets, receiving intravenous infusions at the same time), or as part of the same combination (e.g., a solution comprising a compound provided herein and one or more second doses).

[0713] The combination therapy of the present disclosure can be effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg, and 5 to 40 mg per day are examples of dosages that can be used. The exact dosage will depend on the selected agent, the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0714] Example

[0715] Example 1: Synthesis and characterization of compounds

[0716] On the other hand, the present invention provides a method for preparing an inhibitor as described herein. In some cases, the inhibitor is separated or extracted from one or more plants. In some cases, the inhibitor derived from one or more plants can be further modified. In some cases, the inhibitor is further purified after being separated from one or more plants.

[0717] An exemplary synthetic scheme for an inhibitor having a phenyl core as described herein includes:

[0718]

[0719] Exemplary synthetic schemes for inhibitors having a 6-5 ring core as described herein include:

[0720]

[0721]

[0722]

[0723] In some cases, the synthetic scheme can be a complete synthetic scheme for producing an inhibitor provided herein. In other cases, the synthetic scheme can be a partial scheme for producing an inhibitor provided herein.

[0724] Exemplary synthetic schemes that can be used to synthesize the inhibitors described herein are described herein. The following abbreviations are used:

[0725]

[0726]

[0727] Synthesis of benzimidazole-5-carboxamide analogs with amide changes

[0728] An exemplary scheme for the synthesis of benzimidazole-5-carboxamide analogs with amide changes as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0729]

[0730] Solution 1

[0731] Step-1: Synthesis of methyl 4-fluoro-3-nitrobenzoate (Int-2): To a stirred solution of methyl 4-fluoro-3-nitrobenzoic acid (10 g, 54.02 mmol) in DCM (100 mL) was added oxalyl chloride (9.42 mL, 108.04 mmol, 2 eq) at 0°C and then DMF (1 mL). The RM was stirred for 1 h at 0°C. The reaction was monitored by TLC and after completion of the reaction, it was quenched with methanol (20 mL) and stirred at room temperature for 1 h. The solvent was then evaporated under reduced pressure and diluted with ethyl acetate (100 mL) and washed with saturated NaHCO 3The mixture was washed with 4-fluoro-3-nitrobenzoic acid solution (50 mL) and brine solution (50 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 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 (CDCl 3 ,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).

[0732] Step-2: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (Int-3), (General procedure for #1SNAr reaction): In a sealed autoclave; 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 lid of the steel autoclave was tightly closed, and the resulting reaction mixture was heated to 100°C for 16 h. The reaction was monitored by LCMS / TLC, and after completion of the reaction, it was cooled to room temperature, the volatiles were evaporated, and the reaction mixture was washed with saturated NH 4 The mixture was quenched with Cl (100 mL), extracted with EtOAc (3×50 mL), and the combined organic extracts were washed with brine (50 mL); dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product, which was triturated with ether (100 mL) to afford 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(brs,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).

[0733] 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 NH 4 Cl (10.03 g, 187.55 mmol, 7 eq). The resulting reaction mixture was heated to 100 ° C for 16 h. The reaction was monitored by LCMS / TLC, and after completion, the reaction mixture was filtered through a celite bed and washed with EtOAc (2×100 mL). The volatiles were evaporated and washed with saturated NaHCO 3 The mixture was quenched with 4-nitro-2-nitropropene (100 mL), extracted with EtOAc (3 × 50 mL), and the combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane to obtain methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (7.1 g, 96.07%) as a colloidal 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).

[0734] 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 heated to 100 °C for 16 h until SM was consumed as indicated 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 and washed with saturated NaHCO 3The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to obtain 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (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).

[0735] 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 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester) (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 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 volatiles were evaporated and neutralized with 1 N HCl until pH = 7. The solid was filtered and washed with Et 2 O (200 mL) and dried in vacuo to obtain 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).

[0736] Step 6: General procedure for amide coupling using HATU: To a stirred solution of Int-6 (1 eq) in DMF (10 v) was added HATU (1.5 eq) at 0°C under inert atmosphere, amine (1.2 eq) was added. To this stirred solution was added N,N'-diisopropylethylamine (3 eq) at 0°C, followed by continued stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after the starting material was consumed, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with ice water (2×10 mL) and brine (10 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude product was purified sequentially by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC to obtain the product shown in Scheme 1.

[0737] Synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone

[0738] An exemplary scheme for the synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0739]

[0740] Solution 2

[0741] 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 using 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] + ; 1H NMR(DMSO-d6,400MHz): 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),3.59-3.6 8(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).

[0742] Step-2: Synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone (MF-PGDH-051): A stirred solution of Int-7 (280 mg, 0.63 mmol, 1 eq) in DCM (5 mL) was cooled to 0 °C and 4N HCl in 1,4-dioxane (5 mL) was added and allowed to warm to room temperature and stirring was continued at room temperature for 16 h. The reaction was monitored by LCMS / TLC; after consumption of the starting material, the reaction mixture was concentrated and dissolved in water and washed with EtOAc (20 mL), and the aqueous layer was washed with saturated NaHCO 3 The solution was basified and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide (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] + .

[0743] Synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-064) become:

[0744] An exemplary scheme for the synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0745]

[0746] Solution 3

[0747] 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, iodomethane (136.05 mg, 0.961 mmol, 1.5 eq) was added at 0°C and allowed to warm to room temperature and stirred for 6 h. The reaction was monitored by LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC purification to obtain 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] + .

[0748] Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090)

[0749] An exemplary scheme for the synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0750]

[0751] Solution 4

[0752] Step-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 and oxalyl chloride (92.73 mg, 0.735 mmol, 2.0 eq), DMF (0.1 mL) was added followed by stirring at 0 °C for 30 min. The reaction was monitored by TLC; after complete consumption of the starting material, the reaction mixture was concentrated and then proceeded to the next step. The crude was dissolved in DCM (2 mL), cooled to 0 °C, pyrrolidone (53.60 mg, 121.5 mmol, 1.2 eq) was added, warmed to 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 concentrated in vacuo to obtain the crude. The crude product was purified by preparative HPLC purification to afford 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.

[0753] Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102)

[0754] An exemplary scheme for the synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0755]

[0756] Solution 5

[0757] 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) was added HATU (416 mg, 1.093 mmol, 1.5 eq) at 0 °C under inert atmosphere, NH 4Cl (196.33 mg, 3.669 mmol, 5.0 eq). To this stirred solution was added N,N'-diisopropylethylamine (282 mg, 2.177 mmol, 3.0 eq) at 0 °C, followed by continued stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after complete consumption of the starting material, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with ice water (2×10 mL) and brine (10 mL); dried over sodium sulfate, filtered and concentrated in vacuo to afford 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] + .

[0758] Synthesis of 2-substituted benzimidazole analogs

[0759] An exemplary scheme for the synthesis of 2-substituted benzimidazole analogs as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0760]

[0761] Solution 6

[0762] Step-1: Synthesis of 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (Int-1): In a sealed autoclave; to a stirred solution of 4-fluoro-3-nitrobenzoic acid (5 g, 27.02 mmol, 1 eq) in ethanol (100 mL) was added m-chloroaniline (4.18 g, 32.96 mmol, 1.22 eq) and potassium carbonate (1.86 g, 13.51 mmol, 0.5 eq) in sequence at room temperature, followed by heating to 80°C for 16 h. The reaction was monitored by TLC, and after completion of the reaction, cooled to room temperature and filtered; the solid was washed with ethanol and dried to obtain 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] + .

[0763] 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) was added oxalyl chloride (5.83 g, 46.23 mmol, 3 eq) dropwise at 0°C and stirring was continued for 1 h at 0°C. The reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature and 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 for 5 h at room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography using 5% MeOH / DCM to afford (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] + .

[0764] 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) was added iron powder (7.6 g, 136.11 mmol, 7 eq) and NH 4 Cl (7.4 g, 136.11 mmol, 7 eq). The resulting reaction mixture was heated to 90 ° C for 16 h. The reaction was monitored by TLC; after the starting material was consumed, the reaction mixture was filtered through a celite bed and washed with EtOAc (2×50 mL). The volatiles were evaporated, quenched with water (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was triturated with ether (20 mL) to provide (3-amino-4-((3-chlorophenyl)amino)phenyl)(piperidin-1-yl)methanone (5 g, 77.60%) as a colloidal liquid. LCMS: m / z=330.0[M+H] + .

[0765] 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; to a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq) was added ethyl glyoxylate (186.2 mg, 1.823 mmol, 3 eq) and PTSA (20 mg, 0.116 mmol, 0.2 eq) at room temperature. The resulting reaction mixture was heated to 70 ° C for 16 h. The reaction was monitored by TLC; after complete consumption of the starting material, it was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC purification to obtain MF-PGDH-027 (18.82 mg, 7.55% yield) as an off-white solid.

[0766] 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 (E)-ethyl 3-amino-3-ethoxyacrylate (355 mg, 1.818 mmol, 3 eq) at room temperature. The resulting reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by TLC; after complete consumption of the starting material, it was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified sequentially by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC purification to obtain MF-PGDH-030 (35.4 mg, 13.7%) as an off-white solid.

