PGDH inhibitors and methods of making and using

Abstract

Disclosed herein are compounds capable of inhibiting 15-hydroxyprostaglandin dehydrogenase. Such compounds may be administered to subjects that may benefit from modulation of prostaglandin levels.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of January 22, 2021, an application number of 202180024179.2, and an invention title of "PGDH Inhibitors and Methods of Preparation and Use" (the corresponding PCT application has an application date of January 22, 2021 and an application number of PCT / US2021 / 014783).

[0002] Cross-reference

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 965,062, filed January 23, 2020; U.S. Provisional Application No. 63 / 007,755, filed April 9, 2020; U.S. Provisional Application No. 63 / 029,184, filed May 22, 2020; U.S. Provisional Application No. 63 / 092,116, filed October 15, 2020; U.S. Provisional Application No. 63 / 110,803, filed November 6, 2020; and U.S. Provisional Application No. 63 / 133,965, filed January 5, 2021, each of which is incorporated herein by reference. BACKGROUND OF THE INVENTION

[0004] Prostaglandins are a group of physiologically active lipid compounds with diverse biological actions, including vasodilation, inhibition of platelet aggregation, bronchodilation, bronchoconstriction, immune response, contraction and relaxation of gastrointestinal smooth muscle, gastric acid secretion, gastric mucus secretion, uterine contraction, inhibition of lipolysis, neurotransmission, blood coagulation, hyperalgesia, and fever.

[0005] Treatment of a disease or disorder may require activation of prostaglandins or inhibition of prostaglandin inactivation. Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), are involved in prostaglandin inactivation. Thus, diseases / conditions 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

[0006] 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:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–,

[0010] –SCH2–, –S(O)CH2–, –SO2CH2–;

[0011] each Y is independently selected from N and CR 11 ;

[0012] each R 1 is 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 –SO2R 9 –SO2NR 6 R 7 –NR 10 C(O)R 8 –NR 10 C(O)NR 6 R 7 –NR 10 SO2R 8 –NR 10 SO2NR 6 R 7 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0013] R 2 is H, and R 3 is –CF3; or

[0014] R 2 and R 3 together form an oxo or thioxo group;

[0015] each R 4 is 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 –SO2R9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0016] Each R 5 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0017] R 6 and R 7 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0018] Each R 8 is 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;

[0019] Each R 9 is 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;

[0020] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0021] Each R 11 is independently selected from halo, –NR 9 R 10 –, –OR 11 –, –C(O)R 11 –, –C(O)OR 11 –, –C(O)NR 9 R 10 –, –SOR 12 –, –SO2R 12 –, –SO2NR 9 R 10 –, –NR 13 C(O)R 11 –, –NR 13 C(O)NR 9 R 10 –, –NR 13 SO2R 11 –, –NR 13 SO2NR 9 R 10 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0022] n is 0, 1, 2, 3, 4, or 5;

[0023] m is 0, 1, 2, 3, or 4; and

[0024] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0025] provided that the compound of formula I is not

[0026] In some embodiments, the compound is a compound of formula Ia:

[0027]

[0028]

[0029] or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound is a compound of formula Ib:

[0031]

[0032] or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, the present disclosure provides 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:

[0034]

[0035] or a pharmaceutically acceptable salt thereof, wherein:

[0036] T, U, W, X and Y are independently selected from N and CR 5 ;

[0037] S, V and Z are independently selected from N and C;

[0038] R 1 is 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; wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents 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 、–SO2R 9, –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 5 - to 10 - membered heteroaryl;

[0039] R 2 is H, and R 3 is –CF3; or

[0040] R 2 and R 3 together form an oxo group or a thio group;

[0041] Each R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3 - to 10 - membered heterocycloalkyl, C 6-10 aryl and 5 - to 10 - membered heteroaryl; or

[0042] Two Rs 4Together with the carbon atoms and any intervening atoms to which they are attached, form a C 3-10 cycloalkyl group, and any remaining R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0043] Each R 5 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0044] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0045] Each R 8 is 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;

[0046] Each R 9 is 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;

[0047] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and

[0048] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0049] provided that the compound of formula II is not

[0050]

[0051]

[0052] In some embodiments, the compound is a compound of formula IIa:

[0053]

[0054] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0055] In some embodiments, the compound is a compound of formula IIb:

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0058] In some embodiments, the compound is a compound of formula IIc:

[0059]

[0060] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0061] In some embodiments, the compound is a compound of formula IId:

[0062]

[0063] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0064] In some embodiments, the compound is a compound of formula IIe:

[0065]

[0066] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0067] In some embodiments, the compound is a compound of formula IIf:

[0068]

[0069] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0070] In some embodiments, the compound is a compound of formula IIg:

[0071]

[0072] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0073] In some embodiments, the compound is a compound of formula IIh:

[0074]

[0075] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0076] In some embodiments, the compound is a compound of formula IIi:

[0077]

[0078] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0079] In some embodiments, the compound is a compound of Formula IIj:

[0080]

[0081] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0082] In some embodiments, the compound is a compound of Formula IIn:

[0083]

[0084] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0085] In some embodiments, the compound is a compound of Formula IIp:

[0086]

[0087] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0088] 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:

[0089]

[0090] or a pharmaceutically acceptable salt thereof, wherein:

[0091] each X is independently selected from N and CR 7 ;

[0092] Y is selected from O, S, SO2 and C(R 8 )2;

[0093] R 1 is 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; wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0094] R 2 is H, and R 3 is –CF3; or

[0095] R 2 and R 3 together form an oxo group or a thio group;

[0096] R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0097] R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heteroalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0098] Each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0099] Two Rs attached to the same carbon atom 6 together form an oxo group, a thio group or C 3-10 cycloalkyl, and any remaining R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0100] Each R 7 is 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 、 –SOR12 、 –SO₂R 12 、 –SO₂NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO₂R 11 、 –NR 13 SO₂NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0101] Each R 8 is independently selected from H, halogen, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO₂R 12 、 –SO₂NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO₂R 11 、 –NR 13 SO₂NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0102] Two R 8 may together form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halogen, –NR 9 R 10 、 –OR 11, –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 , C [[alkyl]], C 1-6 , C [[heteroalkyl]], C 1-6 , C [[haloalkyl]], C 3-10 , C [[cycloalkyl]], 3- to 10-membered [[heterocycloalkyl]], C 6-10 , C [[aryl]] and 5- to 10-membered [[heteroaryl]];

[0103] R 9 and R 10 are each independently selected from H, C 1-6 [[alkyl]], C 1-6 [[heteroalkyl]], C 1-6 [[haloalkyl]] and C 3-10 [[cycloalkyl]];

[0104] Each R 11 is independently selected from H, C 1-6 [[alkyl]], C 1-6 [[heteroalkyl]], C 1-6 [[haloalkyl]], C 3-10 [[cycloalkyl]], C 6-10 , C [[aryl]] and 5- to 10-membered [[heteroaryl]];

[0105] Each R 12 is independently selected from C 1-6 [[alkyl]], C 1-6 [[heteroalkyl]], C 1-6 [[haloalkyl]], C 3-10 [[cycloalkyl]],

[0106] C 6-10 , C [[aryl]] and 5- to 10-membered [[heteroaryl]];

[0107] Each R 13 is independently selected from H, C 1-6 [[alkyl]], C 1-6 [[haloalkyl]] and C 3-10 [[cycloalkyl]];

[0108] m is 1 or 2; and

[0109] n is 0, 1, 2, 3 or 4.

[0110] In some embodiments, the compound is a compound of formula IIIa:

[0111]

[0112] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound is a compound of formula IIIb:

[0114]

[0115] or a pharmaceutically acceptable salt thereof, wherein:

[0116] each R 14 is independently selected from halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

[0117] p is 0, 1, 2 or 3.

[0118] In some embodiments, the compound is a compound of formula IIIc:

[0119]

[0120] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound is a compound of Formula IIId:

[0122]

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

[0124] Each R 14 is independently selected from halo, –NR 9 R 10 –OR 11 –C(O)R 11 –C(O)OR 11 –C(O)NR 9 R 10 –SOR 12 –SO2R 12 –SO2NR 9 R 10 –NR 13 C(O)R 11 –NR 13 C(O)NR 9 R 10 –NR 13 SO2R 11 –NR 13 SO2NR 9 R 10 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

[0125] p is 0, 1, 2, or 3.

[0126] In another aspect, provided herein is a compound of Formula IIk:

[0127]

[0128] or a pharmaceutically acceptable salt thereof, wherein:

[0129] 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;

[0130] R 1 is 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: halo, –NR 7 R 8 –OR9 、 –C(O)R 9 、 –C(O)OR 9 、 –C(O)NR 7 R 8 、 –SOR 10 、 –SO2R 10 、 –SO2NR 7 R 8 、 –NR 11 C(O)R 9 、 –NR 11 C(O)NR 7 R 8 、 –NR 11 SO2R 9 、 –NR 11 SO2NR 7 R 8 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5- to 10-membered heteroaryl;

[0131] R 2 is H and R 3 is –CF3; or

[0132] R 2 and R 3 together form an oxo group;

[0133] Each R 4 is independently selected from H and halo;

[0134] R 5 is selected from halo, –NR 7 R 8 、 –OR 9 、 –C(O)R 9 、 –C(O)OR 9 、 –C(O)NR 7 R 8 、 –SOR 10 、 –SO2R 10 、 –SO2NR 7 R 8 、 –NR 11 C(O)R 9 、 –NR 11 C(O)NR 7 R 8 、 –NR 11 SO2R 9 、 –NR 11 SO2NR 7 R 8 、 C1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0135] R 6 is independently 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 、–SO2R 10 、–SO2NR 7 R 8 、–NR 11 C(O)R 9 、–NR 11 C(O)NR 7 R 8 、–NR 11 SO2R 9 、–NR 11 SO2NR 7 R 8 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0136] R 7 and R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;

[0137] Each R 9 is 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;

[0138] Each R 10 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0139] Each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and

[0140] p is 0, 1 or 2.

[0141] In another aspect, the present invention provides a compound of formula IIm:

[0142]

[0143] or a pharmaceutically acceptable salt thereof, wherein:

[0144] R 1 is 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 following: halo, –NR 6 R 7 –, –OR 8 –, –C(O)R 8 –, –C(O)OR 8 –, –C(O)NR 6 R 7 –, –SOR 9 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 5- to 10-membered heteroaryl;

[0145] R 2 is H, and R 3 is –CF3; or

[0146] R 2 and R 3 together form an oxo group;

[0147] Each R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or

[0148] Two Rs 4 together with the carbon atom and any intervening atoms to which they are attached form a C 3-10 cycloalkyl, and any remaining Rs 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0149] R 5 is 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 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0150] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0151] Each R 8 is 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;

[0152] Each R 9 is independently selected from 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;

[0153] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0154] n is 1, 2, 3, or 4;

[0155] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0156] p is 0, 1, 2, or 3.

[0157] In another aspect, the present disclosure provides a compound of Formula IIq:

[0158]

[0159] or a pharmaceutically acceptable salt thereof, wherein:

[0160] R 1 is 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 following: halo, –NR 6 R 7 –, –OR 8 –, –C(O)R 8 –, –C(O)OR 8 –, –C(O)NR 6 R 7 –, –SOR 9 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;

[0161] R 2 is H, and R 3 is –CF3; or

[0162] R 2 and R 3 together form an oxo group;

[0163] Each R 4 is 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 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0164] Two Rs 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining Rs 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 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0165] R 5 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0166] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0167] Each R 8 is 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;

[0168] Each R 9 is 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;

[0169] each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0170] n is 1, 2, 3, or 4;

[0171] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0172] p is 0, 1, 2, or 3.

[0173] In another aspect, the present disclosure provides a compound of Formula IIIc:

[0174]

[0175] or a pharmaceutically acceptable salt thereof, wherein:

[0176] each X is independently selected from N and CR 7 ;

[0177] Y is selected from O, S, SO2, and C(R 8 )2;

[0178] R 1 is 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: halo, –NR 9 R 10 –OR 11 –C(O)R 11 –C(O)OR 11 –C(O)NR 9 R 10 –SOR 12 –SO2R 12 –SO2NR 9 R 10 –NR 13 C(O)R 11 –NR 13 C(O)NR 9 R 10 –NR 13 SO2R 11 –NR 13 SO2NR 9 R10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl;

[0179] R 2 is H, and R 3 is –CF3; or

[0180] R 2 and R 3 together form an oxo group;

[0181] R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 , –NR 9 SO2NR 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

[0182] R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0183] Each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0184] Two Rs attached to the same carbon atom 6 together form an oxo group, and any remaining Rs 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0185] 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 Aryl, and 5- to 10-membered heteroaryl;

[0186] R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 halogenated alkyl, and C 3-6 cycloalkyl;

[0187] Each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 halogenated alkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0188] Each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 halogenated alkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0189] Each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 halogenated alkyl, and C 3-6 cycloalkyl; and

[0190] n is 0, 1, 2, 3, or 4.

[0191] In another aspect, the present disclosure provides a composition comprising a compound selected from:

[0192]

[0193]

[0194] In another aspect, the present disclosure provides a composition comprising a compound selected from:

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205] On the other hand, the present disclosure provides a composition comprising a compound selected from the following:

[0206]

[0207]

[0208] On the other hand, the present disclosure provides a method for promoting and / or stimulating skin pigmentation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0209] On the other hand, the present disclosure provides a method for inhibiting hair loss, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0210] A method for preventing and / or treating skin inflammation and / or damage, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0211] On the other hand, the present disclosure provides 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.

[0212] On the other hand, the present disclosure provides a method for 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.

[0213] On the other hand, the present disclosure provides a method for reducing cardiac ejection fraction, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0214] On the other hand, the present disclosure provides a method for preventing and / or treating gastrointestinal diseases, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0215] In another aspect, the present disclosure provides 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.

[0216] In another aspect, the present disclosure provides a method for stimulating bone resorption and bone formation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0217] In another aspect, the present disclosure provides a method for stimulating tissue regeneration by stimulation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0218] In another aspect, the present disclosure provides a method for regulating cervical ripening, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0219] In another aspect, the present disclosure provides a method for 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.

[0220] In another aspect, the present disclosure provides a method for treating and / or preventing a neurological disorder, neuropsychiatric disorder, nerve injury, neurotoxic disorder, neuropathic pain, or neurodegenerative disorder, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0221] In another aspect, the present disclosure provides a method for 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.

[0222] In another aspect, the present disclosure provides a method for reducing and / or preventing scar formation, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0223] In another aspect, the present disclosure provides a method for treating and / or preventing a muscle disorder, muscle injury, and / or muscle atrophy, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0224] In another aspect, the present disclosure provides a method for treating and / or preventing fibrosis, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0225] In another aspect, the present disclosure provides a method for 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.

[0226] In another aspect, the present disclosure provides a method for treating and / or preventing renal fibrosis, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0227] In another aspect, the present disclosure provides a method for stimulating muscle regeneration, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0228] In another aspect, the present disclosure provides a method for promoting organ health, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0229] In another aspect, the present disclosure provides a method for promoting wound healing, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0230] In another aspect, the present disclosure provides a method for treating acute kidney injury, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0231] In another aspect, the present disclosure provides a method for treating sarcopenia, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0232] In another aspect, the present disclosure provides a method for treating neuromuscular diseases, the method comprising administering one or more of the compositions of any of the preceding claims to a subject in need thereof.

[0233] Incorporation by reference

[0234] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the 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

[0235] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the invention may be understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings, in which:

[0236] Figure 1 Results of cell-based assays of exemplary compounds are shown. DETAILED DESCRIPTION

[0237] DEFINITIONS

[0238] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0239] Unless the context clearly dictates otherwise, as used herein, the singular forms "a," "an," and "the" include plural referents.

[0240] The term "C x-y " when used in conjunction with chemical moieties such as alkyl, haloalkyl, or heteroalkyl is intended to include groups having from x to y carbons in the chain. By way of example, the term "C 1-6 alkyl" refers to a saturated hydrocarbon group, substituted or unsubstituted, having from 1 to 6 carbons, including straight-chain and branched-chain alkyl groups. The term –C x-y alkylene– refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. By way of example, –C 1-6 alkylene– may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which may be optionally substituted.

[0241] "Alkyl" refers to a saturated hydrocarbon group, substituted or unsubstituted, including straight-chain and branched-chain alkyl groups. Alkyl may contain from one to twelve carbon atoms (e.g., C 1-12 alkyl), such as from one to eight carbon atoms (C 1-8 alkyl) or from one to six carbon atoms (C 1-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. Alkyl is attached to the remainder of the molecule by a single bond. Unless specifically stated otherwise in the specification, alkyl is optionally substituted by one or more substituents such as those described herein.

[0242] "Haloalkyl" refers to an alkyl group substituted by 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.

[0243] "Heteroalkyl" refers to a substituted or unsubstituted alkyl having one or more skeletal chain atoms selected from atoms other than carbon. Exemplary skeletal chain atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. If given, a numerical range refers to the overall chain length. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. The attachment to the remainder of the molecule may be through a heteroatom or carbon in the heteroalkyl chain. Unless otherwise specifically stated in the specification, the heteroalkyl is optionally substituted with one or more substituents such as those described herein.

[0244] "Aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl may optionally be substituted. Examples of aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, the aryl may be a monovalent or 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 aryl that is optionally substituted.

[0245] "Heteroaryl" means an aromatic ring of 3 to 12 members containing at least one heteroatom, wherein each heteroatom may independently be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π electron system that complies with Hückel's theory. One or more of the heteroatoms in the heteroaryl may optionally be oxidized. If present, then one or more nitrogen atoms are optionally quaternized. Subject to valence allowances, the heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl such as a carbon or nitrogen atom of the heteroaryl.Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benz[b][1,4]dioxepinyl, benz[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxadienyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl) (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benz[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopentadieno[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadieno[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]azepino[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinone, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, 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-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).Unless specifically stated otherwise in the specification, the heteroaryl is optionally substituted with one or more substituents such as those described herein.

[0246] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each atom forming the ring (i.e., the backbone atom) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spiro or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case, the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl includes groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyls include, 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-dihydronaphthalen-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless specifically stated otherwise in the specification, the cycloalkyl may be optionally substituted.

[0247] The term "heterocycloalkyl" refers to a cycloalkyl that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in the specification, the heterocycloalkyl may be a monocyclic or bicyclic ring system, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl may be partially or fully saturated. Examples of heterocycloalkyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 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, the heterocycloalkyl has 2 to 12 carbons in the ring. It should be understood that when referring to the number of carbon atoms in the heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). Unless specifically stated otherwise in the specification, the heterocycloalkyl may be optionally substituted.

