PGDH inhibitors and methods of making and using same

Abstract

Disclosed herein are 15-hydroxyprostaglandin dehydrogenase (PGDH) inhibitor compounds. Such compounds may be administered to subjects that may benefit from prostaglandin level modulation for the treatment of muscle disorders.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Application No. 63 / 481,508, filed January 25, 2023, which is hereby incorporated in its entirety by reference. Background Technology

[0003] Prostaglandins are a group of physiologically active lipid compounds with a variety of biological functions, including vasodilation, platelet aggregation inhibition, bronchodilation, bronchoconstriction, immune response, contraction and relaxation of gastrointestinal smooth muscle, gastric acid secretion, gastric mucus secretion, uterine contraction, lipolysis inhibition, neurotransmission, coagulation, hyperalgesia, and fever.

[0004] Treatment of diseases or conditions may require the activation or inhibition of prostaglandin inactivation. Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), are involved in prostaglandin inactivation. Therefore, prostaglandin-related diseases / conditions can be prevented, treated, and / or managed using hydroxyprostaglandin dehydrogenase inhibitors such as 15-PGDH inhibitors. Summary of the Invention

[0005] On the one hand, this article provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] Ring Q is a phenyl or a 5- to 10-membered heteroaryl group;

[0009] Z is CR 1 Or N;

[0010] Y is CR 2 Or N;

[0011] R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0012] Each R 2 Independently, it is H, halogen, -OR10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0013] Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them

[0014] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ;

[0015] R4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them

[0016] Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 8-membered heteroaryl;

[0017] Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0018] X A It is NR 5 R 5 OR 5 ;in

[0019] Each R 5 It is independently an H or C1-C6 alkyl group;

[0020] R 5a It is H or CH3;

[0021] Or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl;

[0022] Each R 8 and R9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0023] Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0024] Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0025] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0026] Each R aIndependently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and

[0027] p is 1, 2, 3 or 4.

[0028] In some embodiments, ring Q is a six-membered monocyclic heteroaryl group containing one, two, or three nitrogen atoms. In some embodiments, ring Q is phenyl, pyrimidinyl, or pyridinyl. In some embodiments, yes

[0029]

[0030] in,

[0031] X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ;

[0032] Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -S 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 replace;

[0033] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ;

[0034] Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0035] Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0036] Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0037] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally divided by one or more R groups. a Replace; and

[0038] Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0039] In some implementation schemes, X 1 X 2 X 3 and X 4 Each is CR 3 In some implementations, X 1 It is N and X 2 X 3 and X 4 Each is CR independently 3 In some implementations, X 1 and X 2 Each is N, and X 3 and X 4 Each is CR independently 3 In some implementations, X 1 and X 3 Each is N, and X 2 and X 4 Each is CR independently 3 In some implementations, X 1 and X 4 Each is N, and X 2 and X 3 Each is CR independently 3 In some implementations, X 1 X 2 and X 3 Each is N, and together with X 4 It is CR 3 In some implementations, X1 X 2 and X 4 Each is N, and X 3 It is CR 3 In some implementations, each R 3 Independently selected from H, halogen, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from H, halogens, -C(O)OR 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups.

[0040] In some embodiments, the compound is of formula (II) or a pharmaceutically acceptable salt thereof:

[0041]

[0042] in,

[0043] Z is CR 1 Or N;

[0044] X 1 Is it N or CR? 3a ;

[0045] Y is CR 2 Or N;

[0046] R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0047] Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0048] R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them

[0049] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR10 or -C(O)NR 8 R 9 ;

[0050] R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them

[0051] Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 8-membered heteroaryl;

[0052] Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0053] X A It is NR 5 R 5 OR 5 ;in

[0054] Each R 5 It is independently an H or C1-C6 alkyl group;

[0055] R 5a It is H or CH3;

[0056] Or R 5a And an R 6They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups;

[0057] Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0058] Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0059] Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0060] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replace; and

[0061] Each R aIt is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0062] In some implementation schemes, X A It is NR 5 R 5 In some implementations, X A Is it OR 5 In some implementations, Y is N. In some implementations, Y is CR. 2 .

[0063] In some embodiments, the compound of formula (II) has the structure of formula (IIIa) or a pharmaceutically acceptable salt thereof:

[0064]

[0065] In some embodiments, the compound of formula (II) has the structure of formula (IIIb) or a pharmaceutically acceptable salt thereof:

[0066]

[0067] In some implementations, Z is N. In some implementations, Z is CR. 1 In some implementations, Z is CH.

[0068] In some embodiments, the compound of formula (II) has the structure of formula (IVa) or a pharmaceutically acceptable salt thereof:

[0069]

[0070] In some embodiments, the compound of formula (II) has the structure of formula (IVb) or a pharmaceutically acceptable salt thereof:

[0071]

[0072] In some embodiments, the compound of formula (II) has the structure of formula (IVc) or a pharmaceutically acceptable salt thereof:

[0073]

[0074] In some embodiments, the compound of formula (II) has the structure of formula (IVd) or a pharmaceutically acceptable salt thereof:

[0075]

[0076] In some implementation schemes, X 1 It is N. In some implementations, X 1 It is CR 3a In some implementations, R 3b It is H; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 In some implementations, R 3c It is H; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 In some implementations, R 3a and R 3b It is independently H or halogen; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 In some implementations, R 3c It is -C(O)OR 10 -C(O)NR 8 R 9 Or a substituted or unsubstituted 5-membered heteroaryl group. In some embodiments, R 3a and R 3c Each is either H or halogen; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 In some implementations, R 3b It is -C(O)OR 10 -C(O)NR 8 R 9 Or a substituted or unsubstituted 5-membered heteroaryl group. In some embodiments, R 3b and R 3c Each is either H or halogen; and R 3a Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 In some implementations, R 3a It is -C(O)OR 10 -C(O)NR 8 R 9 Or a substituted or unsubstituted 5-membered heteroaryl group. In some embodiments, each R 2 It is in H. In some implementations, R 5a And an R 6 They combine with the atoms to which they are attached to form C3-C6 cycloalkyl rings. In some embodiments, R 5a It is H. In some implementations, R 5 It is H. In some implementations, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, each of which is substituted or unsubstituted by one or more R 6 Replacement. In some implementations, R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a C1-C8 alkyl group. In some embodiments, R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a 4- to 8-membered heterocycloalkyl, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a C3-C8 cycloalkyl group. In some embodiments, each R 6 Independently, it is halogen, -OR 10C1-C6 alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl.

[0077] On the other hand, this article provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0078] On the other hand, this article provides a method for promoting and / or stimulating skin pigmentation, which includes applying one or more of the compositions described herein to a subject in need.

[0079] On the other hand, this article provides a method for inhibiting hair loss, which includes applying one or more of the compositions described herein to a subject in need.

[0080] Methods for preventing and / or treating skin inflammation and / or injury, comprising applying one or more of the compositions described herein to a subject in need.

[0081] On the other hand, this article provides a method for preventing and / or treating vascular insufficiency, which includes administering one or more of the compositions described herein to a subject in need.

[0082] On the other hand, this article provides a method for preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need.

[0083] On the other hand, this article provides a method for reducing cardiac ejection fraction, which includes administering one or more of the compositions described herein to a subject in need.

[0084] On the other hand, this article provides a method for preventing and / or treating gastrointestinal diseases, which includes administering one or more of the compositions described herein to a subject in need.

[0085] On the other hand, this article provides a method for preventing and / or treating renal dysfunction, which includes administering one or more of the compositions described herein to a subject in need.

[0086] On the other hand, this article provides a method for stimulating bone resorption and bone formation, which includes applying one or more of the compositions described herein to a subject in need.

[0087] On the other hand, this article provides a method for stimulating tissue regeneration by means of stimulation, which includes applying one or more of the compositions described herein to a subject in need.

[0088] On the other hand, this article provides a method for regulating cervical ripening, which includes administering one or more of the compositions described herein to a subject in need.

[0089] On the other hand, this article provides a method for promoting neuroprotection and / or stimulating neuronal regeneration, which includes administering one or more of the compositions described herein to a subject in need.

[0090] On the other hand, this article provides a method for treating and / or preventing neurological disorders, neuropsychiatric disorders, nerve damage, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders, comprising administering one or more of the compositions described herein to a subject in need.

[0091] On the other hand, this article provides a method for treating and / or preventing fibrotic or adhesive diseases, conditions, or illnesses, comprising applying one or more of the compositions described herein to a subject in need.

[0092] On the other hand, this article provides a method for reducing and / or preventing scar formation, which includes applying one or more of the compositions described herein to a subject in need.

[0093] On the other hand, this article provides a method for treating and / or preventing muscle disorders, muscle injuries and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need.

[0094] On the other hand, this article provides a method for treating and / or preventing fibrosis, which includes administering one or more of the compositions described herein to a subject in need.

[0095] On the other hand, this article provides a method for treating and / or preventing idiopathic pulmonary fibrosis, comprising administering one or more of the compositions described herein to a subject in need.

[0096] On the other hand, this article provides a method for treating and / or preventing renal fibrosis, which includes administering one or more of the compositions described herein to a subject in need.

[0097] On the other hand, this article provides a method for stimulating muscle regeneration, which includes administering one or more of the compositions described herein to a subject in need.

[0098] On the other hand, this article provides a method for promoting organ adaptation, which includes administering one or more of the compositions described herein to a subject in need.

[0099] On the other hand, this article provides a method for promoting wound healing, which includes applying one or more of the compositions described herein to a subject in need.

[0100] On the other hand, this article provides a method for treating acute kidney injury, comprising administering one or more of the compositions described herein to a subject in need.

[0101] On the other hand, this article provides a method for treating sarcopenia, which includes administering one or more of the compositions described herein to a subject in need.

[0102] On the other hand, this document provides a method for treating neuromuscular diseases, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

[0103] Incorporation

[0104] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is expressly and individually indicated to be incorporated by reference. Detailed Implementation

[0105] Although various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives may be employed with respect to the embodiments of the invention described herein.

[0106] definition

[0107] 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 invention pertains. All patents and publications cited herein are incorporated herein by reference.

[0108] Unless the context otherwise requires, throughout the specification and subsequent claims, the word “comprising” and its variations such as “including” shall be interpreted in an open, inclusive sense, meaning “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0109] References to "some embodiments" or "implementation" throughout the specification mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in different places throughout the specification do not necessarily all refer to the same implementation. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner. Additionally, as used in this specification and the appended claims, unless otherwise expressly stated, the singular forms "a," "an," and "the / described" include plural indicators. It should also be noted that, unless otherwise expressly stated, the term "or" is generally used in its meaning including "and / or."

[0110] Unless otherwise indicated, the following terms as used herein shall have the following meanings:

[0111] "Oxytochemical" means =O.

[0112] The "carboxyl group" refers to -COOH.

[0113] "Cyano" refers to -CN.

[0114] "Alkyl" refers to a straight-chain or branched monovalent radical of a saturated hydrocarbon having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, numerical ranges such as "C1-C6 alkyl" or "C 1-6 The term "alkyl" implies that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also includes instances where the term "alkyl" does not specify a numerical range. In some embodiments, the alkyl group is C10. 1-10 Alkyl group. In some embodiments, the alkyl group is C10. 1-6 Alkyl group. In some embodiments, the alkyl group is C10. 1-5 Alkyl group. In some embodiments, the alkyl group is C10. 1-4 Alkyl group. In some embodiments, the alkyl group is C10. 1-3 Alkyl group. Unless otherwise expressly stated in the specification, the alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0115] "Alkenyl" refers to a straight-chain or branched hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group may be in cis or trans conformation around the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C 2-6 The term "alkenyl" implies that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also includes the use of the term "alkenyl" where no numerical range is specified. Unless otherwise explicitly stated in the specification, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted with oxo, halogen, -CN, -C(O)OH, -C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0116] "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 ynyl" or "C 2-6 The term "alkynyl" implies that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also includes the use of the term "alkynyl" where no numerical range is specified. Unless otherwise explicitly stated in the specification, the alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with halogen.

[0117] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly stated in the specification, alkylene groups may be optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene groups are optionally substituted with oxo, halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene groups are optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene groups are optionally substituted with halogen.

[0118] "Alkoxy" refers to an alkoxy group with the formula -OR a free radicals, of which R a It is an alkyl radical as defined. Unless otherwise expressly stated in the specification, the alkoxy group may be optionally substituted with, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -C(O)OH, C(O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with a halogen.

[0119] "Aryl" refers to a free radical derived from an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic aromatic hydrocarbon ring system may contain only hydrogen and carbon, and 5 to 18 carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to Hückel's theory. Ring systems that derive aryl groups include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene. Aryl free radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6-membered to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the following hydrocarbon ring systems: anthracene, naphthyl, phenanthrene, anthracene, azulene, benzene, etc. The aryl group can be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogens.

[0120] The term "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which every atom of the ring is carbon. Carbocyclic rings can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridging rings. Each ring in a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. Aromatic rings, such as phenyl, can be fused with saturated or unsaturated rings, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, where valence states permit. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indenyl, and naphthyl. Unless otherwise expressly stated in the specification, carbocyclic rings may optionally be substituted.

[0121] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having 3 to 15 carbon atoms (C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), 3 to 10 carbon atoms (C3-C) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3- to 10-membered fully saturated cycloalkyl groups or 3- to 6-membered cycloalkyl groups or 3- to 6-membered cycloalkyl groups or cycloalkyl groups. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkyl group or a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in the specification, cycloalkyl groups may optionally be substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0122] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including fused ring or bridging ring systems, preferably having 3 to 12 carbon atoms, and containing at least one double bond. In some embodiments, the cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, the cycloalkenyl contains 5 to 7 carbon atoms. The cycloalkenyl can be attached to the remainder of the molecule via a single bond. Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0123] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0124] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical as defined above, which is substituted with one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical may optionally be further substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and tri-halomethanes (e.g., chloroform, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted by more than one halogen radical, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[0125] "Fluoroalkyl" refers to an alkyl radical as defined above that is substituted by one or more fluorine radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0126] "Hydroxyalkyl" refers to an alkyl radical as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0127] "Aminoalkyl" refers to an alkyl radical as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0128] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in the specification, heteroalkyl groups are optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogens.

[0129] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic radical comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise expressly stated in the specification, the heterocyclic alkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded by non-aromatic ring atoms), spiro, or bridging ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having 2 to 15 carbon atoms (C2-C4). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, 2 to 10 carbon atoms (C2-C) 10 Fully saturated heterocyclic alkyl or C2-C10Heterocyclic alkyl groups with 2 to 8 carbon atoms (C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkyl), 2 to 7 carbon atoms (C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkyl), 2 to 6 carbon atoms (C2-C6 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkyl), 2 to 5 carbon atoms (C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkyl), or 2 to 4 carbon atoms (C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkyl). Examples of such heterocyclic alkyl radicals include, but are not limited to, acridine, aziridine, oxaziridine, dioxacyclopentane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, and thiazoalkyl. The terms include tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms (including heteroatoms) constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group.Unless otherwise expressly stated in the specification, heterocyclic alkyl groups may be optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc., as described below. In some embodiments, the heterocyclic alkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with halogen.

[0130] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl radical comprises one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl radical comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl radical comprises one to three nitrogen atoms. In some embodiments, the heteroaryl radical comprises one or two nitrogen atoms. In some embodiments, the heteroaryl radical comprises one nitrogen atom. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl radical is bonded through aromatic ring atoms) or bridging ring system; and the nitrogen, carbon, or sulfur atom in the heteroaryl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl radical is a 5- to 10-membered heteroaryl radical. In some embodiments, the heteroaryl radical is a 5- to 6-membered heteroaryl radical. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, aziridine-containing heteroaryl groups. Benzyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptenyl, 1,4-benzodioxylalkyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl benzothienyl, benzothiophenyl), benzotriazole, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, inazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyridine The following groups are included: alkyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroloyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, pyrroloyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise expressly stated in the specification, heteroaryl groups may be optionally substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -C(O)OH, C(O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0131] The term "substituted" refers to a portion having a substituent that replaces one or more hydrogen atoms or substituted heteroatoms (e.g., NH in the structure). It should be understood that "substituted" or "replaced by" includes the implicit precondition that such substitution conforms to the permissible valence states of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. In some embodiments, "substituted" refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with an oxo, imino, or thioxo group. As used herein, the term "substituted" is envisioned to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents can be one or more and can be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permitted substituents of the organic compounds described herein that satisfy the valence of the heteroatoms.

[0132] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0133] The compounds described herein may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched in 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 variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or can provide compounds useful for studying in vivo drug elimination and metabolic pathways. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0134] "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers whose atoms are arranged differently in space. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used where appropriate to denote racemic mixtures. "Diadiamers" or "diastereomers" refer to stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configuration can be specified as (+) or (-), depending on the direction (dextrorotatory or levorotatory) of their rotational plane-polarized light at the sodium D line wavelength. Some of the compounds described herein contain one or more asymmetric centers and are therefore capable of producing enantiomers, diastereomers, and other stereoisomers, whose asymmetric centers can be defined as (R)- or (S)- according 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 the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation, and the degree of dominance of one stereoisomer relative to another can be determined.

[0135] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Furthermore, some chemical entities can exist in various tautomer forms. Unless otherwise specified, the chemical entities described herein are intended to include all Z, E, and tautomer forms.

[0136] If necessary, the separation and purification of the chemical entities and intermediates described herein can be achieved by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination of these procedures. Specific descriptions of suitable separation and isolation procedures can be found in the examples below. However, other equivalent separation or isolation procedures may also be used.