[0767] Step-4C: Synthesis of MF-PGDH-091 (General procedure for ester hydrolysis using 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 was added LiOH. 2 O (235 mg, 4.7 mmol, 2 eq). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC; after complete consumption of the starting material, it was cooled to room temperature and concentrated in vacuo to obtain a crude product. The crude product was purified sequentially by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC purification to provide MF-PGDH-091 (20.38 mg, 2.9%) as an off-white solid. LCMS: m / z=354.2 [M+H] + .

[0768] 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 of amide coupling with 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] + .

[0769] 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)propanoic 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) at 0 °C under inert atmosphere. The mixture was slowly warmed to room temperature and then heated to 80 °C for 16 h. The reaction was monitored by TLC; after complete consumption of the starting material, the reaction mixture was cooled to room temperature and diluted with ice water (20 mL). The mixture was washed with 10% NaHCO 3 The solution was neutralized and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with ice water (2×10 mL) and brine (10 mL); dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC purification to obtain MF-PGDH-033 (68.36 mg) and MF-PGDH-034 (33.41 mg) as off-white solids.

[0770] 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 autoclave was added a solution of 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; after complete consumption of the starting material, the reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified by preparative HPLC purification to obtain MF-PGDH-035 (33.27 mg, 17.3% yield) as an off-white solid.

[0771] Synthesis of benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations

[0772] An exemplary scheme for the synthesis of benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0773]

[0774] Solution 7

[0775] The synthesis of Int-1 is described in Scheme 1, 1a above.

[0776] 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 into Int-2 using p-anisidine (7.68 g, 60.25 mmol, 1.2 eq) using the general procedure of SNAr reaction #1 to afford 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] + .

[0777] Step-3: Synthesis of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (Int-3): Methyl (4-methoxyphenyl)amino)-3-nitrobenzoate (8.09 g, 26.79 mmol) was converted into methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (7.1 g, 96.07%) using the general procedure of aryl nitro reduction with Fe to provide Int-3 as a gummy liquid. LCMS: 91.32%, m / z=273.2 [M+H] + .

[0778] 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 / cyclopropanal (128.62 mmol, 5 eq) in 1,4-dioxane (80 mL) / DMF was added PTSA (884 mg, 5.144 mmol, 0.2 eq) / Na2SO4. 2 S 2 O 3The resulting reaction mixture was heated to 90 °C for 16 h until SM was consumed according to crude LCMS / TLC. The reaction mixture was filtered through a celite bed and washed with EtOAc (2 × 100 mL). The volatiles were evaporated and washed with saturated NaHCO 3 The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to obtain 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester Int-4a (78.6% yield, m / z=283.3 [M+H] + ) and 2-cyclopropyl-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester (Int-4b) (53.40% yield, m / z = 323.33 [M+H] + ).

[0779] 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-4a / 4b (1 eq) was hydrolyzed using the general procedure for ester hydrolysis with NaOH to afford Int-5a (4.5 g, 81.66% yield, LCMS: m / z=269.2 [M+H]) as a light brown solid. + ) and Int-5b (230 mg, 64.5% yield, LCMS: m / z=309.0 [M+H] + ).

[0780] 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 with HATU to afford MF-DH-008, MF-DH-009 and MF-DH-021.

[0781] Synthesis of benzimidazole-5-carboxamide analogs with aryl / amide variations

[0782] An exemplary scheme for the synthesis of benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0783]

[0784] Solution 8

[0785] The synthesis of Int-1 is described in Scheme 1.

[0786] Step-2: Synthesis of Int-2; General procedure for the SNAr reaction: 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 autoclave was added 5-methoxypyridin-2-amine / 3-chloro-4-methoxyaniline (1.2 eq) and K 2 CO 3 (1.726 g, 1 eq). The steel autoclave was tightly sealed and the reaction mixture was heated to 100 ° C for 16 h. The reaction was monitored by LCMS / TLC. After completion, the reaction mixture was cooled to room temperature and concentrated. The residue was washed with saturated NH 4 Cl (100 mL) was quenched and extracted with EtOAc (3×50 mL), and the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide a crude product. The crude product was triturated with ether (100 mL) to provide Int-2a (50.5% yield, LCMS: m / z=304.1 [M+H]) for obtaining MF-PGDH-22 and MF-DH-141 as a yellow solid. + ).

[0787] Int-1 was converted to Int-2b (51.0% yield, m / z = 337.2 [M+H]) used to obtain MF-PGDH-24 and MF-PGDH-61. + ).

[0788] Using the general procedure of #1SNAr, Int-1 was converted to Int-2c (59.0% yield, LCMS: m / z = 317.1 [M+H]) used to obtain MF-PGDH-62. + ).

[0789] Step-3: Synthesis of Int-3a, Int-3b and Int-3c was achieved using the general procedure of aryl nitro reduction to afford Int-3a as a colloidal liquid (82.3% yield, LCMS: m / z = 274.1 [M+H] + ), Int-3b (79.2% yield, LCMS: m / z=307.1 [M+H] + ) and Int-3c (80.0% yield, LCMS: m / z=287.2 [M+H] + ).

[0790] 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 was added PTSA (884 mg, 0.2 eq) at room temperature. The resulting reaction mixture was heated to 90 °C for 16 h until SM was consumed according to crude LCMS / TLC. The reaction mixture was filtered through a celite bed and washed with EtOAc (2×50 mL). The volatiles were evaporated and washed with saturated NaHCO 3 The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to afford Int-4a (32.7% yield, LCMS: m / z=287.2 [M+H]) as a light brown solid. + ), Int-4b (73.0% yield, LCMS: m / z=317.1 [M+H] + ) and Int-4c (83.0% yield, LCMS: m / z=297.0 [M+H] + ).

[0791] 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 converted to Int-5a (65.2% yield, LCMS: m / z = 270.1 [M+H] + ), Int-5b (70.5% yield, LCMS: m / z=303.2 [M+H] + ) and Int-5c (81.4% yield, LCMS: m / z=282.1 [M+H] + ), all obtained as light brown solids.

[0792] Step-6: Int-5 was coupled to appropriate amines using the general procedure of amide coupling with HATU to afford MF-PGDH-022, MF-PGDH-024, MF-PGDH-062 and MF-DH-141.

[0793] Step-7: Synthesis of (1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone: At 0°C under inert atmosphere, (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) was added to CH 2 Cl 2 BBr (10 mL) was added to the stirred solution 3 (1.62 mL, 1.62 mmol, 3.0 eq, 1 M, in CH 2 Cl 2 ) and stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after the starting material was consumed, the reaction mixture was quenched with MeOH (10 mL), evaporated to dryness, and then washed with saturated NaHCO 3 The solution was quenched with 1- (3-chloro-4-hydroxyphenyl) -1H-benzo [d] imidazole-5-yl) (piperidin-1-yl)methanone MF-PGDH-061 (120 mg, 63%) as an off-white solid.

[0794] Synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations

[0795] An exemplary scheme for the synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0796]

[0797] Scheme 9 and Scheme 10

[0798] Scheme 9 Step 1: As shown in Scheme 9, Int-1 was subjected to amide coupling with an appropriate amine using HATU as previously described to provide Int-2.

[0799] 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 (400 MHz, DMSO-d 6)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).

[0800] (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 (400 MHz, DMSO-d 6 )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).

[0801] (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 (400 MHz, DMSO-d 6 )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).

[0802] Scheme 9 Step-2: General Buchwald procedure for the synthesis of (MF-PGDH-071 and MF-DH-123, 124): In a sealed tube, at room temperature under inert atmosphere, 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) was added Cs 2 CO 3 (422 mg, 1.3 mmol, 2.0 eq) and the corresponding chloro / bromoarene (1.2 eq). Argon was purged for 15 min, and then Xantphos (75.14 mg, 0.13 mmol, 0.2 eq) and Pd were added under argon atmosphere. 2(dba) 3 (59.47 mg, 0.065 mmol, 0.1 eq). The sealed tube was capped tightly and the resulting reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC; after the reaction was complete, the reaction mixture was washed with saturated NH 4 Cl (10mL) quenching, filtered through diatomaceous earth bed, washed with EtOAc (10mL). The mixture was extracted with EtOAc (2×10mL), the combined organic extracts were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography and preparative HPLC purification using 70% EtOAc / heptane, providing MF-PGDH-071 and MF-DH-123, 124.

[0803] 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) was added NCS (906 mg, 6.68 mmol) at 40 °C under inert atmosphere. The resulting reaction mixture was heated to 60 °C for 4 h. The reaction was monitored by crude LCMS / TLC; after complete consumption of the starting material, the reaction mixture was quenched with ice water (20 mL), the solid was filtered and washed with diethyl ether (3×10 mL). The crude product was azeotroped with toluene (2×10 mL) and then dried for 2 h to provide 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-2) (850 mg, yield: 70%) as a light brown solid. LCMS: 88.2%) m / z=195.0 [MH] - ; 1 H NMR (500 MHz, DMSO-d 6 )δ=13.18(br s,1H),12.37(s,1H),8.84(s,1H),8.45(s,1H),7.82(s,1H).