[0248] The term "substituted" refers to substituents replacing hydrogen on one or more carbons or heteroatoms having a replacement structure. It should be understood that "substituted" or "substituted with" includes the implicit conditions that such substitution conforms to the allowable valences of the atoms being substituted and the substituents, and that the substitution results in a stable compound, e.g., a stable compound that does not spontaneously undergo transformations such as those achieved by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all allowable substituents of organic compounds. In a broad aspect, allowable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the allowable 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 allowable substituents that conform to the valence of the heteroatom of the organic compounds described herein. Substituents may include any of the substituents described herein, such as oxo groups, halogens, hydroxyl groups, carbonyl groups (such as carboxyl groups, alkoxycarbonyl groups, formyl groups or acyl groups), thiocarbonyl groups (such as thioesters, thioacetates or thiocarboxylates), alkoxy groups, phosphoryl groups, phosphates, phosphonates, phosphinites, amino groups, amido groups, amidines, imines, cyano groups, nitro groups, azide groups, hydrosulfide groups, alkylthio groups, sulfates, sulfonates, sulfamoyl groups, sulfonamido groups, sulfonyl groups, heterocyclic groups, aralkyl groups, carbocycles, heterocycles, cycloalkyl groups, heterocycloalkyl groups, aromatic and heteroaromatic moieties.

[0249] One of ordinary skill in the art will appreciate that, if appropriate, the substituents themselves may be substituted. Unless specifically stated as "unsubstituted", a chemical moiety referred to herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0250] When substituent groups are specified by their conventional chemical formulas written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0251] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes both the case where the described event or circumstance occurs and the case where it does not occur. For example, "optionally substituted aryl" means that the aryl may or may not be substituted, and the description includes both substituted aryl and aryl without substitution.

[0252] 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.

[0253] The compounds described herein may exhibit their natural isotopic abundances, or one or more atoms may be subjected to artificial enrichment with specific isotopes having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether or not radioactive, are encompassed within the scope of the present disclosure. By way of example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium 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.

[0254] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the 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 designate a racemic mixture. "Diastereomers" or "diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, and the asymmetric centers can be defined as (R)- or (S)- with respect to 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)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of preponderance of one stereoisomer over another can be determined.

[0255] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the 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.

[0256] 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 combinations of these procedures. Specific descriptions of suitable separation and isolation procedures can be obtained by reference to the examples below. However, other equivalent separation or isolation procedures can also be used.

[0257] When no stereochemistry is specified, certain small molecules described herein include, where possible, but are not limited to, their isomers, such as enantiomers and diastereomers; mixtures of enantiomers, including racemates; mixtures of diastereomers; and other mixtures thereof, provided that they can be prepared by one of ordinary skill in the art by routine experimentation. In these cases, a single enantiomer or diastereomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolution of a mixture of a racemate or diastereomers. If possible, resolution of a mixture of a racemate or diastereomers can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral high performance 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 major enantiomer. In addition, certain small molecules include Z and E forms (or cis and trans forms) of certain small molecules having 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.

[0258] 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, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0259] 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 injurious 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 carboxymethyl cellulose, 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 glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, 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 solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0260] The term "effective amount" or "therapeutically effective amount" means that amount of a compound described herein sufficient to achieve a predetermined application, including but not limited to the treatment of diseases, as defined below. A 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., and can be readily determined by one of ordinary skill in the art. The term also applies to doses that can induce a specific response (e.g., a decrease in platelet adhesion and / or cell migration) in target cells. The specific dose may vary depending on the particular 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.

[0261] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, the beneficial or desired result including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, eradication or amelioration of the underlying disorder being treated. Additionally, a therapeutic benefit can include, for example, eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be afflicted with the underlying disorder. In certain embodiments, for a prophylactic benefit, the composition is administered to a subject at risk of manifesting a particular disease, or a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0262] "Therapeutic effect", as the term is used herein, encompasses the therapeutic and / or prophylactic benefits as described above. Prophylactic effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0263] As used herein, the terms "co-administer", "administer in combination with", and their grammatical equivalents encompass administering two or more agents to an animal, including a human, such that the two agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which both agents are present.

[0264] The terms "antagonist" and "inhibitor" are used interchangeably and refer to a compound capable of inhibiting the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological action of the target protein. Although the preferred antagonists herein interact specifically with the target (e.g., bind to the target), the definition specifically includes 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. The preferred biological activities inhibited by the antagonists are associated with the manifestation, growth, or spread of a tumor.

[0265] Whenever a protein is referred to herein, it should be 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.

[0266] Methods for inhibiting 15-PGDH

[0267] Provided herein are methods for inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

[0268] In one aspect, the present disclosure provides 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:

[0269]

[0270] or a pharmaceutically acceptable salt thereof, wherein:

[0271] X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH2–, –S(O)CH2–, –SO2CH2–;

[0272] each Y is independently selected from N and CR 11 ;

[0273] each R 1 is 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 –SO2R 9 –SO2NR 6 R 7 –NR 10 C(O)R 8 –NR 10 C(O)NR 6 R 7 –NR 10 SO2R 8 –NR 10 SO2NR 6 R 7 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0274] R 2 is H, and R 3 is –CF3; or

[0275] R 2 and R 3 together form an oxo or thio group;

[0276] each R 4 is independently selected from halo, –NR6 R 7 、 –OR 8 、 –C(O)R 8 、 –C(O)OR 8 、 –C(O)NR 6 R 7 、 –SOR 9 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0277] Each R 5 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0278] R 6 and R 7 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0279] Each R 8 is 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;

[0280] Each R 9 is 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;

[0281] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0282] Each R 11 is independently selected from a halogen, –NR 6 R 7 –, –OR 8 –, –C(O)R 8 –, –C(O)OR 8 –, –C(O)NR 6 R 7 –, –SOR 9 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10Cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0283] n is 0, 1, 2, 3, 4, or 5;

[0284] m is 0, 1, 2, 3, or 4; and

[0285] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0286] provided that the compound of formula I is not

[0287]

[0288] In some embodiments, X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH2–, –S(O)CH2–, and –SO2CH2–. In some embodiments, X is –OCH2–. In some embodiments, X is –C(O)NH–. In some embodiments, X is –NHC(O)–. In some embodiments, X is –C(O)NMe–. In some embodiments, X is –NMeC(O)–. In some embodiments, X is –SCH2–. In some embodiments, X is –S(O)CH2–. In some embodiments, X is –SO2CH2–.

[0289] 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 11 . In some embodiments, one Y is N and the other Y is CR 11 .

[0290] In some embodiments, each R 1 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 1 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 。 In some embodiments, each R 1 is 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 SO2R 8 and –NR 10 SO2NR 6 R 7 。 In some embodiments, each R 1 is independently selected from halo, –NR 6 R 7 、 –OR 8 、 –C(O)R8 and –C(O)OR 8 。

[0291] In some embodiments, R 2 is H, and R 3 is –CF3. In some embodiments, R 2 and R 3 together form an oxo group. In some embodiments, R 2 and R 3 together form a thio group.

[0292] In some embodiments, each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 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 S02R 8 and –NR 10 SO2NR 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 .

[0293] 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 6 R 7 , C1-6 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 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 S02R 8 and –NR 10 SO2NR 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 .

[0294] In some embodiments, R 6 and R7 independently selected from H, C at each occurrence 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 6 and R 7 are independently selected from H and C 1-6 alkyl.

[0295] In some embodiments, each R 8 is 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. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H and C 1-6 alkyl.

[0296] In some embodiments, each R 9 is 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. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6Halogenated alkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.

[0297] In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 halogenated alkyl, and C 3-10 cycloalkyl. In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, and C 1-6 halogenated alkyl. In some embodiments, each R 10 is independently selected from H and C 1-6 alkyl.

[0298] In some embodiments, each R 11 is independently 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 halogenated alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 is independently 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 、–SO2R9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 。 In some embodiments, each R 11 is 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 SO2R 8 and –NR 10 SO2NR 6 R 7 。 In some embodiments, each R 11 is independently selected from halo, –NR 6 R 7 、 –OR 8 、 –C(O)R 8 and –C(O)OR 8 。

[0299] 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.

[0300] 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.

[0301] 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.

[0302] In some embodiments, the compound is a compound of formula Ia:

[0303]

[0304] or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the compound is a compound of formula Ib:

[0306]

[0307] or a pharmaceutically acceptable salt thereof.

[0308] 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:

[0309]

[0310] or a pharmaceutically acceptable salt thereof, wherein:

[0311] T, U, W, X, and Y are independently selected from N and CR 5 ;

[0312] S, V, and Z are independently selected from N and C;

[0313] R 1 is 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; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the following: halo, –NR 6 R 7 –, –OR 8 –, –C(O)R 8 –, –C(O)OR 8 –, –C(O)NR 6 R7 、 –SOR 9 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;

[0314] R 2 is H, and R 3 is –CF3; or

[0315] R 2 and R 3 together form an oxo group or a thio group;

[0316] Each R 4 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or

[0317] Two Rs 4 Together with the carbon atoms to which they are attached and any intervening atoms form a C 3-10 cycloalkyl group, and any remaining Rs 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0318] Each R 5 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3 - to 10 - membered heteroalkyl, C 6-10 aryl, and 5 - to 10 - membered heteroaryl;

[0319] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0320] each R 8 is 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;

[0321] each R 9 is 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;

[0322] each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; and n is 1, 2, 3, or 4; and

[0323] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0324] provided that the compound of formula II is not

[0325]

[0326]

[0327] In some embodiments, T, U, W, X, and Y are each independently selected from N and CR 5 . In some embodiments, at least one of T, U, W, X, and Y is N, and the remainder are CR 5 . In some embodiments, at least two of T, U, W, X, and Y are N, and the remainder 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.

[0328] 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.

[0329] In some embodiments, R 1 is 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; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the following: halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C1-6 haloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents 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 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents 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 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C1-6 Heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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: halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 . In some embodiments, R 1 is 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: halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0330] In some embodiments, R 2 is H, and R 3 is –CF3. In some embodiments, R 2 and R 3 together form an oxo group. In some embodiments, R 2 and R 3 together form a thio group.

[0331] In some embodiments, each R 4 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 4 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl and C 1-6 haloalkyl. In some embodiments, each R 4 is independently selected from halo, –NR 6 R 7 、 –OR 8 、 –C(O)R 8 、 –C(O)OR 8 、 –C(O)NR6 R 7 , –SOR 9 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 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.

[0332] 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining R 4 is 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 –SO2R 9 –SO2NR 6 R 7 –NR 10 C(O)R 8 –NR 10 C(O)NR 6 R 7 –NR 10 SO2R 8 –NR 10 SO2NR 6 R 7 C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, two R 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining R 4 is 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 –SO2R 9 –SO2NR 6 R 7 –NR 10 C(O)R 8 –NR 10 C(O)NR 6 R 7 –NR 10 SO2R 8 and –NR 10SO2NR 6 R 7 。In some embodiments, two Rs 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining Rs 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 Rs 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining Rs 4 are independently selected from halo. In some embodiments, two Rs 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining Rs 4 is fluoro.

[0333] In some embodiments, each R 5 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 5 is independently selected from H, halo, –NR6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 5 are independently 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 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 5Independently selected from H and halo groups.

[0334] In some embodiments, R 6 and R 7 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl each time they appear. In some embodiments, R 6 and R 7 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl each time they appear. In some embodiments, R 6 and R 7 are independently selected from H and C 1-6 alkyl each time they appear.

[0335] In some embodiments, each R 8 is 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. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H and C 1-6 alkyl.

[0336] In some embodiments, each R 9 is 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. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R9 independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.

[0337] In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 10 is independently selected from H and C 1-6 alkyl.

[0338] 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.

[0339] 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.

[0340] In some embodiments, the compound is a compound of Formula IIa:

[0341]

[0342] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0343] 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.

[0344] In some embodiments, the compound is a compound of Formula IIb:

[0345]

[0346] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0347] 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.

[0348] In some embodiments, the compound is a compound of formula IIc:

[0349]

[0350] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0351] 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.

[0352] In some embodiments, the compound is a compound of formula IId:

[0353]

[0354] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0355] 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.

[0356] In some embodiments, the compound is a compound of formula IIe:

[0357]

[0358] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0359] 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.

[0360] In some embodiments, the compound is a compound of formula IIf:

[0361]

[0362] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0363] 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.

[0364] In some embodiments, the compound is a compound of Formula IIg:

[0365]

[0366] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0367] 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.

[0368] In some embodiments, the compound is a compound of Formula IIh:

[0369]

[0370] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0371] 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.

[0372] In some embodiments, the compound is a compound of Formula IIi:

[0373]

[0374] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0375] 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.

[0376] In some embodiments, the compound is a compound of Formula IIj:

[0377]

[0378] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0379] 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.

[0380] In some embodiments, the compound is a compound of formula IIn:

[0381]

[0382] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0383] 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.

[0384] In some embodiments, the compound is a compound of formula IIp:

[0385]

[0386] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0387] 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.

[0388] 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:

[0389]

[0390] or a pharmaceutically acceptable salt thereof, wherein:

[0391] each X is independently selected from N and CR 7 ;

[0392] Y is selected from O, S, SO2, and C(R 8 )2;

[0393] R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl or heteroaryl is 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 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0394] R 2 is H, and R 3 is –CF3; or

[0395] R 2 and R 3 together form an oxo or thio group;

[0396] R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl; 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 、–SO2R 12 、–SO2NR9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0397] R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heteroalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0398] Each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or

[0399] Two Rs attached to the same carbon atom 6 together form an oxo group, a thio group, or C 3-10 cycloalkyl, and any remaining Rs 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0400] Each R 7 is independently selected from H, a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0401] Each R 8 is independently selected from H, a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C6-10 aryl and 5- to 10-membered heteroaryl; or

[0402] two Rs 8 may together form a C optionally substituted with 1 to 3 substituents independently selected from the following 3-10 cycloalkyl: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0403] R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0404] each R 11 is 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;

[0405] each R 12 is independently selected from 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;

[0406] Each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0407] m is 1 or 2; and

[0408] n is 0, 1, 2, 3, or 4.

[0409] In some embodiments, each X is independently selected from N and CR 7 . In some embodiments, at least one X is N and the remainder are CR 7 . In some embodiments, at least two X are N and the remainder are CR 7 . In some embodiments, each X is N. In some embodiments, each X is CR 7 .

[0410] In some embodiments, Y is selected from O, S, SO2, 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.

[0411] In some embodiments, R 1 is 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; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 , –NR 9 R 10 , –NR 13SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is selected from C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 1 is 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: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR12 、 –SO₂R 12 、 –SO₂NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO₂R 11 and –NR 13 SO₂NR 9 R 10 。 In some embodiments, R 1 is 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: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 and –C(O)NR 9 R 10 。

[0412] In some embodiments, R 2 is H, and R 3 is –CF₃. In some embodiments, R 2 and R 3 together form an oxo group. In some embodiments, R 2 and R 3 together form a thio group.

[0413] In some embodiments, R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO₂R 12 、 –SO₂NR 9 R 10 、 –NR13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11, –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR9 R 10 。

[0414] In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11, –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heteroalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heteroalkyl optionally substituted with 1 to 3 substituents 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 .

[0415] In some embodiments, each R 6 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl and C 1-6 haloalkyl. In some embodiments, each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 S02R 11 and –NR 13 SO2NR 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 .

[0416] 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 , –SO2R 12 、–SO2NR 9 R 10 ,–NR 13 C(O)R 11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 S02R 11 ,–NR 13 SO2NR 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, two R's attached to the same carbon atom 6 together form an oxo group, a thio group, or a C 3-10 cycloalkyl, and any remaining R 6 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, two R's attached to the same carbon atom 6 together form an oxo group, a thio group, or a C 3-10 cycloalkyl, and any remaining R 6 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R11 、 –C(O)OR 11 and –C(O)NR 9 R 10 。

[0417] In some embodiments, each R 7 is 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 7 is 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 7 is 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , and –NR 13 SO2NR 9 R 10 . In some embodiments, each R 7 is 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 .

[0418] In some embodiments, each R 8 is 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 , C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 8 is 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10. In some embodiments, each R 8 is 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 .

[0419] In some embodiments, two R 8 s may together form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 8 s may together form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, two R 8 may together form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 。 In some embodiments, two R 8 may together form a C 3-10 cycloalkyl optionally substituted with 1 to 3 substituents 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 。

[0420] In some embodiments, R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10Naphthenyl. In some embodiments, R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 9 and R 10 are each independently selected from H and C 1-6 alkyl.

[0421] In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 naphthenyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 11 is independently selected from H and C 1-6 alkyl.

[0422] In some embodiments, each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 naphthenyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl.

[0423] In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 naphthenyl. In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 13 is independently selected from H and C 1-6 alkyl.

[0424] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0425] 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.

[0426] In some embodiments, the compound is a compound of Formula IIIa:

[0427]

[0428] or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the compound is a compound of Formula IIIb:

[0430]

[0431] or a pharmaceutically acceptable salt thereof, wherein:

[0432] each R 14 is independently selected from halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

[0433] p is 0, 1, 2, or 3.

[0434] In some embodiments, each R 14 is independently selected from halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 14 is independently selected from halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 14 is 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 。 In some embodiments, each R 14 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 and –C(O)NR 9 R 10 。 In some embodiments, each R 14 is independently halo. In some embodiments, each R 14 is independently fluoro.

[0435] 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.

[0436] In some embodiments, the compound is a compound of formula IIIc:

[0437]

[0438] or a pharmaceutically acceptable salt thereof.

[0439] In some embodiments, the compound is a compound of formula IIId:

[0440]

[0441] or a pharmaceutically acceptable salt thereof, wherein:

[0442] each R 14 is 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

[0443] p is 0, 1, 2, or 3.

[0444] In some embodiments, each R 14 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14 independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 14 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, each R 14 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 . In some embodiments, each R14 is independently a halogen group. In some embodiments, each R 14 is independently a fluorine group.

[0445] 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.