[0137] When no stereochemistry is specified, the specific small molecules described herein include, where possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemic mixtures, mixtures of diastereomers, and other mixtures, provided they can be prepared by those skilled in the art through routine experiments. In those cases, a single enantiomer or diastereomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolving a mixture of racemic or diastereomers. If possible, the resolution of a mixture of racemic or diastereomers can be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or by chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column. Furthermore, mixtures of two enantiomers enriched in one of these can be purified to provide the major enantiomer in a further optically enriched form by recrystallization and / or milling. Additionally, such specific small molecules include the Z and E forms (or cis and trans forms) of specific small molecules having carbon-carbon or carbon-nitrogen double bonds. In cases where a particular small molecule described herein exists in various tautomer forms, the term "particular small molecule" is intended to include all tautomer forms of that particular small molecule.

[0138] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. 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, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from 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, and aluminum. 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 particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0139] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable,” meaning it is compatible with the other components of the formulation and will not cause harm to the patient. Some examples of materials that can be used 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 gum; (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, and corn oil. (10) Soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrogen-free water; (18) Isotonic saline; (19) Ringer's solution; (10) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0140] The term "effective amount" or "therapeutic effective amount" refers to the amount of a compound described herein sufficient to affect the intended application (including, but not limited to, the treatment of a disease as defined below). Therapeutic effective amounts can vary depending on the intended therapeutic application (in vivo) or the subject and the disease condition being treated, such as the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that may induce a specific response in target cells, such as a reduction in platelet adhesion and / or cell migration. Specific doses can vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system carrying it.

[0141] As used herein, "treatment" or "management" refers to a method for obtaining a beneficial or desired outcome regarding a disease, symptom, or medical condition, including but not limited to therapeutic and / or preventative benefits. Therapeutic benefits may include, for example, eradicating or improving an underlying symptom that is being treated. Additionally, therapeutic benefits may include, for example, eradicating or improving one or more physical symptoms associated with an underlying symptom, such that improvement is observed in the subject, although the subject may still be troubled by the underlying symptom. In some embodiments, for preventative benefits, the composition is administered to a patient at risk of developing a specific disease or to a patient who reports one or more physical symptoms of a disease (even if a diagnosis of the disease may not yet have been made).

[0142] As used herein, the term "therapeutic effect" encompasses the therapeutic benefits and / or preventive benefits described above. Preventive 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, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0143] As used herein, the terms “co-administration,” “combination administration,” and their grammatical equivalents cover the administration of two or more agents to an animal (including a human) such that both agents and / or their metabolites are present simultaneously in the subject. 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.

[0144] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function (e.g., activity, expression, binding, protein-protein interactions) of a target protein or enzyme. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological action of the target protein. While the preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other members of a signal transduction pathway in which the target protein is a member are also specifically included in this definition. Preferred biological activities inhibited by antagonists are associated with tumor development, growth, or spread.

[0145] Whenever proteins are mentioned in this article, it will 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, namely 15-hydroxyprostaglandin dehydrogenase.

[0146] compound

[0147] This article provides compounds and methods for inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

[0148] On the one hand, this article provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0149]

[0150] in,

[0151] Ring Q is a phenyl or a 5- to 10-membered heteroaryl group;

[0152] Z is CR 1 Or N;

[0153] Y is CR 2 Or N;

[0154] R1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0155] Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0156] Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them

[0157] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ;

[0158] R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them

[0159] Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 8-membered heteroaryl;

[0160] Or two Rs 6They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0161] X A Yes -NR 5 R 5 or -OR 5 ;in

[0162] Each R 5 It is independently an H or C1-C6 alkyl group;

[0163] R 5a It is H or CH3;

[0164] Or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl;

[0165] Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0166] Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0167] Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0168] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0169] Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3; and

[0170] p is 1, 2, 3 or 4.

[0171] On the one hand, this article provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0172]

[0173] in,

[0174] Ring Q is a phenyl or a 5- to 10-membered heteroaryl group;

[0175] Z is CR 1 Or N;

[0176] Y is the CR of N 2 ;

[0177] R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0178] R 2 It is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Or substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0179] Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups.

[0180] R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, each of which is substituted or unsubstituted by one or more R 6 Replace; among them

[0181] Each R 6 Independently, it is H, halogen, CN, -NO2, -NR 8 R 9 -OH, -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, phenyl or 5- to 8-membered heteroaryl;

[0182] Or two Rs 6 They combine with the atoms to which they are attached to form C3-C6 cyclic alkyl rings;

[0183] X A It is NR 5 R 5 OR 5 ;in

[0184] Each R 5 It is independently an H or C1-C6 alkyl group;

[0185] R 5a It is H or CH3;

[0186] Or R 5a And an R 6 They combine with the atoms to which they are attached to form C3-C6 cyclic alkyl rings;

[0187] Each R 8 and R 9 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C4-C 10 Heterocyclic alkyl groups;

[0188] Each R 10 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups;

[0189] Each R 11Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups;

[0190] Each R 12 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; and

[0191] p is 1, 2, 3 or 4.

[0192] In some embodiments, ring Q is a 5- to 10-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl group. In some embodiments, ring Q is a bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolopyridine. In some embodiments, ring Q is [1,2,4]triazolo[1,5-a]pyridine.

[0193] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl group containing 1, 2, or 3 nitrogen atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is phenyl, pyrimidine, or pyridine. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyrimidine. In some embodiments, ring Q is pyridine.

[0194] In some implementations, ring Q is phenyl, pyridine, or triazolidine.

[0195] In some implementation schemes, yes

[0196] in,

[0197] X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ;

[0198] Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10-SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 replace;

[0199] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ;

[0200] Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0201] Each R 10Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0202] Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0203] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replace; and

[0204] Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0205] In some implementation schemes, X 1 X 2 X 3 and X 4 Each is CR 3 .

[0206] In some implementation schemes, X 1 It is N; and X 2 X3 and X 4 Each is CR 3 .

[0207] In some implementation schemes, X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 .

[0208] In some implementation schemes, X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 .

[0209] In some implementation schemes, X 1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 .

[0210] In some implementation schemes, X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 .

[0211] In some implementation schemes, X 1 X 2 and X 4 Each is N; and X 3 It is CR 3 .

[0212] In some implementations, each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from H, halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from H, halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, each R 3 It is independently selected from H, halogen, substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups.

[0213] In some implementations, each R 3 Independently selected from H or halogen. In some embodiments, each R 3 Independently, it is a substituted or unsubstituted phenyl group and a substituted or unsubstituted 5- to 6-membered heteroaryl group. In some embodiments, each R 3 It is independently a substituted or unsubstituted 5-membered heteroaryl group.

[0214] On the other hand, this article provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0215]

[0216] in,

[0217] Z is CR 1 Or N;

[0218] X 1 Is it N or CR? 3a ;

[0219] Y is CR 2 Or N;

[0220] R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0221] Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups;

[0222] R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them

[0223] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ;

[0224] R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them

[0225] Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 8-membered heteroaryl;

[0226] Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0227] X A It is NR 5 R 5 OR 5 ;in

[0228] Each R 5 It is independently an H or C1-C6 alkyl group;

[0229] R 5a It is H or CH3;

[0230] Or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups;

[0231] Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0232] Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0233] Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0234] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replace; and

[0235] Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0236] On the other hand, this article provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0237]

[0238] in,

[0239] Z is CR 1 Or N;

[0240] X 1 Is it N or CR? 3a ;

[0241] Y is CR 2 Or N;

[0242] R 1 It is H;

[0243] Each R 2 It is independently an H or C1-C6 alkyl group;

[0244] R3a R 3b and R 3c Each is independently selected from H, halogen, -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 heterocyclic alkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them

[0245] Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ;

[0246] R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is determined by one or more R 6 Replace; among them

[0247] Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0248] Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0249] X A Yes - OR 5 ;in

[0250] Each R 5 It is independently an H or C1-C6 alkyl group;

[0251] R 5a It is H or CH3;

[0252] Or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups;

[0253] Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace;

[0254] Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0255] Each R 11Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace;

[0256] Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replace; and

[0257] Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

[0258] In some implementation schemes, X A It is NR 5 R 5 In some implementations, X A Is it OR 5 .

[0259] In some implementations, Y is N. In some implementations, Y is CR. 2 .

[0260] In some embodiments, the compound of formula (II) has the structure of formula (III) or a pharmaceutically acceptable salt thereof:

[0261]

[0262] In some embodiments, the compound of formula (II) has the structure of formula (IIIb) or a pharmaceutically acceptable salt thereof:

[0263]

[0264] In some implementations, Z is N. In some implementations, Z is CR. 1 In some implementations, Z is CH.

[0265] In some embodiments, the compound of formula (II) has the structure of formula (IVa) or a pharmaceutically acceptable salt thereof:

[0266]

[0267] In some embodiments, the compound of formula (II) has the structure of formula (IVb) or a pharmaceutically acceptable salt thereof:

[0268]

[0269] In some embodiments, the compound of formula (II) has the structure of formula (IVc) or a pharmaceutically acceptable salt thereof:

[0270]

[0271] In some embodiments, the compound of formula (II) has the structure of formula (IVd) or a pharmaceutically acceptable salt thereof:

[0272]

[0273] In some implementation schemes, R 1 It is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 Or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R 1 It's H.

[0274] In some implementations, each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 Or substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, each R 2 Independently, it is an H or C1-C6 alkyl group. In some embodiments, each R... 2 It's H.

[0275] In some implementation schemes, X 1 It is CR 3a In some implementations, X 1 It is N.

[0276] In some implementation schemes, R 3a R 3b and R 3cEach is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -S 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12C(O)OR 10 substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and -C(O)R. 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogen, -OR 10 -S 8 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 12 C(O)R 10 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups.

[0277] In some implementation schemes, R 3a R 3b and R 3c Each is independently selected from H, halogen, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, triazole, tetraazole, pyrrolidine, morpholine or C1-C6 alkyl substituted with -C(O)OH.

[0278] In some implementation schemes, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R3b Each is either H or halogen; and R 3c Selected from -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c Selected from substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups. In some embodiments, R 3a and R 3b Each is either H or halogen; and R 3c It is a 5-membered heteroaryl group, either substituted or unsubstituted.

[0279] In some implementation schemes, R 3a It is halogen and R 3b It is H. In some implementations, R 3a It is -Cl or -F; and R 3b It is H. In some implementations, R 3b It is halogen and R 3a It is H. In some implementations, R 3b It is -Cl or -F; and R 3a It's H.

[0280] In some implementation schemes, R 3a and R 3b Each is H.

[0281] In some implementation schemes, R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from halogens, -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is H; and R 3b Selected from -C(O)R 10 -C(O)OR 10 -NR 12 C(O)OR 10 substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 6-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is either H or halogen; and R3b Selected from substituted or unsubstituted C1-C6 alkyl groups, -C(O)R 10 -C(O)NR 8 R 9 C3-C6 heterocyclic alkyl groups and 5-membered heteroaryl groups. In some embodiments, R 3a and R 3c Each is either H or halogen; and R 3b Selected from -C(O)R 10 -C(O)OR 10 And substituted or unsubstituted 5-membered heteroaryl groups.

[0282] In some implementation schemes, R 3a It is halogen and R 3c It is H. In some implementations, R 3a It is H and R 3b It is a halogen. In some implementations, R 3a It is -Cl or -F; and R 3c It is H. In some implementations, R 3c It is -Cl or -F; and R 3a It is H.

[0283] In some implementation schemes, R 3a and R 3c Each is H.

[0284] In some implementations, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from pyrrole, triazole, tetraazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from pyrrole, triazole, and tetraazole. In some embodiments, each R 3 R 3a R 3b and R 3c Each is independently a 5-membered heteroaryl group selected from triazole and tetraazole.

[0285] In some implementations, each R 3 R 3a R 3b or R 3c Selected independently

[0286] In some implementations, each R 3 R 3a R 3b or R 3c Selected independently In some implementations, each R 3 R 3a R 3b or R 3c Selected independently In some implementations, each R 3 R 3a R 3b or R 3c Selected independently

[0287] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a 4- to 8-membered heterocycloalkyl, each of which is substituted or unsubstituted by one or more R 6 Replacement. In some implementations, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 hydroxyalkyl.

[0288] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 alkyl group. In some embodiments, the alkyl group is a straight-chain or branched alkyl group. In some embodiments, R 4 It is a substituted or unsubstituted C1-C8 heteroalkyl group. In some embodiments, the heteroalkyl group is an alkyl chain in which one or more carbon atoms are replaced by O or N atoms. In some embodiments, R 4It is a substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), a substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), -CH2-O-(C1-C4 haloalkyl), -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocyclic alkyl), or -CH2-O-(C3-C6 heterocyclic alkyl). In some embodiments, R 4 It is a substituted or unsubstituted -CH2CH2-O-(C1-C4 alkyl), -CH2-O-(C1-C4 alkyl), a substituted or unsubstituted -CH2CH2-O-(C1-C4 haloalkyl), or -CH2-O-(C1-C4 haloalkyl). In some embodiments, R 4 It is -CH2CH2-O-(C3-C6 cycloalkyl), -CH2-O-(C3-C6 cycloalkyl), -CH2CH2-O-(C3-C6 heterocycloalkyl), or -CH2-O-(C3-C6 heterocycloalkyl). In some embodiments, R 4 It is -CH2CH2-O- (C3-C6 cycloalkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 cycloalkyl). In some embodiments, R 4 It is -CH2CH2-O- (C3-C6 heterocyclic alkyl). In some embodiments, R 4 It is -CH2-O-(C3-C6 heterocyclic alkyl).

[0289] In some implementation schemes, R 4 It is a substituted or unsubstituted C1-C8 alkyl group, which is reacted with one or more halogens, -OR 10 C1-C8 alkyl or C3-C6 cycloalkyl substitution.

[0290] In some implementation schemes, R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a C3-C8 cycloalkyl group. In some embodiments, R 4 It is a monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl group. In some embodiments, R 4 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 4 It is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 It is cyclopropyl. In some implementations, R 4It is cyclobutyl. In some implementations, R 4 It is cyclopentyl. In some implementations, R 4 It is cyclohexyl. In some implementations, R 4 yes

[0291] In some implementation schemes, R 4 It is a substituted or unsubstituted C3-C8 heterocyclic alkyl group, each of which is substituted by one or more R 6 Replacement. In some implementations, R 4 It is a monocyclic, polycyclic, spirocyclic, or bridged heterocyclic alkyl group. In some embodiments, R 4 It is a 4-membered heterocyclic alkyl group. In some embodiments, R 4 It is a 5-membered heterocyclic alkyl group. In some embodiments, R 4 It is a 6-membered cycloalkyl group. In some embodiments, R 4 It is a 7-membered cycloalkyl group. In some embodiments, R 4 It is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R 4 It is tetrahydrofuran or tetrahydropyran.

[0292] In some implementations, each R 6 Independently, it is halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -NR 8 C(O)R 9C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 -C(O)OR 10 -C(O)NR 8 R 9 C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 Or C3-C8 cycloalkyl. In some embodiments, each R 6 Independently is -NR 8 R 9 or -OR 10 In some implementations, each R 6 Independently, it is a C3-C8 cycloalkyl group. In some embodiments, the cycloalkyl group is monocyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, each R... 6 Independently, it is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R... 6 It is halogen independently. In some implementations, each R... 6 It can be H, Cl, F, or Br independently. In some implementations, each R... 6 Independently, it is F. In some implementations, each R... 6 Independently, it is F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH3CH3), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R 6 Independently, it is F, -OH, -CH3, -CF3, -N(CH3)2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 Independently, it is F, -OH, -CH3, or -CF3. In some embodiments, each R 6 Independently, it is F. In some implementations, each R... 6 Independently, it is -OH. In some implementations, each R... 6 Independently, it is -CF3. In some implementations, each R 6 It is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 6 Independently, it is cyclopropyl. In some embodiments, each R...6 It is cyclobutyl.

[0293] In some implementations, two R 6 They combine with the atoms to which they are attached to to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl. In some embodiments, the two R... 6 They combine with the atoms to which they are attached to to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form cyclopropyl or cyclobutyl groups. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form cyclopropyl groups. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form cyclobutyl groups. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form cyclopropyl groups. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form a cyclohexyl group. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form C3-C6 heterocyclic alkyl groups. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form a four-membered heterocyclic alkyl group. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form a 5-membered heterocyclic alkyl group. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form a 6-membered heterocyclic alkyl group. In some embodiments, the two R groups... 6 They combine with the atoms to which they are attached to form pyran, piperazine, piperidine, or morpholine.

[0294] In some implementation schemes, R 4 It includes -CH3, -CH2CH3, -CH2CH3CH3, -CH2(CH2)2CH3, -CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2CH2CH(CH3)2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxacyclobutane, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted tetrahydropyran.

[0295] In some implementations, each R 5 Independently, it is a C1-C6 alkyl group. In some embodiments, each R...5 Independently, it is -CH2CH3 or -CH3. In some implementations, each R 5 Independently, it is -CH2CH3. In some implementations, each R 5 Independently, it is -CH3. In some implementations, each R 5 H stands alone.

[0296] In some implementation schemes, R 5a It is CH3. In some implementations, R 5a It's H.

[0297] In some implementation schemes, R 5a And an R 6 They combine with the atoms to which they are attached to form C3-C6 cycloalkyl groups. In some embodiments, R 5a And an R 6 They combine with the atoms to which they are attached to form cyclopentyl or cyclohexyl groups. In some embodiments, R 5a And an R 6 They combine with the atoms to which they are attached to form cyclohexyl groups. In some implementations, R 5a And an R 6 They combine with the atoms to which they are attached to form cyclopentyl groups.