[0804] Scheme 9, step 2 and Scheme 10, step 3: 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. K 3 PO 4, 0.2 eq. CuI, 0.2 eq. trans-dimethylcyclohexane-1,2-diamine. The reaction mixture was purged with argon for 15 min, and then the reaction was continued at 100° C. for 16 h. The reaction was monitored by TLC, and after the reaction was completed, saturated NH 4 The mixture was quenched with Cl solution (10 mL) and stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and diluted with ethyl acetate (10 mL) and washed with saturated NaHCO 3 The mixture was washed with 4% paraformaldehyde (50 mL) and brine solution (50 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was further purified by preparative HPLC to afford 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.

[0805] Synthesis of Azabenzimidazole Analogs

[0806] An exemplary scheme for the synthesis of azabenzimidazole analogs that are inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0807]

[0808] Solution 11

[0809] 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 #2SNAr conditions to afford Int-1a (Ar = 3-Clphenyl, 95.2% yield, LCMS: m / z = 308.2 [M+H]) as a yellow solid. + ) and Int-1b (Ar = 4-OMe phenyl, 87.6% yield, LCMS: 96.0%, m / z = 304.2 [M+H] as a light yellow solid + ).

[0810] 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 with Fe. The crude was purified by silica gel column chromatography using 60% EtOAc / heptane to obtain Int-2a (Ar = 3-Clphenyl, 97% yield, LCMS: m / z = 278.2 [M+H]) as a yellow solid. + ) and Int-2b (Ar = 4-OMe phenyl, 77% yield, LCMS: m / z = 272.4 [M+H] as a light yellow solid + ).

[0811] Step-3: Synthesis of Int-3 (General procedure for PTSA-catalyzed ring closure of imidazole formation): 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 heated to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC; 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 and washed with saturated NaHCO 3 The solution (20 mL) was quenched and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane to obtain Int-3a (Ar=3-Cl phenyl, 83% yield, LCMS: m / z=288.2 [M+H]) as a yellow solid. + ) and Int-3b (Ar = 4-OMe phenyl, 71% yield, LCMS: m / z = 284.2 [M+H] as a light yellow solid + ).

[0812] Step-4: Synthesis of Int-4, General procedure for ester hydrolysis with 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 for 16 h at room temperature. The reaction was monitored by crude LCMS / TLC; upon completion, the reaction mixture was concentrated and neutralized with 1 N HCl. The resulting solid was filtered and washed with Et 2 O (50 mL), and dried in vacuo to afford Int-4a (Ar = 3-Cl phenyl) as an off-white solid, 65% yield, LCMS: m / z = 274.2 [M+H] + ) and Int-4b (Ar = 4-OMe phenyl, 90.5% yield, LCMS: m / z = 270.1 [M+H] as an off-white solid + ).

[0813] Step-5: Synthesis of MF-PGDH-020, MF-PGDH-077, MF-PGDH-078, MF-PGDH-079 and MF-PGDH-138: As previously described, Int-4 was subjected to amide coupling with appropriate amines using HATU to provide a crude product, which was sequentially purified by silica gel column chromatography using 40% EtOAc:heptane / 5% MeOH:CH2Cl2 and preparative HPLC purification to obtain 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.

[0814] Synthesis of 2-Substituted Azabenzimidazole Analogs MF-DH-115 and MF-DH-116

[0815] An exemplary scheme for the synthesis of 2-substituted azabenzimidazole analogs as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0816]

[0817] Solution 12

[0818] 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 slowly warmed to room temperature and then heated to 80° C. for 16 h. The reaction was monitored by crude LCMS / TLC; after the reaction was completed, it was cooled to room temperature and quenched with water (10 mL), extracted with EtOAc (3×50 mL), the combined organic extracts were washed with brine (50 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain methyl 2-amino-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (1.08 g, 99%) as a gummy liquid. LCMS: 80.63%, m / z=299.2 [M+H] + .

[0819] 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. It was stirred for 10 min at 0°C followed by the addition of acetic anhydride (821 mg, 8.05 mmol, 3 eq). The reaction mixture was allowed to warm to room temperature followed by stirring for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, it was quenched with ice water (10 mL), extracted with EtOAc (3×50 mL); the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography using 20% ​​EtOAc / heptane to provide 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] + .

[0820] 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 with NaOH to provide 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] + .

[0821] 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 previously. The crude was purified by silica gel column chromatography using 5% MeOH / DCM followed by preparative HPLC purification to obtain MF-DH-116 (12.57 mg, 2.12%) as an off-white solid.

[0822] 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) was added K 2 CO 3 (235mg, 1.70mmol, 2.0eq), then continued stirring at room temperature for 16h. The reaction was monitored by rough LCMS / TLC; after the starting material was consumed, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to provide a crude product. The crude product was purified successively by silica gel column chromatography using 5% MeOH / DCM and preparative HPLC purification to obtain MF-DH-115 (12.46mg, 3.96%) as an off-white solid.

[0823] Synthesis of Benzamide Analogs

[0824] An exemplary scheme for the synthesis of benzamide analogs that are inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0825]

[0826] Solution 13

[0827] Step-1: Synthesis of (4-(Hydroxymethyl)phenyl)(piperidin-1-yl)methanone (Int-1): At 0°C under an inert atmosphere, 4-(Hydroxymethyl)benzoic acid (2 g, 13.15 mmol, 1 eq) and piperidine (1.12 g, 13.5 mol, 1 eq) were reacted in CH 2Cl 2 EDCI (3.82 g, 19.72 mol, 1.2 eq) and HOBt (2.13 g, 15.78 mol, 1.2 eq) were added to a stirred solution in 4% ethyl acetate (20 mL). N, N'-diisopropylethylamine (373 mL, 2.14 mol, 3 eq) was added to this stirred solution at 0 ° C, and stirring was continued for 16 h at room temperature. The reaction was monitored by rough LCMS / TLC; after the starting material was consumed, the reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with ice water (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to provide Int-1 (1.6 g, 57.1%) as a light yellow solid. LCMS: m / z=220.1[M+H] + .

[0828] 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) was added TPP (446 mg, 1.7 mol, 1.5 eq) and DIAD (460 mg, 1.07 mmol, 1.5 eq) in THF (5 mL) in sequence under inert atmosphere, followed by continued stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude product was purified sequentially by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC purification to obtain MF-PGDH-036 (yield: 2.05%), MF-PGDH-037 (yield: 2.1%), and MF-PGDH-039 (yield: 2.2%) as off-white solids.

[0829] Synthesis of (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-040)

[0830] An exemplary scheme for the synthesis of (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0831]

[0832] Solution 14

[0833] MF-PGDH-39 (from Scheme 13) (200 mg, 0.578 mmol, 1 eq) was added to CH 2 Cl 2 To a stirred solution in 4% paraformaldehyde (15 mL) was added m-CPBA (196.1 mg, 1.15 mmol, 2 eq), followed by continued stirring at room temperature for 16 h. Another aliquot of m-CPBA (1 eq) was added. The reaction was monitored by crude LCMS / TLC; after the starting material was consumed, the reaction mixture was quenched with ice water (10 mL) and washed with CH 2 Cl 2 The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC purification to obtain (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-040) (21.1 mg, 9.6%) as a brown liquid.

[0834] Synthesis of (4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-045)

[0835] An exemplary scheme for the synthesis of (4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanone as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0836]

[0837] Solution 15

[0838] MF-PGDH-39 (50 mg, 0.144 mmol, 1 eq) was added to CH 3 NaIO4 (61.99 mg, 0.289 mmol, 2 eq) was added to the stirred solution in CN: water, and then stirring was continued for 4 h at room temperature. The reaction was monitored by rough LCMS / TLC; after the starting material was consumed, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified sequentially by silica gel column chromatography and preparative HPLC purification using 40% EtOAc / heptane to provide 35.8 mg of MF-PGDH-045 as a brown liquid.

[0839] Synthesis of MF-PGDH-38, MF-PGDH-098, MF-DH-118 and MF-DH-121

[0840] An exemplary scheme 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 is provided below.

[0841]

[0842] Scheme 16

[0843] Scheme 16A Step-1: Synthesis of methyl 4-(bromomethyl)-3-methoxybenzoate (Int-1): At room temperature, under inert atmosphere, methyl 3-methoxy-4-methylbenzoate / methyl 5-methylpicolinate (2.5 g, 13.87 mmol, 1 eq) was added to CHCl 3 To a stirred solution in 4% paraformaldehyde (20 mL) was added NBS (2.96 g, 16.66 mol, 1.2 eq) and AIBN (0.45 g, 2.74 mol, 0.2 eq), and the resulting reaction mixture was heated to reflux for 16 h. The reaction was monitored by crude LCMS / TLC; after the starting material was consumed, the reaction mixture was washed with saturated Na 2 S 2 O 3 The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to obtain methyl 4-(bromomethyl)-3-methoxybenzoate (Int-1) (2.0 g, 55.7%) as an off-white solid. MS: m / z=261.1[M+2] + .

[0844] 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) was added K 2 CO 3(1.5eq), then heated to reflux for 16h. The reaction was monitored by rough LCMS / TLC; after the starting material was consumed, the reaction mixture was quenched with ice water (10mL) and extracted with EtOAc (3×15mL). The combined organic extracts were washed with ice water (2×10mL) and brine (20mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 15% EtOAc / heptane to obtain Int-2 (430mg; Yield: 71.83%) as an off-white solid. LCMS: 91.35%: m / z=307.3[M+H] + .