[0446] Compound

[0447] In one aspect, provided herein is a compound of Formula IIk:

[0448]

[0449] or a pharmaceutically acceptable salt thereof, wherein:

[0450] 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;

[0451] R 1 is 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: halogen, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR 10 , –SO2R 10 , –SO2NR 7 R 8 , –NR 11 C(O)R 9 , –NR 11 C(O)NR 7 R 8 , –NR 11 SO2R 9 , –NR 11 , –SO2NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl;

[0452] R 2 is H, and R 3 is –CF3; or

[0453] R 2 and R 3 together form an oxo group;

[0454] Each R 4 is independently selected from H and halo;

[0455] R 5 is selected from halo, –NR 7 R 8 、–OR 9 、–C(O)R 9 、–C(O)OR 9 、–C(O)NR 7 R 8 、–SOR 10 、–SO2R 10 、–SO2NR 7 R 8 、–NR 11 C(O)R 9 、–NR 11 C(O)NR 7 R 8 、–NR 11 SO2R 9 、–NR 11 SO2NR 7 R 8 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0456] R 6 is 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 、–SO2R 10 、–SO2NR 7 R 8 、–NR 11 C(O)R 9 、–NR 11 C(O)NR 7 R 8 、–NR 11 SO2R 9 、–NR 11 SO2NR7 R 8 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3 - to 10 - membered hetero - cycloalkyl, C 6-10 aryl and 5 - to 10 - membered heteroaryl;

[0457] R 7 and R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;

[0458] Each R 9 is 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;

[0459] Each R 10 is 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;

[0460] Each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and p is 0, 1, or 2.

[0461] In some embodiments, T, U, and Y are each 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 remainder are CR 6 . In some embodiments, two of T, U, and Y are N and the remainder are CR 6 . In some embodiments, one of T, U, and Y is CR 6 , and the remainder are N. In some embodiments, two of T, U, and Y are CR 6 , and the remainder are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR 6 .

[0462] In some embodiments, R 1 is 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: halo, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR 10 , –SO2R 10 , –SO2NR 7 R 8 , –NR 11 C(O)R 9 , –NR 11 C(O)NR 7 R 8 , –NR 11 SO2R 9 , –NR 11 SO2NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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: halo, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR 10 , –SO2R 10 , –SO2NR 7 R 8 , –NR 11 C(O)R 9 , –NR 11 C(O)NR 7 R 8 , –NR 11 SO2R 9 , –NR 11 SO2NR 7 R 8 , C1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 1 is 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: halo, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR 10 , –SO2R 10 , –SO2NR 7 R 8 , –NR 11 C(O)R 9 , –NR 11 C(O)NR 7 R 8 , –NR 11 SO2R 9 , and –NR 11 SO2NR 7 R 8 . In some embodiments, R 1 is 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: halo, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , and –C(O)NR 7 R 8 .

[0463] In some embodiments, R 2 is H, and R 3 is –CF3. In some embodiments, R 2 and R 3 together form an oxo group.

[0464] In some embodiments, each R 4 is independently selected from H and halo. In some embodiments, each R 4 is independently selected from H and fluoro. In some embodiments, each R 4 is H. In some embodiments, each R 4 is fluoro. In some embodiments, one R4 is H, and one R 4 is a fluoro group.

[0465] In some embodiments, R 5 is selected from halo groups, –NR 7 R 8 –OR 9 –C(O)R 9 –C(O)OR 9 –C(O)NR 7 R 8 –SOR 10 –SO2R 10 –SO2NR 7 R 8 –NR 11 C(O)R 9 –NR 11 C(O)NR 7 R 8 –NR 11 SO2R 9 –NR 11 SO2NR 7 R 8 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, R 5 is selected from halo groups, –NR 7 R 8 –OR 9 –C(O)R 9 –C(O)OR 9 –C(O)NR 7 R 8 –SOR 10 –SO2R 10 –SO2NR 7 R 8 –NR 11 C(O)R 9 –NR 11 C(O)NR 7 R 8 –NR 11 SO2R 9 –NR 11 SO2NR 7 R 8 C 1-6 alkyl, C 1-6 heteroalkyl and C 1-6Haloalkyl. In some embodiments, R 5 is selected from halo, –NR 7 R 8 –OR 9 –C(O)R 9 –C(O)OR 9 –C(O)NR 7 R 8 –SOR 10 –SO2R 10 –SO2NR 7 R 8 –NR 11 C(O)R 9 –NR 11 C(O)NR 7 R 8 –NR 11 SO2R 9 and –NR 11 SO2NR 7 R 8 In some embodiments, R 5 is selected from halo, –NR 7 R 8 –OR 9 –C(O)R 9 –C(O)OR 9 and –C(O)NR 7 R 8 .

[0466] In some embodiments, R 6 is 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 –SO2R 10 –SO2NR 7 R 8 –NR 11 C(O)R 9 –NR 11 C(O)NR 7 R 8 –NR 11 SO2R 9 –NR 11 SO2NR 7 R 8 C 1-6 alkyl, C 1-6Heteroalkyl, 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 , –SO2R 10 、–SO2NR 7 R 8 ,–NR 11 C(O)R 9 ,–NR 11 C(O)NR 7 R 8 ,–NR 11 S02R 9 ,–NR 11 SO2NR 7 R 8 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 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 , –SO2R 10 、–SO2NR 7 R 8 ,–NR 11 C(O)R 9 ,–NR 11 C(O)NR 7 R 8 ,–NR 11 S02R 9 and –NR 11 SO2NR 7 R 8 In some embodiments, R 6 Selected from H, halo, –NR 7 R 8 ,–OR 9 , –C(O)R9 、 –C(O)OR 9 and –C(O)NR 7 R 8 。

[0467] In some embodiments, R 7 and R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl. In some embodiments, R 7 and R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 7 and R 8 are each independently selected from H and C 1-6 alkyl.

[0468] In some embodiments, each R 9 is 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. In some embodiments, each R 9 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 9 is independently selected from H and C 1-6 alkyl.

[0469] In some embodiments, each R 10 is 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. In some embodiments, each R 10 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 10 is independently selected from C 1-6 alkyl.

[0470] In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl. In some embodiments, each R 11 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 11 is independently selected from H and C 1-6 alkyl.

[0471] 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.

[0472] In another aspect, provided herein is a compound of Formula IIm:

[0473]

[0474] or a pharmaceutically acceptable salt thereof, wherein:

[0475] R 1 is 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: halo, –NR 6 R 7 –OR 8 –C(O)R 8 –C(O)OR 8 –C(O)NR 6 R 7 –SOR 9 –SO2R 9 –SO2NR 6 R 7 –NR 10 C(O)R 8 –NR 10 C(O)NR 6 R 7 –NR 10 SO2R 8 –NR 10 SO2NR 6 R 7 –C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;

[0476] R 2is H, and R 3 is –CF3; or

[0477] R 2 and R 3 together form an oxo group;

[0478] Each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or

[0479] Two Rs 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining Rs 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0480] R 5 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0481] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0482] Each R 8 is 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;

[0483] Each R 9 is 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;

[0484] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0485] n is 1, 2, 3, or 4;

[0486] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0487] p is 0, 1, 2, or 3.

[0488] In some embodiments, R 1 is 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: halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 , –SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 6 R 7 In some embodiments, R 1 Selected from C 6-10Aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the following: halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 and –C(O)NR 6 R 7 .

[0489] In some embodiments, R 2 is H, and R 3 is –CF3. In some embodiments, R 2 and R 3 together form an oxo group.

[0490] In some embodiments, each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 4 is 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 、–SO2R9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 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.

[0491] 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 4Independently selected from halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R 4 together with the carbon atom and any intervening atoms to which they are attached form a 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, two R 4Together with the carbon atoms and any intervening atoms to which they are attached, form a C 3-10 cycloalkyl group, and any remaining R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 . In some embodiments, two R 4 together with the carbon atoms and any intervening atoms to which they are attached, form a C 3-10 cycloalkyl group, and any remaining R 4 is 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 .

[0492] In some embodiments, R 5 is selected from halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, R 5 is selected from halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl and C 1-6 haloalkyl. In some embodiments, R 5 is selected from halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 and –NR 10 SO2NR 6 R7 . In some embodiments, R 5 is selected from halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0493] In some embodiments, R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl. In some embodiments, R 6 and R 7 are each independently selected from H and C 1-6 alkyl.

[0494] In some embodiments, each R 8 is 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. In some embodiments, each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H and C 1-6 alkyl.

[0495] In some embodiments, each R 9 is 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. In some embodiments, each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C1-6 Halogenated alkyl. In some embodiments, each R 9 is independently selected from C 1-6 alkyl.

[0496] In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 halogenated alkyl, and C 3-10 cycloalkyl. In some embodiments, each R 10 is independently selected from H, C 1-6 alkyl, and C 1-6 halogenated alkyl. In some embodiments, each R 10 is independently selected from H and C 1-6 alkyl.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] In another aspect, the present invention provides a compound of formula IIq:

[0501]

[0502] or a pharmaceutically acceptable salt thereof, wherein:

[0503] R 1 is 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 following: halogen, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR8 、 –C(O)NR 6 R 7 、 –SOR 9 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;

[0504] R 2 is H, and R 3 is –CF3; or

[0505] R 2 and R 3 together form an oxo group;

[0506] Each R 4 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10An aryl group and a 5- to 10-membered heteroaryl group; or

[0507] Two Rs 4 Together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 Cycloalkyl group, and any remaining Rs 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 An aryl group and a 5- to 10-membered heteroaryl group;

[0508] R 5 Is selected from halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0509] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0510] Each R 8 is 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;

[0511] Each R 9 is 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;

[0512] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0513] n is 1, 2, 3, or 4;

[0514] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0515] p is 0, 1, 2, or 3.

[0516] In some embodiments, R 1 is 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: halo, –NR 6 R 7 –, –OR 8 –, –C(O)R 8 –, –C(O)OR 8 –, –C(O)NR 6 R 7, –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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: halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 1 is 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: halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8, –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 . In some embodiments, R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents 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 .

[0517] In some embodiments, R 2 is H, and R 3 is –CF3. In some embodiments, R 2 and R 3 together form an oxo group.

[0518] In some embodiments, each R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR6 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl and C 1-6 In some embodiments, each R 4 are independently selected from halo, –NR 6 R 7 ,–OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 and –NR 10 SO2NR 6 R 7 In some embodiments, each R 4are 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.

[0519] 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 , –SO2R 9 、–SO2NR 6 R 7 ,–NR 10 C(O)R 8 ,–NR 10 C(O)NR 6 R 7 ,–NR 10 S02R 8 ,–NR 10 SO2NR 6 R 7 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 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 , –SOR9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, two R 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 . In some embodiments, two R 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining R 4 is 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 .

[0520] In some embodiments, R5 Selected from halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 5 is selected from halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 5 is selected from halo, –NR 6 R 7 、–OR8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 and –NR 10 SO2NR 6 R 7 . In some embodiments, R 5 is selected from halo, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 and –C(O)NR 6 R 7 .

[0521] In some embodiments, R 6 and R 7 are each independently selected, at each occurrence, from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 6 and R 7 are each independently selected, at each occurrence, from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl. In some embodiments, R 6 and R 7 are each independently selected, at each occurrence, from H and C 1-6 alkyl.

[0522] In some embodiments, each R 8 is 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. In some embodiments, each R 8 is independently selected from H, C 1-6Alkyl, C 1-6 Heteroalkyl, and C 1-6 Haloalkyl. In some embodiments, each R 8 Is independently selected from H and C 1-6 Alkyl.

[0523] In some embodiments, each R 9 Is 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. In some embodiments, each R 9 Is independently selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl. In some embodiments, each R 9 Is independently selected from C 1-6 Alkyl.

[0524] In some embodiments, each R 10 Is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-10 Cycloalkyl. In some embodiments, each R 10 Is independently selected from H, C 1-6 Alkyl, and C 1-6 Haloalkyl. In some embodiments, each R 10 Is independently selected from H and C 1-6 Alkyl.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] On the other hand, the present disclosure provides a compound of Formula IIIc:

[0529]

[0530] or a pharmaceutically acceptable salt thereof, wherein:

[0531] each X is independently selected from N and CR 7 ;

[0532] Y is selected from O, S, SO2, and C(R 8 )2;

[0533] R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl;

[0534] R 2 is H, and R 3 is –CF3; or

[0535] R 2 and R 3 together form an oxo group;

[0536] R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6Heteroalkyl, C 1-6 Haloalkyl, and C 3-6 Cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 Aryl, and 5- to 10-membered heteroaryl; or

[0537] R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heteroalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0538] Each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or

[0539] Two Rs attached to the same carbon atom 6 together form an oxo group, and any remaining R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0540] Each R 7 and R 8 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0541] R 9 and R 10 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;

[0542] Each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C6-10 Aryl and 5- to 10-membered heteroaryl;

[0543] Each R 12 is 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;

[0544] Each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and

[0545] n is 0, 1, 2, 3 or 4.

[0546] In some embodiments, each X is independently selected from N and CR 7 . In some embodiments, at least one X is N and the remainder are CR 7 . In some embodiments, at least two X are N and the remainder are CR 7 . In some embodiments, each X is N. In some embodiments, each X is CR 7 .

[0547] In some embodiments, Y is selected from O, S, SO2 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.

[0548] In some embodiments, R 1 is 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: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R 1 is 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: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 1 is 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: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, R 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents 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 .

[0549] In some embodiments, R 2 is H, and R 3 is –CF3. In some embodiments, R 2 and R 3 together form an oxo group.

[0550] In some embodiments, R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 , –NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, R 4 and R 5 are independently selected from C 3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR13 C(O)R 11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 S02R 11 ,–NR 13 SO2NR 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 3-10 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 , –SO2R 12 、–SO2NR 9 R 10 ,–NR 13 C(O)R 11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 S02R 11 and –NR 13 SO2NR 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 .

[0551] In some embodiments, R 4 and R 5Together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R 4 and R 5 Together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl and C1-6 Halogenated alkyl. In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halogen, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halogen, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0552] In some embodiments, each R 6 is independently selected from halogen, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11and –NR 13 SO2NR 9 R 10 。In some embodiments, each R 6 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 。

[0553] In some embodiments, two Rs attached to the same carbon atom 6 together form an oxo group, and any remaining Rs 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two Rs attached to the same carbon atom 6 together form an oxo group, and any remaining Rs 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 , –SO2R12 、–SO2NR 9 R 10 ,–NR 13 C(O)R 11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 S02R 11 ,–NR 13 SO2NR 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 , –SO2R 12 、–SO2NR 9 R 10 ,–NR 13 C(O)R 11 ,–NR 13 C(O)NR 9 R 10 ,–NR 13 S02R 11 and –NR 13 SO2NR 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 .

[0554] 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 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 , –NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 7 and R 8 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 , –NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl and C 1-6 haloalkyl. In some embodiments, each R 7 and R 8 is independently selected from halo, –NR 9 R 10 , –OR 11, –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 and –NR 13 SO2NR 9 R 10 . In some embodiments, each R 7 and R 8 is independently selected from halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 and –C(O)NR 9 R 10 .

[0555] In some embodiments, R 9 and R 10 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, R 9 and R 10 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, R 9 and R 10 are independently selected from H and C 1-6 alkyl.

[0556] In some embodiments, each R 11 is 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. In some embodiments, each R 11 is independently selected from H, C1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 11 is independently selected from H and C 1-6 alkyl.

[0557] In some embodiments, each R 12 is 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. In some embodiments, each R 12 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl. In some embodiments, each R 12 is independently selected from C 1-6 alkyl.

[0558] In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl. In some embodiments, each R 13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, each R 13 is independently selected from H and C 1-6 alkyl.

[0559] 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.

[0560] In another aspect, the present disclosure provides a composition comprising a compound selected from the following:

[0561]

[0562] In another aspect, the present disclosure provides a composition comprising a compound selected from the following:

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573] On the other hand, the present disclosure provides a composition comprising a compound selected from the following:

[0574]

[0575]

[0576] In some cases, the solubility and hPGDH IC50 characteristics of the inhibitors are as shown in Tables 1 and 2.

[0577] Table 1: Characteristics of PGDH inhibitors with a 6-5 ring core.

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585] Table 2: Characteristics of PGDH inhibitors with a phenyl core.

[0586]

[0587]

[0588] Analytical data for some of the inhibitors described herein are provided in Table 3.

[0589] Table 3: Analytical data of the selected inhibitors

[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]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682] Method of Use

[0683] In one aspect, the present disclosure provides methods for treating various conditions in a subject in need thereof, the methods comprising administering to the subject a compound described herein. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to prevent or treat diseases or conditions associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and / or with reduced prostaglandin levels. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to prevent or treat diseases or conditions in which it is desirable to increase prostaglandin levels in a subject having a disease or condition.

[0684] In some embodiments, methods for treating a disorder include administering a 15-PGDH inhibitor to the subject. In some embodiments, the compounds described herein are 15-PGDH inhibitors. In some embodiments, the compounds having Formula I, Formula II, or Formula III are 15-PGDH inhibitors. In some embodiments, the method includes administering a therapeutically effective amount of the compounds described herein. In some embodiments, the method includes administering a therapeutically effective amount of the compounds having Formula I, Formula II, or Formula III. In some embodiments, the compounds described herein are 15-PGDH inhibitors. In some embodiments, the compounds having Formula I, Formula II, or Formula III are 15-PGDH inhibitors. In some embodiments, the administration occurs in vitro. In other embodiments, the administration occurs in vivo.

[0685] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor refers to an amount sufficient to achieve a predetermined application including but not limited to treatment of a disease, as defined herein. The use of sub-therapeutic amounts of a 15-PGDH inhibitor to treat a predetermined disease condition is also contemplated in the subject methods.

[0686] The amount of 15-PGDH inhibitor administered can vary depending on the predetermined application (in vitro or 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.

[0687] Measuring inhibition of the biological action of 15-PGDH can include assaying a biological sample such as a sample from a subject. Depending on the assay, any one of a variety of samples can be selected. Examples of samples include but are not limited to blood samples (e.g., plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0688] A subject being treated with a 15-PGDH inhibitor can be monitored to determine the effectiveness of the treatment, and the treatment regimen can be adjusted based on the subject's physiological response to the treatment. For example, if the inhibition of the biological action of 15-PGDH is above or below a threshold, then the dosage or dosing frequency can be decreased or increased, respectively. The method can also include continuing the therapy if the therapy is determined to be effective. The method can include maintaining, tapering, reducing, or stopping the administration of the compound in the therapy if the therapy is determined to be effective. The method can include increasing the administration of the compound in the therapy if the therapy is determined not to be effective. Alternatively, the method can include stopping the therapy if the therapy is determined not to be effective. In some embodiments, treatment with a 15-PGDH inhibitor is discontinued if the inhibition of the biological action is above or below a threshold, such as in the case of lack of response or presence of an adverse reaction. The biological action can be a change in any one of a variety of physiological metrics.

[0689] Generally, a 15-PGDH inhibitor is a compound that inhibits one or more biological actions of 15-PGDH. Such biological actions can be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater.