[0298] In some implementations, each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replacement. In some implementations, each R 8 and R 9 Each time it appears, it is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl. In some embodiments, each R 8 and R 9 Each time it appears, it is independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups. In some embodiments, each R 8and R 9 Each time it appears, it is independently selected from C3-C. 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0299] In some implementations, each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a Replacement. In some implementations, each R 10 Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 Heterocyclic alkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 10 Independently selected from H, C1-C6 alkyl, C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups. In some embodiments, each R 10 Independently selected from H and C1-C6 alkyl groups. In some embodiments, each R 10 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0300] In some implementations, each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a Replacement. In some implementations, each R 11 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C3-C 10 Heterocyclic alkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 11 Independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl. In some embodiments, each R 11 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0301] In some implementations, each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replacement. In some implementations, each R 12 Independently selected from H, straight-chain or branched C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups. In some embodiments, each R 12 Independently selected from H, straight-chain or branched C1-C6 alkyl groups. In some embodiments, each R 12 Independently selected from C3-C 10 cycloalkyl and C3-C 10 Heterocyclic alkyl groups.

[0302] In some implementations, each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2, and -NHC(O)CH3. In some embodiments, each R a Independently selected from -F, -Cl, -Br, -OH, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, each R a It is independently selected from -F, -OH, -CH3, -CF3 or -C(O)OH.

[0303] In some implementations, p is 1, 2, 3, or 4. In some implementations, p is 2 or 3. In some implementations, p is 3. In some implementations, p is 5. In some implementations, p is 4. In some implementations, p is 3. In some implementations, p is 2. In some implementations, p is 1.

[0304] In some implementations, the PDGH inhibitor is a compound described in Table 1 or a pharmaceutically acceptable salt thereof.

[0305] Table 1. Compounds disclosed herein.

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] How to use

[0336] In one aspect, this document provides methods for treating various conditions in subjects in need, comprising administering the compounds described herein to said subject. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to prevent or treat diseases or conditions associated with decreased levels of hydroxyprostaglandin dehydrogenases (such as 15-PGDH) and / or prostaglandins. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to prevent or treat diseases or conditions in which it is desirable to increase prostaglandin levels in subjects suffering from said disease or condition.

[0337] In some embodiments, a method for treating a condition includes administering a 15-PGDH inhibitor to the subject. In some embodiments, the compound described herein is a 15-PGDH inhibitor. In some embodiments, a compound of formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd) is a 15-PGDH inhibitor. In some embodiments, the method includes administering a therapeutically effective amount of the compound described herein. In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd). In some embodiments, the compound described herein is a 15-PGDH inhibitor. In some embodiments, a compound of formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd) is a 15-PGDH inhibitor. In some embodiments, the administration occurs in vitro. In other embodiments, the administration occurs in vivo.

[0338] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor is defined as an amount sufficient to achieve the intended application (including, but not limited to, disease treatment as defined herein). The subject matter approach also envisions the use of a sub-therapeutic amount of the 15-PGDH inhibitor for the treatment of the intended disease condition.

[0339] The amount of 15-PGDH inhibitor applied can vary depending on the intended application (in vitro or in vivo) or the subject and the disease condition being treated, such as the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by a person skilled in the art.

[0340] Measuring the inhibition of the biological effects of 15-PGDH can include assays on biological samples, such as those from a subject. Depending on the assay, any 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, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0341] Subjects being treated with 15-PGDH inhibitors 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 effects of 15-PGDH is above or below a threshold, the dosage or frequency can be reduced or increased, respectively. The method may also include continuing the treatment if it is determined to be effective. The method may include maintaining, gradually reducing, decreasing, or discontinuing the administration of the compound in the treatment if it is determined to be effective. The method may include increasing the administration of the compound in the treatment if it is determined to be ineffective. Alternatively, the method may include discontinuing the treatment if it is determined to be ineffective. In some embodiments, treatment with the 15-PGDH inhibitor is discontinued if the inhibition of the biological effects is above or below a threshold, such as in the absence of a response or in the presence of adverse reactions. Biological effects can be changes in any of a variety of physiological indicators.

[0342] Typically, 15-PGDH inhibitors are compounds that inhibit one or more biological effects of 15-PGDH. These biological effects can be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0343] In some other implementations, the subject-matter approach can be used to treat disease conditions associated with 15-PGDH. Any disease condition directly or indirectly caused by abnormal activity or expression levels of 15-PGDH can be the intended disease condition.

[0344] In one aspect, this document provides a method for promoting and / or stimulating skin pigmentation, comprising applying one or more of the compositions described herein to a subject in need. 15-PGDH inhibitors are known to 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 agents for preventing and / or limiting fading and / or whitening of the skin and / or skin appendages, particularly as agents for preventing and / or limiting gray hair. In some embodiments, the 15-PGDH inhibitors provided herein can be applied to the skin of a subject, e.g., in a surface 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 UV exposure.

[0345] On the other hand, this article provides a method for inhibiting hair loss, which includes administering one or more of the compositions described herein to a subject in need. Prostaglandins are known to play an important role in hair growth. Prostaglandins such as prostaglandin A1, F2a, and E2 are stored in hair follicles or the adjacent skin environment 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 prostaglandin degradation, has been reported to be present in the dermal papilla of the hair follicle, inactivating prostaglandins, particularly PGF2a and PGE2, leading to scalp damage and alopecia (Michelet JF et al., 2008, Exp. Dermatol, 17(10), 821-8). Therefore, the hydroxyprostaglandin dehydrogenase inhibitors described herein, which have suppressive or inhibitory activity against 15-PGDH, can improve scalp damage, prevent alopecia, and promote hair growth, and can be used in pharmaceutical compositions for the prevention of alopecia and the promotion of hair growth.

[0346] On the other hand, this article provides a method for preventing and / or treating skin inflammation and / or damage, comprising applying one or more of the compositions described herein to a subject in need.

[0347] On the other hand, this article provides a method for the prevention and / or treatment of vascular insufficiency, comprising administering one or more of the compositions described herein to a subject in need. Prostaglandins, including prostaglandin homologs produced in vivo, are known to maintain the normal function of the vascular wall, particularly contributing to vasodilation, preventing platelet aggregation, and regulating the proliferation of smooth muscle surrounding the vascular wall (Yan. Cheng et al., 2006, J. Clin., Invest). Furthermore, inhibition of prostaglandin production or loss of its activity can lead to endothelial degeneration of the vascular wall, platelet aggregation, and dysfunction of cellular mechanisms in smooth muscle. Notably, reduced prostaglandin production in the blood vessels has been observed in hypertensive patients, including those with arterial pulmonary hypertension. The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of cardiovascular disease and / or vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and arterial pulmonary hypertension.

[0348] In another aspect, this document provides a method for preventing, treating, minimizing, and / or reversing congestive heart failure and cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need. In another aspect, this document provides a method for reducing cardiac ejection fraction, comprising administering one or more of the compositions described herein to a subject in need. 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 reduce cardiac ejection fraction (Markowitz et al., WO2018 / 187810). Therefore, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to subjects in need to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and / or reduce cardiac ejection fraction.

[0349] On the other hand, this article provides a method for the prevention and / or treatment of gastrointestinal diseases, comprising administering one or more of the compositions described herein to a subject in need. Prostaglandins are essential to the mechanisms of maintaining the protection and defense of the gastric mucosa (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65; SJ Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). The hydroxyprostaglandin dehydrogenase inhibitors described herein exhibit suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect the gastric mucosa. Therefore, hydroxyprostaglandin dehydrogenase inhibitors can be effective in the prevention or treatment of gastrointestinal diseases, especially gastritis and gastric ulcers. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to prevent and / or treat other forms of intestinal injury, including toxicity from radiation and / or chemotherapy and chemotherapy-induced mucositis.

[0350] Furthermore, it has been shown that 15-PGDH inhibitors, alone or in combination with corticosteroids and / or TNF inhibitors, can treat intestinal, gastrointestinal, or bowel conditions such as oral ulcers, gingival diseases, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease (Markowitz et al., WO 2018 / 102552). Therefore, the hydroxyprostaglandin dehydrogenase inhibitors presented herein can be used for the treatment and / or prevention of intestinal, gastrointestinal, or bowel conditions such as oral ulcers, gingival diseases, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0351] On the other hand, this article provides a method for preventing and / or treating renal dysfunction, comprising administering one or more of the compositions described herein to a subject in need. In the kidney, prostaglandins regulate renal blood flow and can regulate urine formation by acting on both renal vessels and renal tubules. In clinical studies, prostaglandin inhibitors have been used to improve creatinine clearance in patients with chronic kidney disease, to prevent graft rejection and cyclosporine toxicity in kidney transplant patients, and to reduce urinary albumin excretion and N-acetyl-β-D-glucosidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64:22E-26E). Furthermore, prostaglandins have been reported to act as vasodilators in the kidney, and therefore, inhibition of prostaglandin production in the kidney can lead to renal dysfunction (Hao. CM, 2008, AnnuRev Physiol, 70, 357. about. 77). The hydroxyprostaglandin dehydrogenase inhibitors described herein have suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins, and can be used for the prevention and / or treatment of kidney disease associated with renal dysfunction.

[0352] On the other hand, this article provides a method for stimulating bone resorption and bone formation, comprising administering one or more of the compositions described herein to a subject in need. Prostaglandins have been shown to stimulate bone resorption and bone formation, thereby increasing bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore, inhibition of 15-PGDH increases callus size and mineralization after fracture (Collier et al., ORS 2017 Annual Meeting Paper No. 0190). Given that 15-PGDH inhibits the activity of prostaglandins as mentioned above, inhibition of 15-PGDH activity may lead to the promotion of bone resorption and bone formation inhibited by 15-PGDH. Therefore, the hydroxyprostaglandin dehydrogenase inhibitors described herein can effectively promote bone resorption and bone formation by inhibiting 15-PGDH activity. The hydroxyprostaglandin dehydrogenase inhibitors described in this article 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-on-bone implants, bone-on-artificial implants, dental implants, and bone grafts.

[0353] On the other hand, this article provides a method for stimulating tissue regeneration by means of stimulation, comprising administering one or more compositions described herein to a subject in need. Prostaglandin PGE2 supports the expansion of several types of tissue stem cells. Inhibition of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enhances tissue regeneration in multiple organs. Studies have shown that inhibition of 15-PGDH increases prostaglandin PGE2 levels in bone marrow and other tissues; accelerates hematopoietic recovery after bone marrow transplantation; and promotes tissue regeneration in colon and liver injuries (Zhang, Y. et al. Science 2015, 348(6240)). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the expansion of tissue stem cells.

[0354] On the other hand, this article provides a method for regulating cervical ripening, comprising administering one or more of the compositions described herein to a subject in need. 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 the loss of its degradative 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 labor. Regulation of 15-PGDH activity can be used to regulate cervical ripening and induce or prevent preterm labor. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used alone or in combination with another labor inducing agent to induce cervical ripening and labor.

[0355] On the other hand, this article provides a method for promoting neuroprotection and / or stimulating neuronal regeneration, comprising administering one or more compositions described herein to a subject in need. Prostaglandins have a variety of physiological functions in the central nervous system via their specific G protein-coupled receptors. The major prostaglandin, prostaglandin E2 (PGE2), can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4 receptors can regulate the production of adenylate cyclase and 3,5'-cyclic adenosine monophosphate (cAMP), while activation of EP1 and EP3 receptors can regulate Ca2+ signaling. Studies have shown that EP1 and EP2 receptors are expressed in neurons and microglia, as well as in neurons of the cerebral cortex, striatum, and hippocampus. In addition, activation of EP2 receptors via PGE2 is associated with long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol. Feb. 1994; 18(1):23-9; Yang et al. J Neurochem. Jan. 2009; 108(1):295-304). Studies have also shown that, upon activation, different PGE2 receptors can promote or prevent N-methyl-D-aspartate (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 EP2 receptors protects neurons from amyloid-β-peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci. November 2005; 22(9):2199-206). Several studies have shown that PGE2 provides neuroprotection through EP2 or EP4 receptors, as both increase cAMP, followed by the protein kinase A (PKA)-dependent pathway (Echeverria et al., Eur J Neurosci. November 2005; 22(9):2199-206; McCulough et al., J Neurosci. January 7, 2004; 24(1):257-68). By applying compounds that inhibit, reduce, and / or antagonize 15-PGDH activity (such as the hydroxyprostaglandin dehydrogenase inhibitors described herein that can inhibit 15-PGDH) to stimulate these receptors with PGE2, it is possible to promote neuroprotection of subjects from axonal degeneration, neuronal cell death, and / or glial cell damage after injury, enhance neuronal signaling for learning and memory, stimulate neuronal regeneration after injury, and / or treat diseases, symptoms, and / or conditions of the nervous system.

[0356] On the other hand, this document provides a method for treating and / or preventing neurological disorders, neuropsychiatric disorders, nerve injuries, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders, comprising administering one or more of the compositions described herein to a subject in need. In some embodiments, diseases, conditions, and / or ailments of the nervous system that can be treated with the hydroxyprostaglandin dehydrogenase inhibitors provided herein may include at least one of neurological disorders, neuropsychiatric disorders, nerve injuries, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders. For example, neurological disorders may include at least one of traumatic or toxic injury to the peripheral or cranial nerves, spinal cord, or brain, such as traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. Neurological disorders may also include at least one of the following: Alzheimer's disease, Alzheimer's-related dementia, Parkinson's disease, Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de Ia Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfield disease.

[0357] In some implementations, nerve damage may 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, vegetations, endocrine disorders, nutritional and metabolic diseases, immune diseases, blood and hematopoietic organ diseases, mental 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 malformations, or perinatal conditions.

[0358] In some embodiments, a hydroxyprostaglandin dehydrogenase inhibitor may be administered to the subject or the subject's neurons to promote the survival, growth, development, and / or function of neurons, particularly those in the central nervous system (CNS), brain, cerebrum, and hippocampus. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitor may be used to stimulate hippocampal neurogenesis for the treatment of neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depressive disorder, 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, radiation therapy, chronic stress, and abuse of neuroactive drugs such as alcohol, opioids, methamphetamine, phencyclidine, and cocaine.

[0359] On the other hand, this article provides a method for treating and / or preventing fibrotic or adhesive diseases, conditions, or ailments, comprising administering one or more of the compositions described herein to a subject in need. Inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, have been shown to be administered to subjects in need to reduce 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, conditions, and ailments characterized wholly or in part by the excessive production of fibrous material, including the excessive production of fibrous material within the extracellular matrix, or the abnormal, nonfunctional, and / or excessive accumulation of matrix-related components replacing normal tissue elements (Markowitz et al., WO2016 / 144958).

[0360] Fibrotic diseases, symptoms, and conditions characterized in whole or in part by an excess of fibrous material can include systemic sclerosis, multifocal fibrosis, renal systemic fibrosis, scleroderma (including scleroderma scleroderma, generalized scleroderma scleroderma, or scleroderma zoster), sclerodermatic graft-versus-host disease, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive nephropathy, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), and pulmonary fibrosis (e.g., pulmonary fibrosis, glomerulosclerotic pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, etc.). Interstitial fibrotic lung disease and chemotherapy / radiation-induced pulmonary fibrosis), oral fibrosis, endocardial myocardial fibrosis, deltoid muscle fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, extensive fibrotic syndrome characterized by varying degrees of fibrous tissue replacing normal muscle tissue, retroperitoneal fibrosis, liver fibrosis, cirrhosis, chronic renal failure; myelofibrosis, drug-induced ergot poisoning, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ-specific fibrosis, etc. The hydroxyprostaglandin dehydrogenase inhibitors provided in this article can be used to treat or prevent fibrotic diseases, symptoms, or conditions.

[0361] The hydroxyprostaglandin dehydrogenase inhibitors described in this article can be used to treat or prevent renal fibrosis, including renal fibrosis caused by dialysis after renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end-stage renal disease, or renal failure, or a combination thereof.

[0362] The hydroxyprostaglandin dehydrogenase inhibitors described in this article 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 liver fibrosis caused by exposure to toxins or combinations thereof.

[0363] The hydroxyprostaglandin dehydrogenase inhibitors described in this article can be used to treat or prevent cardiac fibrosis, such as cardiac fibrosis, endocardial myocardial fibrosis, idiopathic pulmonary fibrosis, and renal fibrosis.

[0364] The hydroxyprostaglandin dehydrogenase inhibitors described in this article can be used to treat or prevent systemic sclerosis.

[0365] The hydroxyprostaglandin dehydrogenase inhibitors described in this article can be used to treat or prevent fibrotic diseases, symptoms, or conditions caused by postoperative adhesions.

[0366] The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to reduce the intensity, severity, or frequency of one or more symptoms or features of fibrotic diseases, conditions, or other related diseases, conditions, or conditions, and / or delay their onset.

[0367] The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to reduce or decrease collagen secretion, collagen deposition, or collagen fiber accumulation, or combinations thereof, in tissues or organs such as the lungs, liver, intestines, colon, skin, or heart.

[0368] Studies have shown that 15-PGDH inhibition improves the inflammatory pathology and fibrosis of pulmonary fibrosis (Smith et al., bioRxiv 2019.12.16.878215; Barnthaler et al., J. Allergy Clin. Immunol. 2019, 145(3), 818-833). In some implementations, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent pulmonary fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, anthrax, allergic pneumonia, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of toxic gases, aerosols, chemical dust, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension and combinations thereof.