[0845] Scheme 16A Step-3: Synthesis of Int-3: Int-2 was hydrolyzed using the general procedure of ester hydrolysis with LiOH to provide Int-3 as a light brown solid (yield: 58.7%). LCMS: m / z = 293.2 [M+H] + .

[0846] 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 coupling agent as previously described to afford MF-PGDH-038, MF-DH-118 as off-white solid.

[0847] Scheme 16B Step-1: Synthesis of methyl 5-(bromomethyl)picolinate (Int-1): Using the general bromination procedure described earlier, methyl 5-methylpicolinate was brominated with NBS to provide Int-1 as an off-white solid (yield: 52%). LCMS: m / z=232.9 [M+2H] + .

[0848] Scheme 16B Step-2: Synthesis of methyl 5-((2-chlorophenoxy)methyl)picolinate (Int-2): Using the substitution reaction procedure described earlier (Scheme 16A), Int-1 was converted to Int-2 with 2-chlorophenol to provide Int-2 as a light yellow solid (yield: 66%). LCMS: m / z=278.1 [M+H] + .

[0849] Scheme 16B Step-3: Synthesis of 4-((2-chlorophenoxy)methyl)benzoic acid (Int-3): Int-2 was hydrolyzed using the general procedure of ester hydrolysis with LiOH to provide Int-3 as an off-white solid (yield: 84%). LCMS: m / z=264.1 [M+H] + .

[0850] 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 a coupling agent as described previously to afford MF-DH-121 as an off-white solid (yield: 61%). LCMS: 99.96%, MS: m / z=349.0 [M+H] + .

[0851] Synthesis of MF-PGDH-095, MF-PGDH-096 and MF-PGDH-097

[0852] An exemplary scheme for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF-PGDH-095, MF-PGDH-096, and MF-DH-097 in Scheme 17 below is provided below.

[0853]

[0854] Solution 17

[0855] Step-1: To a stirred solution of bromine compound MF-PGDH-036 (5 g, 0.013 mol, 1 eq) and corresponding bis(pinacolato)diboron (5.1 g, 0.02 mol, 1.5 eq.) in 1,4-dioxane (5 V, 50 mL / mmol) was added KOAc (3.82 g, 0.04 mmol, 3 eq.) and purged with argon for 15 min. To this solution was added PdCl 2 (dppf).DCM (1 g, 0.0013 mmol, 0.1 eq.) and purged with argon for another 10 min. The resulting reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to provide 2.82 g (51%) of Int-1; LCMS: m / z=422.2 [M+H] + ,340.2[M+H] + .

[0856] 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) was added Na 2 CO 3 (6.5 mmol, 3 eq.) and purged with argon for 15 min. To this solution was added Pd(PPh3 ) 4 The mixture was stirred for 16 h at 90 °C and the reaction mixture was filtered through diatomite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography and preparative HPLC to obtain MF-PGDH-095, MF-PGDH-096 and MF-PGDH-097 as off-white solids.

[0857] Synthesis of MF-PGDH-041, MF-PGDH-042, MF-PGDH-087, MF-PGDH-088 and MF-PGDH-089

[0858] An exemplary scheme for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF-PGDH-041, MF-PGDH-042, and MF-DH-087 in Scheme 18 below is provided below.

[0859]

[0860] Scheme 18

[0861] Step-1: Synthesis of Int-1: 4-Nitrobenzoic acid (2 g, 1 eq) and piperidine / 4,4-difluoropiperidine (1.5 eq) were coupled using HATU as described previously to afford Int-1a (X, X′=F, 85% yield, LCMS: m / z=271.1 [M+H] + ) and Int-1b (X, X'=H, 91% yield, LCMS: m / z=235.1[M+H] + ).

[0862] Step-2: Synthesis of Int-2: Int-1 (1 eq) was converted to Int-2 using the general procedure for aryl nitro reduction with Fe described above to provide Int-2a (X, X' = F, 51.7% yield, LCMS: m / z = 240.1 [M+H] + ) and Int-2b: (X, X'=H, 53.5% yield, LCMS: m / z=205.2[M+H] + ).

[0863] Step-3: Synthesis of Int-3: Int-2 (1 eq) and 2-methoxyphenyl / 2-chlorophenyl / 3-methoxyphenylcarboxylic acid (0.7 eq) were coupled using HATU as previously described to afford MF-PGDH-041, MF-PGDH-087, MF-PGDH-088 and MF-PGDH-089 as off-white solids.

[0864] Step-4: Synthesis of 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) at 0°C to room temperature for 1 h. 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; after the starting material was consumed, the reaction mixture was washed with saturated NH 4 Cl (10ml) quenched, extracted with EtOAc (2 x 50mL). The combined organic extracts were washed with brine (20mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC purification to obtain MF-PGDH-042 (24.42mg, 16.71%) as a light brown solid.

[0865] Synthesis of MF-PGDH-043 and MF-PGDH-044

[0866] An exemplary scheme for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF-PGDH-043 and MF-DH-044 in Scheme 19 below is provided below.

[0867]

[0868] Solution 19

[0869] 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) were coupled in DMF (20 mL) using HATU as described previously to afford Int-1 (2.6 g, yield: 92%) as a pale yellow solid. MS: m / z = 248.1 [M+H] + .

[0870] Step-2: Synthesis of 4-(piperidine-1-carbonyl)benzoic acid (Int-2): Int-1 (2.8 g) was hydrolyzed using the general procedure of ester hydrolysis with NaOH to afford Int-2 (1.8 g, yield: 58%) as an off-white solid. MS: m / z = 234.0 [M+H] + .

[0871] Step-3: Synthesis of N-(2-methoxyphenyl)-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-043): As previously described, 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) to afford MF-PGDH-043 (1 g, yield: 90%) as a light yellow solid.

[0872] Step-4: N-(2-Methoxyphenyl)-N-methyl-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-044): MF-PGDH-043 (300 mg) was methylated with MeI using the general procedure for N-methylation of amides to afford MF-PGDH-044 (64.44 mg, 23.69%) as a light brown solid.

[0873] Synthesis of indoles MF-PGDH-004 and MF-PGDH-005

[0874] An exemplary scheme for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF-PGDH-004 and MF-DH-005 in Scheme 20 below is provided below.

[0875]

[0876] Solution 20

[0877] Step-1: Synthesis of Int-1: For R = Cl in Scheme 1 above, 1H-indole-5-carboxylic acid (2 g) was converted into Int-1 (2.3 g; yield: 95%) using the general procedure of chlorination using NCS. MS: m / z = 196.01 [M+H] + .

[0878] Step-2: Synthesis of Int-2: Int-1 / 1H-indole-5-carboxylic acid was coupled with piperidine using the general procedure of amide coupling with HATU to afford Int-2a (R = H, 71% yield, MS: m / z = 229.1 [M+H] + ) and Int-2b (R = Cl, 68% yield, MS: m / z = 263.6 [M+H] + ).

[0879] 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) were added 3-chloroiodobenzene (1.2 eq), K 2 CO 3(2 eq). The reaction mixture was purged with argon for 15 min. CuI (0.2 eq) and trans-dimethylcyclohexane-1,2-diamine (0.2 eq) were added to this stirred solution, followed by continued stirring at 100 °C for 16 h. The reaction was monitored by TLC, and after complete consumption of the starting material, the mixture was heated to 40 °C with saturated NH 4 Cl solution (10 mL) quenched, filtered, washed with EtOAc. Extracted with EtOAc, washed with ice water (2 × 30 mL) and brine solution (50 mL), the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was further purified by preparative HPLC to provide MF-PGDH-004 and MF-PGDH-005 as off-white solids.

[0880] Synthesis of MF-PGDH-053 and MF-PGDH-054

[0881] An exemplary scheme for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF-PGDH-053 and MF-DH-054 in Scheme 21 below is provided below.

[0882]

[0883] Solution 21

[0884] Step-1: Synthesis of 3-bromo-1H-indole-6-carboxylic acid methyl ester (Int-1): To a stirred solution of 1H-indole-6-carboxylic acid methyl ester (2 g, 11.42 mmol, 1 eq) in DMF (40 mL) was added NBS (3.04 g, 17.14 mmol, 1.5 eq), followed by stirring at room temperature for 2 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, the mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with ice water (2×30 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to obtain Int-1 (1.51 g, 53%) as a light brown solid. MS: m / z=256.1[M+2] + .

[0885] 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) was added Na 2 CO3 (2.39 g, 22.63 mmol, 2.5 eq), and the mixture was purged with argon for 15 min. To this solution was added Pd(PPh 3 ) 4 (1.04 g, 0.90 mmol, 0.1 eq). The resulting reaction mixture was stirred at 80 ° C for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using 40% EtOAc / heptane to obtain Int-2 (550 mg, 22%) as a brown solid. MS: m / z=287.1[M+2] + .

[0886] Step-3: Synthesis of 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (Int-3): 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid methyl ester (550 mg) was converted into Int-3 (500 mg, 95.7%) as a light brown solid using the general procedure of ester hydrolysis with LiOH. MS: m / z=270.1 [MH] + .