[0690] In some other embodiments, the subject methods can be used to treat disease conditions associated with 15-PGDH. Any disease condition caused directly or indirectly by abnormal activity or expression levels of 15-PGDH can be a predetermined disease condition.

[0691] In one aspect, provided herein is a method for promoting and / or stimulating skin pigmentation, the method comprising administering one or more of the compositions described herein to a subject in need thereof. It is known that inhibitors of 15-PGDH promote skin pigmentation (Markowitz et al., WO 2015 / 065716). The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to promote and / or induce and / or stimulate pigmentation of the skin and / or skin appendages, and / or as an agent for preventing and / or restricting depigmentation and / or whitening of the skin and / or skin appendages, particularly as an agent for preventing and / or restricting canities. In some embodiments, the 15-PGDH inhibitor provided herein can be applied to the skin of a subject, for example, in a topical application, to promote and / or stimulate skin pigmentation and / or hair growth, inhibit hair loss, and / or treat skin damage or inflammation, such as skin damage caused by physical or chemical irritants and / or ultraviolet exposure.

[0692] In another aspect, provided herein is a method for inhibiting hair loss, the method comprising administering one or more of the compositions described herein to a subject in need thereof. It is known that prostaglandins play an important role in hair growth. Prostaglandins such as prostaglandin A1, F2a, and E2 are stored in hair follicles or adjacent skin environments and have been shown to be essential for maintaining and increasing hair density (Colombe L et al., 2007, Exp. Dermatol, 16(9), 762-9). 15-PGDH, which is involved in the degradation of prostaglandins, has been reported to be present in the dermal papilla of hair follicles, inactivating prostaglandins, especially PGF2a and PGE2, resulting in scalp damage and hair loss (Michelet J F et al., 2008, Exp. Dermatol, 17(10), 821-8). Thus, the hydroxyprostaglandin dehydrogenase inhibitors described herein, which have containment or inhibitory activity against 15-PGDH, can improve scalp damage, prevent hair loss, and promote hair growth, and can be used in pharmaceutical compositions for preventing hair loss and promoting hair growth.

[0693] In another aspect, the present disclosure provides a method for preventing and / or treating skin inflammation and / or injury, the method comprising administering one or more of the compositions described herein to a subject in need thereof.

[0694] In another aspect, the present disclosure provides 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. It is known that prostaglandins produced in the body, including prostaglandin homologs, maintain the proper functioning of the blood vessel wall, and in particular contribute to vasodilation for blood flow, thereby preventing platelet aggregation and regulating the proliferation of smooth muscle surrounding the blood vessel wall (Yan. Cheng et al., 2006, J. Clin., Invest). In addition, inhibition of prostaglandin production or loss of their activity leads to degeneration of the endothelium in the blood vessel wall, platelet aggregation, and dysfunction of the cellular mechanisms in smooth muscle. Among other things, it has also been shown that in patients with hypertension, including pulmonary hypertension, the production of prostaglandins in the blood vessels is reduced. The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for preventing or treating cardiovascular diseases and / or vascular insufficiency diseases, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary hypertension.

[0695] In another aspect, the present disclosure provides a method for 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. In another aspect, the present disclosure provides a method for reducing the cardiac ejection fraction, the method comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that administration of 15-PGDH inhibitors can be used to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and / or reduced cardiac ejection fraction (Markowitz et al., WO2018 / 187810). Accordingly, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need thereof to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and / or reduced cardiac ejection fraction.

[0696] On the other hand, the present invention provides a method for preventing and / or treating gastrointestinal diseases, the method comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins are necessary to maintain the mechanisms used to protect and maintain the gastric mucosa (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65, S.J. Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). The inhibitors of hydroxyprostaglandin dehydrogenase described herein exhibit containment or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect the gastric mucosa. Thus, inhibitors of hydroxyprostaglandin dehydrogenase can be effectively used for preventing or treating gastrointestinal diseases, particularly gastritis and gastric ulcers. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for preventing and / or treating other forms of intestinal injury, including toxicity caused by radiation and / or chemotherapy, and chemotherapy-induced mucositis.

[0697] In addition, it has been shown that administering 15-PGDH inhibitors alone or in combination with corticosteroids and / or TNF inhibitors can treat intestinal, gastrointestinal or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease and Crohn's disease (Markowitz et al., WO 2018 / 102552). Thus, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for treating and / or preventing treatment of intestinal, gastrointestinal or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease and Crohn's disease.

[0698] On the other hand, the present disclosure provides 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. In the kidney, prostaglandins regulate renal blood flow and can play a role in regulating urine formation by producing both renal vascular effects and tubular effects. In clinical studies, inhibitors of prostaglandins have been used to improve creatinine clearance in patients with chronic kidney disease, prevent graft rejection and cyclosporine toxicity in renal transplant patients, and reduce urinary albumin excretion rate and N-acetyl-β-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64:22E-26E). In addition, prostaglandins have been reported to act as vasodilators in the kidney, and thus, inhibition of prostaglandin production in the kidney can lead to renal dysfunction (Hao. C M, 2008, Annu Rev Physiol, 70, 357-77). The 15-PGDH inhibitors described herein have inhibitory activity against 15-PGDH, which degrades prostaglandins, and can be used to prevent and / or treat kidney diseases associated with renal dysfunction.

[0699] On the other hand, the present disclosure provides a method for stimulating bone resorption and bone formation, the method comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins have been shown to stimulate bone resorption and bone formation to increase bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). In addition, inhibition of 15-PGDH increases callus size and mineralization after fracture (Collier et al., ORS 2017 Annual Meeting Paper No. 0190). Considering that 15-PGDH inhibits the activity of prostaglandins as mentioned above, inhibition of 15-PGDH activity can lead to promotion of bone resorption and bone formation inhibited by 15-PGDH. Thus, by inhibiting 15-PGDH activity, the inhibitors of 15-hydroxyprostaglandin dehydrogenase described herein can be effectively used to promote bone resorption and bone formation. The 15-hydroxyprostaglandin dehydrogenase inhibitors provided herein can also be used to increase bone density, treat osteoporosis, promote fracture healing, promote healing after bone surgery or joint replacement, and / or promote the healing of bone with bone implants, bone with artificial implants, dental implants, and bone grafts.

[0700] On the other hand, the present disclosure provides a method of stimulating tissue regeneration by administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin PGE2 supports the expansion of several types of tissue stem cells. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, enhances tissue regeneration in multiple organs. Studies have shown that inhibition of 15-PGDH increases prostaglandin PGE2 levels in the bone marrow and other tissues; accelerates hematopoietic recovery after bone marrow transplantation; and promotes tissue regeneration in colon and liver injury (Zhang, Y. et al. Science 2015, 348(6240)). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to achieve tissue regeneration by supporting the expansion of tissue stem cells.

[0701] On the other hand, the present disclosure provides a method of modulating cervical ripening by administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates the EP2 receptor signaling pathway in human cervical stromal cells; targets its own synthesis by increasing COX-2 and PTGES expression; and reduces its metabolism by loss of its degrading enzyme 15-PGDH (Word et al., WO2019010482). Downregulation of 15-PGDH has also been found to be crucial for PGE2-induced cervical ripening and preterm birth. Modulation of 15-PDGH activity can be used to modulate cervical ripening; and to induce or prevent preterm birth. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used alone or in combination with another labor-inducing agent to induce cervical ripening and labor.

[0702] On the other hand, the present invention provides a method for 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. Prostaglandins have multiple physiological functions in the central nervous system through their specific G protein-coupled receptors. Prostaglandin E2 (PGE2), as a major prostaglandin, can activate receptor types EP1, EP2, EP3, and EP4. Activation of the EP2 and EP4 receptors can regulate adenylate cyclase and the production of 3,5'-cyclic monophosphate adenosine (cAMP), while activation of the EP1 and EP3 receptors can regulate Ca2+ signaling. Studies have shown that the EP1 and EP2 receptors are expressed in neurons and microglia, as well as in neurons of the cerebral cortex, striatum, and hippocampus. In addition, the activation of the EP2 receptor by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al., Semin Perinatol. February 1994; 18(1):23-9; Yang et al., J Neurochem. January 2009; 108(1):295-304). Studies have also shown that after activation, different PGE2 receptors can contribute to or prevent N-methyl-D-aspartic acid (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med. July 8, 2010; 2(1):12). Other studies have shown that activation of the EP2 receptor protects neurons from β-amyloid peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci. November 2005; 22(9):2199-206). Several studies have shown that the mechanism by which PGE2 provides neuroprotection is achieved sequentially through the EP2 or EP4 receptors (since they both increase cAMP) and the protein kinase A (PKA)-dependent pathway (Echeverria et al., Eur J Neurosci. November 2005; 22(9):2199-206; McCullough et al., J Neurosci. January 7, 2004; 24(1):257-68). Stimulation of these receptors with PGE2, achieved by administering compounds that inhibit, reduce, and / or antagonize 15-PGDH activity, such as the hydroxyprostaglandin dehydrogenase inhibitors that can inhibit 15-PGDH described herein, can promote neuroprotection in a subject against 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.

[0703] On the other hand, the present disclosure provides a method of treating and / or preventing a neurological disorder, neuropsychiatric disorder, nerve injury, neurotoxic disorder, neuropathic pain, or neurodegenerative disorder, the method comprising administering to a subject in need thereof one or more of the compositions described herein. In some embodiments, the diseases, disorders, and / or conditions of the nervous system treatable with the hydroxyprostaglandin dehydrogenase inhibitors provided herein can include at least one of a neurological disorder, neuropsychiatric disorder, nerve injury, neurotoxic disorder, neuropathic pain, or neurodegenerative disorder. For example, the neurological disorder can include at least one of traumatic or toxic injury to the peripheral or cranial nerves such as traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. The neurological disorder 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-Creutzfeldt disease.

[0704] In some embodiments, the nerve injury can be caused by or 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 diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immune diseases, blood and hematopoietic organ diseases, psychological disorders, nervous system diseases, sensory organ diseases, circulatory system diseases, respiratory system diseases, digestive system diseases, genitourinary system diseases, skin and subcutaneous tissue diseases, musculoskeletal system and connective tissue diseases, congenital anomalies, or conditions originating in the perinatal period.

[0705] In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitor can be administered to a subject or to the subject's neurons to promote neuronal survival, growth, development, and / or function, particularly neurons of the central nervous system (CNS), brain, cerebrum, and hippocampus. In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitor can be used to stimulate hippocampal neurogenesis for treating 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 abuse of neuroactive drugs such as alcohol, opioids, methamphetamine, phencyclidine, and cocaine.

[0706] On the other hand, the present disclosure provides a method of treating and / or preventing a fibrotic or adhesive disease, disorder, or condition, the method comprising administering to a subject in need thereof one or more of the compositions described herein. Inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, have been shown to be administered to a subject in need thereof to alleviate fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression, and inflammatory cell infiltration, and to treat and / or prevent various fibrotic diseases, disorders, and conditions characterized wholly or in part by the overproduction of fibrous material, including the overproduction of fibrotic material within the extracellular matrix, or the replacement of normal tissue components by abnormal, non-functional, and / or excessive accumulation of matrix-related components (Markowitz et al., WO2016 / 144958).

[0707] Fibrotic diseases, disorders, and conditions characterized wholly or in part by the overproduction of fibrotic material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), scleroderma-like graft-versus-host disease, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive nephropathy, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, a generalized fibrosis syndrome characterized by the replacement of normal muscle tissue to varying degrees by fibrous tissue, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug-induced ergotism, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ-specific fibrosis, and the like. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders, or conditions.

[0708] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent renal fibrosis, including renal fibrosis caused by dialysis after renal failure, catheter placement, kidney disease, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end-stage kidney disease, or renal failure, or combinations thereof.

[0709] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis caused by chronic liver disease, virus-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, α-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins, or a combination thereof.

[0710] 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.

[0711] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis.

[0712] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders or conditions caused by postoperative adhesion formation.

[0713] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce the intensity, severity or frequency of one or more symptoms or characteristics of a fibrotic disease, disorder or condition or other related diseases, disorders or conditions, and / or delay the onset of said one or more symptoms or characteristics.

[0714] 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.

[0715] 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 arterial hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, anthracosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of harmful gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary arterial hypertension, and combinations thereof.

[0716] In another aspect, the present disclosure provides a method of reducing and / or preventing scar formation, the method comprising administering one or more of the compositions described herein to a subject in need thereof. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation in a subject. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation or scleroderma on the skin.

[0717] On the other hand, the present disclosure provides a method for treating and / or preventing a muscle disorder, muscle injury, and / or muscle atrophy, the method comprising administering one or more of the compositions described herein to a subject in need thereof. Studies have shown that inhibiting PGE2-degrading enzymes such as 15-PGDH enables muscle regeneration and muscle repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020). The inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat muscle disorders, muscle injuries, and / or muscle atrophy in a subject. In some cases, the subject suffering from a muscle disorder, muscle injury, 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, congenital myotonia, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress-induced urinary incontinence, urethral sphincter defect, sarcopenia, or a combination thereof.

[0718] 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 attributable 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 ptosis, rotator cuff muscle atrophy, immobilization-related muscle atrophy, surgery procedure-related muscle atrophy, sarcopenia, or a combination thereof.

[0719] Pharmaceutical composition

[0720] Inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions for treating the diseases and conditions described herein. In some embodiments, the pharmaceutical composition can comprise a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein.

[0721] 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, rectally, intraperitoneally, topically (e.g., transdermally, transepidermally, percutaneous), ophthalmically such as ophthalmic eye drops, intranasally, sublingually, by inhalation, intramuscularly, or transdermally (e.g., patches), all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0722] In some embodiments, the compounds provided herein can be administered as part of a treatment regimen that includes administering one or more second agents (e.g., 1, 2, 3, 4, 5 or more second agents) simultaneously or sequentially with the compounds provided herein. When administered sequentially, the compounds provided herein can be administered before or after one or more second agents. When administered simultaneously, the compounds provided herein and one or more second agents can be administered by the same route (e.g., injection to the same location; oral tablets simultaneously), by different routes (e.g., oral tablets, while receiving an intravenous infusion), or as part of the same combination (e.g., a solution comprising the compounds provided herein and one or more second agents).

[0723] The combination therapies of the present disclosure can be effective over a wide range of doses. By way of example, in treating adults, doses of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of doses that can be used. The exact dose will depend on the agent selected, 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.

[0724] The present invention provides, including but not limited to, the following embodiments:

[0725] 1. 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:

[0726]

[0727] or a pharmaceutically acceptable salt thereof, wherein:

[0728] X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH2–, –S(O)CH2–, –SO2CH2–;

[0729] Each Y is independently selected from N and CR 11 ;

[0730] Each R 1 is independently 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0731] R 2 is H, and R 3 is –CF3; or

[0732] R 2 and R 3 together form an oxo group or a thio group;

[0733] Each R 4 is independently 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 、–SO2R 9 、–SO2NR 6 R7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0734] Each R 5 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0735] R 6 and R 7 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0736] Each R 8 is independently selected from H, C1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0737] each R 9 is 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;

[0738] each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0739] each R 11 is 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 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0740] n is 0, 1, 2, 3, 4, or 5;

[0741] m is 0, 1, 2, 3, or 4; and

[0742] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0743] provided that the compound of formula I is not

[0744] 2. The method according to embodiment 1, wherein the compound is a compound of formula Ia:

[0745]

[0746] or a pharmaceutically acceptable salt thereof.

[0747] 3. The method according to embodiment 1, wherein the compound is a compound of formula Ib:

[0748]

[0749] or a pharmaceutically acceptable salt thereof.

[0750] 4. 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:

[0751]

[0752] or a pharmaceutically acceptable salt thereof, wherein:

[0753] T, U, W, X and Y are independently selected from N and CR 5 ;

[0754] S, V and Z are independently selected from N and C;

[0755] R 1 is 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; wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8, –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 5- to 10-membered heteroaryl;

[0756] R 2 is H, and R 3 is –CF3; or

[0757] R 2 and R 3 together form an oxo or thioxo group;

[0758] Each R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0759] Two R 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining R 4 is independently selected from halo, –NR 6 R7 、 –OR 8 、 –C(O)R 8 、 –C(O)OR 8 、 –C(O)NR 6 R 7 、 –SOR 9 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0760] Each R 5 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0761] R 6 and R 7 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0762] Each R 8 is 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;

[0763] Each R 9 is 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;

[0764] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; and

[0765] n is 1, 2, 3, or 4; and

[0766] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0767] provided that the compound of formula II is not

[0768]

[0769]

[0770] 5. The method according to embodiment 4, wherein the compound is a compound of formula IIa:

[0771]

[0772] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0773] 6. The method according to embodiment 4, wherein the compound is a compound of formula IIb:

[0774]

[0775] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0776] 7. The method according to embodiment 4, wherein the compound is a compound of formula IIc:

[0777]

[0778] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4 or 5.

[0779] 8. The method according to embodiment 4, wherein the compound is a compound of formula IId:

[0780]

[0781] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0782] 9. The method according to embodiment 4, wherein the compound is a compound of formula IIe:

[0783]

[0784] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0785] 10. The method according to embodiment 4, wherein the compound is a compound of formula IIf:

[0786]

[0787] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0788] 11. The method according to embodiment 4, wherein the compound is a compound of formula IIg:

[0789]

[0790] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0791] 12. The method according to embodiment 4, wherein the compound is a compound of formula IIh:

[0792]

[0793] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0794] 13. The method according to embodiment 4, wherein the compound is a compound of formula IIi:

[0795]

[0796] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0797] 14. The method according to embodiment 4, wherein the compound is a compound of formula IIj:

[0798]

[0799]

[0800] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0801] 15. The method according to embodiment 4, wherein the compound is a compound of formula IIn:

[0802]

[0803] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3.

[0804] 16. The method according to embodiment 4, wherein the compound is a compound of formula IIp:

[0805]

[0806] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4.