[0369] On the other hand, this document provides a method for reducing and / or preventing scar formation, comprising applying one or more of the compositions described herein to a subject in need. 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.

[0370] On the other hand, this article provides a method for treating and / or preventing muscle disorders, muscle injuries, and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need. Studies have shown that inhibition of PGE2-degrading enzymes such as 15-PGDH can facilitate muscle regeneration and repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat muscle disorders, muscle injuries, and / or muscle atrophy in subjects. In some cases, the subject with muscle disorders, muscle injuries, 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 deficiency, sarcopenia, or a combination thereof.

[0371] In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat sarcopenia. In another embodiment, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy caused by mechanical ventilation. In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat hereditary or neuromuscular disorders, such as spinal muscular atrophy (SMA). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat ptosis, rotator cuff atrophy, fixation-related muscle atrophy, surgery-related muscle atrophy, sarcopenia, or combinations thereof.

[0372] Pharmaceutical Composition

[0373] Hydroxyprostaglandin dehydrogenase inhibitors can be formulated into pharmaceutical compositions to treat the diseases and conditions described herein. In some embodiments, the pharmaceutical composition may comprise a therapeutically effective amount of one or more hydroxyprostaglandin dehydrogenase inhibitors having the structure of formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt thereof.

[0374] 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, vapors, liposomes, nanoparticles, syrups, and emulsions. In some embodiments, the pharmaceutical compositions can also be administered intravenously (push or infusion), subcutaneously, as suppositories, intraperitoneally, topically (e.g., dermal, epidermal, transdermal), ocularly (e.g., eye drops), intranasally, subcutaneously, inhaled, intramuscularly, or transdermally (e.g., patches), all of which are well known to those skilled in the art of pharmaceutical manufacturing.

[0375] In some embodiments, the compounds provided herein may be administered as part of a treatment regimen that includes the simultaneous or sequential administration of one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents) with the compounds provided herein. When administered sequentially, the compounds provided herein may be administered before or after one or more second agents. When administered simultaneously, the compounds provided herein and one or more second agents may be administered via the same route (e.g., injection at the same site; simultaneous oral administration of tablets), via different routes (e.g., oral administration of tablets while receiving intravenous infusion), or as part of the same combination (e.g., a solution containing the compounds provided herein and one or more second agents).

[0376] Combination therapies according to this disclosure can be effective over a wide dose range. For example, in the treatment of adults, doses of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg / day, and 5 to 40 mg / day are examples of doses that can be used. The exact dose will depend on the chosen agent, route of administration, form of the compound, the patient being treated, the patient's weight, and the preferences and experience of the attending physician.

[0377] Example

[0378] Synthesis and characterization of compounds

[0379] The following embodiments are provided to illustrate, and not to limit, the claimed invention. These embodiments further illustrate the invention, but should not be construed as limiting its scope in any way.

[0380] The following synthetic schemes are provided for illustrative purposes and not for limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to them. It should also be understood that those skilled in the art will be able to prepare them in a similar manner as described below by using suitable starting materials and modifying the synthetic route as needed. Typically, the starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0381] The compounds and salts of formulas (I), (II), (IIIa), (IIIb), (IVa), (IVb), (IVc), and (IVd) can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or any particular substituents, which are for illustrative purposes. Although various steps are described and depicted in the synthetic schemes below, in some cases these steps may be performed in a different order than that shown below. The numbers or R groups in each scheme do not necessarily correspond to the numbers or R groups in the claims or other schemes or tables herein.

[0382] This document describes exemplary synthetic protocols that can be used to synthesize the inhibitors described herein. The following abbreviations are used:

[0383]

[0384]

[0385] Example 1. Used for the synthesis of pyrazolopyridinol: (R)-1-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)- 1H-pyrazolo[3,4-b]pyridin-5-yl)-2-isopropoxyethyl-1-ol and (S)-1-(1-(3-(4H-1,2,4-triazol-3- Representative compounds 18A and 18B are phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-isopropoxyethyl-1-ol. Program A

[0386] Option 1.

[0387]

[0388] To a solution of 2-isopropoxyacetic acid (2.00 g, 16.9 mmol, 1.00 eq.) and N-methoxymethylamine (1.24 g, 20.3 mmol, 1.20 eq.) in DCM (8 mL), DIEA (9.85 g, 76.2 mmol, 13.3 mL, 4.50 eq.), HOBt (4.58 g, 33.9 mmol, 2.00 eq.), and EDCI (6.49 g, 33.9 mmol, 2.00 eq.) were added. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (50 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and then filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to provide the desired product, 2-isopropoxy-N-methoxy-N-methylacetamide (2.10 g, 13.0 mmol, 77% yield), as a yellow liquid. 1 ¹H NMR (400MHz, chloroform-d) δ=4.22(s,2H), 3.73-3.67(m,1H), 3.67(s,3H), 3.16(s,3H), 1.19(d,J=6.1Hz,6H).

[0389] NaH (485 mg, 12.1 mmol, 60% purity, 1.20 eq.) was slowly added to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (2.00 g, 10.1 mmol, 1.00 eq.) in THF (20.0 mL) at 0 °C. After 30 minutes, TIPSCl (2.14 g, 11.1 mmol, 2.38 mL, 1.10 eq.) was added to the reaction mixture, and the mixture was stirred at 0 °C for 30 minutes. The mixture was poured into a saturated aqueous solution of ammonium chloride (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to petroleum ether / ethyl acetate = 10 / 1) to give (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropyl-silane (3.4 g, 8.64 mmol, 85% yield, 90% purity) as a yellow oil. 1 HNMR (400MHz, DMSO-d6) δ = 8.59 (d, J = 2.4Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.37 (s, 1H), 1.85 (quin, J = 7.6Hz, 3H), 1.05 (d, J = 7.6Hz, 18H).

[0390] n-BuLi (2.50 M, 20.7 mL, 5.00 eq.) was added to a solution of (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropyl-silane (3.66 g, 10.3 mmol, 1.00 eq.) in 15 mL of THF at -78 °C, and the reaction was stirred for 2 h. 2-Isopropoxy-N-methoxy-N-methylacetamide (2.00 g, 12.4 mmol, 1.20 eq.) was added to the reaction mixture, and the mixture was heated and stirred at 25 °C for 2 h. The mixture was poured into a saturated aqueous solution of ammonium chloride (50 mL) at 0 °C and then extracted with EA (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and then filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to provide 2-isopropoxy-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) acetone as a yellow oil (1.30 g, 3.46 mmol, 33% yield). LCMS [ESI, M+1]: 376.2. 1 ¹H NMR (400MHz, chloroform-d) δ=9.12(d,J=2.0Hz,1H),8.72(d,J=1.6Hz,1H),8.33(s,1H),4.73(s,2H),3.79-3.69(m,1H),1.46-1.40(m,3H),1.13(d,J=7.6Hz,18H),0.91(t,J=7.2Hz,6H).

[0391] TBAF (1.00 M, 3.20 mL, 1.20 eq.) was added to a solution of 2-isopropoxy-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) ethyl ketone (1.00 g, 2.66 mmol, 1.00 eq.) in THF (10 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain 2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridin-5-yl) ethyl ketone as a yellow solid (210 mg, 900 μmol, 34% yield, 94% purity). LCMS[ESI,M+1]:220.0.

[0392] NaBH4 (32.8 mg, 867 μmol, 1.00 eq.) was added to a solution of 2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridin-5-yl) ethyl ketone (190 mg, 867 μmol, 1.00 eq.) in MeOH (2 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into a saturated aqueous solution of NHCl4 (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and then filtered and concentrated to provide 2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridin-5-yl) ethanol (180 mg, 692 μmol, 80% yield, 85% purity) as a yellow oil. LCMS [ESI, M+1]: 222.1.

[0393] The mixture of 2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethanol (160 mg, 723 μmol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (257 mg, 723 μmol, 1.00 eq.), CuI (68.9 mg, 362 μmol, 0.50 eq.), K3PO4 (307 mg, 1.45 mmol, 2.00 eq.) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (206 mg, 1.45 mmol, 2.00 eq.) in DMA (1.5 mL) was degassed and purged three times with N2 (15 psi), and the mixture was stirred at 90 °C for 3 hours under N2 (15 psi) atmosphere. The mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to provide 2-isopropoxy-1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethanol as a yellow oil (280 mg, 562 μmol, 78% yield, 90% purity). LCMS [ESI, M+1]: 449.3.

[0394] TsOH·H₂O (165 mg, 870 μmol, 1.50 eq.) was added to a solution of 2-isopropoxy-1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethanol (260 mg, 580 μmol, 1.00 eq.) in MeOH (2.5 mL). The mixture was stirred at 50 °C for 1 hour. The mixture was poured into a saturated aqueous solution of NaHCO₃ (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was separated by SFC (column: DAICL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3H2O)]; B%: 55%, isocratic elution mode).

[0395] Compound 18A was given as a white solid (64.7 mg, 174 μmol, 37% yield, 98% purity). LCMS [ESI, M+1]: 365.2. 1 H NMR (400MHz, DMSO-d6) δ=14.56-13.73(m,1H),9.00(t,J=1.6Hz,1H),8.71(d,J=2.0Hz,1H),8.60-8.45 (m,2H),8.44-8.38(m,1H),8.33(d,J=1.6Hz,1H),7.98(d,J=8.0Hz,1H),7.68(t,J=8.0Hz,1H),5.60(br d,J=4.0Hz,1H),5.00-4.73(m,1H),3.62-3.54(m,2H),3.54-3.49(m,1H),1.05(dd,J=6.0,14.8Hz,6H).

[0396] Compound 18B was given as a white solid (72.1 mg, 194 μmol, 42% yield, 98% purity). LCMS [ESI, M+1]: 365.1. 1H NMR (400MHz, DMSO-d6) δ=14.58-13.87(m,1H),9.00(s,1H),8.71(d,J=2.0Hz,1H),8.49(s,2H),8.41(br d,J=7.2Hz,1H),8.33(d,J=1.6Hz,1H),7.98(d,J=7.6Hz,1H),7.68(t,J=7.6Hz,1H),5.60(br d,J=4.4Hz,1H),4.92-4.86(m,1H),3.63-3.54(m,2H),3.54-3.49(m,1H),1.05(dd,J=6.0,14.8Hz,6H).

[0397] Example 2. Used for the synthesis of pyrazolopyridine tertiary alcohol: 2-[1-[3-chloro-5-(4H-1,2,4-triazol-3-yl)phenyl] Representative procedure B for pyrazolo[3,4-b]pyridin-5-yl]prop-2-ol (compound 19)

[0398] Option 2.

[0399]

[0400] SOCl2 (1.82 g, 15.3 mmol, 1.11 mL, 5.00 eq.) was slowly added to a solution of 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (500 mg, 3.06 mmol, 1.00 eq.) in MeOH (10.0 mL) at 20 °C. The mixture was stirred at 20–50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with EA (25 mL). The combined organic layers were washed with a saturated salt solution (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (504 mg, 2.70 mmol, 88% yield, 95% purity) as a yellow solid. LCMS [ESI, M+1]: 178.1.

[0401] The mixture of methyl 1H-pyrazolo[3,4-b]pyridine-5-carboxylate (200 mg, 1.13 mmol, 1.00 eq.), 3-(3-chloro-5-iodo-phenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (528 mg, 1.35 mmol, 1.20 eq.), K3PO4 (479 mg, 2.26 mmol, 2.00 eq.), CuI (108 mg, 564 μmol, 0.50 eq.) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (80.0 mg, 564 μmol, 0.50 eq.) in DMA (3.00 mL) was degassed and purged three times with N2, and the mixture was stirred at 90 °C for 12 hours under N2 atmosphere (15 psi). The reaction mixture was diluted with EA (10 mL) and washed with saturated salt solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give methyl 1-[3-chloro-5-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridine-5-carboxylate (350 mg, 758 μmol, 67% yield, 95% purity) as a white solid. LCMS [ESI, M+1]: 355.1.

[0402] MeMgBr (1.00 M, 2.28 mL, 5.00 eq.) was added to a solution of methyl 1-[3-chloro-5-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridine-5-carboxylate (200 mg, 456 mol, 1.00 eq.) in THF (6.00 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Water (6.00 mL) was added to the reaction mixture, and the mixture was extracted with EA (10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give 2-[1-[3-chloro-5-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]prop-2-ol (75.0 mg, 162 μmol, 36% yield, 95% purity) as a white solid. LCMS [ESI, M+1]: 355.1.

[0403] TsOH·H₂O (33.0 mg, 171 μmol, 1.50 eq.) was added to a solution of 2-[1-[3-chloro-5-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]prop-2-ol (50.0 mg, 114 μmol, 1.00 eq.) in THF (0.50 mL). The mixture was then stirred at 50 °C for 1 hour. The reaction mixture was quenched with NaHCO₃ (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (column: UniSil 3-100C). 18 Ultra (150×25mm×3um); mobile phase: [water(FA)-ACN]; B%: 42%-62%, 7min) purification to give title compound (19) as a white solid (6.50 mg, 18.1 μmol, 16% yield, 99% purity). LCMS [ESI, M+1]: 355.1. 1 HNMR (400MHz, DMSO-d6) δ = 14.82-13.76 (m, 1H), 9.04 (s, 1H), 8.92 (d, J = 2.0Hz, 1H), 8.73-8.60 ( m,1H),8.59(s,1H),8.52(s,1H),8.44(d,J=2.0Hz,1H),7.94(s,1H),5.40(s,1H),1.56(s,6H).

[0404] Example 3. (R)-4-(5-(2-cyclobutoxy-1-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzene Formic acid and 4-[5-[(1S)-2-(cyclobutoxy)-1-hydroxy-ethyl]pyrazolo[3,4-b]pyridin-1-yl]benzoic acid (compound) Synthesis of compounds 42A and 42B

[0405] Option 3.

[0406]

[0407] NaH (17.5 g, 436 mmol, 60% purity, 2.10 eq.) was slowly added to a solution of cyclobutanol (15.0 g, 208.03 mmol, 1.00 eq.) in THF (300 mL) at 0 °C. After stirring the mixture at 20 °C for 2 hours, 2-bromoacetic acid (23.1 g, 166.42 mmol, 11.9 mL, 0.80 eq.) was slowly added at 0 °C, and the reaction was stirred at 20 °C for 12 hours. The reaction mixture was slowly added to water (500 mL) and washed with PE / EA = 1 / 1 (200 mL × 2). The aqueous layer was acidified to pH = 1 with 1 N HCl and then extracted with EA (300 mL × 3). The combined organic layers were washed with brine (600 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(cyclobutoxy)acetic acid (16.0 g, 98.4 mmol, 47% yield, 80% purity) as a brown oil. 1 ¹H NMR (400MHz, chloroform-d) δ=4.06(dd,J=6.8,7.6Hz,1H),4.03(s,2H),2.29-2.19(m,2H),2.05-1.95(m,2H),1.81-1.68(m,1H),1.52(tq,J=8.0,10.4Hz,1H).

[0408] To a solution of 2-(cyclobutoxy)acetic acid (43.0 g, 264 mmol, 1.00 eq.) and N-methoxymethylamine (32.3 g, 528 mmol, 2.00 eq.) in DCM (500 mL), EDCI (101 g, 528 mmol, 2.00 eq.), DIEA (153 g, 1.19 mol, 207 mL, 4.50 eq.), and HOBt (71.4 g, 528 mmol, 2.00 eq.) were added. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with H₂O (300 mL) and EtOAc (300 mL), and then extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 2-(cyclobutoxy)-N-methoxy-N-methylacetamide (41.0 g, 213 mmol, 80% yield, 90% purity) as a yellow oil. 1¹H NMR (400MHz, chloroform-d) δ=4.17(s,2H),4.10-4.03(m,1H),3.69(s,3H),3.20(s,3H),2.29-2.18(m,2H),2.01(br dd,J=1.6,9.6Hz,2H),1.71(q,J=10.4Hz,1H),1.56-1.41(m,1H).

[0409] n-BuLi (2.5 M, 1.69 mL, 1.50 eq.) was added to a solution of (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropyl-silane (1.00 g, 2.82 mmol, 1.00 eq.) in THF (20 mL) at -78 °C, and the mixture was stirred at -78 °C for 0.1 h. Then, 2-(cyclobutoxy)-N-methoxy-N-methylacetamide (733 mg, 4.23 mmol, 1.50 eq.) in THF (5 mL) was added at -78 °C. The reaction was stirred at -78 °C for 1 h, quenched by slow addition of an aqueous solution of NH4Cl (50 mL), and then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 8 / 1) to give 2-(cyclobutoxy)-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) acetone (460 mg, 1.07 mmol, 38% yield, 90% purity), which was a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 9.03 (d, J = 2.0Hz, 1H), 8.83 (d, J = 2.0Hz, 1H), 8.57 (s, 1H), 4.80 (s, 2H), 4.10-3.98 (m ,2H),2.22-2.10(m,2H),1.97-1.82(m,5H),1.63(q,J=10.1Hz,1H),1.48-1.40(m,1H),1.08(d,J=7.6Hz,18H).

[0410] NaBH4 (976 mg, 25.8 mmol, 2.00 eq.) was slowly added to a solution of 2-(cyclobutoxy)-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) ethyl ketone (5.00 g, 12.9 mmol, 1.00 eq.) in THF (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction was quenched at 0 °C with acetone (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(cyclobutoxy)-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) ethanol (5.00 g, 12.45 mmol, 96% yield, 97% purity) as a yellow oil. LCMS[ESI,M+1]: m / z = 390.3.