[0887] Step-4: Synthesis of (3-(3-chlorophenyl)-1H-indol-6-yl)(piperidin-1-yl)methanone MF-PGDH-053: 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (500 mg) was converted into MF-PGDH-053 as an off-white solid using the general procedure of amide coupling with HATU.

[0888] Step-5: Synthesis of (3-(3-chlorophenyl)-1-methyl-1H-indol-6-yl)(piperidin-1-yl)methanone 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) at 0 °C to room temperature for 1 h. 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; after consumption of the starting material, the reaction mixture was washed with saturated NH 4Cl (10 ml) was quenched and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC purification to obtain MF-PGDH-054 (16.94 mg, 81.4%) as an off-white solid.

[0889] Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone MF-PGDH-057

[0890] An exemplary scheme for the synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone MF-PGDH-057 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0891]

[0892] Solution 22

[0893] Step-1: Synthesis of 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (Int-1): Using the general procedure of ester hydrolysis with NaOH, 1,2,3,4-tetrahydroquinoline-6-carboxylic acid methyl ester (1 g) was converted into Int-1 (800 mg, 86.9%) as a brown solid. MS: m / z=178.1 [M+H] + .

[0894] Step-2: Synthesis of piperidin-1-yl(1,2,3,4-tetrahydroquinolin-6-yl)methanone (Int-2): 1,2,3,4-Tetrahydroquinoline-6-carboxylic acid (800 mg) was converted into Int-2 (309 mg, 48%) as a brown solid using the general procedure of amide coupling with HATU. MS: m / z=245.2[M+H] + .

[0895] Step-3: Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone 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 Cs 2 CO 3 (800 mg, 2.45 mmol, 3 eq) and then purged with argon for 15 min. To this solution was added Pd 2 (dba) 3(37.5mg, 0.0409mmol, 0.1eq) and xantphos (47.37mg, 0.0819mmol, 0.1eq), and purged with argon for another 10min. The resulting reaction mixture was stirred for 16h at 90°C. The progress of the reaction was monitored by LCMS / TLC. After the reaction was completed, the mixture was filtered through diatomaceous earth and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine successively, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to provide MF-PGDH-057 (20.4mg, 7.0%) as an off-white solid.

[0896] Synthesis of 1-(3-chlorophenyl)-6-(piperidin-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one MF-PGDH-058

[0897] An exemplary scheme for the synthesis of 1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one MF-PGDH-058 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0898]

[0899] Solution 23

[0900] Step-1: Synthesis of 6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (Int-1): 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) using the general procedure of amide coupling with HATU to obtain Int-1 (1.7 g, 84.1%) as a brown solid. MS: m / z=259.1 [M+H] + .

[0901] Step-2: Synthesis of 1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one 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 procedure of Ullmann coupling. The crude product was purified by preparative HPLC to give MF-PGDH-058 (23.5 mg, 8.2%) as an off-white solid.

[0902] Synthesis of (1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-006

[0903] An exemplary scheme for the synthesis of (1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-006 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0904]

[0905] Solution 24

[0906] Step-1: Synthesis of (1H-indazol-5-yl)(piperidin-1-yl)methanone (Int-1): 1H-indazole-5-carboxylic acid (500 mg) was converted into Int-1 (610 mg, 86.28%) obtained as a brown solid using the general procedure of amide coupling with HATU. MS: m / z=230.1 [M+H] + .

[0907] 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) was added K 2 CO 3 (734mg, 5.32mmol, 2eq), followed by argon purge for 15min. Under argon, cuprous iodide (101mg, 0.532mmol, 0.2eq) and trans-N, N'-dimethylcyclohexane-1,2-diamine (126mg, 0.532mmol, 0.2eq) were added to this solution, and purged for another 10min. The resulting reaction mixture was heated at 90°C for 16h. The progress of the reaction was monitored by LCMS / TLC. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine in sequence, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to provide MF-PGDH-006 (40mg, 4.41%) as a colloidal liquid.

[0908] Synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone MF-PGDH-007

[0909] An exemplary scheme for the synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone MF-PGDH-007 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0910]

[0911] Solution 25

[0912] 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) and bromine (897 mg, 11.36 mmol, 2 eq) in sequence at 0°C, and the mixture was then allowed to warm to room temperature for 1 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, the mixture was washed with saturated Na 2 S 2 O 3 (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with ice water (2×30 mL) and brine (20 mL); dried over sodium sulfate, filtered and concentrated in vacuo to afford Int-1 (900 mg, 62%) as a light brown solid. MS: m / z=256.1 [M+H] + .

[0913] Step-2: Synthesis of 3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (Int-2): Using the general procedure of Suzuki coupling, methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate (600 mg, 2.38 mmol, 1 eq.) and (3-chlorophenyl)boronic acid (371 mg, 2.38 mmol, 1 eq.) were coupled to afford Int-2 (150 mg, 23%) as a brown solid. MS: m / z=273.1 [M+H] + .

[0914] Step-3: Synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-yl)(piperidin-1-yl)methanone MF-PGDH-007: 3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (150 mg) was converted into MF-PGDH-007 (29.28 mg, 15.7%) as an off-white solid using the general procedure of amide coupling using HATU.

[0915] (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-011 synthesis

[0916] An exemplary scheme for the synthesis of (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-011 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0917]

[0918] Scheme 26

[0919] 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, followed by heating to 80°C for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, the mixture was filtered to obtain Int-1 (2.10 g, 56.5%) as a light brown solid. MS: m / z=307.1 [M+H] + .

[0920] Step-2: Synthesis of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (Int-2): Using the general procedure of aryl nitro reduction using Fe, Int-1 (2 g) was converted into Int-2 (1.20 g, 66.6%) obtained as a gummy liquid. MS: m / z = 277.2 [M+H] + .

[0921] Step-3: Synthesis of methyl 1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (Int-3): Methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (700 mg, 2.545 mmol, 1 eq), NaNO 2 (175 mg, 2,545 mmol, 1 eq) was slowly added to a stirred solution of THF:water (1:1, 10 mL) with 6N H 2 SO 4 (2 mL), then allowed to gradually reach room temperature, then heated to reflux for 12 h. The reaction was monitored by crude TLC; after completion of the reaction, the mixture was washed with saturated NaHCO 3 The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to provide Int-3 (300 mg, yield: 41.26%) as an off-white solid. MS: m / z=288.1 [M+H] + .

[0922] Step-4: Synthesis of (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-011: To a stirred solution of 1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid methyl ester (300 mg, 1.045 mmol, 1 eq) in toluene (7 mL) at 0°C, piperidine (107 mg, 1.256 mmol, 1.2 eq) and trimethylaluminum (1.5 mL, 5.22 mmol, 5 eq) were slowly added sequentially, followed by slow heating to 50°C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2×30 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 afford the crude product. The crude product was purified by preparative HPLC to afford MF-PGDH-011 (161.2 mg, 45.29%) as an off-white solid.

[0923] Synthesis of (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone MF-PGDH-012

[0924] An exemplary scheme for the synthesis of (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone MF-PGDH-012 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0925]

[0926] Scheme 27

[0927] Step-1: Synthesis of (3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (Int-1): 3-Bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (500 mg) was coupled with piperidine (212 mg, 2.49 mmol, 1.2 eq) using the general procedure of amide coupling with HATU to obtain Int-1 (309 mg, 48%) as a brown solid. MS: m / z=310.1[M+2H] + .

[0928] Step-2: Synthesis of (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone MF-PGDH-012: Using the general procedure of Suzuki coupling, (3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (300 mg, 0.97 mmol, 1 eq.) and (3-chlorophenyl)boronic acid (227 mg, 1.455 mmol, 1.5 eq.) were coupled to afford MF-PGDH-012 (32.78 mg, 9.9%) as an off-white solid.

[0929] (4-Fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone MF-DH-150 and (3-chloro-4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1- Synthesis of 2-methyl-1-nitro-2-methyl-ketone MF-DH-151

[0930] Provided below is an exemplary scheme for the synthesis of (4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone 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 MF-DH-151 as inhibitors of hydroxyprostaglandin dehydrogenase.

[0931]

[0932] Scheme 28

[0933] Step-1: Synthesis of Int-1: 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 into Int-1 (450 mg; yield: 75.37%) as a gummy liquid using the general procedure of chlorination with NCS. MS: m / z = 212.2 [M+H] + .

[0934] Step-2: Synthesis of Int-2: Int-1 (300 mg, 1.43 mmol, 1 eq) was subjected to the general procedure of amide coupling using HATU to afford Int-2 (250 mg, 62%) as a brown liquid. MS: m / z = 278.1 [M+H] + .

[0935] Step-3: Synthesis of MF-DH-150 and MF-DH-151: Using the general procedure of Ullmann coupling, Int-2 (1 eq) and 2-bromopyrazine (1.2 eq) were converted into MF-DH-150 (35.7% yield) and MF-DH-151 (6.1% yield) which were isolated as off-white solids.