[0807] 17. 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:

[0808]

[0809] or a pharmaceutically acceptable salt thereof, wherein:

[0810] Each X is independently selected from N and CR 7 ;

[0811] Y is selected from O, S, SO2 and C(R 8 )2;

[0812] R 1 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl or heteroaryl is 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 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0813] R 2 is H, and R 3 is –CF3; or

[0814] R 2 and R 3 together form an oxo or thio group;

[0815] R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl; 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 、–SO2R 12 、–SO2NR9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0816] R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heteroalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0817] Each R 6 is independently selected from halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0818] Two Rs attached to the same carbon atom 6 together form an oxo group, a thio group or C 3-10 cycloalkyl, and any remaining Rs 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0819] Each R 7 is independently selected from H, a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0820] Each R 8 is independently selected from H, a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C6-10 aryl and 5- to 10-membered heteroaryl; or

[0821] two Rs 8 may together form a C optionally substituted with 1 to 3 substituents independently selected from 3-10 cycloalkyl: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR 13 C(O)R 11 , –NR 13 C(O)NR 9 R 10 , –NR 13 SO2R 11 , –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0822] R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0823] each R 11 is 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;

[0824] each R 12 is independently selected from 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;

[0825] Each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; m is 1 or 2; and

[0826] n is 0, 1, 2, 3, or 4.

[0827] 18. The method according to embodiment 17, wherein the compound is a compound of formula IIIa:

[0828]

[0829] or a pharmaceutically acceptable salt thereof.

[0830] 19. The method according to embodiment 17, wherein the compound is a compound of formula IIIb:

[0831]

[0832] or a pharmaceutically acceptable salt thereof, wherein:

[0833] Each R 14 is independently selected from halo, –NR 9 R 10 –, –OR 11 –, –C(O)R 11 –, –C(O)OR 11 –, –C(O)NR 9 R 10 –, –SOR 12 –, –SO2R 12 –, –SO2NR 9 R 10 –, –NR 13 C(O)R 11 –, –NR 13 C(O)NR 9 R 10 –, –NR 13 SO2R 11 –, –NR 13 SO2NR 9 R 10 –, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

[0834] p is 0, 1, 2, or 3.

[0835] 20. The method according to embodiment 17, wherein the compound is a compound of formula IIIc:

[0836]

[0837] or a pharmaceutically acceptable salt thereof.

[0838] 21. The method according to embodiment 17, wherein the compound is a compound of formula IIId:

[0839]

[0840] or a pharmaceutically acceptable salt thereof, wherein:

[0841] each R 14 is independently selected from halo, –NR 9 R 10 –OR 11 –C(O)R 11 –C(O)OR 11 –C(O)NR 9 R 10 –SOR 12 –SO2R 12 –SO2NR 9 R 10 –NR 13 C(O)R 11 –NR 13 C(O)NR 9 R 10 –NR 13 SO2R 11 –NR 13 SO2NR 9 R 10 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

[0842] p is 0, 1, 2 or 3.

[0843] 22. A compound of formula IIk:

[0844]

[0845] or a pharmaceutically acceptable salt thereof, wherein:

[0846] T, U and Y are independently selected from N and CR 6provided that when U is N, at least one of T and Y is N;

[0847] R 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the following: halo, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR 10 , –SO2R 10 , –SO2NR 7 R 8 , –NR 11 C(O)R 9 , –NR 11 C(O)NR 7 R 8 , –NR 11 SO2R 9 , –NR 11 SO2NR 7 R 8 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5- to 10-membered heteroaryl;

[0848] R 2 is H, and R 3 is –CF3; or

[0849] R 2 and R 3 together form an oxo group;

[0850] each R 4 is independently selected from H and halo;

[0851] R 5 is selected from halo, –NR 7 R 8 , –OR 9 , –C(O)R 9 , –C(O)OR 9 , –C(O)NR 7 R 8 , –SOR 10 , –SO2R 10 , –SO2NR 7 R 8 , –NR11 C(O)R 9 、 –NR 11 C(O)NR 7 R 8 、 –NR 11 SO2R 9 、 –NR 11 SO2NR 7 R 8 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0852] R 6 is independently 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 、 –SO2R 10 、 –SO2NR 7 R 8 、 –NR 11 C(O)R 9 、 –NR 11 C(O)NR 7 R 8 、 –NR 11 SO2R 9 、 –NR 11 SO2NR 7 R 8 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0853] R 7 and R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;

[0854] Each R 9 is independently selected from H, 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;

[0855] Each R 10 is 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;

[0856] Each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; and

[0857] p is 0, 1, or 2.

[0858] 23. A compound of formula IIm:

[0859]

[0860] or a pharmaceutically acceptable salt thereof, wherein:

[0861] R 1 is 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: halo, –NR 6 R 7 –OR 8 –C(O)R 8 –C(O)OR 8 –C(O)NR 6 R 7 –SOR 9 –SO2R 9 –SO2NR 6 R 7 –NR 10 C(O)R 8 –NR 10 C(O)NR 6 R 7 –NR 10 SO2R 8 –NR 10 SO2NR 6 R 7 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C3-10 a cycloalkyl group and a 5- to 10-membered heteroaryl group;

[0862] R 2 is H, and R 3 is –CF3; or

[0863] R 2 and R 3 together form an oxo group;

[0864] each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0865] two R 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8, –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5 - to 10 - membered heteroaryl;

[0866] R 5 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3 - to 10 - membered heterocycloalkyl, C 6-10 aryl and 5 - to 10 - membered heteroaryl;

[0867] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0868] Each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C3-10 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0869] Each R 9 is 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;

[0870] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0871] n is 1, 2, 3, or 4;

[0872] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0873] p is 0, 1, 2, or 3.

[0874] 24. A compound of formula IIq:

[0875]

[0876] or a pharmaceutically acceptable salt thereof, wherein:

[0877] R 1 is 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 following: halo, –NR 6 R 7 –, –OR 8 –, –C(O)R 8 –, –C(O)OR 8 –, –C(O)NR 6 R 7 –, –SOR 9 –, –SO2R 9 –, –SO2NR 6 R 7 –, –NR 10 C(O)R 8 –, –NR 10 C(O)NR 6 R 7 –, –NR 10 SO2R 8 –, –NR 10 SO2NR 6 R 7 –, C1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 5- to 10-membered heteroaryl;

[0878] R 2 is H, and R 3 is –CF3; or

[0879] R 2 and R 3 together form an oxo group;

[0880] Each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or

[0881] Two Rs 4 together with the carbon atom to which they are attached and any intervening atoms form a C 3-10 cycloalkyl, and any remaining Rs 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 、–SO2R 9 、–SO2NR6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5 - to 10 - membered heteroaryl;

[0882] R 5 is 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 、 –SO2R 9 、 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3 - to 10 - membered heterocycloalkyl, C 6-10 aryl, and 5 - to 10 - membered heteroaryl;

[0883] R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0884] Each R 8 is independently selected from H, C1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0885] Each R 9 is 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;

[0886] Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0887] n is 1, 2, 3 or 4;

[0888] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0889] p is 0, 1, 2 or 3.

[0890] 25. A compound of formula IIIc:

[0891]

[0892] or a pharmaceutically acceptable salt thereof, wherein:

[0893] Each X is independently selected from N and CR 7 ;

[0894] Y is selected from O, S, SO2 and C(R 8 )2;

[0895] R 1 is 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: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 , –SO2NR 9 R 10 , –NR13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5- to 10-membered heteroaryl;

[0896] R 2 is H, and R 3 is –CF3; or

[0897] R 2 and R 3 together form an oxo group;

[0898] R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、 –OR 11 、 –C(O)R 11 、 –C(O)OR 11 、 –C(O)NR 9 R 10 、 –SOR 12 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10 aryl and 5- to 10-membered heteroaryl; or

[0899] R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、

[0900] –NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0901] each R 6 is independently selected from halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0902] two Rs attached to the same carbon atom 6 together form an oxo group, and any remaining Rs 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0903] 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 、 –SO2R 12 、 –SO2NR 9 R 10 、 –NR 13 C(O)R 11 、 –NR13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0904] R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;

[0905] Each R 11 is 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;

[0906] Each R 12 is 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;

[0907] Each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and

[0908] n is 0, 1, 2, 3 or 4.

[0909] 26. A composition comprising a compound selected from:

[0910]

[0911] 27. A composition comprising a compound selected from:

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923] 28. A composition, the composition comprising a compound selected from the following:

[0924]

[0925]

[0926] 29. A method for promoting and / or stimulating skin pigmentation, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0927] 30. A method for inhibiting hair loss, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0928] 31. A method for preventing and / or treating skin inflammation and / or damage, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0929] 32. A method for preventing and / or treating vascular insufficiency, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0930] 33. A method for preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0931] 34. A method of reducing cardiac ejection fraction, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0932] 35. A method of preventing and / or treating gastrointestinal diseases, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0933] 36. A method of preventing and / or treating renal dysfunction, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0934] 37. A method of stimulating bone resorption and bone formation, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0935] 38. A method of stimulating tissue regeneration by stimulation, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0936] 39. A method of regulating cervical ripening, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0937] 40. A method of promoting neuroprotection and / or stimulating neuronal regeneration, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0938] 41. A method of treating and / or preventing neurological disorders, neuropsychiatric disorders, nerve injuries, neurotoxic disorders, neuropathic pain or neurodegenerative disorders, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0939] 42. A method of treating and / or preventing fibrotic or adhesion diseases, disorders or conditions, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0940] 43. A method of reducing and / or preventing scar formation, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0941] 44. A method of treating and / or preventing muscle disorders, muscle injuries and / or muscle atrophy, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0942] 45. A method for treating and / or preventing fibrosis, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0943] 46. A method for treating and / or preventing idiopathic pulmonary fibrosis, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0944] 47. A method for treating and / or preventing renal fibrosis, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0945] 48. A method for stimulating muscle regeneration, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0946] 49. A method for promoting organ health, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0947] 50. A method for promoting wound healing, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0948] 51. A method for treating acute kidney injury, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0949] 52. A method for treating sarcopenia, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0950] 53. A method for treating neuromuscular diseases, the method comprising administering one or more of the compositions of any of the foregoing embodiments to a subject in need thereof.

[0951] Examples

[0952] Example 1: Synthesis and Characterization of Compounds

[0953] In another aspect, methods for preparing the inhibitors described herein are provided. In some cases, the inhibitors are isolated or extracted from one or more plants. In some cases, inhibitors derived from one or more plants can be further modified. In some cases, the inhibitors are further purified after being isolated from one or more plants.

[0954] Exemplary synthetic schemes for inhibitors having a phenyl core as described herein include:

[0955]

[0956]

[0957] Exemplary synthetic schemes for inhibitors having a 6-5 ring core as described herein include:

[0958]

[0959]

[0960] In some cases, the synthetic scheme may be a complete synthetic scheme for generating the inhibitors provided herein. In other cases, the synthetic scheme may be a partial scheme for generating the inhibitors provided herein.

[0961] Exemplary synthetic schemes that can be used to synthesize the inhibitors described herein are described. The following abbreviations are used:

[0962]

[0963]

[0964] Synthesis of benzimidazole-5-carboxamide analogs with amide variations

[0965] An exemplary scheme for synthesizing a benzimidazole-5-carboxamide analogue having amide variations as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0966]

[0967] Scheme 1

[0968] Step - 1: Synthesis of methyl 4-fluoro-3-nitrobenzoate (Int-2): At 0 °C, oxalyl chloride (9.42 mL, 108.04 mmol, 2 eq) was added to a stirred solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 54.02 mmol) in DCM (100 mL), and then DMF (1 mL) was added. The RM was stirred at 0 °C for 1 h. The reaction was monitored by TLC. After the reaction was complete, it was quenched with methanol (20 mL) and stirred at room temperature for 1 h. Then the solvent was evaporated under reduced pressure, diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (50 mL) and brine solution (50 mL), the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 4-fluoro-3-nitrobenzoate as an off-white solid (10.4 g, 96.7%). LCMS: 75.82%, m / z = 199.8 [M+H] + ; 1 H NMR(CDCl 3,400 MHz): δ 8.75 (dd, J = 2.20, 7.21 Hz, 1H), 8.32 (ddd, J = 2.2, 4.3, 8.7 Hz, 1H), 7.39 (dd, J = 8.7, 10.2 Hz, 1H), 3.97 - 3.99 (m, 3H).

[0969] Step - 2: Synthesis of methyl 4 - ((3 - chlorophenyl)amino)-3 - nitrobenzoate (Int - 3), (#1 General procedure for SNAr reaction): In a sealed high - pressure reactor; at room temperature, 3 - chloroaniline (7.68 g, 60.25 mmol, 1.2 eq) was added to a stirred solution of methyl 4 - fluoro - 3 - nitrobenzoate (10 g, 50.21 mmol, 1 eq) in EtOH (100 mL). The steel high - pressure reactor lid was tightened, and then the resulting reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by LCMS / TLC. After the reaction was completed, it was cooled to room temperature, the volatiles were evaporated, quenched with saturated NH4Cl (100 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 the crude product, which was wet - ground with ether (100 mL) to obtain methyl 4 - ((3 - chlorophenyl)amino)-3 - nitrobenzoate as a yellow solid (8.2 g, 53.24%). LCMS: 95.95%, m / z = 307.1 [M + H] + ; 1 1H NMR (CDCl 3, 400 MHz): δ 9.73 (brs, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 1.8, 8.9 Hz, 1H), 7.36 - 7.41 (m, 1H), 7.26 - 7.31 (m, 2H), 7.19 (d, J = 8.9 Hz, 2H), 3.92 (s, 3H).

[0970] Step - 3: Synthesis of methyl 3 - amino - 4 - ((3 - chlorophenyl)amino)benzoate (Int - 4), (General procedure for the aryl nitro reduction using Fe): At room temperature, iron powder (10.47 g, 187.55 mmol, 7 eq) and NH4Cl (10.03 g, 187.55 mmol, 7 eq) were added 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). 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 bed of diatomaceous earth and washed with EtOAc (2 × 100 mL). The volatiles were evaporated, quenched with saturated NaHCO3 (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 the 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 as a gummy liquid (7.1 g, 96.07%). LCMS: 67.71%, m / z = 277.1 [M + H] + ; 1 H NMR(CDCl 3, 400 MHz): δ 7.45 - 7.50 (m, 2H), 7.14 - 7.19 (m, 2H), 6.86 - 6.91 (m, 2H), 6.77 (td, J = 1.2, 8.8 Hz, 1H), 5.55 (br s, 1H), 3.88 (s, 3H).

[0971] Step - 4: Synthesis of methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (Int-5): At room temperature, PTSA (884 mg, 5.144 mmol, 0.2 eq) was added 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). The resulting reaction mixture was heated to 100 °C for 16 h until the SM was consumed as indicated by crude LCMS / TLC. The reaction mixture was filtered through a bed of diatomaceous earth and washed with EtOAc (2 × 100 mL). The volatiles were evaporated, washed with saturated NaHCO3 (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (200 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 to obtain methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate as a light brown solid (5.8 g, 78.6%). LCMS: 89.6%, m / z = 287.2 [M+H] + ; 1 H NMR (CDCl 3, 400 MHz): δ 8.60 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 8.08 (dd, J = 1.5, 8.6 Hz, 1H), 7.53 - 7.58 (m, 3H), 7.42 - 7.51 (m, 2H), 3.97 (s, 3H).

[0972] Step - 5: Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-6), general procedure for ester hydrolysis using NaOH: At room temperature, NaOH (1.21 g, 30.34 mmol, 1.5 eq) was added to a stirred solution of methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (5.8 g, 20.23 mmol, 1 eq) in THF / water (8:2, 60 mL) or MeOH / water (8:2, 60 mL), and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the volatiles were evaporated and neutralized with 1N HCl until pH = 7. The solid was filtered, washed with Et2O (200 mL) and dried in vacuo to obtain 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid as a light brown solid (4.5 g, 81.66%). LCMS: 99.58%, m / z = 273.1 [M+H] + ; 11H NMR (DMSO-d 6, 500 MHz): δ 12.44 - 13.20 (m, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 7.96 (br d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.65 - 7.73 (m, 3H), 7.58 - 7.61 (m, 1H).

[0973] Step 6: General procedure for amide coupling using HATU: At 0 °C, under an inert atmosphere, add HATU (1.5 eq) to a stirred solution of Int-6 (1 eq) in DMF (10 v), and then add amine (1.2 eq). At 0 °C, add N,N'-diisopropylethylamine (3 eq) to this stirred solution, and then continue stirring at room temperature for 16 h. Monitor the reaction by crude LCMS / TLC; after consumption of the starting material, quench the reaction mixture with ice water (10 mL) and extract with EtOAc (2 × 15 mL). Wash the combined organic extracts with ice water (2 × 10 mL) and brine (10 mL); dry over sodium sulfate, filter, and concentrate in vacuo to obtain the crude product. Purify the crude product successively by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC to obtain the product shown in Scheme 1.

[0974] Synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone

[0975] An exemplary scheme for synthesizing (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[0976]

[0977] Scheme 2

[0978] 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, react Int-6 (400 mg, 1.47 mmol) with 3-Boc-aminopyrrolidine (326 mg, 1.76 mmol, 1.2 eq) to provide tert-butyl (1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate (280 mg, 43%) as a pale yellow liquid. LCMS: 81.8%, m / z = 441.2 [M + H] + ; 1 1H NMR (DMSO-d 6,400 MHz): δ 8.76 (s, 1H), 7.85 - 7.98 (m, 2H), 7.49 - 7.74 (m, 4H), 7.20 - 7.29 (m, 1H), 3.87 - 4.12 (m, 1H), 3.59 - 3.68 (m, 2H), 3.08 - 3.35 (m, 2H), 2.81 - 2.89 (m, 1H), 2.65 - 2.73 (m, 1H), 1.94 - 2.09 (m, 1H), 1.69 - 1.89 (m, 1H), 1.30 - 1.40 (m, 9H).

[0979] 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 1,4 - dioxane solution of 4N HCl (5 mL) was added. It was warmed to room temperature and then stirred 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). Then the aqueous layer was basified with saturated NaHCO3 solution and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford (3 - aminopyrrolidin - 1 - yl)(1 - (3 - chlorophenyl)-1H - benzo[d]imidazol - 5 - yl)methanone as an off - white solid (120 mg, 57% yield). LCMS: m / z = 341.2 [M + H] + 。

[0980] Synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-064): Synthesis

[0981] An exemplary protocol for the synthesis of 1 - (3 - chlorophenyl)-N - cyclopropyl - N - methyl - 1H - benzo[d]imidazole - 5 - carboxamide, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[0982]

[0983] Scheme 3

[0984] 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 for 20 min at 0 °C, methyl iodide (136.05 mg, 0.961 mmol, 1.5 eq) was added at 0 °C and the mixture was warmed 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 give the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane followed by preparative HPLC to give 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide as a brown liquid (14.31 mg, 6.84% yield). LCMS: m / z = 326.1 [M+H] + .