[0411] CsF (8.77 g, 57.7 mmol, 2.13 mL, 5.00 eq.) was added to a solution of 2-(cyclobutoxy)-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl)ethanol (4.50 g, 11.5 mmol, 1 eq.) in MeOH (50 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with H₂O (50 mL) and EtOAc (50 mL), and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 2-(cyclobutoxy)-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethanol (2.10 g, 8.91 mmol, 77% yield, 99% purity) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ=13.55(br s,1H),8.50(d,J=2.0Hz,1H),8.16-8.07(m,2H),5.50(d,J=4.4Hz,1H),4.82(q,J=5.6Hz,1H),3.92(quin,J=7.2Hz,1H),3.48 -3.43(m,1H),3.41-3.37(m,1H),2.09(td,J=7.6,15.6Hz,2H),1.85-1.68(m,2H),1.57(q,J=10.0Hz,1H),1.49-1.33(m,1H).

[0412] 2-(cyclobutoxy)-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethanol (1.80 g, 7.72 mmol, 1.00 eq.), methyl 4-iodobenzoate (3.03 g, 11.5 mmol, 1.50 eq.), CuI (734 mg, 3.86 mmol, 0.50 eq.), N 1 N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (548 mg, 3.86 mmol, 0.50 eq.) and K3PO4 (3.28 g, 15.4 mmol, 2 eq.) in DMAC (20 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 2 hours under a N2 atmosphere (15 psi). The reaction mixture was diluted with H2O (50 mL) and EtOAc (50 mL), and then NH3·H2O (10 mL, 25% purity) was added and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give methyl 4-[5-[2-(cyclobutoxy)-1-hydroxy-ethyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (1.90 g, 5.12 mmol, 66% yield, 99% purity), a yellow oil. LCMS [ESI, M+1]: m / z = 368.2. 1 H NMR (400MHz, DMSO-d6) δ = 8.72 (d, J = 1.6Hz, 1H), 8.62-8.50 (m, 3H), 8.34 (d, J = 1.6Hz, 1H), 8.16 (br d,J=8.8Hz,2H),5.67(d,J=4.4Hz,1H),4.91(q,J=5.6Hz,1H),3.98-3.91(m,1H),3.89(s,3H),3. 55-3.39(m,2H),2.18-2.03(m,2H),1.86-1.69(m,2H),1.58(q,J=10.0Hz,1H),1.48-1.34(m,1H).

[0413] Methyl 4-[5-[2-(cyclobutoxy)-1-hydroxy-ethyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (250 mg, 681 μmol, 1.00 eq.) was passed through an SFC column (DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-ACN / i-PrOH (0.1%)). Purified by NH3H2O]; B%: 70%, isocratic elution mode) to give methyl 4-[5-[(1R)-2-(cyclobutoxy)-1-hydroxy-ethyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (115 mg, 305.50 μmol, 44.9% yield, 97.6% purity) and methyl 4-[5-[(1S)-2-(cyclobutoxy)-1-hydroxy-ethyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (120 mg, 324 μmol, 47.6% yield, 99.2% purity) as white solids. LCMS [ESI, M+1]: 368.2.

[0414] A solution of LiOH·H₂O (57.1 mg, 1.36 mmol, 5.00 eq.) in H₂O (2 mL) was added to a solution of the separated racemic mixture (100 mg, 272 μmol, 1.00 eq.) in THF (2 mL), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was removed from the organic solvent under reduced pressure at 40 °C. The pH was then adjusted to 1 with an aqueous solution of HCl (1 M), and a white solid was formed. The mixture was filtered to give compound 42A as a white solid (89.0 mg, 247 μmol, 90.9% yield, 98.2% purity). LCMS [ESI, M+1]: 354.1. 1 H NMR (400MHz, DMSO-d6) δ = 12.98 (br s, 1H), 8.71 (d, J = 1.6Hz, 1H), 8.58-8.49 (m, 3H), 8.34 (s, 1H), 8.14 (d, J = 8.8Hz, 2H), 5.67 (br d,J=4.0Hz,1H),4.91(br d,J=4.4Hz,1H),3.93(quin,J=7.2Hz,1H),3.55-3.41(m,2H),2.18-2.02(m,2H),1.86-1.69(m,2H),1.58(q,J=9.6Hz,1H),1.49-1.34(m,1H).

[0415] A solution of LiOH·H₂O (68.5 mg, 1.63 mmol, 5.00 eq.) in H₂O (2 mL) was added to a solution of the separated racemic mixture (120 mg, 327 μmol, 1.00 eq.) in THF (2 mL), and the mixture was stirred at 25 °C for 4 h. The reaction mixture was removed from the organic solvent under reduced pressure at 40 °C. The pH was then adjusted to 1 with an aqueous solution of HCl (1 M), and a white solid was formed. The mixture was filtered to give compound 42B as a white solid (92.0 mg, 260 μmol, 79.6% yield, 99.8% purity). LCMS [ESI, M+1]: 354.1. 1 H NMR(400MHz,DMSO-d6)δ=12.98(br s,1H),8.71(d,J=2.0Hz,1H),8.56-8.50(m,3H),8.34(d,J=1.6Hz,1H),8.14(d,J=8.8Hz,2H),5.67(d,J=4.4Hz,1H),4.91(q,J=5.6H z,1H),3.93(quin,J=7.2Hz,1H),3.55-3.39(m,2H),2.19-2.01(m,2H),1.84-1.69(m,2H),1.58(q,J=10.0Hz,1H),1.49-1.33(m,1H).

[0416] Example 4: (R)-4-(5-((3,3-difluorocyclobutyl)(hydroxy)methyl)-1H-pyrazolo[3,4-b]pyridine-1- (S)-4-(5-((3,3-difluorocyclobutyl)(hydroxy)methyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzene Synthesis of formic acid (compounds 45A and 45B)

[0417] Option 4.

[0418]

[0419] To a solution of 3,3-difluorocyclobutanecarboxylic acid (9.00 g, 66.1 mmol, 1.00 eq.) and N-methoxymethylamine (6.45 g, 66.1 mmol, 1.00 eq., HCl) in DMF (150 mL), HATU (30.2 g, 79.4 mmol, 1.20 eq.) and DIEA (21.4 g, 165 mmol, 28.8 mL, 2.50 eq.) were added. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain 3,3-difluoro-N-methoxy-N-methyl-cyclobutane formamide (6 g, 31.8 mmol, 48% yield, 95% purity) as a yellow oil.1 ¹H NMR (400MHz, chloroform-d) δ = 3.67 (s, 3H), 3.29–3.22 (m, 1H), 3.19 (s, 3H), 2.92–2.62 (m, 4H).

[0420] n-BuLi (2.5 M, 3.35 mL, 1.50 eq.) was added to a solution of (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropyl-silane (1.98 g, 5.58 mmol, 1.00 eq.) in THF (20 mL) at -78 °C, and the mixture was stirred for 10 min. 3,3-difluoro-N-methoxy-N-methyl-cyclobutaneformamide (1.00 g, 5.58 mmol, 1.00 eq.) in THF (10 mL) was added to the mixture. The mixture was stirred at -78 °C for 50 min, then quenched at 0 °C with a saturated aqueous solution of NH4Cl (30 mL), diluted with water (5 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain (3,3-difluorocyclobutyl)-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) methyl ketone (600 mg, 1.14 mmol, 20% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 9.08 (d, J = 2.0Hz, 1H), 8.89 (d, J = 2.0Hz, 1H), 8.57 (s, 1 H),4.28-3.91(m,1H),3.01-2.80(m,4H),1.99-1.81(m,3H),1.12-1.02(m,18H).

[0421] CsF (521 mg, 3.43 mmol, 3.00 eq.) was added to a solution of (3,3-difluorocyclobutyl)-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl) ketone (600 mg, 1.14 mmol, 1.00 eq.) in DMF (5.00 mL). The mixture was stirred at 20 °C for 1 hour, then diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (3,3-difluorocyclobutyl)-(1H-pyrazolo[3,4-b]pyridin-5-yl) ketone (250 mg, 1.01 mmol, 88% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 14.06 (br s, 1H), 9.08 (d, J = 2.0Hz, 1H), 8.89 (d, J = 2.0Hz, 1H), 8.34 (s, 1H), 4.19-4.06 (m, 1H), 2.96-2.89 (m, 4H).

[0422] NaBH4 (79.7 mg, 2.11 mmol, 2.00 eq.) was added to a solution of (3,3-difluorocyclobutyl)-(1H-pyrazolo[3,4-b]pyridin-5-yl) methyl ketone (250 mg, 1.05 mmol, 1.00 eq.) in MeOH (3.00 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h and then quenched with a saturated aqueous solution of NH4Cl (5 mL) at 0 °C. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (3,3-difluorocyclobutyl)-(1H-pyrazolo[3,4-b]pyridin-5-yl) methanol (220 mg, 828 μmol, 78% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 13.58 (br s, 1H), 8.52 (d, J = 1.8Hz, 1H), 8.15 (d, J = 1.2Hz, 1H), 8.11 (s, 1H), 5.70 (d, J = 4.4Hz, 1H), 4.72 (br s,1H),2.66-2.56(m,1H),2.48-2.28(m,4H).

[0423] (3,3-difluorocyclobutyl)-(1H-pyrazolo[3,4-b]pyridin-5-yl)methanol (200 mg, 836 μmol, 1.00 eq.), methyl 4-iodobenzoate (219 mg, 836 μmol, 1.00 eq.), (1R,2R)-N 1 N 2A mixture of 1,2-dimethylcyclohexane-1,2-diamine (23.8 mg, 167 μmol, 0.20 eq.), K3PO4 (532 mg, 2.51 mmol, 3.00 eq.), and CuI (31.8 mg, 167 μmol, 0.20 eq.) in DMA (5.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 1 hour under a N2 atmosphere (15 psi). The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain methyl 4-[5-[(3,3-difluorocyclobutyl)-hydroxy-methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (150 mg, 361 μmol, 43% yield, 90% purity) as a yellow solid. LCMS [ESI, M+1]: 374.2.

[0424] Racemic methyl 4-[5-[(3,3-difluorocyclobutyl)-hydroxy-methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (150 mg, 402 μmol, 1.00 eq.) was passed through an SFC column (DAICEL CHIRALPAKIG (250 mm * 30 mm, 10 μm); mobile phase: [CO2-ACN / EtOH (0.1%)). Separation was performed using NH3·H2O]; B%: 60%, isocratic elution mode) to obtain methyl 4-[5-[(R)-(3,3-difluorocyclobutyl)-hydroxy-methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (70 mg, 141 μmol, 35% yield, 75% purity) and methyl 4-[5-[(S)-(3,3-difluorocyclobutyl)-hydroxy-methyl]pyrazolo[3,4-b]pyridin-1-yl]benzoate (70 mg, 150 μmol, 37% yield, 80% purity) as white solids.

[0425] A solution of LiOH·H₂O (7.31 mg, 174 μmol, 1.0 eq) in H₂O (0.5 mL) was added to a solution of the separated racemic mixture (65 mg, 174 μmol, 1.0 eq) in THF (0.5 mL). The mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH 7 with 2 M HCl solution and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 34%-64% B over 10 min). The desired fraction was collected and lyophilized to obtain compound 45B as a white solid (32.41 mg, 89.7 μmol, 51% yield, 99.5% purity). LCMS [ESI, M+1]: 360.1. 1 H NMR (400MHz, MeOD-d4) δ = 8.78-8.66 (m, 1H), 8.60-8.47 (m, 2H), 8.38-8.25 (m, 2H), 8.24-8.15 (m, 2H), 5.92-5.57 (m, 1H), 2.74-2.45 (m, 5H).

[0426] A solution of LiOH·H₂O (7.87 mg, 187 μmol, 1.0 eq) in H₂O (0.5 mL) was added to a solution of the separated racemic mixture (70 mg, 187 μmol, 1.0 eq) in THF (0.5 mL). The mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH 7 with 2 M HCl solution and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 42%-62% B for 8 min). The desired fraction was collected and lyophilized to obtain compound 45A as a white solid (31.97 mg, 88.7 μmol, 47% yield, 99.7% purity). LCMS [ESI, M+1]: 360.1. 1 H NMR(400MHz,MeOD-d4)δ=8.75-8.66(m,1H),8.60-8.49(m,2H),8.33(s,1H), 8.30-8.25(m,1H),8.24-8.14(m,2H),5.88-5.50(m,1H),2.72-2.44(m,5H).

[0427] Example 5. Used for the synthesis of pyrrolopyrazine alcohol: (S)-(3,3-difluorocyclobutyl)-[5-[3-(4H-1,2,4-trimethylolpropionate ...[4H-1,2,4-trimethylolpropion [Azol-3-yl)phenyl]pyrrolo[2,3-b]pyrazin-2-yl]methanol and (R)-(3,3-difluorocyclobutyl)-[5-[3-(4H-1,2, Representative procedure C for 4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyrazin-2-yl]methano (compounds 1A and 1B)

[0428] Option 5.

[0429]

[0430] HOBt (8.94 g, 66.1 mmol, 1.00 eq.), EDCI (12.7 g, 66.1 mmol, 2.00 eq.), and DIEA (19.2 g, 149 mmol, 25.9 mL, 4.50 eq.) were added to a solution of 3,3-difluorocyclobutanecarboxylic acid (4.50 g, 33.1 mmol, 1.00 eq.) and N-methoxymethylamine (3.87 g, 39.7 mmol, 1.20 eq., HCl) in DCM (45.0 mL). The mixture was stirred at 20 °C for 2 hours, then diluted with H2O (25.0 mL) and extracted with DCM (25.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give 3,3-difluoro-N-methoxy-N-methyl-cyclobutaneformamide (3.79 g, 20.9 mmol, 63% yield, 99% purity) as a yellow oil. LCMS [ESI, M+1]: 180.2.

[0431] NaH (1.51 g, 37.9 mmol, 60% purity, 1.50 eq.) was added to a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 25.3 mmol, 1.00 eq.) in THF (50.0 mL) at 0 °C under a nitrogen atmosphere (15 psi). The mixture was stirred at 0 °C under a nitrogen atmosphere (15 psi) for 0.5 h, and then TIPSCl (5.84 g, 30.3 mmol, 6.48 mL, 1.20 eq.) was added at 0 °C. The mixture was stirred at a nitrogen atmosphere (15 psi) for 0.5 h, and then quenched with saturated NH4Cl (50.0 mL) at 0 °C. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give (2-bromopyrrolo[2,3-b]pyrazin-5-yl)-triisopropyl-silane (7.80 g, 21.8 mmol, 86% yield, 99% purity) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.38 (s, 1H), 7.96 (d, J = 3.6Hz, 1H), 6.81 (d, J = 3.6Hz, 1H), 1.96-1.74 (m, 3H), 1.03 (d, J = 7.6Hz, 18H).

[0432] n-BuLi (2.5 M, 8.47 mL, 3.00 eq.) was added to a solution of (2-bromopyrrolo[2,3-b]pyrazin-5-yl)-triisopropyl-silane (2.50 g, 7.05 mmol, 1.00 eq.) and 3,3-difluoro-N-methoxy-N-methyl-cyclobutaneformamide (1.39 g, 7.76 mmol, 1.10 eq.) in THF (25.0 mL) at -78 °C under N2 atmosphere (15 psi). The mixture was stirred at -78 °C under N2 atmosphere (15 psi) for 0.5 h, and then quenched at 0 °C with saturated NH4Cl (50.0 mL). The mixture was extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 500 / 1 to 200 / 1) to give (3,3-difluorocyclobutyl)-(5-triisopropylsilylpyrrolo[2,3-b]pyrazin-2-yl) methyl ketone (1.11 g, 2.57 mmol, 36% yield, 91% purity) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.09 (d, J = 3.6Hz, 1H), 6.99 (d, J = 3.6Hz, 1H), 4.30 (dq ,J=2.8,8.4Hz,1H),2.99-2.84(m,4H),1.90(td,J=7.6,15.2Hz,3H),1.06(d,J=7.6Hz,18H).

[0433] NaBH4 (187 mg, 4.95 mmol, 1.50 eq.) was added to a solution of (3,3-difluorocyclobutyl)-(5-triisopropylsilylpyrrolo[2,3-b]pyrazin-2-yl) methyl ketone (1.30 g, 3.30 mmol, 1.00 eq.) in MeOH (13.0 mL) at 0 °C. The mixture was then stirred at 20 °C for 1 hour. The reaction was quenched at 0 °C with saturated NH4Cl (20.0 mL). The mixture was extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a yellow gel-like substance (3,3-difluorocyclobutyl)-(5-triisopropylsilylpyrrolo[2,3-b]pyrazin-2-yl)methanol (1.26 g, 2.29 mmol, 69% yield, 72% purity). LCMS [ESI, M+1]: 396.4.

[0434] TBAF (1M, 3.52mL, 1.20eq.) was added to a solution of (3,3-difluorocyclobutyl)-(5-triisopropylsilylpyrrolo[2,3-b]pyrazin-2-yl)methanol (1.16 g, 2.93 mmol, 1.00 eq.) in THF (12.00 mL), and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with H2O (25.0 mL) and extracted with EtOAc (25.0 mL × 3). The combined organic layers were washed with H2O (20.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give (3,3-difluorocyclobutyl)-(5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (310 mg, 1.30 mmol, 44% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=11.98(br s,1H),8.33(s,1H),7.84(t,J=3.2Hz,1H),6.58(dd,J=1.6,3.2Hz,1H),5.77(d,J=5.2Hz,1H),4.73(t,J=5.2Hz,1H),2.74-2.57(m,2H),2.55(br s,1H),2.49-2.36(m,2H).