[0936] Synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone MF-DH-161

[0937] An exemplary scheme for the synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0938]

[0939] Scheme 29

[0940] Step-1: Synthesis of methyl 1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (Int-1): In a sealed tube; at room temperature under inert atmosphere, 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) was added Cs 2 CO 3 (1.130 g, 3.47 mmol, 3.0 eq) and 2-bromopyrazine (220 mg, 1.38 mmol, 1.2 eq). Argon was purged for 15 min, and then Xantphos (133.7 mg, 0.234 mmol, 0.2 eq) and Pd were added under argon atmosphere. 2 (dba) 3 (105.8 mg, 0.115 mmol, 0.1 eq). The sealed tube was capped tightly and the resulting reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC; after the reaction was complete, the mixture was washed with saturated NH 4 Cl (10 mL) was quenched, filtered through a celite bed and washed with EtOAc (10 mL). The mixture was extracted with EtOAc (2×10 mL), the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 70% EtOAc / heptane to provide Int-1 (220 mg, 56.4%). MS: m / z=338.1[M+H] + .

[0941] 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 of ester hydrolysis with NaOH to afford Int-2 (120 mg, 57.1%) as a brown solid. MS: m / z = 324.2 [M+H] + .

[0942] 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 of amide coupling using HATU to afford MF-DH-161 (17.0% yield) as a semisolid.

[0943] Synthesis of (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

[0944] Provided below is an exemplary scheme for the synthesis of (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) as inhibitors of hydroxyprostaglandin dehydrogenase.

[0945]

[0946] Scheme 30

[0947] 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 with NaOH to obtain Int-1a (R, R′=CH 3, 86.9% yield, MS: 206.1 [M+H] + ), Int-1b (R = H, R' = CH 3 , 74.0% yield, MS: 192.1 [M+H] + ) and Int-1c (R, R'=H, 73.4% yield, MS: 176.1 [MH] - .

[0948] 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 of amide coupling using HATU to afford Int-2a (R, R′=CH 3 , 800 mg, 86.9% yield, MS: 291.1 [M+H] + ), Int-2b (R = H, R' = CH 3 , 650 mg, 75.9% yield, MS: 277.1 [M+H] + ) and Int-2c (R, R'=H, 73.4% yield, MS: 263.1 [MH] - ).

[0949] 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) was added Cs 2 CO 3 (3eq), followed by purging with argon for 15 min. To this solution was added Pd 2 (dba) 3 (0.1 eq) and xantphos (0.1 eq), and purged with argon for another 10 min. The resulting reaction mixture was stirred at 90 ° C for 16 h. Extraction post-treatment produced a crude product, which was purified by column chromatography and preparative HPLC to provide 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.

[0950] Synthesis of (3-chloro-1-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-167; (3-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-168; and (3-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-191

[0951] Provided below is an exemplary scheme for the synthesis of (3-chloro-1-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-167; (3-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-168; and (3-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-191 as inhibitors of hydroxyprostaglandin dehydrogenase.

[0952]

[0953] Scheme 31

[0954] Step-1: Synthesis of Int-1: 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1 g, 6.16 mmol, 1 eq) was converted into Int-1 (850 mg; yield: 70.1%) as a pale yellow solid using the general procedure of chlorination with NCS. MS: m / z = 197.01 [M+H] + .

[0955] 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 of amide coupling using HATU to afford Int-2 (1.1 g, 76%) as a brown solid. MS: m / z = 282.2 [M+H] + .

[0956] Step-3: General procedure for the synthesis of MF-DH-167 as well as MF-DH-168 and MF-DH-191: To a stirred solution of Int-2 (1 eq) in dioxane (10 mL) was added 5-methyl-2-bromopyrazine / 3-methyl-2-bromopyrazine / 4-bromoanisole (1.2 mmol, 1.2 eq), K 3 PO 4(630 mg, 3 mmol, 3 eq). The reaction mixture was purged with argon for 15 min. 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 to this stirred solution, and stirring was continued at 100 ° C for 16 h. The reaction was monitored by TLC, and after the starting material was completely consumed, the mixture was heated with saturated NH 4 Cl solution (10 mL) was quenched, filtered and washed with EtOAc. This was extracted with EtOAc, washed with ice water (2 × 30 mL) and brine (50 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. This was further purified by preparative HPLC to provide MF-DH-167 (16.5% yield), MF-DH-168 (9.5% yield) and MF-DH-191 (16.9% yield) as off-white solids.

[0957] Synthesis of (4-fluoropiperidin-1-yl)(4-(pyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone 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 MF-DH-207; and (4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone MF-DH-209

[0958] Provided below is an exemplary scheme for the synthesis of (4-fluoropiperidin-1-yl)(4-(pyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone 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 MF-DH-207; and (4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone MF-DH-209 as inhibitors of hydroxyprostaglandin dehydrogenase.

[0959]

[0960] Scheme 32

[0961] 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 of ester hydrolysis with NaOH to provide Int-1 (300 mg, 64.7%) as a brown solid. Repeating the same reaction on 500 mg scale provided 310 mg of Int-1. MS: m / z=179.9 [M+H] + .

[0962] 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 of amide coupling using HATU to afford the crude product. The crude product was purified by silica gel column chromatography to obtain Int-2a (X=H, 95% yield, MS: m / z=247.1[M+H] + ) and Int-2b (X = F, 63.3% yield, MS; m / z = 265.1 [M+H] + ).

[0963] Step-3: Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone, MF-DH-159, MF-DH-207 and MF-DH-209: Using the general procedure of Buchwald coupling, Int-2 (0.56 mmol, 1 eq.) and 2-bromopyrazine / 5-bromobenzo[d][1,3]dioxole / 4-bromoanisole (1.2 eq.) were converted into 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.

[0964] Synthesis of (1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone (MF-DH-203)

[0965] An exemplary scheme for the synthesis of (1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone MF-DH-203 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0966]

[0967] Scheme 33

[0968] Step-1: Synthesis of methyl 4-(tert-butylamino)-3-nitrobenzoate (Int-1): In a steel autoclave, to a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 12.56 mmol, 1 eq) in EtOH (100 mL) was added tert-butylamine (918 mg, 12.56 mmol, 1 eq) at room temperature. The lid was tightly closed and the resulting reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by LCMS / TLC and after completion of the reaction, cooled to room temperature. The volatiles were evaporated and washed with saturated NH 4 The mixture was quenched with Cl (100 mL), extracted with EtOAc (3×50 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 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] + .

[0969] 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) was added iron powder (1.33 g, 23.8 mmol, 5 eq), NH 4 Cl (1.27 g, 23.8 mmol, 5 eq). The resulting reaction mixture was heated to 100 ° C for 16 h. The reaction was monitored by LCMS / TLC, and after the reaction was complete, the mixture was filtered through a celite bed and washed with EtOAc (1×30 mL). The volatiles were evaporated and washed with saturated NaHCO 3 (20mL) quenched, extracted with EtOAc (3×30mL); the combined organic extracts were washed with brine (30mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane to obtain methyl 3-amino-4-(tert-butylamino)benzoate (Int-2, 1.0 g, 95.07%) as a colloidal liquid. MS: m / z=223.1[M+H] + .

[0970] 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 heated to 100 °C for 16 h until SM was consumed according to crude LCMS / TLC. The volatiles were evaporated and washed with saturated NaHCO 3 The crude product was purified by silica gel column chromatography using 50% EtOAc / heptane to obtain methyl 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylate (Int-3, 600 mg, 61.1% yield, MS: m / z=233.1 [M+H]) as a light brown solid. + ).

[0971] 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 afford 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-4, 320 mg, 60.2%, MS: m / z=219.2 [M+H]) as a light brown sticky solid. + ).

[0972] 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 of amide coupling using HATU to afford MF-DH-203 (20.4% yield) as an off-white solid.

[0973] Synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone MF-DH-165

[0974] An exemplary scheme for the synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone MF-DH-165 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0975]

[0976] Scheme 34

[0977] 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 at 0 °C over 15 min. 3 (2.15 g, 34.27 mmol, 3 eq). The resulting reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated and the residue was purified by evaporation with NaHCO 3 Neutralized to pH = 7. The mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography to provide indoline-5-carboxylic acid methyl ester Int-1 (1.65 g, 81.6%) as a brown solid. LCMS: 97.65%, m / z=178.2 [M+H] + .

[0978] Step-2: Synthesis of methyl 1-(pyrazin-2-yl)indoline-5-carboxylate (Int-2): Using the general procedure of 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 into Int-2 (310 mg, 42.9%). LCMS: 95.10%, m / z=257.1 [M+H] + .

[0979] 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 of ester hydrolysis with NaOH to afford 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] + .

[0980] Step-4: Synthesis of ((4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone (MF-DH-165) (General procedure for amide coupling with EDCI): To a stirred solution of 1-(pyrazin-2-yl)indolin-5-carboxylic acid (80 mg, 0.32 mmol, 1 eq) in DCM (10 v) was added EDCI (92 mg, 0.48 mmol, 1.5 eq) and HOBt (52 mg, 0.38 mmol, 1.2 eq) under inert atmosphere. The mixture was cooled to 0 °C and 4-fluoropiperidine (44 mg, 0.32 mmol, 1 .0eq). To this stirred solution was added N,N'-diisopropylethylamine (0.13mL, 0.96mmol, 3eq), DMAP (5mg) at 0°C, and the mixture was then warmed and stirred at room temperature for 16h. The reaction mixture was quenched with ice water (10mL) and extracted with EtOAc (2×15mL). The combined organic extracts were washed with ice water (2×10mL) and brine (10mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography and preparative HPLC to provide MF-DH-165 (7.2% yield) as an off-white solid.