[0985] Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090)

[0986] An exemplary protocol for the synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[0987]

[0988] Scheme 4

[0989] Steps - 1 and 2: Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090): A stirred solution of Int-6 (100 mg, 0.367 mmol, 1 eq) in DCM (2 mL) was cooled to 0 °C, and oxalyl chloride (92.73 mg, 0.735 mmol, 2.0 eq), DMF (0.1 mL) were added, and then stirred 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 subjected to the next step. The crude product was dissolved in DCM (2 mL), cooled to 0 °C, pyrrolidinone (53.60 mg, 121.5 mmol, 1.2 eq) was added, warmed to room temperature, and then stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by preparative HPLC to give 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090, 4.8 mg, 3.85% yield) as a brown liquid.

[0990] Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102) An exemplary protocol for synthesizing 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[0991]

[0992] Scheme 5

[0993] Step - 1: Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102): At 0 °C, under an inert atmosphere, HATU (416 mg, 1.093 mmol, 1.5 eq) was added to a stirred solution of Int-6 (200 mg, 0.733 mmol, 1 eq) in DMF (5 mL), and NH4Cl (196.33 mg, 3.669 mmol, 5.0 eq) was added. At 0 °C, N,N'-diisopropylethylamine (282 mg, 2.177 mmol, 3.0 eq) was added to this stirred solution, and then stirring was continued 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 obtain 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide as an off-white solid (138.52 mg, 69.51%). LCMS: m / z = 272.1 [M+H] + 。

[0994] Synthesis of benzimidazole analogs with 2-substituents

[0995] An exemplary protocol for synthesizing 2-substituted benzimidazole analogs as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[0996]

[0997] Scheme 6

[0998] Step - 1: Synthesis of 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (Int-1): In a sealed high-pressure reactor; at room temperature, m-chloroaniline (4.18 g, 32.96 mmol, 1.22 eq) and potassium carbonate (1.86 g, 13.51 mmol, 0.5 eq) were sequentially added to a stirred solution of 4-fluoro-3-nitrobenzoic acid (5 g, 27.02 mmol, 1 eq) in ethanol (100 mL), and then heated to 80 °C for 16 h. The reaction was monitored by TLC, and after completion of the reaction, it was cooled to room temperature and filtered; the solid was washed with ethanol and dried to obtain 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid as an off-white solid (5.2 g, 65.8% yield). LCMS: m / z = 293.0 [M+H] + 。

[0999] Step - 2: Synthesis of (4 - ((3 - chlorophenyl)amino)-3 - nitrophenyl)(piperidin - 1 - yl)methanone (Int - 2): At 0 °C, oxalyl chloride (5.83 g, 46.23 mmol, 3 eq) was added dropwise to a stirred solution of Int - 1 (4.5 g, 15.41 mmol, 1 eq) in DCM (45 mL), and then stirring was continued at 0 °C for 1 h. The reaction was monitored by TLC. After the reaction was complete, it was cooled to room temperature and the volatiles were evaporated. This was dissolved in DCM (45 mL), and piperidine (1.57 g, 18.49 mmol, 1.2 eq) was added to this stirred solution. Stirring was carried out at room temperature for 5 h, and it was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography using 5% MeOH / DCM to obtain (4 - ((3 - chlorophenyl)amino)-3 - nitrophenyl)(piperidin - 1 - yl)methanone as a yellow solid (5.7 g, 89% yield). LCMS: 87.89%, m / z = 360.0 [M + H] + 。

[1000] Step - 3: Synthesis of (3 - amino - 4 - ((3 - chlorophenyl)amino)phenyl)(piperidin - 1 - yl)methanone (Int - 3): At room temperature, iron powder (7.6 g, 136.11 mmol, 7 eq) and NH4Cl (7.4 g, 136.11 mmol, 7 eq) were added to a stirred solution of Int - 2 (7 g, 19.44 mmol, 1 eq) in EtOH:water (1:1, 120 mL). 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 bed of diatomaceous earth 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 the crude product. The crude product was triturated with ether (20 mL) to afford (3 - amino - 4 - ((3 - chlorophenyl)amino)phenyl)(piperidin - 1 - yl)methanone as a gummy liquid (5 g, 77.60%). LCMS: m / z = 330.0 [M + H] + 。

[1001] 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; at room temperature, ethyl glyoxylate (186.2 mg, 1.823 mmol, 3 eq) and PTSA (20 mg, 0.116 mmol, 0.2 eq) were added to a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq). 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 successively by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC to give MF-PGDH-027 as an off-white solid (18.82 mg, 7.55% yield).

[1002] Step - 4B: Synthesis of ethyl 2-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)acetate (MF-PGDH-030): At room temperature, ethyl (E)-3-amino-3-ethoxyacrylate (355 mg, 1.818 mmol, 3 eq) was added to a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq) in DMF (3 mL). 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 successively by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC to give MF-PGDH-030 as an off-white solid (35.4 mg, 13.7%).

[1003] Step - 4C: Synthesis of MF-PGDH-091 (General procedure for ester hydrolysis using LiOH): At 0 °C, LiOH·H2O (235 mg, 4.7 mmol, 2 eq) was added 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. 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 the crude product. The crude product was purified successively by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC to afford MF-PGDH-091 as an off-white solid (20.38 mg, 2.9%). LCMS: m / z = 354.2 [M+H] + 。

[1004] 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 using HATU to afford methyl 4 - ((2 - ((3 - chlorophenyl)amino)-5-(piperidine - 1 - carbonyl)phenyl)amino)-4 - oxobutanoate as an off - white solid (600 mg, 89.1%). LCMS: m / z = 444.1 [M + H] + .

[1005] Step - 4E: Synthesis of ethyl 3-(1-(3 - chlorophenyl)-5-(piperidine - 1 - carbonyl)-1H - benzo[d]imidazol - 2 - yl)propionate (MF - PGDH - 033) and 3-(1-(3 - chlorophenyl)-5-(piperidine - 1 - carbonyl)-1H - benzo[d]imidazol - 2 - yl)propanoic acid (MF - PGDH - 034): At 0 °C, under an inert atmosphere, trifluoroacetic acid (TFA) (10 mL) was added to a stirred solution of Int - 4 (1 g, 2.252 mmol, 1 eq) in DCE (20 mL). The 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 diluted with ice - cold water (20 mL). It was neutralized with 10% NaHCO3 solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with ice - cold water (2 × 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to obtain MF - PGDH - 033 (68.36 mg) and MF - PGDH - 034 (33.41 mg) as off - white solids.

[1006] Step - 4F: Synthesis of 3-(1-(3 - chlorophenyl)-5-(piperidine - 1 - carbonyl)-1H - benzo[d]imidazol - 2 - yl)propanamide (MF - PGDH - 035): At 0 °C, a solution of ammonia (10 mL) in MeOH was added to a stirred solution of MF - PGDH - 034 (200 mg, 2.252 mmol, 1 eq) in a steel autoclave. 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 give the crude product. The crude product was purified by preparative HPLC to obtain MF - PGDH - 035 (33.27 mg, 17.3% yield) as an off - white solid.

[1007] Synthesis of benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations

[1008] An exemplary protocol for synthesizing benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1009]

[1010] Protocol 7

[1011] The synthesis of Int-1 is described in Scheme 1, 1a above.

[1012] Step - 2: Synthesis of methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate (Int-2): Using the general procedure for #1SNAr reaction, methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1 eq) in EtOH (100 mL) was converted to Int-2 using p-methoxyaniline (7.68 g, 60.25 mmol, 1.2 eq) 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] + 。

[1013] Step - 3: Synthesis of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (Int-3): Using the general procedure for the reduction of aryl nitro groups with Fe, (4-methoxyphenyl)amino)-3-nitrobenzoate (8.09 g, 26.79 mmol) was converted to methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (7.1 g, 96.07%) to afford Int-3 as a gummy liquid. LCMS: 91.32%, m / z = 273.2 [M+H] + 。

[1014] 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): At room temperature, PTSA (884 mg, 5.144 mmol, 0.2 eq) / Na2S2O3 (1 eq) was added to a stirred solution of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (7.02 g, 25.72 mmol, 1 eq) and triethyl orthoformate / cyclopropanecarbaldehyde (128.62 mmol, 5 eq) in 1,4-dioxane (80 mL) / DMF. The resulting reaction mixture was heated to 90 °C for 16 h until the SM was consumed according to crude LCMS / TLC. The reaction mixture was filtered through a bed of diatomaceous earth and washed with EtOAc (2 × 100 mL). The volatiles were evaporated, washed with saturated NaHCO3 (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (200 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 to obtain methyl 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate Int-4a (78.6% yield, m / z = 283.3 [M+H] + ) and methyl 2-cyclopropyl-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-4b) (53.40% yield, m / z = 323.33 [M+H] + ).

[1015] 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] + ) and Int-5b (230 mg, 64.5% yield, LCMS: m / z = 309.0 [M+H] + ).

[1016] Step - 6: Synthesis of MF-DH-008, MF-DH-009 and MF-DH-021: Int-5a / 5b was subjected to the general procedure for amide coupling with HATU to afford MF-DH-008, MF-DH-009 and MF-DH-021.

[1017] Synthesis of benzimidazole-5-carboxamide analogs with aryl / amide variations

[1018] An exemplary protocol for synthesizing benzimidazole-5-carboxamide analogs with aryl / alkyl / amide variations as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1019]

[1020] Protocol 8

[1021] The synthesis of Int-1 is described in Protocol 1.

[1022] Step - 2: Synthesis of Int-2; General procedure for #2 SNAr reaction: At room temperature, 5-methoxypyridin-2-amine / 3-chloro-4-methoxyaniline (1.2 eq) and K2CO3 (1.726 g, 1 eq) were added 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 high-pressure reactor. The steel high-pressure reactor 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 quenched with saturated NH4Cl (100 mL) 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 give the crude product. The crude product was triturated with ether (100 mL) to give Int-2a as a yellow solid for obtaining MF-PGDH-22 and MF-DH-141 (50.5% yield, LCMS: m / z = 304.1 [M+H] + )

[1023] Int-1 was converted to Int-2b for obtaining MF-PGDH-24 and MF-PGDH-61 (51.0% yield, m / z = 337.2 [M+H] + )

[1024] Using the general procedure for #1 SNAr, Int-1 was converted to Int-2c for obtaining MF-PGDH-62 (59.0% yield, LCMS: m / z = 317.1 [M+H] + )

[1025] Step - 3: The synthesis of Int-3a, Int-3b, and Int-3c was achieved using the general procedure for aryl nitro reduction to give Int-3a as a gummy 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] + ).

[1026] Step - 4: Synthesis of Int-4a, Int-4b and Int-4c: At room temperature, PTSA (884 mg, 0.2 eq) was added 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. The resulting reaction mixture was heated to 90 °C for 16 h until the SM was consumed according to crude LCMS / TLC. The reaction mixture was filtered through a bed of diatomaceous earth and washed with EtOAc (2 × 50 mL). The volatiles were evaporated, washed with saturated NaHCO3 (20 mL); extracted with EtOAc (3 × 30 mL), and the combined organic extracts were washed with brine (30 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 to obtain Int-4a as a light brown solid (32.7% yield, LCMS: m / z = 287.2 [M+H] + ), 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] + ).

[1027] 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.

[1028] Step - 6: Using the general procedure of amide coupling with HATU, Int-5 was coupled to the appropriate amine to provide MF-PGDH-022, MF-PGDH-024, MF-PGDH-062 and MF-DH-141.

[1029] Step - 7: Synthesis of (1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone: At 0 °C, under an inert atmosphere, BBr3 (1.62 mL, 1.62 mmol, 3.0 eq, 1 M in CH2Cl2) was added to a stirred solution of (1-(3-chloro-4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-024 (200 mg, 0.54 mmol, 1 eq) in CH2Cl2 (10 mL), and the mixture was stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with MeOH (10 mL), evaporated to dryness, and then quenched with saturated NaHCO3 solution (5 mL). It was extracted with EtOAc (2 × 15 mL), the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to afford (1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-061 as an off-white solid (120 mg, 63%).

[1030] Synthesis of pyrrolo[3,2-d]pyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations The following provides an exemplary protocol for the synthesis of pyrrolo[2,3-b]pyridine-5-carboxamide analogs with amide / aryl / heteroaryl variations as inhibitors of hydroxyprostaglandin dehydrogenase.

[1031]

[1032] Scheme 9 and Scheme 10

[1033] Scheme 9 Step 1: As shown in Scheme 9 and as previously described, Int-1 was subjected to amide coupling with the appropriate amine using HATU to provide Int-2.

[1034] Piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (950 mg, yield: 79%); LCMS: m / z = 230.2 [M+H,] + ; 1 1H NMR (400 MHz, DMSO-d6) δ = 11.84 (s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.56 (d, J = 1.83 Hz, 1H), 6.51 (d, J = 1.89 Hz, 1H), 3.67 - 3.38 (m, 4H), 1.68 - 1.43 (m, 6H).

[1035] (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-d6) δ = 11.83 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.65 (d, J = 1.84 Hz, 1H), 6.78 (d, J = 1.86 Hz, 1H), 3.76 - 3.35 (m, 4H), 1.98 - 1.54 (m, 4H).

[1036] (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-d6) δ = 13.11 (br s, 1H), 12.35 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 7.80 (s, 1H), 5.03 - 4.80 (m, 1H), 3.82 - 3.33 (m, 4H), 2.04 - 1.64 (m, 4H).

[1037] 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 an inert atmosphere, Cs2CO3 (422 mg, 1.3 mmol, 2.0 eq) and the corresponding chloro / bromoarene (1.2 eq) were added 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). The mixture was purged with argon for 15 min, followed by the addition of Xantphos (75.14 mg, 0.13 mmol, 0.2 eq) and Pd2(dba)3 (59.47 mg, 0.065 mmol, 0.1 eq) under an argon atmosphere. The lid of the sealed tube was tightened, and the resulting reaction mixture was heated to 100 °C for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, the reaction mixture was quenched with saturated NH4Cl (10 mL), filtered through a bed of diatomaceous earth, 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 the crude product. The crude product was purified successively by silica gel column chromatography using 70% EtOAc / heptane and preparative HPLC to afford MF - PGDH - 071 and MF - DH - 123, 124.

[1038] 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): At 40 °C, under an inert atmosphere, NCS (906 mg, 6.68 mmol) was added 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). 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 ether (3 × 10 mL). The crude product was azeotroped with toluene (2 × 10 mL), followed by drying for 2 h to afford 3 - chloro - 1H - pyrrolo[2,3 - b]pyridine - 5 - carboxylic acid (Int - 2) as a light brown solid (850 mg, yield: 70%). LCMS: 88.2%) m / z = 195.0 [M - H] - ; 11H NMR (500 MHz, DMSO-d6) δ = 13.18 (br s, 1H), 12.37 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.82 (s, 1H).

[1039] Scheme 9 Step 2 and Scheme 10 Step 3: General Ullmann coupling procedure: At room temperature, 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. K3PO4, 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 completion, quenched with saturated NH4Cl 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), washed with saturated NaHCO3 solution (50 mL) and brine solution (50 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was further purified by preparative HPLC to give the final products MF-PGDH-014, MF-PGDH-067, MF-PGDH-069, MF-PGDH-070, MF-PGDH-073, MF-PGDH-074, MF-PGDH-075, MF-PGDH-076, MF-DH-128, MF-DH-129, MF-DH-131, MF-DH-132, MF-DH-133, MF-DH-134, MF-DH-135, MF-DH-139, MF-DH-140, MF-DH-145 and MF-DH-157.

[1040] Synthesis of azabenzimidazole analogs

[1041] An exemplary scheme for synthesizing azabenzimidazole analogs as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1042]

[1043] Scheme 11

[1044] Step - 1: Synthesis of Int-1: 6-Chloro-5-nicotinoyl ester (7 g, 32.31 mmol, 1 eq) and 3-Cl / 4-methoxyaniline (1 eq) were subjected to #2 SNAr conditions to give Int-1a as a yellow solid (Ar = 3-Cl phenyl, 95.2% yield, LCMS: m / z = 308.2 [M+H] +) and Int-1b (Ar = 4-OMe phenyl) as a light yellow solid (87.6% yield, LCMS: 96.0%, m / z = 304.2 [M+H] + ).

[1045] Step - 2: Synthesis of Int-2: Subject 6-((4-methoxyphenyl)amino)-5-nicotinamide / 6-((3-chlorophenyl)amino)-5-nicotinamide (Int-1) to the general procedure of aryl nitro reduction using Fe. Purify the crude product by silica gel column chromatography using 60% EtOAc / heptane to obtain Int-2a (Ar = 3-Cl phenyl) as a yellow solid (97% yield, LCMS: m / z = 278.2 [M+H] + ) and Int-2b (Ar = 4-OMe phenyl) as a light yellow solid (77% yield, LCMS: m / z = 272.4 [M+H] + ).

[1046] Step - 3: Synthesis of Int-3 (general procedure for PTSA-catalyzed ring closure to form imidazole): At room temperature, add PTSA (0.2 eq) to a stirred solution of 5-amino-6-((4-methoxyphenyl)amino)nicotinamide / 5-amino-6-((3-chlorophenyl)amino)nicotinamide (Int-2) (1 g, 1 eq) and triethyl orthoformate (5 eq) in dioxane (20 mL). Heat the resulting reaction mixture to 100 °C for 16 h. Monitor the reaction by crude LCMS / TLC; after consumption of the starting material, filter the reaction mixture through a bed of diatomaceous earth and wash with EtOAc (2 × 50 mL). Evaporate the volatiles, quench with saturated NaHCO3 solution (20 mL) and extract with EtOAc (3 × 50 mL). Wash the combined organic extracts with brine (20 mL), dry over sodium sulfate, filter and concentrate in vacuo to obtain the crude product. Purify the crude product by silica gel column chromatography using 50% EtOAc / heptane to obtain Int-3a (Ar = 3-Cl phenyl) as a yellow solid (83% yield, LCMS: m / z = 288.2 [M+H] + ) and Int-3b (Ar = 4-OMe phenyl) as a light yellow solid (71% yield, LCMS: m / z = 284.2 [M+H] + ).

[1047] Step - 4: Synthesis of Int - 4, using the general procedure of ester hydrolysis with LiOH: At room temperature, LiOH (2.5 eq) was added 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), and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after completion, the reaction mixture was concentrated and neutralized with 1N HCl. The resulting solid was filtered, washed with Et2O (50 mL), and dried in vacuo to afford Int - 4a (Ar = 3 - Cl phenyl, 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 off - white solids.