[0435] Under a nitrogen atmosphere (15 psi), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (77.3 mg, 543 μmol, 0.50 eq), CuI (104 mg, 543 μmol, 0.50 eq) and K3PO4 (461 mg, 2.17 mmol, 2.00 eq) in a solution of (3,3-difluorocyclobutyl)-(5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (260 mg, 1.09 mmol, 1.00 eq) and 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (463 mg, 1.30 mmol, 1.20 eq) in DMA (3.00 mL) were added, and the mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere (15 psi). The reaction mixture was diluted with H2O (25.0 mL) and extracted with EtOAc (25.0 mL × 3). The combined organic layers were washed with H2O (20.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give a yellow gel-like substance (3,3-difluorocyclobutyl)-[5-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyrazin-2-yl]methanol (490 mg, 1.01 mmol, 92% yield, 96% purity). LCMS [ESI, M+1]: 467.2.

[0436] A solution of (3,3-difluorocyclobutyl)-[5-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyrazin-2-yl]methanol (440 mg, 943 μmol, 1.00 eq.) in HCl (9.00 mL) and H₂O (9.00 mL) was stirred at 0 °C for 0.5 h. The pH was adjusted to 7 at 0 °C with 1 M NaOH. The reaction mixture was diluted with H₂O (25.0 mL) and extracted with EtOAc (25.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give (3,3-difluorocyclobutyl)-[5-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyrazin-2-yl]methanol (230 mg, 577 μmol, 61% yield, 96% purity) as a white solid. LCMS [ESI, M+1]: 383.2

[0437] Racemic (5-(3-(4H-1,2,4-triazol-3-yl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)(3,3-difluorocyclobutyl)methanol (230 mg, 602 μmol, 1.00 eq.) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3·H2O)]; B%: 40%, isocratic elution mode) to give peak 1 (compound 1A) (49.9 mg, 129 μmol, 21% yield, 99% purity) and peak 2 (compound 1B) (36.8 mg, 92.4 μmol, 15% yield, 96% purity) as a white solid.

[0438] Peak 1 - Compound 1A: LCMS [ESI, M+1]: 383.1. 1 H NMR (400MHz, DMSO-d6) δ = 14.29 (br s, 1H), 8.56 (s, 2H), 8.48 (s, 1H), 8.44 (d, J = 4.0Hz, 1H), 8.03 (d, J = 7.6Hz, 1H), 7.92 (br d,J=7.6Hz,1H),7.76-7.60(m,1H),6.92(d,J=4.0Hz,1H),5.91(br s,1H),4.79(br d,J=4.0Hz,1H),2.79-2.62(m,2H),2.61-2.52(m,2H),2.48-2.40(m,1H).

[0439] 1 H NMR (400MHz, methanol-d4) δ = 8.50 (d, J = 2.0Hz, 1H), 8.49 (s, 1H), 8.46 (br s,1H),8.21(d,J=4.0Hz,1H),8.05(d,J=7.6Hz,1H),7.96(dd,J=1.6,8.0Hz,1H),7.68(t,J= 8.0Hz, 1H), 6.87 (d, J = 4.0Hz, 1H), 4.88-4.87 (m, 1H), 2.80-2.64 (m, 2H), 2.63-2.37 (m, 3H).

[0440] Peak 2 - Compound 1B: LCMS [ESI, M+1]: 383.1. 1H NMR (400MHz, DMSO-d6) δ = 14.27 (br s, 1H), 8.56 (s, 2H), 8.48 (s, 1H), 8.44 (d, J = 3.6Hz, 1H), 8.03 (d, J = 7.6Hz, 1H), 7.92 (br d,J=7.6Hz,1H),7.74-7.64(m,1H),6.92(d,J=3.6Hz,1H),5.90(br d,J=3.6Hz,1H),4.80(br s,1H),2.79-2.62(m,2H),2.61-2.52(m,2H),2.48-2.40(m,1H).

[0441] 1 H NMR (400MHz, methanol-d4) δ = 8.50 (t, J = 2.0Hz, 1H), 8.49 (s, 1H), 8.46 (br s,1H),8.22(d,J=4.0Hz,1H),8.06(d,J=8.0Hz,1H),8.01-7.92(m,1H),7.68(t,J=8.0H z, 1H), 6.87 (d, J = 4.0Hz, 1H), 4.88-4.87 (m, 1H), 2.85-2.64 (m, 2H), 2.63-2.38 (m, 3H).

[0442] Example 6. Used for the synthesis of azaindole diol: (1R,2R)-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3- [1S,2S]-4-methyl-1-[1-[3-(4H-1,2,2-]pyridine-5-yl]pentane-1,2-diol, (1S,2S)-4-methyl-1-[1-[3-(4H-1,2,2-]pyridine-5-yl]pentane-1,2-diol, 4-Triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol, (1R,2S)-4-methyl-1-[1-[3- [(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol and (1S,2R)-4-methyl 1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol (compound) Representative procedure D for items 3A, 3B, 3C, and 3D)

[0443] Option 6.

[0444]

[0445] The following were added: 1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (4.00 g, 27.4 mmol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (10.7 g, 30.1 mmol, 1.10 eq.), K3PO4 (11.6 g, 54.7 mmol, 2.00 eq.), CuI (2.61 g, 13.7 mmol, 0.50 eq.), and (1R,2R)-N 1 N 2The mixture of 1,2-dimethylcyclohexane-1,2-diamine (1.95 g, 13.7 mmol, 0.50 eq.) in DMA (40.0 mL) was degassed and purged three times with N2. The mixture was then stirred at 50 °C for 12 h under N2 atmosphere (15 psi). The mixture was filtered, diluted with H2O (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give 1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine-5-carboxaldehyde (4.50 g, 10.2 mmol, 37% yield, 85% purity) as a yellow oil. LCMS[ESI,M-83]:290.2. 1 H NMR (400MHz, DMSO-d6) δ=10.15(s,1H),8.85(br d,J=12.8Hz,2H),8.61(br s,1H),8.50(br s,1H),8.16(br d,J=2.4Hz,1H),8.05(br d,J=7.2Hz,1H),7.89(br d,J=7.2Hz,1H),7.69(br t,J=7.8Hz,1H),6.96(br d,J=2.8Hz,1H),5.62(br d,J=9.2Hz,1H),3.97(br d,J=11.2Hz,1H),3.78-3.55(m,1H),2.15(br s,1H),2.08-1.89(m,2H),1.70(br s,1H),1.57(br s,2H).

[0446] A mixture of 1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine-5-carboxaldehyde (4.00 g, 10.7 mmol, 1.00 eq.), 3-methylbutyraldehyde (13.8 g, 160 mmol, 17.6 mL, 15.0 eq.), 2-(2,3,4,5,6-pentafluorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-onium tetrafluoroborate (388 mg, 1.07 mmol, 0.10 eq.), and Cs₂CO₃ (349 mg, 1.07 mmol, 0.10 eq.) in toluene (40.0 mL) was degassed and purged three times with N₂. The mixture was then stirred at 90 °C for 6 hours under a N₂ atmosphere (15 psi). The reaction mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 1), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give 1-hydroxy-4-methyl-1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (1.70 g, 3.63 mmol, 34% yield, 98% purity) as a white solid. LCMS [ESI, M+1]: 460.3.

[0447] TsOH·H₂O (931 mg, 4.90 mmol, 1.50 eq.) was added to a solution of 1-hydroxy-4-methyl-1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (1.50 g, 3.26 mmol, 1.00 eq.) in THF (15.0 mL). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with saturated NaHCO₃ (50.0 mL) and extracted with EA (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 1), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give 1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (600 mg, 1.44 mmol, 44% yield, 90% purity) as a yellow solid. LCMS [ESI, M+1]: 376.2. 1H NMR (400MHz, DMSO-d6) δ=14.72-13.86(m,1H),8.58-8.34(m,3H),8.08-8.02(m,2H),8.00(d,J=7.6Hz,1H),7.93(br d,J=8.0Hz,1H),7.69-7.62(m,1H),6.78(d,J=3.6Hz,1H),6.41-5.84(m,1H),5.2 4(s,1H),2.46-2.33(m,2H),1.98(td,J=6.8,13.2Hz,1H),0.76(d,J=6.8Hz,6H).

[0448] 1-Hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pent-2-one (600 mg, 1.44 mmol, 44% yield, 90% purity) was further passed through an SFC (column: DAICELCHIRALPAKIC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1%)). Separation was performed using NH3H2O; B%: 60%, isocratic elution mode) to give (1R)-1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (240 mg, 620 μmol, 39% yield, 97% purity) and (1S)-1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (230 mg, 594 μmol, 37% yield, 97% purity) as white solids.

[0449] (1R)-1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pent-2-one: LCMS[ESI,M+1]:376.2. 1H NMR(400MHz, DMSO-d6)δ=14.51-14.01(m,1H),8.61-8.45(m,2H),8.35(d,J=2.0Hz ,1H),8.05(d,J=1.6Hz,1H),8.03(d,J=3.6Hz,1H),8.00(d,J=7.6Hz,1H),7.93(br d,J=7.6Hz,1H),7.72-7.59(m,1H),6.78(d,J=3.6Hz,1H),6.09(br s,1H),5.24(s,1H),2.46-2.34(m,2H),1.98(q,J=6.8Hz,1H),0.76(dd,J=2.0,6.8Hz,6H).

[0450] (1S)-1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pent-2-one: LCMS[ESI,M+1]:376.2. 1 H NMR(400MHz,DMSO-d6)δ=13.56(br s,1H),8.60-8.47(m,2H),8.35(d,J=2.0Hz,1H),8.05(d,J=2.0Hz,1H),8.03(d,J=3.6Hz,1H) ,8.00(d,J=7.8Hz,1H),7.95-7.91(m,1H),7.71-7.61(m,1H),6.78(d,J=3.6Hz,1H),6.10(br s,1H),5.24(s,1H),2.46-2.34(m,2H),1.98(t,J=6.8Hz,1H),0.76(dd,J=2.0,6.8Hz,6H).

[0451] NaBH4 (44.3 mg, 1.17 mmol, 2.00 eq.) was added to a solution of (1R)-1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (220 mg, 586 μmol, 1.00 eq.) in MeOH (2.00 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction was quenched at 0 °C with saturated NH4Cl (20.0 mL) and then extracted with EtOAc (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The crude product was ground with EtOAc (5.00 mL) at 20 °C to give (1R)-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol (190 mg, 483 μmol, 82% yield, 96% purity) as a white solid, a mixture of two diastereomers. LCMS [ESI, M+3]: 378.2. 1 H NMR (400MHz, DMSO-d6) δ=14.79-13.94(m,1H),8.76-8.50(m,2H),8.29(br d,J=1.6Hz,1H),8.17-7.85(m,4H),7.76-7.57(m,1H),6.75(br s,1H),5.30(d,J=4.4Hz,1H),4.63-4.50(m,1H),4.50-4.36(m,1H),3.73-3.57(m ,1H),1.83-1.68(m,1H),1.39-1.21(m,1H),1.14-0.94(m,1H),0.89-0.75(m,6H).

[0452] NaBH4 (46.3 mg, 1.23 mmol, 2.00 eq.) was added to a solution of (1S)-1-hydroxy-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentan-2-one (230 mg, 612 μmol, 1 eq) in MeOH (2.00 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched at 0 °C with saturated NH4Cl (20.0 mL). The mixture was extracted with EtOAc (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The crude product was ground with EtOAc (5.00 mL) at 20 °C to give (1S)-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol (180 mg, 462 μmol, 75% yield, 97% purity) as a white solid, a mixture of two diastereomers. LCMS [ESI, M+1]: 378.2. 1 H NMR (400MHz, DMSO-d6) δ=14.69-14.08(m,1H),8.76-8.50(m,2H),8.29(br d,J=1.6Hz,1H),8.12-7.84(m,4H),7.72-7.58(m,1H),6.75(br s,1H),5.30(d,J=4.0Hz,1H),4.63-4.35(m,2H),3.74-3.55(m,1H),1.8 4-1.62(m,1H),1.40-1.21(m,1H),1.14-0.93(m,1H),0.91-0.76(m,6H).

[0453] (1R)-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol (190 mg, 503 μmol, 1.00 eq.) was passed through an SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) and an SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]). 2-[i-PrOH(0.1% NH3H2O)]; B%: 50%, isocratic elution mode) to give compound 3A (80.0 mg, 205 μmol, 40% yield, 97% purity) as a white solid and (1R,2S)-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol (3C) (40.0 mg, 101 μmol, 20% yield, 95% purity) as a white solid.

[0454] Compound 3A: LCMS[ESI,M+1]: 378.2. 1 H NMR (400MHz, DMSO-d6) δ = 14.27 (br s, 1H), 8.60 (s, 1H), 8.50 (br s,1H),8.29(d,J=1.6Hz,1H),8.06-7.83(m,4H),7.65(t,J=8.0Hz,1H),6.75(d,J=3.6Hz,1H),5.30(br s,1H),4.58(br s,1H),4.53(d,J=5.6Hz,1H),3.67(br d,J=6.4Hz,1H),1.83-1.63(m,1H),1.15(ddd,J=4.4,10.0,13.6Hz,1H),1.05-0.93(m,1H),0.79(dd,J=6.8,12.8Hz,6H).

[0455] Compound 3C: LCMS[ESI,M+1]: 378.2. 1 H NMR (400MHz, DMSO-d6) δ=14.34-14.16(m,1H),8.60(s,1H),8.57-8.42(m,1H),8.28(d,J=2 .0Hz,1H),8.02(d,J=1.6Hz,1H),8.00-7.92(m,3H),7.65(t,J=8.0Hz,1H),6.74(d,J=3.6H z,1H),5.30(d,J=4.4Hz,1H),4.47(t,J=4.8Hz,1H),4.40(d,J=6.0Hz,1H),3.69-3.60(m,1 H),1.84-1.71(m,1H),1.37-1.28(m,1H),1.23-1.18(m,1H),0.84(dd,J=6.4,17.2Hz,6H).

[0456] (1S)-4-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]pentane-1,2-diol (180 mg, 477 μmol, 1.00 eq.) was eluted by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) and SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]). [NH3H2O]; B%: 55%, isocratic elution mode) to separate compound 3B (80.0 mg, 205 μmol, 43% yield, 97% purity) and compound 3D (45.0 mg, 118 μmol, 25% yield, 99% purity) as white solids.

[0457] Compound 3B: LCMS[ESI,M+1]: 378.2. 1 H NMR(400MHz,DMSO-d6)δ=14.24(br s,1H),8.67-8.42(m,2H),8.29(d,J=1.6Hz,1H),8.06-7.87(m,4H),7.73-7.55(m,1H),6.75(d,J=3.6Hz,1H),5.30(br s,1H),4.58(br d,J=2.8Hz,1H),4.53(br d,J=5.6Hz,1H),3.66(br s,1H),1.82-1.60(m,1H),1.21-1.10(m,1H),1.03-0.94(m,1H),0.79(dd,J=6.8,12.8Hz,6H).

[0458] Compound 3D: LCMS[ESI,M+1]:378.2. 1H NMR (400MHz, DMSO-d6) δ=14.39-14.12(m,1H),8.60(s,1H),8.57-8.41(m,1H),8.28(d,J= 2.0Hz,1H),8.02(d,J=1.6Hz,1H),8.01-7.92(m,3H),7.70-7.60(m,1H),6.74(d,J=3.6Hz ,1H),5.30(d,J=4.4Hz,1H),4.47(t,J=4.8Hz,1H),4.40(d,J=6.0Hz,1H),3.71-3.59(m,1 H),1.84-1.71(m,1H),1.39-1.28(m,1H),1.24-1.16(m,1H),0.84(dd,J=6.8,17.2Hz,6H).

[0459] Example 7. Used for the synthesis of azaindole monools: (R)-(3,3-difluorocyclobutyl)-[1-[3-(4H-1,2,4-trimethylolpropionate)-[R ...R-(3,3-difluorocyclobutyl)-[R- [Azol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]methanol and (S)-(3,3-difluorocyclobutyl)-[1-[3-(4H-1,2, Representative sequence D of compounds 7A and 7B: [4-triazol-3-yl]phenyl]pyrrolo[2,3-b]pyridin-5-yl]methanol

[0460] Option 7.

[0461]

[0462] NaH (6.09 g, 152 mmol, 60% purity, 1.50 eq.) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (20.0 g, 102 mmol, 1.00 eq.) in THF (200 mL) at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 0.5 h. TIPSCl (23.5 g, 122 mmol, 26.1 mL, 1.20 eq.) was added, and the reaction was stirred at 0 °C under N2 (15 psi) for 0.5 h. The reaction was quenched at 0 °C with saturated NH4Cl (200 mL). The mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0) to give (5-bromopyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane (35.0 g, 99.1 mmol, 97% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ = 8.26 (d, J = 2.4Hz, 1H), 8.19 (d, J = 2.4Hz, 1H), 7.53 (d, J = 3 .2Hz, 1H), 6.60 (d, J = 3.6Hz, 1H), 1.83 (quin, J = 7.6Hz, 3H), 1.04 (d, J = 7.6Hz, 18H).