[0981] Synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations

[0982] An exemplary scheme for the synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0983]

[0984] Scheme 35

[0985] 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 and Scheme 10.

[0986] 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 of Ullmann coupling using appropriate aryl bromide. The crude product was purified by flash chromatography to provide MF-DH-285, MF-DH-294, MF-DH-295, MF-DH-296, MF-DH-297, MF-DH-298, MF-DH-300, M F-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.

[0987] Synthesis of pyrrolopyridine-5-carboxamide analogs with N-aryl variations

[0988] An exemplary scheme for the synthesis of pyrrolopyridine-5-carboxamide analogs with N-aryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0989]

[0990] Scheme 36

[0991] General Procedure for Oxidation of Nitriles (MF-DH-299 and MF-DH-301)

[0992] To a stirred solution of Int-2 (0.5 mmol, 1 eq) in DMSO (10 mL) was added K 2 CO 3 (2.0eq), H 2 O 2 (2 eq). The reaction mixture was heated to 80°C for 16 h. The reaction was monitored by LCMS / TLC and after completion, quenched with ice water (20 mL) and The bed was filtered and washed with EtOAc (20 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was further purified by flash chromatography to provide MF-DH-299 and MF-DH-301.

[0993] General Procedure for Reduction of Nitriles (MF-DH-303 and MF-DH-304)

[0994] To a stirred solution of nitrile Int-2 (0.5 mmol, 1 eq) in MeOH (15 mL) was added Ra-Ni (20 mol%) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h under a hydrogen balloon atmosphere. The reaction was monitored by LCMS / TLC; after the reaction was complete, the solid was purified by The bed was filtered, washed with EtOAc (20 mL), and the volatiles were evaporated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the combined organic extracts were washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude product, which was further purified by flash chromatography to provide MF-DH-303 and MF-DH-304.

[0995] General Procedure for Reduction of Aldehydes (MF-DH-307 and MF-DH-308)

[0996] To a stirred solution of aldehyde Int-2 (0.5 mmol, 1 eq) in MeOH (15 mL) was added NaBH portionwise at 0 °C for 15 min. 4 (5 eq). The reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by LCMS / TLC; upon completion, the reaction mixture was washed with saturated NH 4 The mixture was quenched with 1,2-dichloro-2-nitropropene (20 mL) and quenched with 1,2-dichloro-2-nitropropene (20 mL). The mixture was quenched with 1,2-dichloro-2-nitropropene (20 mL) and evaporating the volatiles. The aqueous phase was extracted with ethyl acetate (2 × 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 provide a crude product, which was further purified by flash chromatography to provide MF-DH-307 and MF-DH-308.

[0997] Synthesis of 3-chloro-pyrrolopyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations

[0998] An exemplary scheme for the synthesis of 3-chloro-pyrrolopyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0999]

[1000] Scheme 37

[1001] The synthesis of Int-1a (X=H) is described in Scheme 9. The synthesis of Int-1b (X=F) is described in Scheme 31.

[1002] 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 into the title compounds according to the general procedure of Ullmann coupling using appropriate aryl bromide.

[1003] Synthesis of MF-DH-146

[1004] An exemplary scheme for the synthesis of MF-DH-146 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1005]

[1006] Scheme 38

[1007] Step-1: SM 4-chloro1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was converted into Int-1 using the general procedure of HATU coupling to afford Int-1 as a brown solid (70%). MS: m / z=282.2[M+H] + .

[1008] Step-2: Int-2 was converted into MF-DH-146 using the general procedure of Buchwald coupling to afford MF-DH-146 as an off-white solid.

[1009] Synthesis of MF-DH-147

[1010] An exemplary scheme for the synthesis of MF-DH-147 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1011]

[1012] Scheme 39

[1013] Step-1: SM was converted to Int-1 using the general procedure of chlorination with NCS to provide Int-1 (334 mg; yield: 70.1%) as a pale yellow solid. MS: m / z = 231.10 [M+H] + .

[1014] Step-2: Int-1 was converted to Int-2 using the general procedure of HATU coupling to afford Int-2 (323 mg, 76%) as a brown solid. MS: m / z = 299.2 [M+2H] + .

[1015] Step-3: Int-2 was converted into MF-DH-147 using the general procedure of Buchwald coupling to afford MF-DH-147 as an off-white solid.

[1016] Synthesis of MF-DH-148

[1017] An exemplary scheme for the synthesis of MF-DH-148 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1018]

[1019] Scheme 40

[1020] Step-1: SM 6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid was converted to Int-1 using the general procedure of HATU coupling to afford Int-1 as a brown liquid (60%). MS: m / z=262.1 [M+H] + .

[1021] Step-2: Synthesis of MF-DH-148: Int-1 (0.95 mmol, 1 eq) and 2-bromopyrazine (183 mg, 1.14 mmol, 1.2 eq) were reacted using the general procedure of Buchwald coupling to afford the crude product, which was purified sequentially by silica gel column chromatography using 70% EtOAc / heptane and preparative HPLC purification to afford MF-DH-148.

[1022] Synthesis of MF-DH-149

[1023] An exemplary scheme for the synthesis of MF-DH-149 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1024]

[1025] Scheme 41

[1026] Step-1: 6-Methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (SM) was converted into Int-1 using the general procedure of chlorination with NCS to provide Int-1 (300 mg; yield: 84.2%) as a gummy liquid. MS: m / z=211.2 [M+H] + ,212.2[M+2H] + .

[1027] Step-2: Int-1 was converted to Int-2 using the general procedure of HATU coupling to provide Int-2 (259 mg / 168 mg, 63%) as a brown liquid. MS: m / z = 278.1 [M+H] + .

[1028] Step-3: Synthesis of MF-DH-149: Int-2 (0.95 mmol, 1 eq) and 2-bromopyrazine were reacted using the general procedure of Buchwald coupling to afford the crude product, which was purified sequentially by silica gel column chromatography using 70% EtOAc / heptane and preparative HPLC purification to afford MF-DH-149.

[1029] Synthesis of (1-(Methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-311) and piperidin-1-yl(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (MF-DH-312)

[1030] Provided below is an exemplary scheme for the 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 as inhibitors of hydroxyprostaglandin dehydrogenase.

[1031]

[1032] Scheme 42

[1033] The synthesis of Int-1 is described in Scheme 9.

[1034] 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, toluenesulfonyl chloride and methanesulfonyl 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; after complete consumption of the starting material, the reaction mixture was washed with saturated NH 4Cl (10ml) is quenched and extracted with EtOAc (2 × 50mL). The combined organic extracts are washed with brine (20mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. The crude product is purified by silica gel column chromatography using 60% EtOAc / heptane to provide (1- (methylsulfonyl) -1H- pyrrolo [2,3-b] pyridine -5- bases) (piperidin -1- bases) ketone (MF-DH-311) and piperidin -1- bases (1- tosyl -1H- pyrrolo [2,3-b] pyridine -5- bases) ketone (MF-DH-312) in off-white solid.

[1035] Synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations

[1036] An exemplary scheme for the synthesis of 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 as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1037]

[1038] Scheme 43

[1039] 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.

[1040] Int-1a was converted to MF-DH-318 using the general procedure of Ullmann coupling with 7-bromoimidazo[1,2-a]pyridine to provide MF-DH-318 as a sticky solid.

[1041] Int-1a was converted to MF-DH-320 using the general procedure of Ullmann coupling with 3-bromo-5-methylpyridine and Int-1 to afford MF-DH-320 as an off-white solid.

[1042] Int-1a was converted to MF-DH-322 using the general procedure of Ullmann coupling with 5-bromopyridin-3-amine to afford MF-DH-322 as an off-white solid.

[1043] Int-1b was converted to MF-DH-342 using the general procedure of Ullmann coupling with 4-bromobenzonitrile to afford MF-DH-342 as an off-white solid.

[1044] Int-1b was converted to MF-DH-344 using the general procedure of Ullmann coupling with 3-bromobenzonitrile to afford MF-DH-344 as an off-white solid.

[1045] Int-1b was converted to MF-DH-346 using the general procedure of Ullmann coupling with 4-bromo-N,N-dimethylaniline to afford MF-DH-346 as an off-white solid.

[1046] Int-1a was converted to MF-DH-366 using the general procedure of Ullmann coupling with 5-bromo-N,N-dimethylpyridin-2-amine to afford MF-DH-346 as an off-white solid.

[1047] Int-1a was converted to MF-DH-389 using the general procedure of Ullmann coupling with 5-bromopicolinonitrile to afford MF-DH-389 as an off-white solid.

[1048] Int-1a was converted to MF-DH-397 using the general procedure of Ullmann coupling with 5-bromopyrimidine-2-carbonitrile to afford MF-DH-397 as an off-white solid.