[1048] Step - 5: Synthesis of MF - PGDH - 020, MF - PGDH - 077, MF - PGDH - 078, MF - PGDH - 079, and MF - PGDH - 138: As described previously, Int - 4 was subjected to amide coupling with the appropriate amine using HATU to provide the crude product, which was purified successively by silica gel column chromatography using 40% EtOAc:heptane / 5% MeOH:CH2Cl2 and preparative HPLC to afford 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.

[1049] Synthesis of 2-substituted azabenzimidazole analogs MF-DH-115 and MF-DH-116

[1050] An exemplary scheme for the synthesis of 2 - substituted azabenzimidazole analogs as inhibitors of hydroxyprostaglandin dehydrogenase is provided below.

[1051]

[1052] Scheme 12

[1053] Step - 1: Synthesis of methyl 2 - amino - 3-(4 - methoxyphenyl)-3H - imidazo[4,5 - b]pyridine - 6 - carboxylate (Int - 3): At 0 °C, cyanogen bromide (1.1 g, 10.63 mmol, 3 eq) was added 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). 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 completion of the reaction, it was cooled to room temperature and quenched with water (10 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 afford methyl 2 - amino - 3-(4 - methoxyphenyl)-3H - imidazo[4,5 - b]pyridine - 6 - carboxylate as a gummy liquid (1.08 g, 99%). LCMS: 80.63%, m / z = 299.2 [M + H] + .

[1054] Step - 2: Synthesis of methyl 2 - acetamido - 3-(4 - methoxyphenyl)-3H - imidazo[4,5 - b]pyridine - 6 - carboxylate (Int - 4): At 0 °C, triethylamine (829 mg, 8.05 mmol, 3 eq) was added to a stirred solution of Int - 3 (800 mg, 2.68 mmol, 1 eq) in DCM (8 mL). It was stirred at 0 °C for 10 min and then acetic anhydride (821 mg, 8.05 mmol, 3 eq) was added. The reaction mixture was warmed to room temperature and then stirred for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, it was quenched with ice - water (10 mL) and 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 give the crude product. The crude product was purified by silica gel column chromatography using 20% EtOAc / heptane to afford methyl 2 - acetamido - 3-(4 - methoxyphenyl)-3H - imidazo[4,5 - b]pyridine - 6 - carboxylate as an off - white solid (550 mg, 60.3%). LCMS: m / z = 341.0 [M + H] + .

[1055] 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 afford 2 - acetamido - 3-(4 - methoxyphenyl)-3H - imidazo[4,5 - b]pyridine - 6 - carboxylic acid as a light brown solid (400 mg, 96%). LCMS: m / z = 327.0 [M + H] + .

[1056] Step - 4: Synthesis of MF - DH - 116: As described previously, 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. The crude product was purified successively by silica gel column chromatography using 5% MeOH / DCM and preparative HPLC to afford MF - DH - 116 as an off - white solid (12.57 mg, 2.12%).

[1057] Step - 5: Synthesis of MF - DH - 115: At room temperature, under an inert atmosphere, K2CO3 (235 mg, 1.70 mmol, 2.0 eq) was added to a stirred solution of MF - DH - 116 (350 mg, 0.85 mmol, 1 eq) in methanol (5 mL), and stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified successively by silica gel column chromatography using 5% MeOH / DCM and preparative HPLC to afford MF - DH - 115 as an off - white solid (12.46 mg, 3.96%).

[1058] Synthesis of benzamide analogs

[1059] An exemplary protocol for synthesizing a benzamide analogue as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1060]

[1061] Scheme 13

[1062] Step - 1: Synthesis of (4-(hydroxymethyl)phenyl)(piperidin-1-yl)methanone (Int-1): At 0 °C, under an inert atmosphere, EDCI (3.82 g, 19.72 mmol, 1.2 eq) and HOBt (2.13 g, 15.78 mmol, 1.2 eq) were added to a stirred solution of 4-(hydroxymethyl)benzoic acid (2 g, 13.15 mmol, 1 eq) and piperidine (1.12 g, 13.5 mmol, 1 eq) in CH2Cl2 (20 mL). At 0 °C, N,N'-diisopropylethylamine (373 mL, 2.14 mmol, 3 eq) was added to this stirred solution, and then stirring was continued at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting materials, 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 the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc / heptane to afford Int-1 as a pale yellow solid (1.6 g, 57.1%). LCMS: m / z = 220.1 [M+H] + .

[1063] Step - 2: Synthesis of MF-PGDH-036, MF-PGDH-037, and MF-PGDH-039: Under an inert atmosphere, TPP (446 mg, 1.7 mmol, 1.5 eq) and DIAD (460 mg, 1.07 mmol, 1.5 eq) in THF (5 mL) were sequentially added 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), and then stirring was continued 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 successively by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC to afford MF-PGDH-036 as an off-white solid (yield: 2.05%), MF-PGDH-037 (yield: 2.1%), and MF-PGDH-039 (yield: 2.2%).

[1064] Synthesis of (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-040)

[1065] An exemplary protocol for synthesizing (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1066]

[1067] Scheme 14

[1068] To a stirred solution of MF-PGDH-39 (from Scheme 13) (200 mg, 0.578 mmol, 1 eq) in CH2Cl2 (15 mL) was added m-CPBA (196.1 mg, 1.15 mmol, 2 eq), and stirring was continued at room temperature for 16 h. Another aliquot (1 equivalent) of m-CPBA was added. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with ice water (10 mL) and extracted with CH2Cl2 (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified successively by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC to give (4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-040) as a brown liquid (21.1 mg, 9.6%).

[1069] Synthesis of (4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanone (MF-PGDH-045)

[1070] An exemplary protocol for synthesizing (4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanone as an inhibitor of hydroxyprostaglandin dehydrogenase is provided below.

[1071]

[1072] Scheme 15

[1073] To a stirred solution of MF-PGDH-39 (50 mg, 0.144 mmol, 1 eq) in CH3CN: water was added NaIO4 (61.99 mg, 0.289 mmol, 2 eq), and stirring was continued at room temperature for 4 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified successively by silica gel column chromatography using 40% EtOAc / heptane and preparative HPLC to give 35.8 mg of MF-PGDH-045 as a brown liquid.

[1074] Synthesis of MF-PGDH-38, MF-PGDH-098, MF-DH-118 and MF-DH-121

[1075] An exemplary protocol for synthesizing inhibitors of hydroxyprostaglandin dehydrogenases labeled as MF-PGDH-38, MF-PGDH-098, MF-DH-118, and MF-DH-121 in Scheme 16 below is provided.

[1076]

[1077] Scheme 16

[1078] Scheme 16 Step - 1: Synthesis of methyl 4-(bromomethyl)-3-methoxybenzoate (Int-1): At room temperature, under an inert atmosphere, NBS (2.96 g, 16.66 mmol, 1.2 eq) and AIBN (0.45 g, 2.74 mmol, 0.2 eq) were added to a stirred solution of methyl 3-methoxy-4-methylbenzoate / methyl 5-methylpyridinecarboxylate (2.5 g, 13.87 mmol, 1 eq) in CHCl3 (20 mL). Subsequently, the resulting reaction mixture was heated to reflux for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with saturated Na2S2O3 (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 the crude product. The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to obtain methyl 4-(bromomethyl)-3-methoxybenzoate (Int-1) as an off-white solid (2.0 g, 55.7%). MS: m / z = 261.1 [M+2] + 。

[1079] Scheme 16A Step - 2: Synthesis of Int - 2: At room temperature, under an inert atmosphere, K2CO3 (1.5 eq) was added to a stirred solution of Int - 1 (500 mg, 1.93 mmol, 1 eq) and 2 - chlorophenol (1 eq) in DMF (10 mL), and then the mixture was heated to reflux for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting materials, the reaction mixture was quenched with ice - water (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with ice - water (2 × 10 mL) and brine (20 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 15% EtOAc / heptane to obtain Int - 2 as an off - white solid (430 mg; yield: 71.83%). LCMS: 91.35%: m / z = 307.3 [M + H] + 。

[1080] Scheme 16A Step - 3: Synthesis of Int - 3: Using the general procedure for ester hydrolysis with LiOH, Int - 2 was hydrolyzed to give Int - 3 as a light - brown solid (yield: 58.7%). LCMS: m / z = 293.2 [M + H] + 。

[1081] Scheme 16A Step - 4: Synthesis of MF - PGDH - 038, MF - DH - 118: As described previously, using HATU as a coupling agent, Int - 3 (200 mg, 1 eq) was coupled with piperidine / 4 - fluoropiperidine (1.2 eq) to give MF - PGDH - 038, MF - DH - 118 as off - white solids.

[1082] 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 give Int - 1 as an off - white solid (yield: 52%). LCMS: m / z = 232.9 [M + 2H] + 。

[1083] 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 give Int - 2 as a light - yellow solid (yield: 66%). LCMS: m / z = 278.1 [M + H] + 。

[1084] Scheme 16B Step - 3: Synthesis of 4 - ((2 - chlorophenoxy)methyl)benzoic acid (Int - 3): Using the general procedure of ester hydrolysis with LiOH, Int - 2 was hydrolyzed to give Int - 3 as an off - white solid (yield: 84%). LCMS: m / z = 264.1 [M + H] + 。

[1085] Scheme 16B Step - 4: Synthesis of (5 - ((2 - chlorophenoxy)methyl)pyridin - 2 - yl)(4 - fluoropiperidin - 1 - yl)methanone (MF - DH - 121): As described previously, using HATU as a coupling agent, Int - 3 was coupled with 4 - fluoropiperidine to give MF - DH - 121 as an off - white solid (yield: 61%). LCMS: 99.96%, MS: m / z = 349.0 [M + H] + 。

[1086] Synthesis of MF-PGDH-095, MF-PGDH-096 and MF-PGDH-097

[1087] An exemplary scheme for synthesizing inhibitors of hydroxysteroid dehydrogenases labeled as MF - PGDH - 095, MF - PGDH - 096, and MF - DH - 097 in Scheme 17 below is provided.

[1088]

[1089] Scheme 17

[1090] Step - 1: To a stirred solution of the bromo - compound MF - PGDH - 036 (5 g, 0.013 mol, 1 eq) and the corresponding bis(pinacolato)diboron (5.1 g, 0.02 mol, 1.5 eq.) in 1,4 - dioxane (5V, 50 mL / mmol) was added KOAc (3.82 g, 0.04 mmol, 3 eq.), and the mixture was purged with argon for 15 min. To this solution was added PdCl2(dppf).DCM (1 g, 0.0013 mmol, 0.1 eq.), and the mixture was 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 diatomaceous earth and evaporated to dryness. The residue was dissolved in ethyl acetate, washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to give 2.82 g (51%) of Int - 1; LCMS: m / z = 422.2 [M + H] + ,340.2 [M + H] + 。

[1091] 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), add Na2CO3 (6.5 mmol, 3 eq.), and purge with argon for 15 min. Add Pd(PPh3)4 (0.21 mmol, 0.1 eq.) to this solution, and purge with argon for another 10 min. Stir the resulting reaction mixture at 90 °C for 16 h. Monitor the progress of the reaction by TLC. After the reaction is complete, filter the mixture through celite and evaporate to dryness. Dissolve the residue in ethyl acetate, wash successively with water and brine, dry over anhydrous sodium sulfate and evaporate under reduced pressure. Purify the crude product successively by column chromatography and preparative HPLC to obtain MF - PGDH - 095, MF - PGDH - 096, and MF - PGDH - 097 as off - white solids.

[1092] Synthesis of MF-PGDH-041, MF-PGDH-042, MF-PGDH-087, MF-PGDH-088 and MF-PGDH-089

[1093] An exemplary protocol for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF - PGDH - 041, MF - PGDH - 042, and MF - DH - 087 in Scheme 18 below is provided.

[1094]

[1095] Scheme 18

[1096] Step - 1: Synthesis of Int - 1: As described previously, couple 4 - nitrobenzoic acid (2 g, 1 eq) and piperidine / 4,4 - difluoropiperidine (1.5 eq) using HATU 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] + ).

[1097] Step - 2: Synthesis of Int - 2: Using the general procedure for aryl nitro reduction with Fe as described above, convert Int - 1 (1 eq) to Int - 2 to afford 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] + ).

[1098] Step - 3: Synthesis of Int - 3: As described previously, using HATU, Int - 2 (1 eq) and 2 - methoxyphenyl / 2 - chlorophenyl / 3 - methoxyphenyl formic acid (0.7 eq) were coupled to afford MF - PGDH - 041, MF - PGDH - 087, MF - PGDH - 088, and MF - PGDH - 089 as off - white solids.

[1099] Step - 4: Synthesis of MF - PGDH - 042 (General procedure for N - methylation of amide): At 0 °C to room temperature, over 1 h, NaH (60%, in mineral oil) (30 mg, 0.625 mmol, 1.5 eq) was added to a stirred solution of MF - PGDH - 041 (140 mg, 0.414 mmol, 1 eq) in THF (5 mL). Mel (88.18 mg, 0.625 mmol, 1.5 eq) was added to this stirred suspension, and then the resulting reaction mixture was stirred for 6 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl (10 ml), and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified successively by silica gel column chromatography using 50% EtOAc / heptane and preparative HPLC to afford MF - PGDH - 042 as a light brown solid (24.42 mg, 16.71%).

[1100] Synthesis of MF-PGDH-043 and MF-PGDH-044

[1101] An exemplary protocol for the synthesis of inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF - PGDH - 043 and MF - DH - 044 in Scheme 19 below is provided.

[1102]

[1103] Scheme 19

[1104] Step - 1: Synthesis of methyl 4 - (piperidine - 1 - carbonyl) benzoate (Int - 1): As described previously, using HATU, 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) to afford Int - 1 as a light yellow solid (2.6 g, yield: 92%). MS: m / z = 248.1 [M + H] + 。

[1105] Step - 2: Synthesis of 4-(piperidine-1-carbonyl)benzoic acid (Int-2): Using the general procedure of ester hydrolysis with NaOH, Int-1 (2.8 g) was hydrolyzed to afford Int-2 (1.8 g, yield: 58%) as an off-white solid. MS: m / z = 234.0 [M+H] + .

[1106] Step - 3: Synthesis of N-(2-methoxyphenyl)-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-043): As previously described, using HATU (2 g, 5.14 mmol, 1.5 eq), 4-(piperidine-1-carbonyl)benzoic acid (800 mg, 3.43 mmol, 1 eq) was coupled with 2-methoxyaniline (0.5 mL, 4.12 mmol, 1.2 eq) to afford MF-PGDH-043 (1 g, yield: 90%) as a light yellow solid.

[1107] Step - 4: N-(2-methoxyphenyl)-N-methyl-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-044): Using the general procedure of N-methylation of amides, MF-PGDH-043 (300 mg) was methylated with MeI to afford MF-PGDH-044 (64.44 mg, 23.69%) as a light brown solid.

[1108] Synthesis of indoles MF-PGDH-004 and MF-PGDH-005

[1109] An exemplary protocol for synthesizing inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF-PGDH-004 and MF-DH-005 in Scheme 20 below is provided.

[1110]

[1111] Scheme 20

[1112] Step - 1: Synthesis of Int-1: For R = Cl in Scheme 1 above, using the general procedure of chlorination with NCS, 1H-indole-5-carboxylic acid (2 g) was converted to Int-1 (2.3 g; yield: 95%). MS: m / z = 196.01 [M+H] + .

[1113] Step - 2: Synthesis of Int-2: Using the general procedure of amide coupling with HATU, Int-1 / 1H-indole-5-carboxylic acid was coupled with piperidine 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]+ )。

[1114] Step - 3: Synthesis of MF - PGDH - 004 and MF - PGDH - 005: At room temperature, 3 - chloroiodobenzene (1.2 eq) and K2CO3 (2 eq) were added to a stirred solution of Int - 2a / Int - 2b (1 eq) in DMF (10 mL). 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, and then stirring was continued at 100 °C for 16 h. The reaction was monitored by TLC. After complete consumption of the starting materials, it was quenched with saturated NH4Cl solution (10 mL), filtered, and washed with EtOAc. It was extracted with EtOAc, washed with ice - cold 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 the crude product, which was further purified by preparative HPLC to afford MF - PGDH - 004 and MF - PGDH - 005 as off - white solids.

[1115] Synthesis of MF-PGDH-053 and MF-PGDH-054

[1116] An exemplary protocol for the synthesis of inhibitors of hydroxyprostaglandin dehydrogenase labeled as MF - PGDH - 053 and MF - DH - 054 in Scheme 21 below is provided.

[1117]

[1118] Scheme 21

[1119] Step - 1: Synthesis of methyl 3 - bromo - 1H - indole - 6 - carboxylate (Int - 1): NBS (3.04 g, 17.14 mmol, 1.5 eq) was added to a stirred solution of methyl 1H - indole - 6 - carboxylate (2 g, 11.42 mmol, 1 eq) in DMF (40 mL), and then stirring was continued 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 - cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with ice - cold water (2×30 mL) and brine (20 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 30% EtOAc / heptane to obtain Int - 1 as a light - brown solid (1.51 g, 53%). MS: m / z = 256.1 [M + 2] + 。

[1120] 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 Na2CO3 (2.39 g, 22.63 mmol, 2.5 eq), and then the mixture was purged with argon for 15 min. Under argon, Pd(PPh3)4 (1.04 g, 0.90 mmol, 0.1 eq) was added to this solution. The resulting reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed successively 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 afford Int-2 as a brown solid (550 mg, 22%). MS: m / z = 287.1 [M+2] + 。

[1121] Step - 3: Synthesis of 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (Int-3): Using the general procedure for ester hydrolysis with LiOH, methyl 3-(3-chlorophenyl)-1H-indole-6-carboxylate (550 mg) was converted to Int-3 as a light brown solid (500 mg, 95.7%). MS: m / z = 270.1 [M-H] + 。

[1122] Step - 4: Synthesis of (3-(3-chlorophenyl)-1H-indol-6-yl)(piperidin-1-yl)methanone MF-PGDH-053: Using the general procedure for amide coupling with HATU, 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (500 mg) was converted to MF-PGDH-053 as an off-white solid.

[1123] Step - 5: Synthesis of (3-(3-chlorophenyl)-1-methyl-1H-indol-6-yl)(piperidin-1-yl)methanone MF-PGDH-054: At 0 °C to room temperature, for 1 h, NaH (60%, in mineral oil) (3 mg, 0.11 mmol, 2 eq) was added to a stirred solution of MF-PGDH-053 (20 mg, 0.059 mmol, 1 eq) in THF (0.2 mL). MeI (16 mg, 0.11 mmol, 2 eq) was added to this stirred suspension, and then 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 quenched with saturated NH4Cl (10 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 50% EtOAc / heptane followed by preparative HPLC purification to obtain MF-PGDH-054 as an off-white solid (16.94 mg, 81.4%).