[0463] n-BuLi (2.5 M, 9.17 mL, 3.00 eq.) was added to a solution of (5-bromopyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane (2.70 g, 7.64 mmol, 1.00 eq.) and 3,3-difluoro-N-methoxy-N-methyl-cyclobutaneformamide (1.51 g, 8.40 mmol, 1.10 eq.) in THF (27.0 mL) at -78 °C under N2 (15 psi) for 0.5 h, and then quenched with water (100 mL) at 0 °C. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (3,3-difluorocyclobutyl)-(1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl) ketone (4.10 g, crude product), which was a yellow oil.

[0464] NaBH4 (732 mg, 19.4 mmol, 2.00 eq.) was added to a solution of (3,3-difluorocyclobutyl)-(1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl) ketone (3.80 g, 9.68 mmol, 1.00 eq.) in THF (40.00 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction was quenched at 0 °C with saturated NH4Cl (100 mL). The mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give (3,3-difluorocyclobutyl)-(1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl)methanol (1.40 g, 2.70 mmol, 27% yield, 76% purity) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ=8.19(d,J=1.6Hz,1H),7.89(d,J=1.6Hz,1H),7.45(d,J=3.2Hz,1H),6.58(d,J=3.2Hz,1H),5.53(d,J=4.4Hz,1H),4.63(br t,J=4.4Hz,1H),2.61(br dd,J=6.8,12.4Hz,1H),2.37-2.28(m,2H),2.07-2.00(m,2H),1.85(td,J=7.6,15.2Hz,3H),1.06(d,J=7.6Hz,18H).

[0465] A solution of (3,3-difluorocyclobutyl)-(1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl)methanol (1.40 g, 3.55 mmol, 1.00 eq.) and TBAF (1 M, 4.26 mL, 1.20 eq.) in THF (14.0 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with H2O (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give (3,3-difluorocyclobutyl)-(1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (330 mg, 1.39 mmol, 39% yield) as a colorless gel. 1 H NMR(400MHz,DMSO-d6)δ=11.55(br s,1H),8.19(d,J=2.0Hz,1H),7.88(d,J=1.6Hz,1H),7.53-7.33(m,1H),6.41(dd,J=2.0,3.6 Hz, 1H), 5.52 (d, J = 4.4Hz, 1H), 4.63 (t, J = 4.8Hz, 1H), 2.71-2.53 (m, 2H), 2.47-2.30 (m, 3H).

[0466] Under N2, CuI (132 mg, 693 μmol, 0.50 eq.), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (98.5 mg, 693 μmol, 0.50 eq.), and K3PO4 (588 mg, 2.77 mmol, 2.00 eq.) were added to a solution of (3,3-difluorocyclobutyl)-(1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (330 mg, 1.39 mmol, 1.00 eq.) and 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (590 mg, 1.66 mmol, 1.20 eq.) in DMA (3.00 mL). The mixture was stirred at 90 °C under N2 for 3 hours, then diluted with H2O (25.0 mL) and extracted with EtOAc (25.0 mL × 3). The combined organic layers were washed with brine (20 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give a yellow gel-like substance (3,3-difluorocyclobutyl)-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]methanol (470 mg, 999 μmol, 72% yield, 99% purity). LCMS (ESI, M+1): m / z = 466.2.

[0467] A solution of (3,3-difluorocyclobutyl)-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]methanol (470 mg, 1.01 mmol, 1.00 eq.) in HCl (2.00 mL) and H₂O (2.00 mL) was stirred at 0 °C for 0.5 h. The pH was then adjusted to 7 at 0 °C with 1 M NaOH.

[0468] The reaction mixture was diluted with H₂O (25.0 mL) and extracted with EtOAc (25.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (FA)-ACN]; gradient: 30%–60% B for 15 min). The desired fraction was collected and lyophilized to give (3,3-difluorocyclobutyl)-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]methanol (250 mg, 649 μmol, 64% yield, 99% purity) as a white solid.1 H NMR (400MHz, DMSO-d6) δ=14.65-13.81(m,1H),8.57(t,J=1.6Hz,1H),8.54-8.45(m,1H),8.33 (d,J=2.0Hz,1H),8.05(d,J=2.0Hz,1H),8.00(d,J=3.6Hz,1H),7.98(d,J=7.6Hz,1H),7.93(br d,J=7.6Hz,1H),7.65(t,J=7.6Hz,1H),6.74(d,J=3.6Hz,1H),5.65(br d,J=3.2Hz,1H),4.71(br s,1H),2.65-2.53(m,2H),2.48-2.35(m,3H).

[0469] Racemic (3,3-difluorocyclobutyl)-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridin-5-yl]methanol (250 mg, 656 μmol, 1.00 eq.) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3·H2O)]; 40% B isocratic elution mode) to give compound 7A (93.9 mg, 244 μmol, 37% yield, 99% purity) and compound 7B (89.7 mg, 233 μmol, 35% yield, 99% purity) as white solids.

[0470] Compound 7A.LCMS[ESI,M+1]:382.1. 1 H NMR (400MHz, DMSO-d6) δ=8.58(s,1H),8.55-8.41(m,1H),8.33(d,J=1.6Hz,1H),8.05(d,J=1.6Hz,1H),8.01(d,J=3.6Hz,1H),7.99(br s,1H),7.93(br d,J=7.2Hz,1H),7.71-7.60(m,1H),6.75(d,J=3.6Hz,1H),5.66(brd,J=4.4Hz,1H),4.71(br s,1H),2.66-2.55(m,2H),2.48-2.36(m,3H).

[0471] Compound 7B.LCMS[ESI,M+1]:382.1. 1H NMR(400MHz,DMSO-d6)δ=14.27(br s,1H),8.58(s,1H),8.56-8.40(m,1H),8.34(d,J=2.0Hz,1H),8.05(d,J=2.0Hz,1H),8.01(d,J=3.6Hz,1H),7.98(d,J=7.6Hz,1H),7.93(br d,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),6.75(d,J=3.6Hz,1H),5.66(br d,J=4.0Hz,1H),4.71(br s,1H),2.66-2.54(m,2H),2.48-2.36(m,3H).

[0472] Example 8: Synthesis of diol via olefins: (R)-1-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyridine Azo[3,4-b]pyridin-5-yl)-2-methylpropane-1,2-diol and (S)-1-(1-(3-(4H-1,2,4-triazol-3-yl)benzene (3,4-b)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-methylpropane-1,2-diol (compounds 33A and 33B)

[0473] Option 8.

[0474]

[0475] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 15.2 mmol, 1.00 eq.), 2-methylprop-1-enylboronic acid (2.27 g, 22.7 mmol, 1.50 eq.), Cs₂CO₃ (9.87 g, 30.3 mmol, 2.00 eq.), cyclopentyl(diphenyl)phosphine, palladium dichlorophosphate, and iron (1.11 g, 1.51 mmol, 0.10 eq.) in dioxane (50.0 mL) and H₂O (10.0 mL) was degassed and purged three times with N₂ (15 psi). The mixture was then stirred at 90 °C for 3 hours under N₂ (15 psi) atmosphere. The mixture was poured into a saturated aqueous solution of NaHCO₃ (100 mL) and extracted with EA (30.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give the compound 5-(2-methylprop-1-enyl)-1H-pyrazolo[3,4-b]pyridine (2.00 g, 11.0 mmol, 72% yield) as a yellow solid. LCMS [ESI, M+1]: 174.2.

[0476] 5-(2-methylprop-1-enyl)-1H-pyrazolo[3,4-b]pyridine (330 mg, 1.91 mmol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (812 mg, 2.29 mmol, 1.20 eq.), CuI (181 mg, 953 μmol, 0.50 eq.), K3PO4 (809 mg, 3.81 mmol, 2.00 eq.), and (1R,2R)-N 1 N 2 The mixture of 1,2-dimethylcyclohexane-1,2-diamine (542 mg, 3.81 mmol, 2.00 eq.) in DMA (5.00 mL) was degassed and purged three times with N2 (15 psi). The mixture was then stirred at 90 °C for 3 hours under N2 (15 psi) atmosphere. The mixture was poured into a saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to provide 5-(2-methylprop-1-enyl)-1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridine as a yellow solid (550 mg, 1.30 mmol, 68.% yield). LCMS[ESI,M+1]:401.2.

[0477] Add OsO4 (476 mg, 1.87 mmol, 97.2 μL, 0.50 eq.) in H2O (10 mL) to a solution of 5-(2-methylprop-1-enyl)-1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridine (1.50 g, 3.75 mmol, 1.00 eq.) in n-BuOH (20 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated sodium sulfite solution (80 mL). The mixture was extracted with EA (100 mL × 3), and the organic layer was washed with brine (100 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to provide 2-methyl-1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]propane-1,2-diol as a white solid (1.40 g, 3.06 mmol, 82% yield). LCMS [ESI, M+1]: 435.3.

[0478] HCl (4 M, 575 μL, 2.00 eq.) was added to a solution of 2-methyl-1-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]propane-1,2-diol (500 mg, 1.15 mmol, 1.00 eq.) in THF (1.00 mL). The mixture was stirred at 0 °C for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenexluna C18 150×40mm×15um; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B for 10 min) to give 2-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]propane-1,2-diol (380 mg, 1.06 mmol, 92% yield) as a white solid. LCMS [ESI, M+1]: 351.1.

[0479] Racemic 2-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]propane-1,2-diol (150 mg, 428 μmol, 1.00 eq.) was resolved by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-ACN / MeOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode) to give compound 33B (56.0 mg, 158 μmol, 37% yield) and compound 33A (34.0 mg, 95.1 μmol, 22% yield) as white solids.

[0480] Compound 33B.LCMS[ESI,M+1]:351.1. 1 H NMR (400MHz, DMSO-d6) δ=14.19(br s,1H),9.12-8.89(m,1H),8.69(br d,J=1.2Hz,2H),8.55-8.48(m,1H),8.41(br s,1H),8.28(s,1H),7.98(br d,J=7.6Hz,1H),7.79-7.57(m,1H),5.57(br s,1H),4.57(br s,1H),4.45(br s,1H),1.16(s,3H),1.01(s,3H).

[0481] Compound 33A.LCMS[ESI,M+1]:351.1. 1 H NMR (400MHz, DMSO-d6) δ = 14.19 (br s, 1H), 9.04 (br s,1H),8.69(d,J=1.6Hz,2H),8.56-8.48(m,1H),8.29(d,J=1.6Hz,1H),7.98(brd,J=7.2Hz,1H),7.84-7.58(m,1H),5.56(br s,1H),4.57(s,1H),4.45(br s,1H),1.16(s,3H),1.01(s,3H).

[0482] Example 9. (1R)-2-ethoxy-2-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazol [3,4-b]pyridin-5-yl]prop-1-ol and (1S)-2-ethoxy-2-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)benzene] [3,4-b]pyrazolo[3,4-b]pyridin-5-yl]prop-1-ol (compounds 34A and 34B)

[0483] Option 9.

[0484]

[0485] At 0 °C and under a nitrogen atmosphere (15 psi), a solution of methyl 2-hydroxy-2-methylpropionate (2.00 g, 16.9 mmol, 1.96 mL, 1.00 eq.) in THF (5.00 mL) was slowly added to a solution of NaH (1.40 g, 35.0 mmol, 60% purity, 2.07 eq.) in DMF (11.0 mL). The mixture was stirred at 0 °C for 0.5 h, and then ethane iodide (6.00 g, 38.5 mmol, 3.08 mL, 2.27 eq.) was added at 0 °C. The mixture was stirred at 20 °C for 12 h, and then quenched with saturated NH4Cl (50.0 mL) at 0 °C. The mixture was extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 2-ethoxy-2-methylpropionate (2.00 g, 13.7 mmol, 80% yield) as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ = 3.73 (s, 3H), 3.42 (q, J = 6.8Hz, 2H), 1.43–1.41 (m, 6H), 1.21 (t, J = 7.2Hz, 3H).

[0486] n-BuLi (2.5 M, 5.08 mL, 1.50 eq.) was added to a solution of (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropylsilane (3.00 g, 8.47 mmol, 1.00 eq.) in THF (30.0 mL) at -78 °C under a nitrogen atmosphere (15 psi), and the mixture was stirred at -78 °C for 0.5 h under a nitrogen atmosphere (15 psi). Methyl 2-ethoxy-2-methylpropionate (1.60 g, 9.31 mmol, 1.10 eq.) was added to the mixture, and the reaction was stirred at -78 °C for 0.5 h under a nitrogen atmosphere (15 psi). The reaction was then quenched at -78 °C with saturated NH4Cl (50.0 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to give 2-ethoxy-2-methyl-1-(1-triisopropylsilylpyrazolo[3,4-b]pyridin-5-yl)prop-1-one (1.49 g, 3.82 mmol, 45% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ = 9.21 (d, J = 2.0Hz, 1H), 9.13 (d, J = 2.0Hz, 1H), 8.58 (s, 1H), 3.37 -3.32(m,2H),1.91-1.85(m,3H),1.48(s,6H),1.08(d,J=2.4Hz,18H),1.00-0.96(m,3H).

[0487] The resulting ketone was reduced under the standard conditions (sodium borohydride) of other examples, followed by TBAF desilylation and HCl deprotection of THP to provide a racemic product.

[0488] 2-Ethoxy-2-methyl-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]prop-1-ol (200 mg, 529 μmol, 1.00 eq.) was separated by SFC (column: DAICL CHIRALPAKIG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3·H2O)]; B%: 55%, isocratic elution mode) to give compound 34A (83.9 mg, 219 μmol, 41% yield, 99% purity) as a grayish-white solid and compound 34B (83.4 mg, 218 μmol, 41% yield, 99% purity) as a white solid.

[0489] Compound 34A.LCMS[ESI,M+1]:379.2. 1 H NMR (400MHz, DMSO-d6) δ = 14.27 (s, 1H), 9.00 (s, 1H), 8.67 (d, J = 2.0Hz, 1H), 8.53 (br s,1H),8.49(s,1H),8.45-8.40(m,1H),8.28(d,J=1.6Hz,1H),7.98(br d,J=7.6Hz,1H),7.68(t,J=8.0Hz,1H),5.60(br s,1H),4.70(s,1H),3.53-3.45(m,1H),3.43-3.37(m,1H),1.21(s,3H),1.06(t,J=6.8Hz,3H),0.99(s,3H).

[0490] Compound 34B.LCMS[ESI,M+1]:379.1. 1H NMR (400MHz, DMSO-d6) δ = 14.30 (s, 1H), 9.00 (s, 1H), 8.67 (d, J = 2.0Hz, 1H), 8.54 (br s, 1H), 8.49 (s, 1H), 8.43 (br d,J=8.0Hz,1H),8.28(d,J=1.6Hz,1H),7.98(br d,J=7.6Hz,1H),7.68(t,J=8.0Hz,1H),5.60(br s,1H),4.70(s,1H),3.53-3.45(m,1H),3.42-3.36(m,1H),1.21(s,3H),1.06(t,J=6.8Hz,3H),0.99(s,3H).

[0491] Example 10. (R)-1-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine- 5-yl)-2-(isopropylamino)ethanol-1-ol and (S)-1-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrazol) [3,4-b]pyridin-5-yl)-2-(isopropylamino)ethanol-1-ol (compounds 27A and 27B)

[0492] Option 12.

[0493]

[0494] Ozone (933 mg, 19.4 mmol, 2.00 eq.) was bubbled into a solution of N-allyl-N-tert-butoxycarbonyl-tert-butyl carbamate (2.50 g, 9.72 mmol, 1.00 eq.) in DCM (20 mL) for 0.5 h at -78 °C. Me₂S (1.21 g, 19.4 mmol, 1.43 mL, 2 eq.) was added to the reaction mixture, and the reaction mixture was stirred at -78 °C to 20 °C for 12 h. The reaction mixture was degassed with nitrogen to remove excess ozone. The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give N-tert-butoxycarbonyl-N-(2-oxoethyl)carbamate (2.30 g, 8.87 mmol, 91% yield) as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ = 9.48 (s, 1H), 4.31 (s, 2H), 1.43 (s, 18H).

[0495] To a solution of (5-bromopyrazolo[3,4-b]pyridin-1-yl)-triisopropyl-silane (1.00 g, 2.82 mmol, 1.00 eq.) in THF (15.0 mL), n-BuLi (2.5 M, 3.39 mL, 3.00 eq.) and N-tert-butoxycarbonyl-N-(2-oxoethyl)carbamate tert-butyl ester (878 mg, 3.39 mmol, 1.20 eq.) were added. The mixture was stirred at -78 °C for 2 hours, then slowly poured into saturated NH4Cl (60 mL) at 0 °C and extracted with EA (80 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give N-[2-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethyl]carbamate tert-butyl ester (650 mg, 2.34 mmol, 83% yield) as a yellow solid. LCMS [ESI, M+1]: 279.2.

[0496] The following substances were added: N-[2-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethyl]carbamate tert-butyl ester (100 mg, 359 μmol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (140 mg, 395 μmol, 1.10 eq.), CuI (34.2 mg, 180 μmol, 0.50 eq.), K3PO4 (153 mg, 719 μmol, 2.00 eq.), and (1R,2R)-N 1 N 2 The mixture of dimethylcyclohexane-1,2-diamine (102 mg, 719 μmol, 2.00 eq.) in DMA (5.00 mL) was degassed and purged three times with N2, then stirred at 90 °C for 2 hours under N2 (15 psi) atmosphere. The mixture was poured into H2O (50 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give N-[2-hydroxy-2-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethyl]tert-butyl carbamate (90.0 mg, 169 μmol, 47% yield) as a yellow oil. LCMS[ESI,M+1]:506.4.