[1049] Synthesis of (1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-319)

[1050] An exemplary scheme for the synthesis of (1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone MF-DH-319 as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1051]

[1052] Scheme 44

[1053] 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) was added NaH (60% in mineral oil) (0.24 g, 6.08 mmol, 1.2 eq) at 0 °C to room temperature for 1 h. 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; after complete consumption of the starting material, the reaction mixture was washed with saturated NH 4Cl (10ml) quenched and extracted with EtOAc (2×50mL). The combined organic extracts were washed with brine (20mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to provide 5-bromo-1-(4-methoxybenzyl)-1H-indazole Int-A (0.81g, 50.06%) and 5-bromo-1-(4-methoxybenzyl)-2H-indazole Int-A' (0.55g, 34.3%) as off-white solids. LCMS: 98.3%, m / z=318.1[M+2H] + .

[1054] Step-1: The synthesis of Int-1 is described in Scheme 9. Int-1 was converted into MF-DH-337 using the general procedure of Ullmann coupling with 5-bromo-1-(4-methoxybenzyl)-1H-indazole (Int-A) and Int-1 to afford MF-DH-337 as a sticky solid.

[1055] Step-3: Int-1 was converted into MF-DH-340 using the general procedure of Ullmann coupling with 5-bromo-1-(4-methoxybenzyl)-2H-indazole (Int-A') and Int-1 to afford MF-DH-340 as an off-white solid.

[1056] 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 followed by heating to 80°C for 16 h. The reaction was monitored by crude LCMS / TLC; after complete consumption of the starting material, the reaction mixture was washed with saturated NaHCO 3 The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to provide 5 (1- (1H-indazole-5-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (piperidin-1-yl) ketone (MF-DH-319) as a viscous liquid.

[1057] Synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations

[1058] An exemplary scheme for the synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1059]

[1060] Scheme 45

[1061] The synthesis of Int-1a (X, X'=H) and Int-1b (X=H, X'=F) is described in Scheme 9.

[1062] 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) was added HATU (84.44 g, 222.2 mmol, 1.3 eq) and 4,4-difluoropiperidine (31.98 g, 203.7 mmol, 1.1 eq) at 0°C under inert atmosphere. To this stirred solution was added N,N'-diisopropylethylamine (119.6 g, 925.9 mmol, 5 eq) at 0°C and stirring was continued at room temperature for 16 h. The reaction mixture was quenched with ice water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with ice water (2×100 mL) and brine (100 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude was purified by flash column chromatography to afford 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=2.8Hz,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] + .

[1063] Step-1: Convert Int-1a, Int-1b and Int-1c into Int-2a: (Ar 1 =pyridine-2-CN; X, X'=H) 30% yield, MS: m / z=332.2 [M+H] + ; Int-2b: (Ar 1 =pyrazine-2-CN; X, X'=H) 68% yield, MS: m / z=333.2 [M+H] + ; Int-2c: (Ar 1=4-CHO-Ph; X, X'=H) 83% yield, MS: m / z=334.1 [M+H] + ; Int-2d: (Ar 1 =3-CHO-Ph; X, X'=H) 53% yield, MS: m / z=334.1 [M+H] + , Int-2e: (Ar 1 =4-CH 3 C=O-Ph;X, X'=H) 62% yield, MS: m / z=348.1[M+H] + ; Int-2f: (Ar 1 =3-CH 3 C=O-Ph;X, X'=H) 60% yield, MS: m / z=348.1[M+H] + , Int-2g: (Ar 1 =4-CHO-Ph; X = H, X' = F) 58% yield, MS: m / z = 353.1 [M+H] + ; Int-2h: (Ar 1 =3-CHO-Ph, X=H, X'=F) 78% yield, MS: m / z=353.1 [M+H] + , and Int-2i: (Ar 1 =4-CN-Ph, X=H, X'=F) 43% yield, MS: m / z=349.2 [M+H] + .

[1064] 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.

[1065] Using the general procedure for the reduction of aldehydes / ketones, MF-DH-347, MF-DH-348, MF-DH-347, and MF-DH-348 were obtained as viscous liquids.

[1066] General Procedure for Aldehyde / Ketone Alkylation

[1067] 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) portionwise at 0 °C for 15 min. The reaction mixture was stirred for 5 h at room temperature. The reaction was monitored by LCMS / TLC. After completion, the reaction mixture was washed with saturated NH 4 The reaction mixture was quenched with Cl (20 mL), extracted with EtOAc (2×20 mL), and the combined organic extracts were washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was further purified by flash chromatography to afford MF-DH-370, MF-DH-374, MF-DH-371, and MF-DH-375 as off-white solids and viscous liquids.

[1068] 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 NaBH portionwise at 0 °C for 15 min. 4 The reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated in vacuo, diluted with water, and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with saline solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude product, which was further purified by flash chromatography to provide MF-DH-347 and MF-DH-348 as off-white solids.

[1069] Synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations (MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327, MF-DH-328, MF-DH-329)

[1070] An exemplary scheme for the synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1071]

[1072] Scheme 46

[1073] Step-1: Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (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) and DMF (0.5 mL) sequentially at 0 °C for 30 min, followed by stirring at room temperature for 1 h. The reaction was monitored by TLC, and after completion of the reaction, it was quenched with methanol (20 mL) and stirred at room temperature for 12 h. The solvent was then evaporated under reduced pressure and diluted with ethyl acetate (100 mL), washed with saturated NaHCO 3 The solution was washed with 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester Int-1 (5.38 g, 99%). LCMS: 96.42%, m / z=177.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.08(brs,1H),8.78(s,1H),8.50(s,1H),7.56(s,1H),6.57(s,1H),3.81(s,3H).

[1074] Step-2 Synthesis of methyl 1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Int-2): Using the general procedure of Ullmann reaction, Int-1 (2.5 g, 14.1 mmol) was converted into Int-2 (2.51 g, 62.5%) which was isolated as an off-white solid. LCMS: 99.12%, m / z=283.1 [M+H] + .

[1075] 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 of ester hydrolysis with NaOH to afford Int-3 (1.5 g, 65.21%) as a light brown sticky solid. LCMS: 96.35 m / z = 269.1 [M+H] + .

[1076] Step-4: Synthesis of MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327, MF-DH-328 and MF-DH-329: The general procedure of HATU coupling was used to convert Int-3 into 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 solid / sticky solid after purification.

[1077] Synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations

[1078] An exemplary scheme for the synthesis of pyrrolopyridine-5-carboxamide analogs with amide / aryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1079]

[1080] Scheme 47

[1081] The synthesis of Int-1a (X=H) and Int-1b (X=F) is described in Scheme 9.

[1082] Step-1: Int-1a / 1b was converted to Int-2a / 2b using the general procedure of Ullmann coupling with 4-bromobenzoate to afford Int-2a (X = H, 55% yield, MS: m / z = 364.1 [M+1]) as an off-white solid. + ) and Int-2b (X = F, 60.74% yield, MS: m / z = 382.1 [M+1] + ).

[1083] Step-2: Int-2 was converted to Int-3a (X = H, 86% yield, m / z = 350.1 [M+1]) using the general procedure of ester hydrolysis with NaOH. + ) and Int-3b (X = F, 89% yield, MS: m / z = 366.1 [MH] - ). The crude product was used in the next stage without purification.

[1084] Step-3: Int-3 was subjected to the general procedure of amide coupling with HATU to afford MF-DH-357, MF-DH-367, MF-DH-358, MF-DH-368, MF-DH-359 and MF-DH-360.

[1085] Synthesis of Azabenzimidazole Analogs with Aryl / Amide Variations:

[1086] An exemplary scheme for the synthesis of azabenzimidazole analogs with amide / aryl variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1087]

[1088] Scheme 48

[1089] Step-1: Synthesis of Int-1, general procedure: In a sealed autoclave, methyl 6-chloro-5-nitronicotinate (7 g, 32.31 mmol, 1 eq), arylamine (Ar-NH 2 , 1 eq) was dissolved in EtOH (70 mL). To this stirred solution was added K 2 CO 3 (1 eq). The steel autoclave was capped and the reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction; cooled...

Claims

1. A compound of formula IIq: Formula IIq or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl and 5- to 10-membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 S02R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 5- to 10-membered heteroaryl; R 2 and R 3 Together they form an oxo group; Each R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 5 Selected from halogen, –NR 6 R 7 ,–OR 8 , C 1-6 Alkyl, and C 1-6 Haloalkyl; R 6 and R 7 independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; Each R 8 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; Each R 9 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; Each R 10 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; n is 1, 2, or 3; m is 0, 1, 2, or 3; and p is 0, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently halo. 3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; and n is 2 or 3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen and C 1-6 alkyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 0.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl and 5- to 10-membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SO2R 9 , C 1-6 alkyl, and 5-membered heteroaryl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl and 5- to 10-membered heteroaryl; wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, -NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 It is phenyl.

9. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl group selected from the group consisting of isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl, isoindolyl, indolizinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl and triazolyl.

10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a muscle disorder in a subject in need thereof.

13. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing muscle damage in a subject in need thereof.

14. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing muscle atrophy in a subject in need thereof.

15. The use according to claim 12, 13 or 14, wherein the medicament enables muscle regeneration and muscle repair after injury.

16. The method of claim 12, wherein the muscle disorder is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), distal muscular dystrophy (DD), hereditary myopathy, myotonic dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Aime-Dreyfus muscular dystrophy, or sarcopenia.

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