[1124] Synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone MF-PGDH-057

[1125] An exemplary protocol for the synthesis of (1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone MF-PGDH-057, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[1126]

[1127] Scheme 22

[1128] Step - 1: Synthesis of 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (Int-1): Using a general procedure for ester hydrolysis with NaOH, methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (1 g) was converted to Int-1 as a brown solid (800 mg, 86.9%). MS: m / z = 178.1 [M+H] + 。

[1129] Step - 2: Synthesis of piperidin-1-yl(1,2,3,4-tetrahydroquinolin-6-yl)methanone (Int-2): Using a general procedure for amide coupling with HATU, 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (800 mg) was converted to Int-2 as a brown solid (309 mg, 48%). MS: m / z = 245.2 [M+H] + 。

[1130] 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 Cs2CO3 (800 mg, 2.45 mmol, 3 eq), and then purged with argon for 15 min. To this solution was added Pd2(dba)3 (37.5 mg, 0.0409 mmol, 0.1 eq) and xantphos (47.37 mg, 0.0819 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 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 successively with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to afford MF-PGDH-057 as an off-white solid (20.4 mg, 7.0%).

[1131] Synthesis of 1-(3-chlorophenyl)-6-(piperidin-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one MF-PGDH-058

[1132] An exemplary protocol for the synthesis of 1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one MF-PGDH-058, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[1133]

[1134] Scheme 23

[1135] Step - 1: Synthesis of 6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (Int-1): Using the general procedure for amide coupling with HATU, 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (1.5 g) was coupled with piperidine (806 mg, 9.46 mmol, 1.2 eq) to obtain Int-1 as a brown solid (1.7 g, 84.1%). MS: m / z = 259.1 [M+H] + 。

[1136] 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 afford MF-PGDH-058 (23.5 mg, 8.2%) as an off-white solid.

[1137] Synthesis of (1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-006

[1138] An exemplary protocol for the synthesis of (1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-006, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[1139]

[1140] Scheme 24

[1141] Step - 1: Synthesis of (1H-indazol-5-yl)(piperidin-1-yl)methanone (Int-1): Using the general procedure of amide coupling with HATU, 1H-indazole-5-carboxylic acid (500 mg) was converted to Int-1 (610 mg, 86.28%) obtained as a brown solid. MS: m / z = 230.1 [M+H] + 。

[1142] 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 K2CO3 (734 mg, 5.32 mmol, 2 eq.), and then the mixture was purged with argon for 15 min. Under argon, copper(I) iodide (101 mg, 0.532 mmol, 0.2 eq.) and trans - N,N′ - dimethylcyclohexane - 1,2 - diamine (126 mg, 0.532 mmol, 0.2 eq.) were added to this solution, and it was purged again for 10 min. The resulting reaction mixture was heated at 90 °C for 16 h. 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 successively with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to afford MF - PGDH - 006 as a gummy liquid (40 mg, 4.41%).

[1143] Synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone MF-PGDH-007

[1144] An exemplary protocol for the synthesis of (3 - (3 - chlorophenyl)imidazo[1,2 - a]pyridin - 7 - yl)(piperidin - 1 - yl)methanone MF - PGDH - 007, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[1145]

[1146] Scheme 25

[1147] Step - 1: Synthesis of methyl 3 - bromoimidazo[1,2 - a]pyridine - 7 - carboxylate (Int - 1): At 0 °C, to a stirred solution of methyl imidazo[1,2 - a]pyridine - 7 - carboxylate (1 g, 5.68 mmol, 1 eq.) in ethanol (10 mL) were added successively 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.), and then the mixture was warmed to room temperature and stirred for 1 h. The reaction was monitored by crude LCMS / TLC; after the reaction was completed, the mixture was quenched with saturated Na2S2O3 (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with ice - cold water (2 × 30 mL) and brine (20 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain Int - 1 as a light brown solid (900 mg, 62%). MS: m / z = 256.1 [M + H] + 。

[1148] Step - 2: Synthesis of 3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (Int-2): Using the general procedure for 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] + 。

[1149] Step - 3: Synthesis of (3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone MF-PGDH-007: Using the general procedure for amide coupling with HATU, 3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (150 mg) was converted to MF-PGDH-007 (29.28 mg, 15.7%) as an off-white solid.

[1150] (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-011 Synthesis

[1151] An exemplary protocol for the synthesis of (1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone MF-PGDH-011, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[1152]

[1153] Protocol 26

[1154] Step - 1: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (Int-1): At room temperature, 4-methoxyaniline (1.72 g, 13.50 mmol, 1 eq) was added to a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 13.50 mmol, 1 eq) in ethanol (25 mL), and then the mixture was heated 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] + 。

[1155] Step - 2: Synthesis of methyl 3 - amino - 4 - ((3 - chlorophenyl)amino)benzoate (Int - 2): Using the general procedure for the reduction of aryl nitro groups with Fe, Int - 1 (2 g) was converted to Int - 2 (1.20 g, 66.6%) obtained as a gummy liquid. MS: m / z = 277.2 [M + H] + .

[1156] Step - 3: Synthesis of methyl 1 - (3 - chlorophenyl)-1H - benzo[d][1,2,3]triazole - 5 - carboxylate (Int - 3): At 0 °C, under an inert atmosphere, 6 N H2SO4 (2 mL) was slowly added over 15 min to a stirred solution of methyl 3 - amino - 4 - ((3 - chlorophenyl)amino)benzoate (700 mg, 2.545 mmol, 1 eq), NaNO2 (175 mg, 2,545 mmol, 1 eq) in THF:water (1:1, 10 mL), then it was allowed to reach room temperature gradually, and then heated to reflux for 12 h. The reaction was monitored by crude TLC; after the reaction was complete, the mixture was quenched with saturated NaHCO3 (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 obtain the crude product. The crude product was purified by silica gel column chromatography using 30% EtOAc / heptane to afford Int - 3 (300 mg, yield: 41.26%) as an off - white solid. MS: m / z = 288.1 [M + H] + .

[1157] Step - 4: Synthesis of (1 - (3 - chlorophenyl)-1H - benzo[d][1,2,3]triazol - 5 - yl)(piperidin - 1 - yl)methanone MF - PGDH - 011: At 0 °C, piperidine (107 mg, 1.256 mmol, 1.2 eq) and trimethylaluminum (1.5 mL, 5.22 mmol, 5 eq) were successively added slowly to a stirred solution of methyl 1 - (3 - chlorophenyl)-1H - benzo[d][1,2,3]triazole - 5 - carboxylate (300 mg, 1.045 mmol, 1 eq) in toluene (7 mL), then slowly heated to 50 °C for 16 h. The reaction was monitored by TLC; after the reaction was complete, 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 × 30 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 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.

[1158] (3-(3-Chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone Synthesis of MF-PGDH-012

[1159] The following provides an exemplary protocol for synthesizing (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone MF-PGDH-012, which is an inhibitor of hydroxyprostaglandin dehydrogenase.

[1160]

[1161] Protocol 27

[1162] Step - 1: Synthesis of (3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (Int-1): Using a general procedure for amide coupling with HATU, 3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (500 mg) was coupled with piperidine (212 mg, 2.49 mmol, 1.2 eq) to obtain Int-1 (309 mg, 48%) as a brown solid. MS: m / z = 310.1 [M+2H] + .

[1163] Step - 2: Synthesis of (3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone MF-PGDH-012: Using a general procedure for 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 provide MF-PGDH-012 (32.78 mg, 9.9%) as an off-white solid.

[1164] (4-Fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone Synthesis of 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

[1165] The following provides an exemplary protocol for synthesizing (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, which are inhibitors of hydroxyprostaglandin dehydrogenase.

[1166]

[1167] Protocol 28

[1168] Step - 1: Synthesis of Int - 1: Using the general procedure for chlorination with NCS, a solution of 1H - pyrrolo[2,3 - b]pyridine - 5 - carboxylic acid (500 mg, 2.83 mmol, 1 eq) in DMF (15 mL) was converted to Int - 1 as a gummy liquid (450 mg; yield: 75.37%). MS: m / z = 212.2 [M + H] + 。

[1169] Step - 2: Synthesis of Int - 2: Int - 1 (300 mg, 1.43 mmol, 1 eq) was subjected to the general procedure for amide coupling using HATU to afford Int - 2 as a brown liquid (250 mg, 62%). MS: m / z = 278.1 [M + H] + 。

[1170] Step - 3: Synthesis of MF - DH - 150 and MF - DH - 151: Using the general procedure for Ullmann coupling, Int - 2 (1 eq) and 2 - bromopyrazine (1.2 eq) were converted to MF - DH - 150 (35.7% yield) and MF - DH - 151 (6.1% yield) isolated as off - white solids.

[1171] Synthesis of (4 - fluoropiperidin - 1 - yl)(1 - (pyrazin - 2 - yl)-2 - (trifluoromethyl)-1,2,3,4 - tetrahydroquinolin - 6 - yl)methanone MF - DH - 161

[1172] An exemplary protocol for the synthesis of (4 - fluoropiperidin - 1 - yl)(1 - (pyrazin - 2 - yl)-2 - (trifluoromethyl)-1,2,3,4 - tetrahydroquinolin - 6 - yl)methanone, an inhibitor of hydroxyprostaglandin dehydrogenase, is provided below.

[1173]

[1174] Scheme 29

[1175] 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 an inert atmosphere, Cs2CO3 (1.130 g, 3.47 mmol, 3.0 eq) and 2-bromopyrazine (220 mg, 1.38 mmol, 1.2 eq) were added 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). The mixture was purged with argon for 15 min, and then Xantphos (133.7 mg, 0.234 mmol, 0.2 eq) and Pd2(dba)3 (105.8 mg, 0.115 mmol, 0.1 eq) were added under an argon atmosphere. The lid of the sealed tube was tightened, 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 quenched with saturated NH4Cl (10 mL), filtered through a bed of diatomaceous earth 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 the crude product. The crude product was purified by silica gel column chromatography using 70% EtOAc / heptane, providing Int-1 (220 mg, 56.4%). MS: m / z = 338.1 [M+H] + .

[1176] 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] + .

[1177] 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 (5v) was subjected to the general procedure of amide coupling using HATU to afford MF-DH-161 (17.0% yield) as a semi-solid.

[1178] (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 Synthesis

[1179] An exemplary protocol 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), which are inhibitors of hydroxyprostaglandin dehydrogenase, is provided below.

[1180]

[1181] Protocol 30

[1182] Step - 1: Synthesis of Int-1: The 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’ = CH3, 86.9% yield, MS: 206.1 [M+H] + ), Int-1b (R = H, R’ = CH3, 74.0% yield, MS: 192.1 [M+H] + ), and Int-1c (R, R’ = H, 73.4% yield, MS: 176.1 [M-H] - .

[1183] Step - 2: Synthesis of (Int-2): The 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 provide Int-2a (R, R’ = CH3, 800 mg, 86.9% yield, MS: 291.1 [M+H] + ), Int-2b (R = H, R’ = CH3, 650 mg, 75.9% yield, MS: 277.1 [M+H] + ), and Int-2c (R, R’ = H, 73.4% yield, MS: 263.1 [M-H]- )。

[1184] 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 Cs2CO3 (3 eq.), and then the mixture was purged with argon for 15 min. Pd2(dba)3 (0.1 eq.) and xantphos (0.1 eq.) were added to this solution, and the mixture was purged with argon again for 10 min. The resulting reaction mixture was stirred at 90 °C for 16 h. Post - extraction workup gave a crude product, which was purified successively by column chromatography and preparative HPLC to afford 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.

[1185] (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 synthesis

[1186] The following provides an exemplary protocol for the s...

Claims

1. 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: or a pharmaceutically acceptable salt thereof, wherein: X is selected from –OCH2–, –C(O)NH–, –NHC(O)–, –C(O)NMe–, –NMeC(O)–, –SCH2–, –S(O)CH2–, –SO2CH2–; Each Y is independently selected from N and CR 11 ; Each R 1 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group or a thio group; Each R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 5 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl each time it appears Each R 8 is 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; Each R 9 is 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; Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; Each R 11 is independently selected from a halogen group, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 , –SOR 9 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Provided that the compound of formula I is not 2. 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: or a pharmaceutically acceptable salt thereof, wherein: T, U, W, X, and Y are independently selected from N and CR 5 ; S, V and Z are independently selected from N and C; R 1 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; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group or a thio group; Each R 4 is 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 , –SO2R 9 , –SO2NR 6 R 7 , –NR 10 C(O)R 8 , –NR 10 C(O)NR 6 R 7 , –NR 10 SO2R 8 , –NR 10 SO2NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or Two Rs 4 together with the carbon atoms to which they are attached and any intervening atoms form a C 3-10 cycloalkyl group, and any remaining Rs 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 、–SO2R 9 、 –SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 5 is independently selected from H, a halogen group, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 –C(O)NR 6 R 7 –SOR 9 –SO2R 9 –SO2NR 6 R 7 、 –NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、 –NR 10 SO2NR 6 R 7 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 6 and R 7 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; Each R 8 is 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; Each R 9 is 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; Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; and n is 1, 2, 3 or 4; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Provided that the compound of formula II is not 3. A method for 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: or a pharmaceutically acceptable salt thereof, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2 and C(R 8 )2; R 1 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; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、 –SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group or a thio group; R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; 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 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered hetero cycloalkyl 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 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; Each R 6 is independently selected from halo, -NR 9 R 10 , -OR 11 , -C(O)R 11 , –C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or Two Rs attached to the same carbon atom 6 together form an oxo group, a thio group or a C 3-10 cycloalkyl group, and any remaining Rs 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 、–SO2R 12 、 –SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 7 is independently selected from H, a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Each R 8 is independently selected from H, a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or Two Rs 8 may together form a C optionally substituted with 1 to 3 substituents independently selected from the following 3-10 cycloalkyl: halo, –NR 9 R 10 –, –OR 11 –, –C(O)R 11 , –C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 9 and R 10 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl each time it appears Each R 11 is 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; Each R 12 is 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; Each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3 or 4.

4. A compound of formula IIk: or a pharmaceutically acceptable salt thereof, wherein: 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; R 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 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 and –SO2R 10 、–SO2NR 7 R 8 、–NR 11 C(O)R 9 、–NR 11 C(O)NR 7 R 8 、 –NR 11 SO2R 9 、–NR 11 SO2NR 7 R 8 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group; Each R 4 is independently selected from H and a halogen group; R 5 Selected from halo, –NR 7 R 8 、–OR 9 、–C(O)R 9 、–C(O)OR 9 、–C(O)NR 7 R 8 、–SOR 10 、–SO2R 10 、–SO2NR 7 R 8 、–NR 11 C(O)R 9 、 –NR 11 C(O)NR 7 R 8 、–NR 11 SO2R 9 、–NR 11 SO2NR 7 R 8 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 6 selected from H, a halogen group, –NR 7 R 8 、–OR 9 、–C(O)R 9 、–C(O)OR 9 、 –C(O)NR 7 R 8 、 –SOR 10 、 –SO2R 10 、 –SO2NR 7 R 8 、 –NR 11 C(O)R 9 、 –NR 11 C(O)NR 7 R 8 、 –NR 11 SO2R 9 、 –NR 11 SO2NR 7 R 8 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 7 and R 8 are each independently selected, at each occurrence, from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; Each R 9 is 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; Each R 10 is 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; Each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; and p is 0, 1 or 2.

5. A compound of formula IIm: or a pharmaceutically acceptable salt thereof, wherein: R 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 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 ​ –SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group; Each R 4 is 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 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or Two Rs 4 together with the carbon atoms to which they are attached and any intervening atoms form a C 3-10 cycloalkyl group, and any remaining Rs 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 、–SO2R 9 、 –SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 5 Selected from halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 6 and R 7 each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; Each R 8 is 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; Each R 9 is 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; Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and p is 0, 1, 2 or 3.

6. A compound of formula IIq: or a pharmaceutically acceptable salt thereof, wherein: R 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 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 and –SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、 –NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group; Each R 4 is independently selected from a halogen group, –NR 6 R 7 , –OR 8 , –C(O)R 8 , –C(O)OR 8 , –C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or Two Rs 4 together with the carbon atoms to which they are attached and any intervening atoms form a C 3-10 cycloalkyl group, and any remaining Rs 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 、–SO2R 9 、 –SO2NR 6 R 7 、–NR 10 C(O)R 8 、–NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 5 Selected from halo, –NR 6 R 7 、–OR 8 、–C(O)R 8 、–C(O)OR 8 、–C(O)NR 6 R 7 、–SOR 9 、–SO2R 9 、–SO2NR 6 R 7 、–NR 10 C(O)R 8 、 –NR 10 C(O)NR 6 R 7 、–NR 10 SO2R 8 、–NR 10 SO2NR 6 R 7 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; Each R 8 is 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; Each R 9 is 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; Each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and p is 0, 1, 2 or 3.

7. A compound of formula IIIc: or a pharmaceutically acceptable salt thereof, wherein: Each X is independently selected from N and CR 7 ; Y is selected from O, S, SO2, and C(R 8 )2; R 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 , –C(O)NR 9 R 10 , –SOR 12 , –SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、 –NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 5- to 10-membered heteroaryl; R 2 is H, and R 3 is –CF3; or R 2 and R 3 together form an oxo group; R 4 and R 5 are independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently 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 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from: halo, –NR 9 R 10 、–OR 11 、–C(O)R 11 、–C(O)OR 11 、–C(O)NR 9 R 10 、 –SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、 –NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、–NR 13 SO2NR 9 R 10 、C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; Each R 6 is independently selected from a halogen group, –NR 9 R 10 , –OR 11 , –C(O)R 11 , –C(O)OR 11 、–C(O)NR 9 R 10 、–SOR 12 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; or Two Rs attached to the same carbon atom 6 together form an oxo group, and any remaining Rs 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 、–SO2R 12 、–SO2NR 9 R 10 、 –NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 、 C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; 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 、–SO2R 12 、–SO2NR 9 R 10 、–NR 13 C(O)R 11 、–NR 13 C(O)NR 9 R 10 、–NR 13 SO2R 11 、 –NR 13 SO2NR 9 R 10 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered hetero cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; Each R 11 is 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; Each R 12 is 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; Each R 13 is 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.

8. A composition, the composition comprising a compound selected from the following:

9. A composition, the composition comprising a compound selected from the following:

10. A composition, the composition comprising a compound selected from the following:

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