[0497] A mixture of N-[2-hydroxy-2-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethyl]tert-butyl carbamate (300 mg, 593 μmol, 1.00 eq.) and HCl / dioxane (4 M, 148 μL, 1.00 eq.) in dioxane (3.00 mL) was stirred at 25 °C under a N2 (15 psi) atmosphere for 3 h. The reaction mixture was concentrated under vacuum. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give the compound 2-amino-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethanol (165 mg, 488 μmol, 82% yield) as a yellow solid. LCMS[ESI,M+1]:362.1.

[0498] To a solution of 2-amino-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethanol (150 mg, 467 μmol, 1.00 eq.) and acetone (40.7 mg, 700 μmol, 51.5 μl, 1.50 eq.) in MeOH (5.00 mL), NaBH4 (35.3 mg, 934 μmol, 2.00 eq.) was added. The mixture was stirred at 0 °C for 2 hours. The mixture was poured into NH4Cl (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to provide the compound 2-(isopropylamino)-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethanol as a white solid (140 mg, 378 μmol, 81% yield). LCMS [ESI, M+1]: 364.3.

[0499] Racemic 2-(isopropylamino)-1-[1-[3-(4H-1,2,4-triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]ethanol (80 mg, 220 μmol, 1.00 eq.) was separated by SFC (column: DAICL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 70%, isocratic elution mode) to give compound 27A (31.0 mg, 83.6 μmol, 38% yield) as a white solid and compound 27B (29.0 mg, 78.2 μmol, 36% yield) as a pale yellow solid.

[0500] Compound 27A.LCMS[ESI,M+1]:364.2. 1 H NMR (400MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.76 (d, J = 1.6Hz, 1H), 8.61-8.49 (m, 2H), 8.41 (dd, J = 1.2, 8.2Hz, 1H), 8.31 (br s,1H),7.99(d,J=7.6Hz,1H),7.69(t,J=8.0Hz,1H),5.07-4.94(m,1H),3.06-2.96(m,2H),2.94(brd,J=8.4Hz,1H),1.10(br d,J=6.0Hz,6H).

[0501] Compound 27B.LCMS[ESI,M+1]:364.3. 1 H NMR (400MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.72 (d, J = 2.0Hz, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.41 (br d,J=8.0Hz,1H),8.33(d,J=1.6Hz,1H),8.02-7.95(m,1H),7.68(t,J=8.0H z,1H),4.95-4.65(m,1H),2.90-2.66(m,3H),0.98(dd,J=6.0,8.8Hz,6H).

[0502] Example 11. (R)-3-(2-fluoro-4-(5-(1-hydroxy-2-isopropoxyethyl)-1H-pyrazolo[3,4-b]pyrazol (Pyridin-1-yl)phenyl)propionic acid and (S)-3-(2-fluoro-4-(5-(1-hydroxy-2-isopropoxyethyl)-1H-pyrazolo[3,4-b]) Pyridin-1-yl)phenyl)propionic acid (compounds 70A and 70B)

[0503] Option 11.

[0504]

[0505] The following were added: (1R)-2-isopropoxy-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethanol (50.0 mg, 226 μmol, 1.00 eq.), 3-(2-fluoro-4-iodophenyl)propionic acid (66.5 mg, 226 μmol, 1.00 eq.), CuI (21.5 mg, 113 μmol, 0.50 eq.), K3PO4 (143.9 mg, 678 μmol, 3.00 eq.), and N 1 N 2The mixture of 1,2-dimethylcyclohexane-1,2-diamine (32.1 mg, 226 μmol, 1.00 eq.) in DMA (0.50 mL) was degassed and purged three times with N2 (15 psi). The mixture was then stirred at 90 °C for 1 hour under N2 atmosphere (15 psi). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenexluna C18150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 39%-69%, 10 min).

[0506] The desired compound was obtained as a yellow solid (14.48 mg, 36.63 μmol, 28% yield, 98% purity). LCMS [ESI, M+1]: 388.2. 1 H NMR (400MHz, DMSO-d6) δ=8.69(d,J=1.6Hz,1H),8.46(s,1H),8.32(d,J=1.6Hz,1H),8.15(dd,J=2.0,12.0Hz,1H),8.10(dd,J=2 .0,8.4Hz,1H),7.51(t,J=8.4Hz,1H),5.70-5.50(m,1H),4.88(t,J=6.0Hz,1H),3.61-3.53(m,2H),3.52-3.48(m,1H),2.90(br t, J=7.6Hz, 2H), 2.58 (t, J=7.6Hz, 2H), 1.05 (dd, J=6.0, 14.8Hz, 6H).

[0507] Another enantiomer was prepared from the opposite enantiomers of the raw material under the same conditions.

[0508] The desired compound was obtained as a white solid (15.68 mg, 40.07 μmol, 31.05% yield, 99% purity). LCMS [ESI, M+1]: 388.2. 1H NMR (400MHz, DMSO-d6) δ = 8.69 (d, J = 2.0Hz, 1H), 8.46 (s, 1H), 8.32 (d, J = 1.6Hz, 1H), 8. 15(dd,J=2.0,11.6Hz,1H),8.10(dd,J=2.0,8.4Hz,1H),7.51(t,J=8.4Hz,1H),5.60(br d,J=3.6Hz,1H),4.88(br s,1H),3.61-3.54(m,2H),3.52-3.48(m,1H),2.90(t,J=7.6Hz,2H),2.58(t,J=7.6Hz,2H),1.05(dd,J=6.0,14.8Hz,6H).

[0509] The following compounds were prepared by a method similar to that used in Examples 1-12.

[0510] Table 2. Analytical data of representative compounds in this application.

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540] Biological Examples

[0541] Example B-1. Biochemical assay for screening hPGDH inhibitors

[0542] The synthetic inhibitors provided herein can be evaluated using biochemical assays for screening hydroxyprostaglandin dehydrogenase inhibition. Exemplary biochemical assays for screening hPGDH inhibitors are provided herein.

[0543] In vitro biochemical assays of the test / tool ​​compounds were performed in white 384 plates using a total reaction volume of 20 μl at 10 points using a dose-response profile. This reaction volume consisted of 10 nM of 15-PGDH / HPGD (R&D System #5660-DH), 15 μM of prostaglandin E2 (Sigma, catalog number P5640-10MG), and 0.25 mM of sodium β-nicotinamide adenine dinucleotide (Sigma, catalog number N0632-5G), prepared in reaction buffer (50 mM Tris-HCl, pH 7.5, 0.01% Tween 20). Briefly, 5 μl (4x) of the compound solution and 5 μl (final concentration, 10 nM) of the enzyme solution were added to a white 384-well plate and incubated at 37 °C for 10 min. Add 5 μl (4X) of prostaglandin E2 and 5 μl (4X) of sodium β-nicotinamide adenine dinucleotide to the wells and incubate at room temperature for 10 min. Record fluorescence at ex / em = 340 nm / 485 nm. Determine the percentage inhibition (%) of enzyme activity relative to the positive control (1% DMSO) and calculate IC50 using GraphPad Prism software (four-parameter variable slope equation). Exemplary data are shown in Table 3.

[0544] Table 3. Inhibitory efficacy of hPGDH.

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552] A<0.1μM; 0.1μM≤B<1μM; 1μM≤C

[0553] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art will recognize various modifications or variations thereof, which will be included within the spirit and scope of this application and the appended claims. For all purposes, all publications, patents, and patent applications cited herein are hereby incorporated in their entirety by reference.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, Ring Q is a phenyl or a 5- to 10-membered heteroaryl group; Z is CR 1 Or N; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted or unsubstituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 8-membered heteroaryl; Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A Yes -NR 5 R 5 or -OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C6 heterocycloalkyl; each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally divided by one or more R groups. a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each optionally substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each optionally substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is optionally divided by one or more R groups. a replace; Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3; and p is 1, 2, 3 or 4.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring Q is a 6-membered monocyclic heteroaryl group containing 1, 2 or 3 N atoms.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring Q is phenyl, pyrimidinyl or pyridinyl.

4. The compound of claim 1 or 3 or a pharmaceutically acceptable salt thereof, wherein when Q is phenyl, then R 3 One of them is not H.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... yes in, X 1 X 2 X 3 and X 4 Each is independently N or CR 3 ; Each R 3 Independently selected from H, halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 replace; Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups Each of them is controlled by one or more R a Replace; and Each R a Independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 X 2 X 3 and X 4 Each is CR 3 .

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 It is N; and X 2 X 3 and X 4 Each is CR 3 .

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is N; and X 3 and X 4 Each is CR 3 .

9. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 3 Each is N; and X 2 and X 4 Each is CR 3 .

10. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 4 Each is N; and X 2 and X 3 Each is CR 3 .

11. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 X 2 and X 3 Each is N; and X 4 It is CR 3 .

12. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X 1 X 2 and X 4 Each is N; and X 3 It is CR 3 .

13. The compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein each R 3 Independently selected from H, halogen, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein each R 3 Independently selected from H, halogens, -C(O)OR 10 -C(O)NR 8 R 9 And substituted or unsubstituted 5-membered heteroaryl groups.

15. The compound of claim 1, wherein the compound has the structure of formula (II) or a pharmaceutically acceptable salt thereof: in, Z is CR 1 Or N; X 1 Is it N or CR? 3a ; Y is CR 2 Or N; R 1 It is H, halogen, -CN, -OR 10 -C(O)R 10 -C(O)OR 10 -NR 8 R 9 -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups; Each R 2 Independently, it is H, halogen, -OR 10 -C(O)R 10 -C(O)OR 10 -CN, -C(O)NR 8 R 9 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted C3-C8 cycloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogen, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; among them Each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 ; R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted by one or more R 6 Replace; among them Each R 6 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -NR 8 C(O)R 9 Substituted or unsubstituted C1-C6 alkyl, substituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 8-membered heteroaryl; Or two Rs 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted C3-C8 heterocycloalkyl; X A It is NR 5 R 5 OR 5 ;in Each R 5 It is independently an H or C1-C6 alkyl group; R 5a It is H or CH3; Or R 5a And an R 6 They combine with the atoms to which they are attached to form substituted or unsubstituted C3-C6 cycloalkyl groups; Each R 8 and R 9 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl groups and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a replace; Each R 10 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 11 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl groups and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R groups. a replace; Each R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C 10 Heterocyclic alkyl groups, each of which is bound by one or more R a Replace; and Each R a It is independently selected from halogens, -OH, -CH3, -CF3, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)OH, -OC(O)NH2 and -NHC(O)CH3.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein X A It is NR 5 R 5 .

17. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein X A OR 5 .

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein Y is a CR 2 .

19. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein Y is N.

20. The compound of claim 15, wherein the compound of formula (II) has the structure of formula (IIIa) or a pharmaceutically acceptable salt thereof:

21. The compound of claim 15, wherein the compound of formula (II) has the structure of formula (IIIb) or a pharmaceutically acceptable salt thereof:

22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein Z is N.

23. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein Z is a CR 1 .

24. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein Z is CH.

25. The compound of claim 15, wherein the compound of formula (II) has the structure of formula (IVa) or a pharmaceutically acceptable salt thereof:

26. The compound of claim 15, wherein the compound of formula (II) has the structure of formula (IVb) or a pharmaceutically acceptable salt thereof:

27. The compound of claim 15, wherein the compound of formula (II) has the structure of formula (IVc) or a pharmaceutically acceptable salt thereof:

28. The compound of claim 15, wherein the compound of formula (II) has the structure of formula (IVd) or a pharmaceutically acceptable salt thereof:

29. The compound of any one of claims 15-28 or a pharmaceutically acceptable salt thereof, wherein X 1 It is N.

30. The compound of any one of claims 15-29 or a pharmaceutically acceptable salt thereof, wherein R 3b It is H; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 3b It is H; and R 3c Selected from halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

32. The compound of any one of claims 15-29 or a pharmaceutically acceptable salt thereof, wherein R 3c It is H; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

33. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 3c It is H; and R 3b Selected from halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

34. The compound of any one of claims 15-28 or a pharmaceutically acceptable salt thereof, wherein X 1 It is CR 3a .

35. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 15-28 or 34, wherein R 3a and R 3b It is independently H or halogen; and R 3c Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R 3c Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 3c It is -C(O)OR 10 -C(O)NR 8 R 9 Or a substituted or unsubstituted 5-membered heteroaryl group.

38. The compound of any one of claims 35-37 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b Each is H.

39. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 15-28 or 34, wherein R 3a and R 3c It is independently H or halogen; and R 3b Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

41. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R 3b It is -C(O)OR 10 -C(O)NR 8 R 9 Or a substituted or unsubstituted 5-membered heteroaryl group.

42. The compound of any one of claims 39-41 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3c Each is H.

43. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 15-28 or 34, wherein R 3b and R 3c Each is either H or halogen; and R 3a Selected from halogens, -CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 -SO2NR 8 R 9 -NR 12 C(O)R 10 -NR 12 C(O)OR 10 -NR 12 C(O)NR 8 R 9 -NR 12 SO2R 10 -NR 12 SO2NR 8 R 9 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, each of which is substituted by one or more R 13 Replace; where each R 13 Independently, it is halogen, CN, -NO2, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 or -C(O)NR 8 R 9 .

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from H, halogens, -NR 8 R 9 -OR 10 -SR 8 -C(O)R 10 -C(O)OR 10 -C(O)NR 8 R 9 -SOR 11 -SO2R 11 Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 haloalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C3-C8 heterocycloalkyl groups, and substituted or unsubstituted 5-membered heteroaryl groups.

45. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 3a It is -C(O)OR 10 -C(O)NR 8 R 9 Or a substituted or unsubstituted 5-membered heteroaryl group.

46. ​​The compound of any one of claims 43-45 or a pharmaceutically acceptable salt thereof, wherein R 3b and R 3c Each is H.

47. The compound of any one of claims 1-46 or a pharmaceutically acceptable salt thereof, wherein each R 2 It is H.

48. The compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, wherein R 5a And an R 6 They combine with the atoms to which they are attached to form C3-C6 cycloalkyl groups.

49. The compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, wherein R 5a It is H.

50. The compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, wherein R 5 It is H.

51. The compound of any one of claims 1-50 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 aminoalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, a substituted or unsubstituted C1-C8 hydroxyalkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted C3-C8 heterocycloalkyl, each of which is substituted or unsubstituted by one or more R 6 replace.

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a substituted or unsubstituted C1-C8 alkyl or a substituted or unsubstituted C1-C8 heteroalkyl, each of which is substituted by one or more R 6 replace.

53. The compound of any one of claims 1-50 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a substituted or unsubstituted C3-C8 cycloalkyl or a 4- to 8-membered heterocycloalkyl, each of which is substituted by one or more R 6 replace.

54. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein R 4 It is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl.

55. The compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof, wherein each R 6 Independently, it is halogen, -NR 8 R 9 -OR 10 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl.

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein each R 6 Independently, it is halogen, -OR 10 C1-C6 alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl.

57. The compound of claim 55 or 56 or a pharmaceutically acceptable salt thereof, wherein each R 6 Independently, it is -F, -CH3, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

58. The compound of any one of claims 1-57, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.

59. A pharmaceutical composition comprising a compound as described in any one of claims 1-58 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

60. A method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject of interest, comprising administering to the subject a therapeutically effective amount of the compound as described in any one of claims 1-58 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 59.

61. A method of promoting and / or stimulating skin pigmentation, comprising applying to a subject in need one or more compositions as described in any of the preceding claims.

62. A method for inhibiting hair loss, comprising applying to a subject in need one or more compositions as described in any of the preceding claims.

63. A method for preventing and / or treating skin inflammation and / or injury, comprising applying one or more compositions as described in any of the preceding claims to a subject in need.

64. A method for preventing and / or treating vascular insufficiency, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

65. A method for preventing, treating, minimizing, and / or reversing congestive heart failure or cardiomyopathy, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

66. A method for reducing cardiac ejection fraction, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

67. A method for preventing and / or treating gastrointestinal diseases, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

68. A method for preventing and / or treating renal dysfunction, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

69. A method for stimulating bone resorption and bone formation, comprising applying to a subject in need one or more compositions as described in any of the preceding claims.

70. A method for stimulating tissue regeneration by means of stimulation, comprising applying one or more compositions as described in any one of the preceding claims to a subject in need.

71. A method for regulating cervical ripening, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

72. A method for promoting neuroprotection and / or stimulating neuronal regeneration, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

73. A method for treating and / or preventing neurological disorders, neuropsychiatric disorders, nerve damage, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

74. A method of treating and / or preventing fibrotic or adhesive diseases, conditions or illnesses, comprising applying one or more compositions as described in any of the preceding claims to a subject in need.

75. A method for reducing and / or preventing scar formation, comprising applying to a subject in need one or more compositions as described in any of the preceding claims.

76. A method for treating and / or preventing muscle disorders, muscle injuries and / or muscle atrophy, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

77. A method of treating and / or preventing fibrosis, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

78. A method of treating and / or preventing idiopathic pulmonary fibrosis, comprising administering to a subject in need one or more compositions as described in any of the preceding claims.

79. A method of treating and / or preventing renal fibrosis, comprising administering to a subject in need one or more compositions as described in any of the preceding claims.

80. A method for stimulating muscle regeneration, comprising applying one or more compositions as described in any of the preceding claims to a subject in need.

81. A method for promoting organ adaptation, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

82. A method for promoting wound healing, comprising applying to a subject in need one or more compositions as described in any of the preceding claims.

83. A method of treating acute kidney injury, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

84. A method of treating sarcopenia, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

85. A method of treating a neuromuscular disease, comprising administering one or more compositions as described in any of the preceding claims to a subject in need.

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